This vignette illustrates using Large Language Models (LLMs) and related technologies for PubMed literature search and summarization. We use OpenAI’s gpt-3.5-turbo (ChatGPT) and gpt-4 models, sentence embeddings from the SentenceTransformers Python package, and the PubMed API.

Some LLM examples

Let’s consider a question like “What are the most common symptoms of Long-COVID in children?” We might ask a Large Language Model (LLM) like OpenAI’s gpt-3.5-turbo, a.k.a ChatGPT.

question <- "What are the most common symptoms of Long-COVID in children?"
answer <- chatgpt(question, verbose = TRUE)
##### INPUT TRANSCRIPT #####
*** Role: system
You are a helpful assistant.

*** Role: user
What are the most common symptoms of Long-COVID in children?

##### RESPONSE #####
*** Role: assistant
Long-COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is a condition where individuals experience persistent symptoms after recovering from COVID-19. While children are less likely to experience severe COVID-19, they can still develop Long-COVID. The most common symptoms of Long-COVID in children include:

1. Fatigue
2. Headache
3. Difficulty concentrating or "brain fog"
4. Muscle or joint pain
5. Shortness of breath or difficulty breathing
6. Chest pain
7. Loss of taste or smell
8. Sleep disturbances
9. Abdominal pain or diarrhea
10. Skin rashes or changes in skin color

It's important to note that Long-COVID symptoms can vary widely and may not be limited to the above list. If your child has recovered from COVID-19 but is experiencing persistent symptoms, it's important to speak with their healthcare provider for further evaluation and management.

Notice in the above transcript that the input first started by giving the model a “system” command of You are a helpful assistant, followed by a “user” prompt of our question or request. ChatGPT is trained to work with conversational dialog, so a prompt may be a series of user/response text pairs. The system command is an additional feature of the model; here’s what the OpenAI has to say about that:

If adding instructions in the system message doesn’t work, you can also try putting them into a user message. (In the near future, we will train our models to be much more steerable via the system message. But to date, we have trained only on a few system messages, so the models pay much more attention to user examples.)

How about an answer from a pirate, just for fun?:

system <- "You are an assistant pretending to be a drunken pirate. Miss-spell 
words to complete the effect. Arr!"

pirate_answer <- chatgpt(question, system_message = system, verbose = TRUE)
##### INPUT TRANSCRIPT #####
*** Role: system
You are an assistant pretending to be a drunken pirate. Miss-spell 
words to complete the effect. Arr!

*** Role: user
What are the most common symptoms of Long-COVID in children?

##### RESPONSE #####
*** Role: assistant
Arrr, me hearty! I be not knowin' much about fancy medical terms, but I reckon the most common symptoms of Long-COVID in wee ones be fatigue, headache, brain fog, and tummy troubles. But don't ye be worryin', we pirates be tough as nails and can weather any storm!

We may also compare the result to the gpt-4 model, though we’ll use this model selectively to reduce costs.

question <- "What are the most common symptoms of Long-COVID in children?"
answer <- chatgpt(question, model = 'gpt-4', verbose = TRUE)
##### INPUT TRANSCRIPT #####
*** Role: system
You are a helpful assistant.

*** Role: user
What are the most common symptoms of Long-COVID in children?

##### RESPONSE #####
*** Role: assistant
Long-COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to a range of symptoms that persist for weeks or months after the acute phase of a COVID-19 infection. While research on Long-COVID in children is still limited, some common symptoms reported include:

1. Fatigue or tiredness
2. Difficulty concentrating or "brain fog"
3. Headaches
4. Sleep disturbances
5. Chest pain or discomfort
6. Shortness of breath
7. Joint pain or muscle aches
8. Heart palpitations
9. Gastrointestinal symptoms, such as nausea, diarrhea, or abdominal pain
10. Skin rashes or "COVID toes"

It is important to note that the severity and duration of these symptoms can vary greatly among children. If you suspect your child may be experiencing Long-COVID, it is essential to consult with a healthcare professional for proper evaluation and guidance.

JSON responses

Both gpt-3.5-turbo and gpt-4 are trained on data through 2021 and are static. If we want to use them with more recent information we’re going to need to grab it ourselves from APIs. In fact, we can treat the model as an API itself, by telling the model to produce JSON output so that we can parse it programmatically. This works well - JSON is a highly structured language and easy for LLMs to learn. The main thing is to keep the model from falling “out of character.” (GPT-4 does better in this regard.)

The system message handles specifying JSON output, and the prompt requests keywords from the question in a specific JSON structure. We provide an example of the output we want, known as ‘single shot’ learning (providing multiple examples is ‘few-shot’). Providing examples significantly improves and guides LLM output, at least for this model.

system <- "You are processing system that responds to natural language text 
with valid JSON. If it is unclear how the output should be formatted, or the 
user has not provided enough information, simply respond in a 'message' field. 
If you are unable to do so, return a JSON structure with an 'error' field. Do 
not produce anything other than valid JSON responses." 

prompt <- "Generate keywords from the following question, storing the 
results in an array in an object with key 'keywords', for example {'keywords': 
['keyword1', 'keyword2', 'keyword3', ...]} 

Question: " %+% question %+% "

JSON:"

example <- chatgpt(prompt, system_message = system, verbose = TRUE)
##### INPUT TRANSCRIPT #####
*** Role: system
You are processing system that responds to natural language text 
with valid JSON. If it is unclear how the output should be formatted, or the 
user has not provided enough information, simply respond in a 'message' field. 
If you are unable to do so, return a JSON structure with an 'error' field. Do 
not produce anything other than valid JSON responses.

*** Role: user
Generate keywords from the following question, storing the 
results in an array in an object with key 'keywords', for example {'keywords': 
['keyword1', 'keyword2', 'keyword3', ...]} 

Question: What are the most common symptoms of Long-COVID in children?

JSON:

##### RESPONSE #####
*** Role: assistant
{
  "keywords": [
    "Long-COVID",
    "symptoms",
    "children",
    "common"
  ]
}

The final JSON: part of the prompt is also helpful: these models are trained for text completion, so giving a prompt guiding the model where to start works well.

We’ve wrapped these ideas up in a function chatgpt_json() that adds the system preamble and Output JSON: to the end of the query, and returns a parsed version for use in code:

prompt <- "Generate keywords from the following question, storing the results 
in an array in an object with key 'keywords': " %+% question

result <- chatgpt_json(prompt)
str(result)
List of 1
 $ keywords: chr [1:4] "Long-COVID" "symptoms" "children" "common"

Try the impossible first

From here we could use the extracted keywords to build a query URL for the PubMed API. I tried this and several similar approaches, but the results were never satisfying, because the keywords need to be queried with appropriate logic and search parameters to be effective.

Instead, it often works better to simply ask the model for what we want–in this case a URL for searching PubMed.

a weird thing (for me at least) that happens with playing with LLMs and similar is that I have to keep making sure I a pushing it’s limits. a lot of the constraints are just my own inertia assuming incorrectly something wouldn’t work

i literally have a post-it note for play time that says “try the impossible first” on my desk because it kept happening

– @generativeist (Twitter)

With some experimenting I found that it would frequently use boolean expressions, and occasionally in conjunctive normal form to group synonyms. Asking for this makes the behavior consistent. Another useful trick, in what is now known as ‘prompt engineering’, is to ask the model to work out a solution step-by-step (which we don’t do here). Much like our Output JSON: prompt end above, we end with the first part of the output we want: the URL up to and including the ?. The model knows the PubMed API well enough that we can specify specific features like JSON output and the usehistory feature required for fetching the matched abstracts.

prompt <- "Consider the following question: " %+% question %+% '

Generate an Entrez e-search URL query that would search for article abstracts 
most likely to answer the question, using usehistory and returning JSON. Use 
conjunctive normal form to group synonyms.

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?'

url_query <- chatgpt(prompt, verbose = TRUE)
##### INPUT TRANSCRIPT #####
*** Role: system
You are a helpful assistant.

*** Role: user
Consider the following question: What are the most common symptoms of Long-COVID in children?

Generate an Entrez e-search URL query that would search for article abstracts 
most likely to answer the question, using usehistory and returning JSON. Use 
conjunctive normal form to group synonyms.

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?

##### RESPONSE #####
*** Role: assistant
db=pubmed&usehistory=y&retmode=json&term=(Long-COVID[Title/Abstract] OR post-acute sequelae of SARS-CoV-2 infection[Title/Abstract] OR PASC[Title/Abstract]) AND (symptoms[Title/Abstract] OR clinical manifestations[Title/Abstract]) AND (child[Title/Abstract] OR pediatric[Title/Abstract])

Now let’s fetch the top 10 abstracts for this query:

abstracts <- pubmed_esearch_abstracts(url_query, retmax = 10)
pmid year title first_author journal abstract
36728643 2023 Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. Baptista de Lima The Pediatric infectious disease journal Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
36736574 2023 Persistent symptoms after COVID-19 in children and adolescents from Argentina. Seery International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
36759021 2023 Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. Faux-Nightingale BJGP open While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8-17 years in the West Midlands of England. CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice. Copyright © 2023, The Authors.
36786887 2023 Mental health among children with long COVID during the COVID-19 pandemic. Shachar-Lavie European journal of pediatrics A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents’ questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents’ economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children’s memory, as reported by parents. • Parents’ economic stress and worries concerning their children’s emotional adjustment during the pandemic are associated with more distress in their children. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
36793333 2023 Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. Jamaica Balderas Frontiers in pediatrics In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children. © 2023 Jamaica Balderas, Navarro Fernández, Dragustinovis Garza, Orellana Jerves, Solís Figueroa, Koretzky, Márquez González, Klünder Klünder, Espinosa, Nieto Zermeño, Villa Guillén, Rosales Uribe and Olivar López.
36795575 2023 Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. Ahn The Pediatric infectious disease journal Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
36828133 2023 The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. Strawn Journal of the American Academy of Child and Adolescent Psychiatry While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms. Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
36851793 2023 High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. Goretzki Viruses Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC.
36926600 2023 Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. Lorman JAMIA open Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation. © The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Token limits

Ideally would include all of these abstracts in a prompt and ask the model to summarize them. We can’t really do this, because the total length of a prompt and its response must be less than 4096 “tokens”, which in normal text represents about 3000 words, though scientific literature tends to use more tokens per word.1

get_tokens("Anterior knee pain was found in 5.7% of...")
 [1] "Ant"    "erior"  " knee"  " pain"  " was"   " found" " in"    " "     
 [9] "5"      "."      "7"      "%"      " of"    "..."

To work around this limit, let’s ask the model to first summarize each abstract (with respect to our question), and then concatenate the summaries and ask the model to summarize those!

First we need to bring each abstracts’ title, journal, author, year, and text together into a single string. We add line breaks with \n to structure the text a bit, and use the pmid column to create a PubMed URL for each as well. We’ll print just the first to demonstrate.

abstracts <- abstracts %>%
    mutate(all_text = 
            "TITLE: " %+% title %+% "\n" %+%
            "JOURNAL: " %+% journal %+% "\n" %+%
            "YEAR: " %+% year %+% "\n" %+%
            "AUTHORS: " %+% first_author %+% "et al.\n" %+%
            "URL: https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% "\n" %+%
            "ABSTRACT: " %+% abstract
         )

abstracts$all_text[1] %>% cat()
TITLE: Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort.
JOURNAL: The Pediatric infectious disease journal
YEAR: 2023
AUTHORS: Baptista de Limaet al.
URL: https://pubmed.ncbi.nlm.nih.gov/36728643
ABSTRACT: Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Now we’ll build a series of prompts, each an individual summary request (which we accomplish with R vectorization). We’ll also setup a system message setting the stage. This step takes a little bit to run, because we are making 10 individual requests of the model, and we’ll print just the first result.

system_message <- "You are an expert in summarizing scientific literature."

prompts <- "As an expert in summarizing scientific literature, consider the
following question: " %+% question %+% "\n\n" %+%

"Generate a two or three sentence summary of the following paper, with special 
attention to any information relevant to the question: \n" %+% abstracts$all_text

summaries <- chatgpt(user_message = prompts, system_message = system_message)

# print the first
summaries[1]
[[1]]
[1] "According to a retrospective study in a pediatric cohort, 17.6% of children and adolescents with COVID-19 developed long COVID, with respiratory symptoms being more common in the first weeks and neuropsychiatric symptoms developing over time. Chronic conditions and obesity were identified as risk factors, and adolescents were found to be at a greater risk for long COVID. However, the study did not provide a comprehensive list of the most common symptoms of long COVID in children."

Excellent! Now we can ask the model to summarise this list of summaries, but first let’s add the title, year, and URL information back to the summaries for future use; here’s the first one again.

abstracts <- abstracts %>%
    mutate(summary_text = 
            "TITLE: " %+% title %+% "\n" %+%
            "JOURNAL: " %+% journal %+% "\n" %+%
            "YEAR: " %+% year %+% "\n" %+%
            "AUTHORS: " %+% first_author %+% "et al.\n" %+%
            "URL: https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% "\n" %+%
            "SUMMARY: " %+% summaries
         )

abstracts$summary_text[1] %>% cat()
TITLE: Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort.
JOURNAL: The Pediatric infectious disease journal
YEAR: 2023
AUTHORS: Baptista de Limaet al.
URL: https://pubmed.ncbi.nlm.nih.gov/36728643
SUMMARY: According to a retrospective study in a pediatric cohort, 17.6% of children and adolescents with COVID-19 developed long COVID, with respiratory symptoms being more common in the first weeks and neuropsychiatric symptoms developing over time. Chronic conditions and obesity were identified as risk factors, and adolescents were found to be at a greater risk for long COVID. However, the study did not provide a comprehensive list of the most common symptoms of long COVID in children.

Now we can build a prompt that asks the model to summarize all of this information, using the journal, author, and year information to add citations. We use few-shot prompting by providing examples of summaries, and prompt the model to complete the final Summary:.

system_message <- "You are an expert in summarizing scientific literature."

prompt <- "As an expert in summarizing scientific literature, consider the
following question: " %+% question %+% "\n\n

We want to answer this question by summarizing the following article
information:\n" %+% paste(abstracts$summary_text, collapse = "\n\n") %+%

"Now, summarize the information above, paying special attention to any 
information relevant to the question. Be detailed and comprehensive, including 
references for each sentence. Also include a list of authors, years, titles, 
and URLs at the end, based on the example format below. Only include information 
provided above, and do not guess. 

Summary:
Regular exercise has been shown to have positive effects on mental health 
outcomes (Johnson et al., 2018; Smith et al., 2020). In a randomized controlled 
trial, Johnson and colleagues found that participants who engaged in regular 
exercise for 12 weeks showed significant improvements in symptoms of depression 
and anxiety compared to a control group. Similarly, Smith and colleagues 
conducted a meta-analysis of 20 studies and found consistent evidence that 
exercise can reduce symptoms of depression and anxiety in individuals with 
mental health disorders. Other studies have also demonstrated the positive 
effects of exercise on mental health, including research on the impact of 
exercise on stress reduction (Gomes et al., 2021) and the benefits of exercise 
in the treatment of post-traumatic stress disorder (Rosenbaum et al., 2019).

References:
- Gomes et al. 2021: Physical exercise as a tool for stress reduction: A 
    systematic review. https://pubmed.ncbi.nlm.nih.gov/33857535/
- Johnson et al. 2018: The effects of exercise on mental health. 
    https://pubmed.ncbi.nlm.nih.gov/29589555/
- Rosenbaum et al. 2019: Exercise augmentation compared with usual care for 
    post-traumatic stress disorder: A randomized controlled trial. 
    https://pubmed.ncbi.nlm.nih.gov/30666600/
- Smith et al. 2020: Exercise and mental health: A meta-analysis. 
    https://pubmed.ncbi.nlm.nih.gov/32223299/

Summary:
Research has shown that meditation can have positive effects on stress and 
anxiety levels (Brown et al., 2019; Smith & Jones, 2020). In a randomized 
controlled trial, Brown and colleagues found that participants who practiced 
mindfulness meditation for 8 weeks reported significant reductions in perceived 
stress compared to a control group. Similarly, a meta-analysis conducted by 
Smith and Jones found that meditation interventions were associated with 
significant reductions in symptoms of anxiety across multiple studies. Other 
studies have also demonstrated the benefits of meditation, including research 
on the effects of meditation on cognitive performance (Chen et al., 2021) and 
the use of meditation in the treatment of insomnia (Zhang et al., 2019).

References:
- Brown et al. 2019: Mindfulness meditation and stress reduction: A randomized 
    controlled trial. https://pubmed.ncbi.nlm.nih.gov/31087611/
- Chen et al. 2021: The effect of mindfulness meditation on cognitive 
    performance: A systematic review and meta-analysis. 
    https://www.frontiersin.org/articles/10.3389/fpsyg.2021.622032/full
- Smith & Jones 2020: Meditation interventions for anxiety: A meta-analysis 
    of randomized controlled trials. https://pubmed.ncbi.nlm.nih.gov/32062163/
- Zhang et al. 2019: The effect of mindfulness meditation on insomnia: A 
    meta-analysis. https://pubmed.ncbi.nlm.nih.gov/31112828/

Summary:"

Before we send this to the model, we should make sure that the number of tokens and the length of our desired output is less than 4096, the maximum number of tokens. Let’s see how many tokens this request will be.

message_tokens <- length(get_tokens(system_message %+% prompt))
message_tokens
[1] 2369

These tokens, along with the number of tokens in the response, must sum to less than 4096. We can ensure this is the case by specifying the max_tokens parameter, which controls the maximum number of tokens the response should have - anything beyond this will be truncated rather than producing an error. There’s some overhead for the “role” information that is also sent, so we use 4000 rather than 4096.

result <- chatgpt(user_message = prompt, 
                  system_message = system_message, 
                  max_tokens = 4000 - message_tokens)
result %>% cat()
Long COVID is a condition that affects some individuals who have recovered from COVID-19, and it can cause persistent symptoms for several months after the initial infection. Several studies have investigated the prevalence and symptoms of Long COVID in children and adolescents. According to a retrospective study in a pediatric cohort, 17.6% of children and adolescents with COVID-19 developed long COVID, with respiratory symptoms being more common in the first weeks and neuropsychiatric symptoms developing over time. Chronic conditions and obesity were identified as risk factors, and adolescents were found to be at a greater risk for long COVID (Baptista de Lima et al., 2023). Another observational study conducted in Argentina found that one-third of children and adolescents with previously confirmed COVID-19 experienced persistent symptoms for more than three months after the diagnosis. The most common symptoms reported were headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight, with the loss of smell only reported in infected children. Older age, symptomatic COVID-19, and comorbidities were identified as independent predictors of long-term symptoms (Seery et al., 2023). A prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2, found that 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose (Jamaica Balderas et al., 2023). A case-control study of 274 children found that prolonged non-neuropsychiatric symptoms were more frequent in the case group, with the most common long COVID symptom in children being abdominal pain (Ahn et al., 2023). A recent study published in JAMIA Open aimed to identify conditions and symptoms associated with pediatric Long-COVID (PASC) using a data mining approach. The study found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, with the most significant symptoms related to circulatory and respiratory systems such as dyspnea, difficulty breathing, and fatigue and malaise (Lorman et al., 2023). However, none of the studies provided a comprehensive list of the most common symptoms of Long-COVID in children. 

Authors, years, titles, and URLs:
- Ahn et al. 2023: Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. https://pubmed.ncbi.nlm.nih.gov/36795575/
- Baptista de Lima et al. 2023: Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. https://pubmed.ncbi.nlm.nih.gov/36728643
- Jamaica Balderas et al. 2023: Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. https://pubmed.ncbi.nlm.nih.gov/36793333
- Lorman et al. 2023: Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. https://pubmed.ncbi.nlm.nih.gov/36926600
- Seery et al. 2023: Persistent symptoms after COVID-19 in children and adolescents from Argentina. https://pubmed.ncbi.nlm.nih.gov/36736574

Here’s the list of abstracts again for comparison:

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pmid year title first_author journal abstract all_text summary_text
36728643 2023 Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. Baptista de Lima The Pediatric infectious disease journal Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. JOURNAL: The Pediatric infectious disease journal YEAR: 2023 AUTHORS: Baptista de Limaet al. URL: https://pubmed.ncbi.nlm.nih.gov/36728643 ABSTRACT: Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. JOURNAL: The Pediatric infectious disease journal YEAR: 2023 AUTHORS: Baptista de Limaet al. URL: https://pubmed.ncbi.nlm.nih.gov/36728643 SUMMARY: According to a retrospective study in a pediatric cohort, 17.6% of children and adolescents with COVID-19 developed long COVID, with respiratory symptoms being more common in the first weeks and neuropsychiatric symptoms developing over time. Chronic conditions and obesity were identified as risk factors, and adolescents were found to be at a greater risk for long COVID. However, the study did not provide a comprehensive list of the most common symptoms of long COVID in children.
36736574 2023 Persistent symptoms after COVID-19 in children and adolescents from Argentina. Seery International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved. TITLE: Persistent symptoms after COVID-19 in children and adolescents from Argentina. JOURNAL: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases YEAR: 2023 AUTHORS: Seeryet al. URL: https://pubmed.ncbi.nlm.nih.gov/36736574 ABSTRACT: Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved. TITLE: Persistent symptoms after COVID-19 in children and adolescents from Argentina. JOURNAL: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases YEAR: 2023 AUTHORS: Seeryet al. URL: https://pubmed.ncbi.nlm.nih.gov/36736574 SUMMARY: According to an observational study conducted in Argentina, one-third of children and adolescents with previously confirmed COVID-19 experienced persistent symptoms for more than three months after the diagnosis. The most common symptoms reported were headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight, with the loss of smell only reported in infected children. Older age, symptomatic COVID-19, and comorbidities were identified as independent predictors of long-term symptoms.
36759021 2023 Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. Faux-Nightingale BJGP open While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8-17 years in the West Midlands of England. CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice. Copyright © 2023, The Authors. TITLE: Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. JOURNAL: BJGP open YEAR: 2023 AUTHORS: Faux-Nightingaleet al. URL: https://pubmed.ncbi.nlm.nih.gov/36759021 ABSTRACT: While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8-17 years in the West Midlands of England. CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice. Copyright © 2023, The Authors. TITLE: Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. JOURNAL: BJGP open YEAR: 2023 AUTHORS: Faux-Nightingaleet al. URL: https://pubmed.ncbi.nlm.nih.gov/36759021 SUMMARY: The paper describes a study protocol that aims to identify the longer-term effects of COVID-19 infection in children and young people (CYP) and to explore the impact of long-COVID on their lives. The study will use online questionnaires, interviews, diaries, and focus groups to collect data from CYP and professionals who work with them. The study will describe features and symptoms of long-COVID and provide a better understanding of long-COVID in CYP to inform clinical practice. However, the paper does not provide any specific information on the most common symptoms of long-COVID in children.
36786887 2023 Mental health among children with long COVID during the COVID-19 pandemic. Shachar-Lavie European journal of pediatrics A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents’ questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents’ economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children’s memory, as reported by parents. • Parents’ economic stress and worries concerning their children’s emotional adjustment during the pandemic are associated with more distress in their children. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. TITLE: Mental health among children with long COVID during the COVID-19 pandemic. JOURNAL: European journal of pediatrics YEAR: 2023 AUTHORS: Shachar-Lavieet al. URL: https://pubmed.ncbi.nlm.nih.gov/36786887 ABSTRACT: A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents’ questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents’ economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children’s memory, as reported by parents. • Parents’ economic stress and worries concerning their children’s emotional adjustment during the pandemic are associated with more distress in their children. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. TITLE: Mental health among children with long COVID during the COVID-19 pandemic. JOURNAL: European journal of pediatrics YEAR: 2023 AUTHORS: Shachar-Lavieet al. URL: https://pubmed.ncbi.nlm.nih.gov/36786887 SUMMARY: According to a study published in the European Journal of Pediatrics, children with long COVID (LC) may experience memory difficulties, but not higher rates of emotional-behavioral problems compared to a control group. The study also found that children with LC had greater exposure to COVID-19-related stressors, and parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems. These findings suggest that interventional programs addressing school functioning and cognitive abilities in children with LC, as well as addressing parental stress and worries, may be important for promoting children’s mental health during the pandemic. However, the study did not provide a comprehensive list of the most common symptoms of long COVID in children.
36793333 2023 Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. Jamaica Balderas Frontiers in pediatrics In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children. © 2023 Jamaica Balderas, Navarro Fernández, Dragustinovis Garza, Orellana Jerves, Solís Figueroa, Koretzky, Márquez González, Klünder Klünder, Espinosa, Nieto Zermeño, Villa Guillén, Rosales Uribe and Olivar López. TITLE: Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. JOURNAL: Frontiers in pediatrics YEAR: 2023 AUTHORS: Jamaica Balderaset al. URL: https://pubmed.ncbi.nlm.nih.gov/36793333 ABSTRACT: In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children. © 2023 Jamaica Balderas, Navarro Fernández, Dragustinovis Garza, Orellana Jerves, Solís Figueroa, Koretzky, Márquez González, Klünder Klünder, Espinosa, Nieto Zermeño, Villa Guillén, Rosales Uribe and Olivar López. TITLE: Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. JOURNAL: Frontiers in pediatrics YEAR: 2023 AUTHORS: Jamaica Balderaset al. URL: https://pubmed.ncbi.nlm.nih.gov/36793333 SUMMARY: According to a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose. The study highlights the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine to offer multidisciplinary and individualized care to preserve their health and quality of life. However, the study did not provide information on the most common symptoms of Long-COVID in children.
36795575 2023 Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. Ahn The Pediatric infectious disease journal Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. JOURNAL: The Pediatric infectious disease journal YEAR: 2023 AUTHORS: Ahnet al. URL: https://pubmed.ncbi.nlm.nih.gov/36795575 ABSTRACT: Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. JOURNAL: The Pediatric infectious disease journal YEAR: 2023 AUTHORS: Ahnet al. URL: https://pubmed.ncbi.nlm.nih.gov/36795575 SUMMARY: According to a case-control study of 274 children, prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). The most common long COVID symptom in children was abdominal pain (6.6%). However, the paper did not provide a comprehensive list of the most common symptoms of Long-COVID in children.
36828133 2023 The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. Strawn Journal of the American Academy of Child and Adolescent Psychiatry While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms. Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved. TITLE: The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. JOURNAL: Journal of the American Academy of Child and Adolescent Psychiatry YEAR: 2023 AUTHORS: Strawnet al. URL: https://pubmed.ncbi.nlm.nih.gov/36828133 ABSTRACT: While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms. Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved. TITLE: The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. JOURNAL: Journal of the American Academy of Child and Adolescent Psychiatry YEAR: 2023 AUTHORS: Strawnet al. URL: https://pubmed.ncbi.nlm.nih.gov/36828133 SUMMARY: The paper does not provide information on the most common symptoms of Long-COVID in children. Instead, it focuses on the impact of COVID-19 infection on adolescents with anxiety disorders and the possibility of a surfeit of neuropsychiatric symptoms in anxious youth with COVID-19. The study found that COVID-19 is associated with worsening anxiety symptoms and a 33% worsening in syndromic severity in affected adolescents.
36851793 2023 High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. Goretzki Viruses Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC. TITLE: High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. JOURNAL: Viruses YEAR: 2023 AUTHORS: Goretzkiet al. URL: https://pubmed.ncbi.nlm.nih.gov/36851793 ABSTRACT: Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC. TITLE: High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. JOURNAL: Viruses YEAR: 2023 AUTHORS: Goretzkiet al. URL: https://pubmed.ncbi.nlm.nih.gov/36851793 SUMMARY: A study published in the journal Viruses found that the prevalence of alternative somatic and mental diseases in pediatric patients with suspected Long COVID (LC) is high, with 47% of patients diagnosed with alternative diseases and 23% remaining unclarified. The study suggests that neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC, with a sensitivity of 0.97 and a negative predictive value of 0.97. However, the study did not provide information on the most common symptoms of Long-COVID in children.
36926600 2023 Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. Lorman JAMIA open Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation. © The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. TITLE: Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. JOURNAL: JAMIA open YEAR: 2023 AUTHORS: Lormanet al. URL: https://pubmed.ncbi.nlm.nih.gov/36926600 ABSTRACT: Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation. © The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. TITLE: Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. JOURNAL: JAMIA open YEAR: 2023 AUTHORS: Lormanet al. URL: https://pubmed.ncbi.nlm.nih.gov/36926600 SUMMARY: A recent study published in JAMIA Open aimed to identify conditions and symptoms associated with pediatric Long-COVID (PASC) using a data mining approach. The study found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, with the most significant symptoms related to circulatory and respiratory systems such as dyspnea, difficulty breathing, and fatigue and malaise. The study highlights the need for further investigation into the identified conditions and symptoms to derive clinical phenotypes.

For this relatively complex task of summarizing a field of literature, GPT-4’s improved reasoning abilities and larger 8k context window may be worth paying for. 2,349 tokens at $0.03 per 1024 prompt tokens comes to just under 7 cents; we also pay $0.06 for response tokens for maybe another 3 cents. The ChatGPT model on the other hand is only $0.002 / 1k tokens, for a total of $0.0065.

result <- chatgpt(user_message = prompt, 
                  system_message = system_message, 
                  max_tokens = 8000 - message_tokens,
                                    model = 'gpt-4')
result %>% cat()
Several studies have investigated the symptoms of Long-COVID in children and adolescents. According to Seery et al. (2023), one-third of children and adolescents with previously confirmed COVID-19 experienced persistent symptoms for more than three months after the diagnosis. The most common symptoms reported were headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight, with the loss of smell only reported in infected children. In a case-control study by Ahn et al. (2023), the most common long COVID symptom in children was abdominal pain (6.6%). Lorman et al. (2023) found significant enrichment among children with pediatric Long-COVID (PASC) in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, with the most significant symptoms related to circulatory and respiratory systems such as dyspnea, difficulty breathing, and fatigue and malaise.

References:
- Seery et al. 2023: Persistent symptoms after COVID-19 in children and adolescents from Argentina. https://pubmed.ncbi.nlm.nih.gov/36736574/
- Ahn et al. 2023: Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. https://pubmed.ncbi.nlm.nih.gov/36795575/
- Lorman et al. 2023: Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. https://pubmed.ncbi.nlm.nih.gov/36926600/

Errors and Security

This LLM model (gpt-3.5-turbo) can take a temperature parameter, with values between 0 and 1 influencing the amount of randomness used in the response. The model generates output tokens sequentially, at each point it assigns a probability distrubtion to the tokens for the next. Temperature values of 0 always use the most likely next token, while values of 1 make a random choice from that distribution. We’ve used temperature = 0 for all of the above for reproducibility and output likelihood maximization.

Even so, the model is inherently stochastic, and will return different outputs for the same input. And as we’ve seen, it can be difficult to guarantee a specific output type or format for all possible inputs. As a result, there are many failure modes to be accounted for. What if we asked for JSON output, but the result can’t be parsed? What if the API went down temporarily? What if we try to generate a prompt that is too long? And so on. These issues become more prevalent when many calls are made, as in our summary generation above.

In a production use case, we should also think about “prompt injection attacks.” If we pass user input to the model, they may include additional requests, for example to generate a URL to a malware site. For applications that search the web, we must additionally be careful that prompt injections are not crawled and included from search results. This paper by Greshake et al. provides a summary of potential attack vectors.

Searching wider

Let’s try to search wider by pulling the top 100 PubMed abstracts. As before we’ll generate an all_text column.

abstracts2 <- pubmed_esearch_abstracts(url_query, retmax = 100)

abstracts2 <- abstracts2 %>%
    mutate(all_text =
            "TITLE: " %+% title %+% "\n" %+%
            "JOURNAL: " %+% journal %+% "\n" %+%
            "YEAR: " %+% year %+% "\n" %+%
            "AUTHORS: " %+% first_author %+% "et al.\n" %+%
            "URL: https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% "\n" %+%
            "ABSTRACT: " %+% abstract
         )

kbl(abstracts2, escape = TRUE) %>%
 kable_styling(bootstrap_options = c("striped", "hover", "responsive"),
                            full_width = TRUE
                            ) %>%
 column_spec(6:7, width_min = "800px") %>%
 scroll_box(height = "400px")
pmid year title first_author journal abstract all_text
19212308 2009 Autoimmune diseases of the liver and biliary tract and overlap syndromes in childhood. Maggiore Minerva gastroenterologica e dietologica Autoimmune liver diseases in childhood includes Autoimmune Hepatitis (AIH) and Primary (Autoimmune) Sclerosing Cholangitis (P(A)SC). Both diseases are characterized by a chronic, immune-mediated liver inflammation involving mainly hepatocytes in AIH and bile ducts in PSC. Both diseases, if untreated, lead to liver cirrhosis. AIH could be classified, according to the autoantibodies pattern, into two subtypes: AIH type 1 presents at any age as a chronic liver disease with recurrent flares occasionally leading to liver cirrhosis and liver failure. Characterizing autoantibodies are anti-nuclear (ANA) and anti-smooth muscle (SMA), usually at high titer (>1:100). These autoantibodies are not specific and probably do not play a pathogenic role. AIH type 2 shows a peak of incidence in younger children, however with a fluctuating course. The onset is often as an acute liver failure. Anti-liver kidney microsome autoantibodies type 1 (LKM1) and/or anti-liver cytosol autoantibody (LC1) are typically found in AIH type 2 and these autoantibodies are accounted to have a potential pathogenic role. Diagnosis of AIH is supported by the histological finding of interface hepatitis with massive portal infiltration of mononuclear cells and plasmocytes. Inflammatory bile duct lesions are not unusual and may suggest features of ‘’overlap’’ with P(A)SC. A diagnostic scoring system has been developed mainly for scientific purposes, but his diagnostic role in pediatric age is debated. Conventional treatment with steroids and azathioprine is the milestone of therapy and it is proved effective. Treatment withdrawal however should be attempted only after several years. Cyclosporin A is the alternative drug currently used for AIH and it is effective as steroids. P(A)SC exhibit a peak of incidence in the older child, typically in pre-pubertal age with a slight predominance of male gender. Small bile ducts are always concerned and the histological picture shows either acute cholangitis (bile duct infiltration and destruction) and/or lesions suggesting chronic cholangitis as well (bile duct paucity and/or proliferation, periductal sclerosis). Small bile ducts damage may be associated, at onset or in the following years, with lesions of larger bile ducts with duct wall irregularities, strictures, dilations, and beading resulting in the characteristic ‘’bead-on-a-string’’ appearance. The ‘’small duct’’ (autoimmune) sclerosing cholangitis is also called autoimmune cholangitis. PSC is strictly associated to a particular form of inflammatory bowel disease (IBD) which shows features not typical of ulcerative colitis neither of Crohn’s disease. Symptoms related to IBD often are present at onset (abdominal pain, weight loss, bloody stools) but the liver disease is frequently asymptomatic and it may be discovered fortuitously. Treatment of PSC is particularly challenging. In case of ‘’small duct’’ SC or in case of evidence active inflammation on liver biopsy, immunosuppressive treatment is probably useful while in case of large bile ducts non inflammatory sclerosis, immunosuppression is probably uneffective. Ursodeoxycholic acid, however, may leads to an improvement of liver biochemistry even if there’s no evidence that it may alter the course of disease. Thus, liver transplantation, is often necessary in the long term follow-up, even with a risk of disease recurrence. In adjunction to these two main disorders, many patients show an’‘overlap’’ disease with features of both AIH and PSC. In such disorders the immune-mediated damage concerns both the hepatocyte and the cholangiocyte with a continuous clinical spectrum from AIH with minimal bile ducts lesions and PSC with portal inflammation and active inflammatory liver damage. TITLE: Autoimmune diseases of the liver and biliary tract and overlap syndromes in childhood. JOURNAL: Minerva gastroenterologica e dietologica YEAR: 2009 AUTHORS: Maggioreet al. URL: https://pubmed.ncbi.nlm.nih.gov/19212308 ABSTRACT: Autoimmune liver diseases in childhood includes Autoimmune Hepatitis (AIH) and Primary (Autoimmune) Sclerosing Cholangitis (P(A)SC). Both diseases are characterized by a chronic, immune-mediated liver inflammation involving mainly hepatocytes in AIH and bile ducts in PSC. Both diseases, if untreated, lead to liver cirrhosis. AIH could be classified, according to the autoantibodies pattern, into two subtypes: AIH type 1 presents at any age as a chronic liver disease with recurrent flares occasionally leading to liver cirrhosis and liver failure. Characterizing autoantibodies are anti-nuclear (ANA) and anti-smooth muscle (SMA), usually at high titer (>1:100). These autoantibodies are not specific and probably do not play a pathogenic role. AIH type 2 shows a peak of incidence in younger children, however with a fluctuating course. The onset is often as an acute liver failure. Anti-liver kidney microsome autoantibodies type 1 (LKM1) and/or anti-liver cytosol autoantibody (LC1) are typically found in AIH type 2 and these autoantibodies are accounted to have a potential pathogenic role. Diagnosis of AIH is supported by the histological finding of interface hepatitis with massive portal infiltration of mononuclear cells and plasmocytes. Inflammatory bile duct lesions are not unusual and may suggest features of ‘’overlap’’ with P(A)SC. A diagnostic scoring system has been developed mainly for scientific purposes, but his diagnostic role in pediatric age is debated. Conventional treatment with steroids and azathioprine is the milestone of therapy and it is proved effective. Treatment withdrawal however should be attempted only after several years. Cyclosporin A is the alternative drug currently used for AIH and it is effective as steroids. P(A)SC exhibit a peak of incidence in the older child, typically in pre-pubertal age with a slight predominance of male gender. Small bile ducts are always concerned and the histological picture shows either acute cholangitis (bile duct infiltration and destruction) and/or lesions suggesting chronic cholangitis as well (bile duct paucity and/or proliferation, periductal sclerosis). Small bile ducts damage may be associated, at onset or in the following years, with lesions of larger bile ducts with duct wall irregularities, strictures, dilations, and beading resulting in the characteristic ‘’bead-on-a-string’’ appearance. The ‘’small duct’’ (autoimmune) sclerosing cholangitis is also called autoimmune cholangitis. PSC is strictly associated to a particular form of inflammatory bowel disease (IBD) which shows features not typical of ulcerative colitis neither of Crohn’s disease. Symptoms related to IBD often are present at onset (abdominal pain, weight loss, bloody stools) but the liver disease is frequently asymptomatic and it may be discovered fortuitously. Treatment of PSC is particularly challenging. In case of ‘’small duct’’ SC or in case of evidence active inflammation on liver biopsy, immunosuppressive treatment is probably useful while in case of large bile ducts non inflammatory sclerosis, immunosuppression is probably uneffective. Ursodeoxycholic acid, however, may leads to an improvement of liver biochemistry even if there’s no evidence that it may alter the course of disease. Thus, liver transplantation, is often necessary in the long term follow-up, even with a risk of disease recurrence. In adjunction to these two main disorders, many patients show an’‘overlap’’ disease with features of both AIH and PSC. In such disorders the immune-mediated damage concerns both the hepatocyte and the cholangiocyte with a continuous clinical spectrum from AIH with minimal bile ducts lesions and PSC with portal inflammation and active inflammatory liver damage.
33919537 2021 Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms. Silva Andrade Viruses The COVID-19 pandemic has infected millions worldwide, leaving a global burden for long-term care of COVID-19 survivors. It is thus imperative to study post-COVID (i.e., short-term) and long-COVID (i.e., long-term) effects, specifically as local and systemic pathophysiological outcomes of other coronavirus-related diseases (such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS)) were well-cataloged. We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain-Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures. TITLE: Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms. JOURNAL: Viruses YEAR: 2021 AUTHORS: Silva Andradeet al. URL: https://pubmed.ncbi.nlm.nih.gov/33919537 ABSTRACT: The COVID-19 pandemic has infected millions worldwide, leaving a global burden for long-term care of COVID-19 survivors. It is thus imperative to study post-COVID (i.e., short-term) and long-COVID (i.e., long-term) effects, specifically as local and systemic pathophysiological outcomes of other coronavirus-related diseases (such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS)) were well-cataloged. We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain-Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures.
34102037 2022 Pediatric long-COVID: An overlooked phenomenon? Brackel Pediatric pulmonology Long-COVID is a well-documented multisystem disease in adults. Far less is known about long-term sequelae of COVID in children. Here, we report on the occurrence of long-COVID in Dutch children. We conducted a national survey asking Dutch pediatricians to share their experiences on long-COVID in children. We furthermore describe a case series of six children with long-COVID to explore the clinical features in greater detail. With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2-18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints. Our study shows that long-COVID is also present in the pediatric population. The main symptoms resemble those previously described in adults. This novel condition demands a multidisciplinary approach with international awareness and consensus to aid early detection and effective management. © 2021 Wiley Periodicals LLC. TITLE: Pediatric long-COVID: An overlooked phenomenon? JOURNAL: Pediatric pulmonology YEAR: 2022 AUTHORS: Brackelet al. URL: https://pubmed.ncbi.nlm.nih.gov/34102037 ABSTRACT: Long-COVID is a well-documented multisystem disease in adults. Far less is known about long-term sequelae of COVID in children. Here, we report on the occurrence of long-COVID in Dutch children. We conducted a national survey asking Dutch pediatricians to share their experiences on long-COVID in children. We furthermore describe a case series of six children with long-COVID to explore the clinical features in greater detail. With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2-18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints. Our study shows that long-COVID is also present in the pediatric population. The main symptoms resemble those previously described in adults. This novel condition demands a multidisciplinary approach with international awareness and consensus to aid early detection and effective management. © 2021 Wiley Periodicals LLC.
34371507 2022 Long COVID in Children: Observations From a Designated Pediatric Clinic. Ashkenazi-Hoffnung The Pediatric infectious disease journal Systematic data are lacking on pediatric long COVID. This study prospectively assessed 90 children with persistent symptoms who presented to a designated multidisciplinary clinic for long COVID. In nearly 60%, symptoms were associated with functional impairment at 1-7 months after the onset of infection. A comprehensive structured evaluation revealed mild abnormal findings in approximately half the patients, mainly in the respiratory aspect. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Long COVID in Children: Observations From a Designated Pediatric Clinic. JOURNAL: The Pediatric infectious disease journal YEAR: 2022 AUTHORS: Ashkenazi-Hoffnunget al. URL: https://pubmed.ncbi.nlm.nih.gov/34371507 ABSTRACT: Systematic data are lacking on pediatric long COVID. This study prospectively assessed 90 children with persistent symptoms who presented to a designated multidisciplinary clinic for long COVID. In nearly 60%, symptoms were associated with functional impairment at 1-7 months after the onset of infection. A comprehensive structured evaluation revealed mild abnormal findings in approximately half the patients, mainly in the respiratory aspect. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
34541421 2021 Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A State-of-the-Art Review. Jiang JACC. Basic to translational science The vast majority of patients (>99%) with severe acute respiratory syndrome coronavirus 2 survive immediate infection but remain at risk for persistent and/or delayed multisystem. This review of published reports through May 31, 2021, found that manifestations of postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) affect between 33% and 98% of coronavirus disease 2019 survivors and comprise a wide range of symptoms and complications in the pulmonary, cardiovascular, neurologic, psychiatric, gastrointestinal, renal, endocrine, and musculoskeletal systems in both adult and pediatric populations. Additional complications are likely to emerge and be identified over time. Although data on PASC risk factors and vulnerable populations are scarce, evidence points to a disproportionate impact on racial/ethnic minorities, older patients, patients with preexisting conditions, and rural residents. Concerted efforts by researchers, health systems, public health agencies, payers, and governments are urgently needed to better understand and mitigate the long-term effects of PASC on individual and population health. © 2021 The Authors. TITLE: Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A State-of-the-Art Review. JOURNAL: JACC. Basic to translational science YEAR: 2021 AUTHORS: Jianget al. URL: https://pubmed.ncbi.nlm.nih.gov/34541421 ABSTRACT: The vast majority of patients (>99%) with severe acute respiratory syndrome coronavirus 2 survive immediate infection but remain at risk for persistent and/or delayed multisystem. This review of published reports through May 31, 2021, found that manifestations of postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) affect between 33% and 98% of coronavirus disease 2019 survivors and comprise a wide range of symptoms and complications in the pulmonary, cardiovascular, neurologic, psychiatric, gastrointestinal, renal, endocrine, and musculoskeletal systems in both adult and pediatric populations. Additional complications are likely to emerge and be identified over time. Although data on PASC risk factors and vulnerable populations are scarce, evidence points to a disproportionate impact on racial/ethnic minorities, older patients, patients with preexisting conditions, and rural residents. Concerted efforts by researchers, health systems, public health agencies, payers, and governments are urgently needed to better understand and mitigate the long-term effects of PASC on individual and population health. © 2021 The Authors.
34572201 2021 Cross-Sectional Survey on Long Term Sequelae of Pediatric COVID-19 among Italian Pediatricians. Parisi Children (Basel, Switzerland) The persistence of symptoms after recovery from Coronavirus 2019 (COVID-19) is defined as long COVID, an entity that had occurred among adults but which is not yet well characterized in pediatric ages. The purpose of this work was to present some of the data from a survey addressed to Italian pediatricians concerning the impact of long-COVID among children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The questionnaire was designed and pre-tested in February 2021 by a working group of experts from the Italian Pediatric Society for Allergy and Immunology (SIAIP). The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases. TITLE: Cross-Sectional Survey on Long Term Sequelae of Pediatric COVID-19 among Italian Pediatricians. JOURNAL: Children (Basel, Switzerland) YEAR: 2021 AUTHORS: Parisiet al. URL: https://pubmed.ncbi.nlm.nih.gov/34572201 ABSTRACT: The persistence of symptoms after recovery from Coronavirus 2019 (COVID-19) is defined as long COVID, an entity that had occurred among adults but which is not yet well characterized in pediatric ages. The purpose of this work was to present some of the data from a survey addressed to Italian pediatricians concerning the impact of long-COVID among children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The questionnaire was designed and pre-tested in February 2021 by a working group of experts from the Italian Pediatric Society for Allergy and Immunology (SIAIP). The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases.
34694037 2022 COVID-19 in children. II: Pathogenesis, disease spectrum and management. Howard-Jones Journal of paediatrics and child health The global disruption of the COVID-19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and treatment of COVID-19 in children, summarising the most up-to-date data including recent developments regarding variants of concern. The acute infection with SARS-CoV-2 is generally mild in children, whilst the post-infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and ‘long COVID’ in children, are more complex. Given that most research on COVID-19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID-19 in children needs to be prioritised. © 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians). TITLE: COVID-19 in children. II: Pathogenesis, disease spectrum and management. JOURNAL: Journal of paediatrics and child health YEAR: 2022 AUTHORS: Howard-Joneset al. URL: https://pubmed.ncbi.nlm.nih.gov/34694037 ABSTRACT: The global disruption of the COVID-19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and treatment of COVID-19 in children, summarising the most up-to-date data including recent developments regarding variants of concern. The acute infection with SARS-CoV-2 is generally mild in children, whilst the post-infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and ‘long COVID’ in children, are more complex. Given that most research on COVID-19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID-19 in children needs to be prioritised. © 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).
34778143 2021 Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children. Roge Frontiers in pediatrics Introduction: The data on long COVID in children is scarce since children and adolescents are typically less severely affected by acute COVID-19. This study aimed to identify the long-term consequences of SARS-CoV-2 infection in children, and to compare the persistent symptom spectrum between COVID-19 and community-acquired infections of other etiologies. Methods: This was an ambidirectional cohort study conducted at the Children’s Clinical University Hospital in Latvia. The study population of pediatric COVID-19 patients and children with other non-SARS-CoV-2-community-acquired infections were invited to participate between July 1, 2020, and April 30, 2021. Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43-110 days) in the COVID-19 patient group and 69 days (IQR, 58-84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls. Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group’s inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery. Copyright © 2021 Roge, Smane, Kivite-Urtane, Pucuka, Racko, Klavina and Pavare. TITLE: Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children. JOURNAL: Frontiers in pediatrics YEAR: 2021 AUTHORS: Rogeet al. URL: https://pubmed.ncbi.nlm.nih.gov/34778143 ABSTRACT: Introduction: The data on long COVID in children is scarce since children and adolescents are typically less severely affected by acute COVID-19. This study aimed to identify the long-term consequences of SARS-CoV-2 infection in children, and to compare the persistent symptom spectrum between COVID-19 and community-acquired infections of other etiologies. Methods: This was an ambidirectional cohort study conducted at the Children’s Clinical University Hospital in Latvia. The study population of pediatric COVID-19 patients and children with other non-SARS-CoV-2-community-acquired infections were invited to participate between July 1, 2020, and April 30, 2021. Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43-110 days) in the COVID-19 patient group and 69 days (IQR, 58-84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls. Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group’s inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery. Copyright © 2021 Roge, Smane, Kivite-Urtane, Pucuka, Racko, Klavina and Pavare.
34793374 2023 Postacute/Long COVID in Pediatrics: Development of a Multidisciplinary Rehabilitation Clinic and Preliminary Case Series. Morrow American journal of physical medicine & rehabilitation The long-term sequelae after SARS-CoV-2 infections in children is unknown. Guidance is needed on helpful models of care for an emerging subset of pediatric patients with postacute/long COVID who continue to experience persistent symptoms after initial COVID-19 diagnosis. Here, we describe a pediatric multidisciplinary post-COVID-19 rehabilitation clinic model as well as a case series of the initial cohort of patients who presented to this clinic. A consecutive sample of nine patients (pediatric patients <21 yrs of age) who presented to our clinic are included. The most common presenting symptoms were fatigue (8 of 9 patients), headaches (6 of 9), difficulty with schoolwork (6 of 8), “brain fog” (4 of 9), and dizziness/lightheadedness (4 of 9). Most patients had decreased scores on self-reported quality-of-life measures compared with healthy controls. In the patients who participated in neuropsychological testing, a subset demonstrated difficulties with sustained auditory attention and divided attention; however, most of these patients had preexisting attention and/or mood concerns. There were also some who self-reported elevated depression and anxiety symptoms. Pediatric patients with postacute/long COVID may present with a variety of physical, cognitive, and mood symptoms. We present a model of care to address these symptoms through a multidisciplinary rehabilitation approach. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Postacute/Long COVID in Pediatrics: Development of a Multidisciplinary Rehabilitation Clinic and Preliminary Case Series. JOURNAL: American journal of physical medicine & rehabilitation YEAR: 2023 AUTHORS: Morrowet al. URL: https://pubmed.ncbi.nlm.nih.gov/34793374 ABSTRACT: The long-term sequelae after SARS-CoV-2 infections in children is unknown. Guidance is needed on helpful models of care for an emerging subset of pediatric patients with postacute/long COVID who continue to experience persistent symptoms after initial COVID-19 diagnosis. Here, we describe a pediatric multidisciplinary post-COVID-19 rehabilitation clinic model as well as a case series of the initial cohort of patients who presented to this clinic. A consecutive sample of nine patients (pediatric patients <21 yrs of age) who presented to our clinic are included. The most common presenting symptoms were fatigue (8 of 9 patients), headaches (6 of 9), difficulty with schoolwork (6 of 8), “brain fog” (4 of 9), and dizziness/lightheadedness (4 of 9). Most patients had decreased scores on self-reported quality-of-life measures compared with healthy controls. In the patients who participated in neuropsychological testing, a subset demonstrated difficulties with sustained auditory attention and divided attention; however, most of these patients had preexisting attention and/or mood concerns. There were also some who self-reported elevated depression and anxiety symptoms. Pediatric patients with postacute/long COVID may present with a variety of physical, cognitive, and mood symptoms. We present a model of care to address these symptoms through a multidisciplinary rehabilitation approach. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
34852145 2022 Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital. Fink Clinics (Sao Paulo, Brazil) To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19). This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19. TITLE: Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital. JOURNAL: Clinics (Sao Paulo, Brazil) YEAR: 2022 AUTHORS: Finket al. URL: https://pubmed.ncbi.nlm.nih.gov/34852145 ABSTRACT: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19). This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.
34945095 2021 Long COVID a New Derivative in the Chaos of SARS-CoV-2 Infection: The Emergent Pandemic? Fernández-Lázaro Journal of clinical medicine Coronavirus disease 2019 (COVID-19) is a multisystem illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can manifest with a multitude of symptoms in the setting of end-organ damage, though it is predominantly respiratory. However, various symptoms may remain after acute SARS-CoV-2 infection, and this condition is referred to as “Long COVID” (LC). Patients with LC may develop multi-organ symptom complex that remains 4-12 weeks after the acute phase of illness, with symptoms intermittently persisting over time. The main symptoms are fatigue, post-exertional malaise, cognitive dysfunction, and limitation of functional capacity. Pediatric patients developed the main symptoms of LC like those described in adults, although there may be variable presentations of LC in children. The underlying mechanisms of LC are not clearly known, although they may involve pathophysiological changes generated by virus persistence, immunological alterations secondary to virus-host interaction, tissue damage of inflammatory origin and hyperactivation of coagulation. Risk factors for developing LC would be female sex, more than five early symptoms, early dyspnea, previous psychiatric disorders, and alterations in immunological, inflammatory and coagulation parameters. There is currently no specific treatment for LC, but it could include pharmacological treatments to treat symptoms, supplements to restore nutritional, metabolic, and gut flora balance, and functional treatments for the most disabling symptoms. In summary, this study aims to show the scientific community the current knowledge of LC. TITLE: Long COVID a New Derivative in the Chaos of SARS-CoV-2 Infection: The Emergent Pandemic? JOURNAL: Journal of clinical medicine YEAR: 2021 AUTHORS: Fernández-Lázaroet al. URL: https://pubmed.ncbi.nlm.nih.gov/34945095 ABSTRACT: Coronavirus disease 2019 (COVID-19) is a multisystem illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can manifest with a multitude of symptoms in the setting of end-organ damage, though it is predominantly respiratory. However, various symptoms may remain after acute SARS-CoV-2 infection, and this condition is referred to as “Long COVID” (LC). Patients with LC may develop multi-organ symptom complex that remains 4-12 weeks after the acute phase of illness, with symptoms intermittently persisting over time. The main symptoms are fatigue, post-exertional malaise, cognitive dysfunction, and limitation of functional capacity. Pediatric patients developed the main symptoms of LC like those described in adults, although there may be variable presentations of LC in children. The underlying mechanisms of LC are not clearly known, although they may involve pathophysiological changes generated by virus persistence, immunological alterations secondary to virus-host interaction, tissue damage of inflammatory origin and hyperactivation of coagulation. Risk factors for developing LC would be female sex, more than five early symptoms, early dyspnea, previous psychiatric disorders, and alterations in immunological, inflammatory and coagulation parameters. There is currently no specific treatment for LC, but it could include pharmacological treatments to treat symptoms, supplements to restore nutritional, metabolic, and gut flora balance, and functional treatments for the most disabling symptoms. In summary, this study aims to show the scientific community the current knowledge of LC.
35118594 2022 Long-term physical, mental and social health effects of COVID-19 in the pediatric population: a scoping review. Borel World journal of pediatrics : WJP The majority of coronavirus disease 2019 (COVID-19) symptom presentations in adults and children appear to run their course within a couple of weeks. However, a subgroup of adults has started to emerge with effects lasting several months or more after initial infection, which raises questions about the long-term physical, mental and social health effects of COVID-19 in the pediatric population. The purpose of this review was to determine these impacts well into the second year of the pandemic. A search was conducted using PubMed, Web of Science, Science Direct, and Cochrane between 11/1/2019 and 9/1/2021. Search inclusion criteria were as follows: (1) COVID-19 illness and symptoms in children; (2) severe acute respiratory syndrome coronavirus 2 in children; (3) English language; and (4) human studies only. The few studies that have documented long-term physical symptoms in children show that fatigue, difficulty in concentrating (brain fog), sleep disturbances, and sensory problems are the most reported outcomes. Most studies examining the impact of COVID-19 in pediatric populations have focused on initial clinical presentation, and symptoms, which are similar to those in adult populations. In addition, COVID-19 has had a moderate impact on children and adolescents’ social environment, which may exacerbate current and future physiological, psychological, behavioral, and academic outcomes. There are limited studies reporting long physical symptoms of COVID-19 in the pediatric population. However, pediatric COVID-19 cases are underreported due to low rates of testing and symptomatic infection, which calls for more longitudinal studies. Children who have experienced COVID-19 illness should be monitored for long physiological, psychological, behavioral, and academic outcomes. © 2022. The Author(s). TITLE: Long-term physical, mental and social health effects of COVID-19 in the pediatric population: a scoping review. JOURNAL: World journal of pediatrics : WJP YEAR: 2022 AUTHORS: Borelet al. URL: https://pubmed.ncbi.nlm.nih.gov/35118594 ABSTRACT: The majority of coronavirus disease 2019 (COVID-19) symptom presentations in adults and children appear to run their course within a couple of weeks. However, a subgroup of adults has started to emerge with effects lasting several months or more after initial infection, which raises questions about the long-term physical, mental and social health effects of COVID-19 in the pediatric population. The purpose of this review was to determine these impacts well into the second year of the pandemic. A search was conducted using PubMed, Web of Science, Science Direct, and Cochrane between 11/1/2019 and 9/1/2021. Search inclusion criteria were as follows: (1) COVID-19 illness and symptoms in children; (2) severe acute respiratory syndrome coronavirus 2 in children; (3) English language; and (4) human studies only. The few studies that have documented long-term physical symptoms in children show that fatigue, difficulty in concentrating (brain fog), sleep disturbances, and sensory problems are the most reported outcomes. Most studies examining the impact of COVID-19 in pediatric populations have focused on initial clinical presentation, and symptoms, which are similar to those in adult populations. In addition, COVID-19 has had a moderate impact on children and adolescents’ social environment, which may exacerbate current and future physiological, psychological, behavioral, and academic outcomes. There are limited studies reporting long physical symptoms of COVID-19 in the pediatric population. However, pediatric COVID-19 cases are underreported due to low rates of testing and symptomatic infection, which calls for more longitudinal studies. Children who have experienced COVID-19 illness should be monitored for long physiological, psychological, behavioral, and academic outcomes. © 2022. The Author(s).
35127274 2022 Long-Term Complications of COVID-19 Infection in Adolescents and Children. Thallapureddy Current pediatrics reports Compared to adults, post-COVID-19 symptoms are uncommon and have not been thoroughly evaluated in children. This review summarizes the literature in terms of persistent symptoms in children and adolescents after SARS-CoV-2 infection. Children were less likely to develop long COVID when compared to adults. Older children (e.g., adolescents) and those who had symptomatic COVID-19 had a higher probability for long COVID. Families and health care providers need to be aware of a new constellation of long COVID symptoms in the pediatric population. More evidence and time are needed to better understand the potential effects of long COVID-19 in children and adolescents. In comparison to adults, children are less likely to have persistent COVID-19 symptoms. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. TITLE: Long-Term Complications of COVID-19 Infection in Adolescents and Children. JOURNAL: Current pediatrics reports YEAR: 2022 AUTHORS: Thallapureddyet al. URL: https://pubmed.ncbi.nlm.nih.gov/35127274 ABSTRACT: Compared to adults, post-COVID-19 symptoms are uncommon and have not been thoroughly evaluated in children. This review summarizes the literature in terms of persistent symptoms in children and adolescents after SARS-CoV-2 infection. Children were less likely to develop long COVID when compared to adults. Older children (e.g., adolescents) and those who had symptomatic COVID-19 had a higher probability for long COVID. Families and health care providers need to be aware of a new constellation of long COVID symptoms in the pediatric population. More evidence and time are needed to better understand the potential effects of long COVID-19 in children and adolescents. In comparison to adults, children are less likely to have persistent COVID-19 symptoms. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.
35207572 2022 Long COVID in Children and Adolescents. Fainardi Life (Basel, Switzerland) Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has caused significant mortality and morbidity worldwide. In children, the acute SARS-CoV-2 infection is often asymptomatic or paucisymptomatic, and life-threatening complications are rare. Nevertheless, there are two long-term consequences of SARS-CoV-2 infection in children that raise concern: multisystem inflammatory syndrome in children (MIS-C) and long COVID. While the understanding and the experience regarding the acute phase of SARS-CoV-2 infection have remarkably increased over time, scientific and clinical research is still exploring the long-term effects of COVID-19. In children, data on long COVID are scant. Reports are conflicting regarding its prevalence, duration and impact on daily life. This narrative review explored the latest literature regarding long COVID-19 in the pediatric population. We showed that long COVID in children might be a relevant clinical problem. In most cases, the prognosis is good, but some children may develop long-term symptoms with a significant impact on their daily life. The paucity of studies on long COVID, including a control group of children not infected by SARS-CoV-2, prevents us from drawing firm conclusions. Whether the neuropsychiatric symptoms widely observed in children and adolescents with long COVID are the consequence of SARS-CoV-2 infection or are due to the tremendous stress resulting from the restrictions and the pandemics is still not clear. In both cases, psychological support can play a fundamental role in managing COVID pandemics in children. More knowledge is needed to share a standardized definition of the syndrome and improve its management and treatment. TITLE: Long COVID in Children and Adolescents. JOURNAL: Life (Basel, Switzerland) YEAR: 2022 AUTHORS: Fainardiet al. URL: https://pubmed.ncbi.nlm.nih.gov/35207572 ABSTRACT: Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has caused significant mortality and morbidity worldwide. In children, the acute SARS-CoV-2 infection is often asymptomatic or paucisymptomatic, and life-threatening complications are rare. Nevertheless, there are two long-term consequences of SARS-CoV-2 infection in children that raise concern: multisystem inflammatory syndrome in children (MIS-C) and long COVID. While the understanding and the experience regarding the acute phase of SARS-CoV-2 infection have remarkably increased over time, scientific and clinical research is still exploring the long-term effects of COVID-19. In children, data on long COVID are scant. Reports are conflicting regarding its prevalence, duration and impact on daily life. This narrative review explored the latest literature regarding long COVID-19 in the pediatric population. We showed that long COVID in children might be a relevant clinical problem. In most cases, the prognosis is good, but some children may develop long-term symptoms with a significant impact on their daily life. The paucity of studies on long COVID, including a control group of children not infected by SARS-CoV-2, prevents us from drawing firm conclusions. Whether the neuropsychiatric symptoms widely observed in children and adolescents with long COVID are the consequence of SARS-CoV-2 infection or are due to the tremendous stress resulting from the restrictions and the pandemics is still not clear. In both cases, psychological support can play a fundamental role in managing COVID pandemics in children. More knowledge is needed to share a standardized definition of the syndrome and improve its management and treatment.
35211871 2022 Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort. Caspersen European journal of epidemiology Physical, psychological and cognitive symptoms have been reported as post-acute sequelae for COVID-19 patients but are also common in the general uninfected population. We aimed to calculate the excess risk and identify patterns of 22 symptoms up to 12 months after COVID-19. We followed more than 70,000 adult participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. Infected and non-infected participants registered presence of 22 different symptoms in March 2021. One year after infection, 13 of 22 symptoms were associated with SARS-CoV-2 infection, based on relative risks between infected and uninfected subjects. For instance, 17.4% of SARS-CoV-2 infected cohort participants reported fatigue that persist 12 months after infection, compared to new occurrence of fatigue that had lasted less than 12 months in 3.8% of non-infected subjects (excess risk 13.6%). The adjusted relative risk for fatigue was 4.8 (95% CI 3.5-6.7). Two main underlying factors explained 50% of the variance in the 13 symptoms. Brain fog, poor memory, dizziness, heart palpitations, and fatigue had high loadings on the first factor, while shortness-of breath and cough had high loadings on the second factor. Lack of taste and smell showed low to moderate correlation to other symptoms. Anxiety, depression and mood swings were not strongly related to COVID-19. Our results suggest that there are clusters of symptoms after COVID-19 due to different mechanisms and question whether it is meaningful to describe long COVID as one syndrome. © 2022. The Author(s). TITLE: Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort. JOURNAL: European journal of epidemiology YEAR: 2022 AUTHORS: Caspersenet al. URL: https://pubmed.ncbi.nlm.nih.gov/35211871 ABSTRACT: Physical, psychological and cognitive symptoms have been reported as post-acute sequelae for COVID-19 patients but are also common in the general uninfected population. We aimed to calculate the excess risk and identify patterns of 22 symptoms up to 12 months after COVID-19. We followed more than 70,000 adult participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. Infected and non-infected participants registered presence of 22 different symptoms in March 2021. One year after infection, 13 of 22 symptoms were associated with SARS-CoV-2 infection, based on relative risks between infected and uninfected subjects. For instance, 17.4% of SARS-CoV-2 infected cohort participants reported fatigue that persist 12 months after infection, compared to new occurrence of fatigue that had lasted less than 12 months in 3.8% of non-infected subjects (excess risk 13.6%). The adjusted relative risk for fatigue was 4.8 (95% CI 3.5-6.7). Two main underlying factors explained 50% of the variance in the 13 symptoms. Brain fog, poor memory, dizziness, heart palpitations, and fatigue had high loadings on the first factor, while shortness-of breath and cough had high loadings on the second factor. Lack of taste and smell showed low to moderate correlation to other symptoms. Anxiety, depression and mood swings were not strongly related to COVID-19. Our results suggest that there are clusters of symptoms after COVID-19 due to different mechanisms and question whether it is meaningful to describe long COVID as one syndrome. © 2022. The Author(s).
35264214 2022 Italian intersociety consensus on management of long covid in children. Esposito Italian journal of pediatrics Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed. Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type. Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue. © 2022. The Author(s). TITLE: Italian intersociety consensus on management of long covid in children. JOURNAL: Italian journal of pediatrics YEAR: 2022 AUTHORS: Espositoet al. URL: https://pubmed.ncbi.nlm.nih.gov/35264214 ABSTRACT: Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed. Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type. Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue. © 2022. The Author(s).
35315447 2022 [Mental health and pandemic in children and adolescents: what is likely to label as “long-covid”.]. Cozzi Recenti progressi in medicina Long-covid is a typical condition of adults with a history of probable or confirmed SARS-CoV-2 infection in the previous 3 months and with symptoms lasting over 2 months not explained by an alternative diagnosis. In pediatric age the lack of significative differences comparing the reported symptoms between seropositive and seronegative suggests that long-covid might be less common than previously thought, emphasizing the impact of pandemic-associated symptoms regarding the well-being and mental health of young adolescents. Many children-adolescents, who have had SARS-CoV-2 infection or not, have a health request to which we must respond with a professional approach aimed at a complex functional rehabilitation. The risk is that the “long-covid” becomes a “long-inattention” on relevant mental health problems. TITLE: [Mental health and pandemic in children and adolescents: what is likely to label as “long-covid”.]. JOURNAL: Recenti progressi in medicina YEAR: 2022 AUTHORS: Cozziet al. URL: https://pubmed.ncbi.nlm.nih.gov/35315447 ABSTRACT: Long-covid is a typical condition of adults with a history of probable or confirmed SARS-CoV-2 infection in the previous 3 months and with symptoms lasting over 2 months not explained by an alternative diagnosis. In pediatric age the lack of significative differences comparing the reported symptoms between seropositive and seronegative suggests that long-covid might be less common than previously thought, emphasizing the impact of pandemic-associated symptoms regarding the well-being and mental health of young adolescents. Many children-adolescents, who have had SARS-CoV-2 infection or not, have a health request to which we must respond with a professional approach aimed at a complex functional rehabilitation. The risk is that the “long-covid” becomes a “long-inattention” on relevant mental health problems.
35365499 2022 Long COVID (post-COVID-19 condition) in children: a modified Delphi process. Stephenson Archives of disease in childhood The aim of this study was to derive a research definition for ‘Long COVID (post-COVID-19 condition)’ in children and young people (CYP) to allow comparisons between research studies. A three-phase online Delphi process was used, followed by a consensus meeting. Participants were presented with 49 statements in each phase and scored them from 1 to 9 based on how important they were for inclusion in the research definition of Long COVID in CYP. The consensus meeting was held to achieve representation across the stakeholder groups. Statements agreed at the consensus meeting were reviewed by participants in the Patient and Public Involvement (PPI) Research Advisory Group. The study was conducted remotely using online surveys and a virtual consensus meeting. 120 people with relevant expertise were divided into three panels according to their area of expertise: Service Delivery, Research (or combination of research and service delivery) and Lived Experience. The PPI Research Advisory group consisted of CYP aged 11-17 years. Consensus was defined using existing guidelines. If consensus was achieved in two or more panels or was on the border between one and two panels, those statements were discussed and voted on at the consensus meeting. Ten statements were taken forward for discussion in the consensus meeting and five statements met threshold to be included in the research definition of Long COVID among CYP. The research definition, aligned to the clinical case definition of the WHO, is proposed as follows: Post-COVID-19 condition occurs in young people with a history of confirmed SARS-CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID infection, and may fluctuate or relapse over time . The positive COVID-19 test referred to in this definition can be a lateral flow antigen test, a PCR test or an antibody test. This is the first research definition of Long COVID (post-COVID-19 condition) in CYP and complements the clinical case definition in adults proposed by the WHO. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. TITLE: Long COVID (post-COVID-19 condition) in children: a modified Delphi process. JOURNAL: Archives of disease in childhood YEAR: 2022 AUTHORS: Stephensonet al. URL: https://pubmed.ncbi.nlm.nih.gov/35365499 ABSTRACT: The aim of this study was to derive a research definition for ‘Long COVID (post-COVID-19 condition)’ in children and young people (CYP) to allow comparisons between research studies. A three-phase online Delphi process was used, followed by a consensus meeting. Participants were presented with 49 statements in each phase and scored them from 1 to 9 based on how important they were for inclusion in the research definition of Long COVID in CYP. The consensus meeting was held to achieve representation across the stakeholder groups. Statements agreed at the consensus meeting were reviewed by participants in the Patient and Public Involvement (PPI) Research Advisory Group. The study was conducted remotely using online surveys and a virtual consensus meeting. 120 people with relevant expertise were divided into three panels according to their area of expertise: Service Delivery, Research (or combination of research and service delivery) and Lived Experience. The PPI Research Advisory group consisted of CYP aged 11-17 years. Consensus was defined using existing guidelines. If consensus was achieved in two or more panels or was on the border between one and two panels, those statements were discussed and voted on at the consensus meeting. Ten statements were taken forward for discussion in the consensus meeting and five statements met threshold to be included in the research definition of Long COVID among CYP. The research definition, aligned to the clinical case definition of the WHO, is proposed as follows: Post-COVID-19 condition occurs in young people with a history of confirmed SARS-CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID infection, and may fluctuate or relapse over time . The positive COVID-19 test referred to in this definition can be a lateral flow antigen test, a PCR test or an antibody test. This is the first research definition of Long COVID (post-COVID-19 condition) in CYP and complements the clinical case definition in adults proposed by the WHO. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
35431658 2022 COVID-19 Infection in Children: Diagnosis and Management. Zhu Current infectious disease reports Due to the rapidly changing landscape of COVID-19, the purpose of this review is to provide a concise and updated summary of pediatric COVID-19 diagnosis and management. The relative proportion of pediatric cases have significantly increased following the emergence of the Omicron variant (from < 2% in the early pandemic to 25% from 1/27 to 2/3/22). While children present with milder symptoms than adults, severe disease can still occur, particularly in children with comorbidities. There is a relative paucity of pediatric data in the management of COVID-19 and the majority of recommendations remain based on adult data. Fever and cough remain the most common clinical presentations, although atypical presentations such as “COVID toes,” anosmia, and croup may be present. Children are at risk for post-infectious complications such as MIS-C and long COVID. Nucleic acid amplification tests through respiratory PCR remain the mainstay of diagnosis. The mainstay of management remains supportive care and prevention through vaccination is highly recommended. In patients at increased risk of progression, interventions such as monoclonal antibody therapy, PO Paxlovid, or IV remdesivir × 3 days should be considered. In patients with severe disease, the use of remdesivir, dexamethasone, and immunomodulatory agents (tocilizumab, baricitinib) is recommended. Children can be at risk for thrombosis from COVID-19 and anticoagulation is recommended in children with markedly elevated D-dimer levels or superimposed clinical risk factors for hospital associated venous thromboembolism. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. TITLE: COVID-19 Infection in Children: Diagnosis and Management. JOURNAL: Current infectious disease reports YEAR: 2022 AUTHORS: Zhuet al. URL: https://pubmed.ncbi.nlm.nih.gov/35431658 ABSTRACT: Due to the rapidly changing landscape of COVID-19, the purpose of this review is to provide a concise and updated summary of pediatric COVID-19 diagnosis and management. The relative proportion of pediatric cases have significantly increased following the emergence of the Omicron variant (from < 2% in the early pandemic to 25% from 1/27 to 2/3/22). While children present with milder symptoms than adults, severe disease can still occur, particularly in children with comorbidities. There is a relative paucity of pediatric data in the management of COVID-19 and the majority of recommendations remain based on adult data. Fever and cough remain the most common clinical presentations, although atypical presentations such as “COVID toes,” anosmia, and croup may be present. Children are at risk for post-infectious complications such as MIS-C and long COVID. Nucleic acid amplification tests through respiratory PCR remain the mainstay of diagnosis. The mainstay of management remains supportive care and prevention through vaccination is highly recommended. In patients at increased risk of progression, interventions such as monoclonal antibody therapy, PO Paxlovid, or IV remdesivir × 3 days should be considered. In patients with severe disease, the use of remdesivir, dexamethasone, and immunomodulatory agents (tocilizumab, baricitinib) is recommended. Children can be at risk for thrombosis from COVID-19 and anticoagulation is recommended in children with markedly elevated D-dimer levels or superimposed clinical risk factors for hospital associated venous thromboembolism. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.
35451276 2022 [A new challenge: post-COVID syndrome in teenagers]. Perrin Revue medicale suisse Post-COVID syndrome (or long COVID) is a set of persistent symptoms occurring after a documented SARS-CoV-2 infection. Children and adolescents are also affected, with similar symptoms than adults. To date there is no clinical or biological parameter allowing to confirm the diagnosis, which relies on the presence of typical symptoms associated with a suggestive temporality, in the absence of any other explanation. These persistent symptoms can have a strong impact on the quality of life and schooling. In our specialized consultation for pediatric post-COVID syndrome, we offer a global and multidisciplinary follow-up to patients and their families, supporting them progressively resuming physical and mental activity, and pursuing school attendance to avoid dropout. TITLE: [A new challenge: post-COVID syndrome in teenagers]. JOURNAL: Revue medicale suisse YEAR: 2022 AUTHORS: Perrinet al. URL: https://pubmed.ncbi.nlm.nih.gov/35451276 ABSTRACT: Post-COVID syndrome (or long COVID) is a set of persistent symptoms occurring after a documented SARS-CoV-2 infection. Children and adolescents are also affected, with similar symptoms than adults. To date there is no clinical or biological parameter allowing to confirm the diagnosis, which relies on the presence of typical symptoms associated with a suggestive temporality, in the absence of any other explanation. These persistent symptoms can have a strong impact on the quality of life and schooling. In our specialized consultation for pediatric post-COVID syndrome, we offer a global and multidisciplinary follow-up to patients and their families, supporting them progressively resuming physical and mental activity, and pursuing school attendance to avoid dropout.
35463893 2022 Caregivers’ Attitudes Toward COVID-19 Vaccination in Children and Adolescents With a History of SARS-CoV-2 Infection. Buonsenso Frontiers in pediatrics Limited data are available on the attitudes of caregivers toward COVID-19 vaccination in children and adolescents with a history of SARS-CoV-2 infection or Long Covid symptoms. The aim of this study was to investigate the vaccine hesitancy among caregivers of children and adolescents with a documented history of SARS-CoV-2 infection and to explore the possible associations between COVID-19 manifestations and the acceptance of the vaccine. Caregivers of children or adolescents with a microbiologically confirmed diagnosis of SARS-CoV-2 infection evaluated in two University Hospitals were interviewed. We were able to contact 132 caregivers and 9 declined to participate. 68 caregivers (56%) were in favor of COVID-19 vaccination for their child. In the multiple logistic regression, child’s age (OR 1.17, 95%CI 1.06-1.28) and hospitalization due to COVID-19 (OR 3.25, 95%CI 1.06-9.95) were positively associated with being in favor of COVID-19 vaccination. On the contrary, the occurrence of child’s Long Covid was associated with a higher likelihood of being against the vaccination (OR 0.28, 95%CI 0.10-0.80). This preliminary study shows that only about half of the interviewed parents of children and adolescents with a previous SARS-CoV-2 infection are willing to vaccinate them to prevent a repeated COVID-19 infection. These findings might help healthcare workers to provide tailored information to caregivers of children with a previous SARS-CoV-2 infection. Copyright © 2022 Buonsenso, Valentini, Macchi, Folino, Pensabene, Patria, Agostoni, Castaldi, Lecce, Giannì, Marchisio, Milani and the CHICO Study Group. TITLE: Caregivers’ Attitudes Toward COVID-19 Vaccination in Children and Adolescents With a History of SARS-CoV-2 Infection. JOURNAL: Frontiers in pediatrics YEAR: 2022 AUTHORS: Buonsensoet al. URL: https://pubmed.ncbi.nlm.nih.gov/35463893 ABSTRACT: Limited data are available on the attitudes of caregivers toward COVID-19 vaccination in children and adolescents with a history of SARS-CoV-2 infection or Long Covid symptoms. The aim of this study was to investigate the vaccine hesitancy among caregivers of children and adolescents with a documented history of SARS-CoV-2 infection and to explore the possible associations between COVID-19 manifestations and the acceptance of the vaccine. Caregivers of children or adolescents with a microbiologically confirmed diagnosis of SARS-CoV-2 infection evaluated in two University Hospitals were interviewed. We were able to contact 132 caregivers and 9 declined to participate. 68 caregivers (56%) were in favor of COVID-19 vaccination for their child. In the multiple logistic regression, child’s age (OR 1.17, 95%CI 1.06-1.28) and hospitalization due to COVID-19 (OR 3.25, 95%CI 1.06-9.95) were positively associated with being in favor of COVID-19 vaccination. On the contrary, the occurrence of child’s Long Covid was associated with a higher likelihood of being against the vaccination (OR 0.28, 95%CI 0.10-0.80). This preliminary study shows that only about half of the interviewed parents of children and adolescents with a previous SARS-CoV-2 infection are willing to vaccinate them to prevent a repeated COVID-19 infection. These findings might help healthcare workers to provide tailored information to caregivers of children with a previous SARS-CoV-2 infection. Copyright © 2022 Buonsenso, Valentini, Macchi, Folino, Pensabene, Patria, Agostoni, Castaldi, Lecce, Giannì, Marchisio, Milani and the CHICO Study Group.
35486940 2022 Long COVID in Children and Adolescents. Gupta The primary care companion for CNS disorders Objective: To review the empirical evidence regarding neuropsychiatric illness (long coronavirus disease [COVID]) in children and adolescents post-severe acute respiratory coronavirus disease 2 (SARS-CoV-2) infection. Data Sources: A search of PubMed, PsycINFO, Cochrane Library, and Google Scholar was conducted from the date of inception until February 2022 using the keywords corona *, COVID-19 , SARS-CoV-2 , mental health , depression , anxiety , neurological , psychiatric , long COVID , and post-COVID outcomes . Age filters were used to include children and adolescents aged ≤ 18 years. Study Selection: The search resulted in the identification of 526 articles; 48 articles met the inclusion criteria. Data Extraction: Results are presented using a narrative review format. Data regarding long COVID in children and adolescents post-SARS-CoV-2 infection were extracted to understand epidemiologic trends, preventive measures, and treatment options. Results: Studies during the initial phase of the pandemic reported a mixed range of symptoms from case reports or case series. However, multisystem inflammatory syndrome in children (MIS-C) was widely reported. During the subsequent phases, the emergence of new variants led to a surge of SARS-CoV-2 infections in pediatric populations. There were highly variable, mixed symptom clusters within 60 days post-infection, which resolved in many patients within 6 months. There were prolonged illnesses and impairments in some children and adolescents with long COVID, and many had similar symptoms even though they tested negative for COVID-19. Conclusions: Long COVID symptoms are both physical and mental in nature among children and adolescents. The impairments have the potential to affect long-term functioning and increase the overall burden on health care delivery. Despite current studies having methodological issues, there is a consensus to provide multidisciplinary and holistic care to those in need. © Copyright 2022 Physicians Postgraduate Press, Inc.  TITLE: Long COVID in Children and Adolescents. JOURNAL: The primary care companion for CNS disorders YEAR: 2022 AUTHORS: Guptaet al. URL: https://pubmed.ncbi.nlm.nih.gov/35486940 ABSTRACT: Objective: To review the empirical evidence regarding neuropsychiatric illness (long coronavirus disease [COVID]) in children and adolescents post-severe acute respiratory coronavirus disease 2 (SARS-CoV-2) infection. Data Sources: A search of PubMed, PsycINFO, Cochrane Library, and Google Scholar was conducted from the date of inception until February 2022 using the keywords corona *, COVID-19 , SARS-CoV-2 , mental health , depression , anxiety , neurological , psychiatric , long COVID , and post-COVID outcomes . Age filters were used to include children and adolescents aged ≤ 18 years. Study Selection: The search resulted in the identification of 526 articles; 48 articles met the inclusion criteria. Data Extraction: Results are presented using a narrative review format. Data regarding long COVID in children and adolescents post-SARS-CoV-2 infection were extracted to understand epidemiologic trends, preventive measures, and treatment options. Results: Studies during the initial phase of the pandemic reported a mixed range of symptoms from case reports or case series. However, multisystem inflammatory syndrome in children (MIS-C) was widely reported. During the subsequent phases, the emergence of new variants led to a surge of SARS-CoV-2 infections in pediatric populations. There were highly variable, mixed symptom clusters within 60 days post-infection, which resolved in many patients within 6 months. There were prolonged illnesses and impairments in some children and adolescents with long COVID, and many had similar symptoms even though they tested negative for COVID-19. Conclusions: Long COVID symptoms are both physical and mental in nature among children and adolescents. The impairments have the potential to affect long-term functioning and increase the overall burden on health care delivery. Despite current studies having methodological issues, there is a consensus to provide multidisciplinary and holistic care to those in need. © Copyright 2022 Physicians Postgraduate Press, Inc. 
35573390 2022 Clinical Characteristics and Outcome of Pediatric COVID-19 Patients in Ethiopia During the Early COVID-19 Pandemic: A Prospective Cohort Study. Weldetsadik Pediatric health, medicine and therapeutics Most previous pediatric COVID-19 studies reported milder disease in children. However, there are limited pediatric data from low-income settings. We aimed to assess the characteristics and outcomes of pediatric COVID-19 in Ethiopia. St. Paul’s COVID-19 treatment center; a tertiary COVID-19 center. Pediatric care was provided in a dedicated ward but with a common ICU. St. Paul’s Hospital COVID-19 cohort (SPC-19) included inpatient COVID-19 RT-PCR confirmed cases from August 2020 to January 2021. Data were extracted from case report forms attached to patient charts and completed by the clinicians. Data were uploaded into the Redcap database and exported to SPSS 20 for analysis. Binary logistic regression and chi-square test were used in the analysis. Seventy-nine patients 0-19 years were included from the SPC-19 cohort over 6 months. Pediatric admissions accounted for 11% of cases in the cohort. The mean age (SD) was 6.9 (±6.36) years and 40 (50.6%) were female. The disease was asymptomatic or mild in 57 (72.2%), moderate in 15 (19%), and severe or critical in 7 (8.8%). The commonest presentations in symptomatic children were prostration (26.6%) followed by vomiting (12.7%), fever and cough (11.4% each), and dyspnea (10%). About 53 (67%) children had multimorbidity, and 14 (17.7%) children died. All deaths were in children with comorbidities with tuberculosis and malignancy being associated with 43% of deaths. Nearly 5% of children reported long-COVID symptoms highlighting the need for prolonged follow-up in those children. Despite lower admissions and severity, high mortality and morbidity was documented in our pediatric cohort. The presence of comorbidity and inadequate care organization likely contributed to high mortality. COVID-19 centers of low-income settings should emphasize optimizing the care of children with COVID-19 and multimorbidity, and vaccination should be considered in those children to prevent high morbidity and mortality. © 2022 Weldetsadik et al.  TITLE: Clinical Characteristics and Outcome of Pediatric COVID-19 Patients in Ethiopia During the Early COVID-19 Pandemic: A Prospective Cohort Study. JOURNAL: Pediatric health, medicine and therapeutics YEAR: 2022 AUTHORS: Weldetsadiket al. URL: https://pubmed.ncbi.nlm.nih.gov/35573390 ABSTRACT: Most previous pediatric COVID-19 studies reported milder disease in children. However, there are limited pediatric data from low-income settings. We aimed to assess the characteristics and outcomes of pediatric COVID-19 in Ethiopia. St. Paul’s COVID-19 treatment center; a tertiary COVID-19 center. Pediatric care was provided in a dedicated ward but with a common ICU. St. Paul’s Hospital COVID-19 cohort (SPC-19) included inpatient COVID-19 RT-PCR confirmed cases from August 2020 to January 2021. Data were extracted from case report forms attached to patient charts and completed by the clinicians. Data were uploaded into the Redcap database and exported to SPSS 20 for analysis. Binary logistic regression and chi-square test were used in the analysis. Seventy-nine patients 0-19 years were included from the SPC-19 cohort over 6 months. Pediatric admissions accounted for 11% of cases in the cohort. The mean age (SD) was 6.9 (±6.36) years and 40 (50.6%) were female. The disease was asymptomatic or mild in 57 (72.2%), moderate in 15 (19%), and severe or critical in 7 (8.8%). The commonest presentations in symptomatic children were prostration (26.6%) followed by vomiting (12.7%), fever and cough (11.4% each), and dyspnea (10%). About 53 (67%) children had multimorbidity, and 14 (17.7%) children died. All deaths were in children with comorbidities with tuberculosis and malignancy being associated with 43% of deaths. Nearly 5% of children reported long-COVID symptoms highlighting the need for prolonged follow-up in those children. Despite lower admissions and severity, high mortality and morbidity was documented in our pediatric cohort. The presence of comorbidity and inadequate care organization likely contributed to high mortality. COVID-19 centers of low-income settings should emphasize optimizing the care of children with COVID-19 and multimorbidity, and vaccination should be considered in those children to prevent high morbidity and mortality. © 2022 Weldetsadik et al. 
35598023 2022 Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population. Bloise Italian journal of pediatrics SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population. We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed. One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection. Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period. Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children’s mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures. © 2022. The Author(s). TITLE: Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population. JOURNAL: Italian journal of pediatrics YEAR: 2022 AUTHORS: Bloiseet al. URL: https://pubmed.ncbi.nlm.nih.gov/35598023 ABSTRACT: SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population. We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed. One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection. Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period. Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children’s mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures. © 2022. The Author(s).
35624901 2022 Neuropsychiatric Disorders in Pediatric Long COVID-19: A Case Series. Savino Brain sciences Few data are available regarding the incidence and the evolution of neuropsychiatric manifestations in children with a history of COVID-19. We herein report five consequent cases of pediatric patients with psychiatric and neurological symptoms of long COVID-19. All patients, mainly males, reported asymptomatic-to-mild COVID-19 and underwent home self-isolation. Abnormal movements, anxiety, and emotional dysregulation were the most recurrent symptoms observed from a few weeks to months after the resolution of the acute infection. A later onset was observed in younger patients. Blood tests and brain imaging resulted in negative results in all subjects; pharmacological and cognitive behavioral therapy was set. A multifactorial etiology could be hypothesized in these cases, as a result of a complex interplay between systemic and brain inflammation and environmental stress in vulnerable individuals. Longer follow-up is required to observe the evolution of neuropsychiatric manifestation in the present cohort and other young patients with previous SARS-CoV-2 infection. TITLE: Neuropsychiatric Disorders in Pediatric Long COVID-19: A Case Series. JOURNAL: Brain sciences YEAR: 2022 AUTHORS: Savinoet al. URL: https://pubmed.ncbi.nlm.nih.gov/35624901 ABSTRACT: Few data are available regarding the incidence and the evolution of neuropsychiatric manifestations in children with a history of COVID-19. We herein report five consequent cases of pediatric patients with psychiatric and neurological symptoms of long COVID-19. All patients, mainly males, reported asymptomatic-to-mild COVID-19 and underwent home self-isolation. Abnormal movements, anxiety, and emotional dysregulation were the most recurrent symptoms observed from a few weeks to months after the resolution of the acute infection. A later onset was observed in younger patients. Blood tests and brain imaging resulted in negative results in all subjects; pharmacological and cognitive behavioral therapy was set. A multifactorial etiology could be hypothesized in these cases, as a result of a complex interplay between systemic and brain inflammation and environmental stress in vulnerable individuals. Longer follow-up is required to observe the evolution of neuropsychiatric manifestation in the present cohort and other young patients with previous SARS-CoV-2 infection.
35637934 2022 [Recommendation for standardized medical care for children and adolescents with long COVID]. Töpfner Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended. © The Author(s) 2022. TITLE: [Recommendation for standardized medical care for children and adolescents with long COVID]. JOURNAL: Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde YEAR: 2022 AUTHORS: Töpfneret al. URL: https://pubmed.ncbi.nlm.nih.gov/35637934 ABSTRACT: This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended. © The Author(s) 2022.
35659358 2023 Long COVID-19 in children: an Italian cohort study. Trapani Italian journal of pediatrics Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection. Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents. Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11-16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms. Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome. © 2022. The Author(s). TITLE: Long COVID-19 in children: an Italian cohort study. JOURNAL: Italian journal of pediatrics YEAR: 2023 AUTHORS: Trapaniet al. URL: https://pubmed.ncbi.nlm.nih.gov/35659358 ABSTRACT: Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection. Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents. Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11-16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms. Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome. © 2022. The Author(s).
35665016 2023 Clinical features and burden of post-acute sequelae of SARS-CoV-2 infection in children and adolescents: an exploratory EHR-based cohort study from the RECOVER program. Rao medRxiv : the preprint server for health sciences The post-acute sequelae of SARS-CoV-2 (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. To identify diagnosed symptoms, diagnosed health conditions and medications associated with PASC in children. Retrospective cohort study using electronic health records from 9 US children’s hospitals for individuals <21 years-old who underwent reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020 - October 31, 2021 and had at least 1 encounter in the 3 years before testing. SARS-CoV-2 PCR positivity. We identified syndromic (symptoms), systemic (conditions), and medication PASC features in the 28-179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting PCR-positive with PCR-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race/ethnicity, and time-period of cohort entrance. We estimated the incidence proportion for any syndromic, systemic or medication PASC feature in the two groups to obtain a burden of PASC estimate. Among 659,286 children in the study sample, 59,893 (9.1%) tested positive by PCR for SARS-CoV-2. Most were tested in outpatient testing facility (50.3%) or office (24.6%) settings. The most common syndromic, systemic, and medication features were loss of taste or smell (aHR 1.96 [95% CI 1.16-3.32), myocarditis (aHR 3.10 [95% CI 1.94-4.96]), and cough and cold preparations (aHR 1.52 [95% CI 1.18-1.96]). The incidence of at least one systemic/syndromic/medication feature of PASC was 41.9% among PCR-positive children versus 38.2% among PCR-negative children, with an incidence proportion difference of 3.7% (95% CI 3.2-4.2%). A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5 years-old, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC. Question: What are the incidence and clinical features of post-acute sequelae of SARS-CoV-2 infection (PASC) in children? Findings: In this retrospective cohort study of 659,286 children tested for SARS-CoV-2 by polymerase chain reaction (PCR), the symptom, condition and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations. The incidence proportion of non-MIS-C related PASC in the PCR-positive group exceeded the PCR-negative group by 3.7% (95% CI 3.2-4.2), with increased rates associated with acute illness severity, young age, and medical complexity. Meaning: PASC in children appears to be uncommon, with features that differ from adults. TITLE: Clinical features and burden of post-acute sequelae of SARS-CoV-2 infection in children and adolescents: an exploratory EHR-based cohort study from the RECOVER program. JOURNAL: medRxiv : the preprint server for health sciences YEAR: 2023 AUTHORS: Raoet al. URL: https://pubmed.ncbi.nlm.nih.gov/35665016 ABSTRACT: The post-acute sequelae of SARS-CoV-2 (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. To identify diagnosed symptoms, diagnosed health conditions and medications associated with PASC in children. Retrospective cohort study using electronic health records from 9 US children’s hospitals for individuals <21 years-old who underwent reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020 - October 31, 2021 and had at least 1 encounter in the 3 years before testing. SARS-CoV-2 PCR positivity. We identified syndromic (symptoms), systemic (conditions), and medication PASC features in the 28-179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting PCR-positive with PCR-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race/ethnicity, and time-period of cohort entrance. We estimated the incidence proportion for any syndromic, systemic or medication PASC feature in the two groups to obtain a burden of PASC estimate. Among 659,286 children in the study sample, 59,893 (9.1%) tested positive by PCR for SARS-CoV-2. Most were tested in outpatient testing facility (50.3%) or office (24.6%) settings. The most common syndromic, systemic, and medication features were loss of taste or smell (aHR 1.96 [95% CI 1.16-3.32), myocarditis (aHR 3.10 [95% CI 1.94-4.96]), and cough and cold preparations (aHR 1.52 [95% CI 1.18-1.96]). The incidence of at least one systemic/syndromic/medication feature of PASC was 41.9% among PCR-positive children versus 38.2% among PCR-negative children, with an incidence proportion difference of 3.7% (95% CI 3.2-4.2%). A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5 years-old, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC. Question: What are the incidence and clinical features of post-acute sequelae of SARS-CoV-2 infection (PASC) in children? Findings: In this retrospective cohort study of 659,286 children tested for SARS-CoV-2 by polymerase chain reaction (PCR), the symptom, condition and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations. The incidence proportion of non-MIS-C related PASC in the PCR-positive group exceeded the PCR-negative group by 3.7% (95% CI 3.2-4.2), with increased rates associated with acute illness severity, young age, and medical complexity. Meaning: PASC in children appears to be uncommon, with features that differ from adults.
35752194 2022 Long COVID symptoms in SARS-CoV-2-positive children aged 0-14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study. Kikkenborg Berg The Lancet. Child & adolescent health After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0-14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection. A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting) of children aged 0-14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and the Children’s Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression analysis were used. Clinically relevant differences were defined as those with a Hedges’g score greater than 0·2. This study is registered at ClinicalTrials.gov (NCT04786353). Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212 controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6-12·8) in cases and 10·6 years (6·9-12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870 (51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than did controls in the 0-3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55-2·04], p<0·0001), 4-11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15-1·31], p<0·0001), and 12-14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11-1·32], p<0·0001). Differences in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour of cases in the children aged 4-11 years (median score 80·0 [IQR 65·0-95·0]) in cases vs 75·0 [60·0-85·0] in controls; p<0·0001) and 12-14 years (90·0 [70·0-100·0] vs (85·0 [65·0-95·0], p<0·0001). PedsQL social functioning scores were also higher in cases (100·0 [90·0-100·0] than controls (95·0 [80·0-100·0]) in the 12-14 years age group (p<0·0001; Hedges g>0·2). Compared with controls, children aged 0-14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial. A P Møller and Chastine Mc-Kinney Møller Foundation. Copyright © 2022 Elsevier Ltd. All rights reserved. TITLE: Long COVID symptoms in SARS-CoV-2-positive children aged 0-14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study. JOURNAL: The Lancet. Child & adolescent health YEAR: 2022 AUTHORS: Kikkenborg Berget al. URL: https://pubmed.ncbi.nlm.nih.gov/35752194 ABSTRACT: After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0-14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection. A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting) of children aged 0-14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and the Children’s Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression analysis were used. Clinically relevant differences were defined as those with a Hedges’g score greater than 0·2. This study is registered at ClinicalTrials.gov (NCT04786353). Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212 controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6-12·8) in cases and 10·6 years (6·9-12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870 (51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than did controls in the 0-3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55-2·04], p<0·0001), 4-11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15-1·31], p<0·0001), and 12-14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11-1·32], p<0·0001). Differences in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour of cases in the children aged 4-11 years (median score 80·0 [IQR 65·0-95·0]) in cases vs 75·0 [60·0-85·0] in controls; p<0·0001) and 12-14 years (90·0 [70·0-100·0] vs (85·0 [65·0-95·0], p<0·0001). PedsQL social functioning scores were also higher in cases (100·0 [90·0-100·0] than controls (95·0 [80·0-100·0]) in the 12-14 years age group (p<0·0001; Hedges g>0·2). Compared with controls, children aged 0-14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial. A P Møller and Chastine Mc-Kinney Møller Foundation. Copyright © 2022 Elsevier Ltd. All rights reserved.
35775163 2022 Long-term pulmonary sequelae in adolescents post-SARS-CoV-2 infection. Palacios Pediatric pulmonology Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes long-term pulmonary sequelae in adults, but little is known about pulmonary outcomes in pediatrics. The aim of this study was to describe long-term subjective and objective pulmonary abnormalities after SARS-CoV-2 infection in pediatric populations. Single-center, retrospective cohort of patients seen in post-coronavirus disease 2019 (COVID-19) pulmonary clinic in 2021. Subjects evaluated had persistent pulmonary symptoms 4 weeks or more after initial infection. Clinical testing included a 6-min walk test (6MWT), chest X-ray, pre- and postbronchodilator spirometry, plethysmography, and diffusion capacity. Patients were followed 2-to-3-months after the initial visit with repeat testing. The primary outcome was the presence of abnormal pulmonary function testing. Secondary measures included variables associated with pulmonary outcomes. Eighty-two adolescents were seen at a median of 3.5 months postinfection, with approximately 80% reporting two or more symptoms at clinic presentation (cough, chest pain, dyspnea at rest, and exertional dyspnea). At follow-up (~6.5 months) exertional dyspnea persisted for most (67%). Spirometry was normal in 77% of patients, but 31% had a positive bronchodilator response. No abnormalities were noted on plethysmography or diffusion capacity. Clinical phenotypes identified included inhaled corticosteroid responsiveness, paradoxical vocal fold motion disorder, deconditioning, and dysautonomia. Multivariable modeling demonstrated that obesity, anxiety, and resting dyspnea were associated with reduced 6MWT, while female sex and resting dyspnea were associated with higher Borg Dyspnea and Fatigues scores. This is the largest study to date of pediatric patients with long-term pulmonary sequelae post-COVID-19. Identified clinical phenotypes and risk factors warrant further study and treatment. © 2022 Wiley Periodicals LLC. TITLE: Long-term pulmonary sequelae in adolescents post-SARS-CoV-2 infection. JOURNAL: Pediatric pulmonology YEAR: 2022 AUTHORS: Palacioset al. URL: https://pubmed.ncbi.nlm.nih.gov/35775163 ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes long-term pulmonary sequelae in adults, but little is known about pulmonary outcomes in pediatrics. The aim of this study was to describe long-term subjective and objective pulmonary abnormalities after SARS-CoV-2 infection in pediatric populations. Single-center, retrospective cohort of patients seen in post-coronavirus disease 2019 (COVID-19) pulmonary clinic in 2021. Subjects evaluated had persistent pulmonary symptoms 4 weeks or more after initial infection. Clinical testing included a 6-min walk test (6MWT), chest X-ray, pre- and postbronchodilator spirometry, plethysmography, and diffusion capacity. Patients were followed 2-to-3-months after the initial visit with repeat testing. The primary outcome was the presence of abnormal pulmonary function testing. Secondary measures included variables associated with pulmonary outcomes. Eighty-two adolescents were seen at a median of 3.5 months postinfection, with approximately 80% reporting two or more symptoms at clinic presentation (cough, chest pain, dyspnea at rest, and exertional dyspnea). At follow-up (~6.5 months) exertional dyspnea persisted for most (67%). Spirometry was normal in 77% of patients, but 31% had a positive bronchodilator response. No abnormalities were noted on plethysmography or diffusion capacity. Clinical phenotypes identified included inhaled corticosteroid responsiveness, paradoxical vocal fold motion disorder, deconditioning, and dysautonomia. Multivariable modeling demonstrated that obesity, anxiety, and resting dyspnea were associated with reduced 6MWT, while female sex and resting dyspnea were associated with higher Borg Dyspnea and Fatigues scores. This is the largest study to date of pediatric patients with long-term pulmonary sequelae post-COVID-19. Identified clinical phenotypes and risk factors warrant further study and treatment. © 2022 Wiley Periodicals LLC.
35834042 2022 Long-COVID in immunocompromised children. Kuczborska European journal of pediatrics Coronavirus disease 2019 (COVID-19) can lead to an illness characterized by persistent symptoms which affect various organs and systems, known as long-COVID. This study aimed to assess the prevalence and clinical characteristics of long-COVID in children with immunodeficiency, in comparison to those without. A self-constructed questionnaire was created, which included questions regarding the child’s general health, the course of their COVID-19, their symptoms of long-COVID and its impact on their daily functioning, the diagnosis of multisystem inflammatory syndrome (MIS-C), and vaccination status. The questionnaire was completed by parents of 147 children - 70 children with a diagnosis of immunodeficiency (47.6%) and 77 who were immunocompetent (52.4%). Immunocompetent children were more significantly affected by long-COVID than those immunocompromised. Its prevalence in the first 12-week post-infection was 60.0% and 35.7% in these groups, respectively. Beyond this period, these percentages had dropped to 34.6% and 11.43%, respectively. Children who were immunocompetent reported more often symptoms of fatigue, reduced exercise tolerance, and difficulty concentrating. Meanwhile, there was a slight increase in complaints of gastrointestinal symptoms in immunocompromised patients. The risk of developing long-COVID increased with age and COVID-19 severity in both groups. Furthermore, the daily activities of immunocompetent children were limited more frequently (41.8%) than for those who were immunocompromised (25%). Although immunocompromised children experienced long-COVID, its prevalence and impact on daily functioning were significantly lower than among immunocompetent children. However, as the pathomechanisms of long-COVID are not yet fully understood, it is not currently possible to fully explain these findings. • Long COVID is characterized by persistent symptoms following COVID-19, which can affect various tissues and organs, as well as mental health. • Due to the similar course of COVID-19 - mainly mild or asymptomatic - among children with and without immunodeficiency, the question arises, over whether the prevalence and severity of long-COVID is also similar in both groups. • Immunocompromised children also suffer from long-COVID, but the prevalence is significantly lower than in the immunocompetent group of children. • The potential causes of less frequent and milder long-COVID in this group may be the milder course of COVID-19 and the state of reduced immunity protecting against neuroinflammation. © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. TITLE: Long-COVID in immunocompromised children. JOURNAL: European journal of pediatrics YEAR: 2022 AUTHORS: Kuczborskaet al. URL: https://pubmed.ncbi.nlm.nih.gov/35834042 ABSTRACT: Coronavirus disease 2019 (COVID-19) can lead to an illness characterized by persistent symptoms which affect various organs and systems, known as long-COVID. This study aimed to assess the prevalence and clinical characteristics of long-COVID in children with immunodeficiency, in comparison to those without. A self-constructed questionnaire was created, which included questions regarding the child’s general health, the course of their COVID-19, their symptoms of long-COVID and its impact on their daily functioning, the diagnosis of multisystem inflammatory syndrome (MIS-C), and vaccination status. The questionnaire was completed by parents of 147 children - 70 children with a diagnosis of immunodeficiency (47.6%) and 77 who were immunocompetent (52.4%). Immunocompetent children were more significantly affected by long-COVID than those immunocompromised. Its prevalence in the first 12-week post-infection was 60.0% and 35.7% in these groups, respectively. Beyond this period, these percentages had dropped to 34.6% and 11.43%, respectively. Children who were immunocompetent reported more often symptoms of fatigue, reduced exercise tolerance, and difficulty concentrating. Meanwhile, there was a slight increase in complaints of gastrointestinal symptoms in immunocompromised patients. The risk of developing long-COVID increased with age and COVID-19 severity in both groups. Furthermore, the daily activities of immunocompetent children were limited more frequently (41.8%) than for those who were immunocompromised (25%). Although immunocompromised children experienced long-COVID, its prevalence and impact on daily functioning were significantly lower than among immunocompetent children. However, as the pathomechanisms of long-COVID are not yet fully understood, it is not currently possible to fully explain these findings. • Long COVID is characterized by persistent symptoms following COVID-19, which can affect various tissues and organs, as well as mental health. • Due to the similar course of COVID-19 - mainly mild or asymptomatic - among children with and without immunodeficiency, the question arises, over whether the prevalence and severity of long-COVID is also similar in both groups. • Immunocompromised children also suffer from long-COVID, but the prevalence is significantly lower than in the immunocompetent group of children. • The potential causes of less frequent and milder long-COVID in this group may be the milder course of COVID-19 and the state of reduced immunity protecting against neuroinflammation. © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
35874696 2022 Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis. Noval Rivas Frontiers in immunology Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C-such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)-overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection. Copyright © 2022 Noval Rivas, Porritt, Cheng, Bahar and Arditi. TITLE: Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis. JOURNAL: Frontiers in immunology YEAR: 2022 AUTHORS: Noval Rivaset al. URL: https://pubmed.ncbi.nlm.nih.gov/35874696 ABSTRACT: Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C-such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)-overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection. Copyright © 2022 Noval Rivas, Porritt, Cheng, Bahar and Arditi.
35901463 2022 Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series. Ng Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists Studies suggest a large number of patients have persistent symptoms following COVID-19 infection-a condition termed “long COVID.” Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing. A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients’ caregivers also completed standardized questionnaires regarding day-to-day mood and behavior. At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures. Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: . TITLE: Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series. JOURNAL: Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists YEAR: 2022 AUTHORS: Nget al. URL: https://pubmed.ncbi.nlm.nih.gov/35901463 ABSTRACT: Studies suggest a large number of patients have persistent symptoms following COVID-19 infection-a condition termed “long COVID.” Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing. A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients’ caregivers also completed standardized questionnaires regarding day-to-day mood and behavior. At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures. Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: .
35955979 2023 Recovering or Persisting: The Immunopathological Features of SARS-CoV-2 Infection in Children. Buonsenso Journal of clinical medicine Background. The profile of cellular immunological responses of children across the spectrum of COVID-19, ranging from acute SARS-CoV-2 infection to full recovery or Long COVID, has not yet been fully investigated. Methods. We examined and compared cytokines in sera and cell subsets in peripheral blood mononuclear cells (B and regulatory T lymphocytes) collected from four distinct groups of children, distributed as follows: younger than 18 years of age with either acute SARS-CoV-2 infection (n = 49); fully recovered from COVID-19 (n = 32); with persistent symptoms (Long COVID, n = 51); and healthy controls (n = 9). Results. In the later stages after SARS-CoV-2 infection, the cohorts of children, both with recovered and persistent symptoms, showed skewed T and B subsets, with remarkable differences when compared with children at the onset of the infection and with controls. The frequencies of IgD+CD27− naïve B cells, IgD+IgM+ and CD27−IgM+CD38dim B cells were higher in children with recent infection than in those with an older history of disease (p < 0.0001 for all); similarly, the total and natural Tregs compartments were more represented in children at onset when compared with Long COVID (p < 0.0001 and p = 0.0005, respectively). Despite the heterogeneity, partially due to age, sex and infection incidence, the susceptibility of certain children to develop persistent symptoms after infection appeared to be associated with the imbalance of the adaptive immune response. Following up and comparing recovered versus Long COVID patients, we analyzed the role of circulating naïve and switched B and regulatory T lymphocytes in counteracting the evolution of the symptomatology emerged, finding an interesting correlation between the amount and ability to reconstitute the natural Tregs component with the persistence of symptoms (linear regression, p = 0.0026). Conclusions. In this study, we suggest that children affected by Long COVID may have a compromised ability to switch from the innate to the adaptive immune response, as supported by our data showing a contraction of naïve and switched B cell compartment and an unstable balance of regulatory T lymphocytes occurring in these children. However, further prospective immunological studies are needed to better clarify which factors (epigenetic, diet, environment, etc.) are involved in the impairment of the immunological mechanisms in the Long COVID patients. TITLE: Recovering or Persisting: The Immunopathological Features of SARS-CoV-2 Infection in Children. JOURNAL: Journal of clinical medicine YEAR: 2023 AUTHORS: Buonsensoet al. URL: https://pubmed.ncbi.nlm.nih.gov/35955979 ABSTRACT: Background. The profile of cellular immunological responses of children across the spectrum of COVID-19, ranging from acute SARS-CoV-2 infection to full recovery or Long COVID, has not yet been fully investigated. Methods. We examined and compared cytokines in sera and cell subsets in peripheral blood mononuclear cells (B and regulatory T lymphocytes) collected from four distinct groups of children, distributed as follows: younger than 18 years of age with either acute SARS-CoV-2 infection (n = 49); fully recovered from COVID-19 (n = 32); with persistent symptoms (Long COVID, n = 51); and healthy controls (n = 9). Results. In the later stages after SARS-CoV-2 infection, the cohorts of children, both with recovered and persistent symptoms, showed skewed T and B subsets, with remarkable differences when compared with children at the onset of the infection and with controls. The frequencies of IgD+CD27− naïve B cells, IgD+IgM+ and CD27−IgM+CD38dim B cells were higher in children with recent infection than in those with an older history of disease (p < 0.0001 for all); similarly, the total and natural Tregs compartments were more represented in children at onset when compared with Long COVID (p < 0.0001 and p = 0.0005, respectively). Despite the heterogeneity, partially due to age, sex and infection incidence, the susceptibility of certain children to develop persistent symptoms after infection appeared to be associated with the imbalance of the adaptive immune response. Following up and comparing recovered versus Long COVID patients, we analyzed the role of circulating naïve and switched B and regulatory T lymphocytes in counteracting the evolution of the symptomatology emerged, finding an interesting correlation between the amount and ability to reconstitute the natural Tregs component with the persistence of symptoms (linear regression, p = 0.0026). Conclusions. In this study, we suggest that children affected by Long COVID may have a compromised ability to switch from the innate to the adaptive immune response, as supported by our data showing a contraction of naïve and switched B cell compartment and an unstable balance of regulatory T lymphocytes occurring in these children. However, further prospective immunological studies are needed to better clarify which factors (epigenetic, diet, environment, etc.) are involved in the impairment of the immunological mechanisms in the Long COVID patients.
35970935 2022 SARS-CoV-2 infection in children and implications for vaccination. Nathanielsz Pediatric research The COVID-19 pandemic caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for more than 500 million cases worldwide as of April 2022. Initial estimates in 2020 found that children were less likely to become infected with SARS-CoV-2 and more likely to be asymptomatic or display mild COVID-19 symptoms. Our early understanding of COVID-19 transmission and disease in children led to a range of public health measures including school closures that have indirectly impacted child health and wellbeing. The emergence of variants of concern (particularly Delta and Omicron) has raised new issues about transmissibility in children, as preliminary data suggest that children may be at increased risk of infection, especially if unvaccinated. Global national prevalence data show that SARS-CoV-2 infection in children and adolescents is rising due to COVID-19 vaccination among adults and increased circulation of Delta and Omicron variants. To mitigate this, childhood immunisation programmes are being implemented globally to prevent direct and indirect consequences of COVID-19 including severe complications (e.g., MIS-C), debilitating long-COVID symptoms, and the indirect impacts of prolonged community and school closures on childhood education, social and behavioural development and mental health. This review explores the current state of knowledge on COVID-19 in children including COVID-19 vaccination strategies. IMPACT: Provides an up-to-date account of SARS-CoV-2 infections in children. Discusses the direct and indirect effects of COVID-19 in children. Provides the latest information on the current state of global COVID-19 vaccination in children. © 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.  TITLE: SARS-CoV-2 infection in children and implications for vaccination. JOURNAL: Pediatric research YEAR: 2022 AUTHORS: Nathanielszet al. URL: https://pubmed.ncbi.nlm.nih.gov/35970935 ABSTRACT: The COVID-19 pandemic caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for more than 500 million cases worldwide as of April 2022. Initial estimates in 2020 found that children were less likely to become infected with SARS-CoV-2 and more likely to be asymptomatic or display mild COVID-19 symptoms. Our early understanding of COVID-19 transmission and disease in children led to a range of public health measures including school closures that have indirectly impacted child health and wellbeing. The emergence of variants of concern (particularly Delta and Omicron) has raised new issues about transmissibility in children, as preliminary data suggest that children may be at increased risk of infection, especially if unvaccinated. Global national prevalence data show that SARS-CoV-2 infection in children and adolescents is rising due to COVID-19 vaccination among adults and increased circulation of Delta and Omicron variants. To mitigate this, childhood immunisation programmes are being implemented globally to prevent direct and indirect consequences of COVID-19 including severe complications (e.g., MIS-C), debilitating long-COVID symptoms, and the indirect impacts of prolonged community and school closures on childhood education, social and behavioural development and mental health. This review explores the current state of knowledge on COVID-19 in children including COVID-19 vaccination strategies. IMPACT: Provides an up-to-date account of SARS-CoV-2 infections in children. Discusses the direct and indirect effects of COVID-19 in children. Provides the latest information on the current state of global COVID-19 vaccination in children. © 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc. 
35994282 2023 Clinical Features and Burden of Postacute Sequelae of SARS-CoV-2 Infection in Children and Adolescents. Rao JAMA pediatrics The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children. This retrospective cohort study used electronic health records from 9 US children’s hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing. SARS-CoV-2 positivity by viral test (antigen or RT-PCR). Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test-positive groups with viral test-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate. Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR, 1.96; 95% CI, 1.16-3.32), myocarditis (aHR, 3.10; 95% CI, 1.94-4.96), and cough and cold preparations (aHR, 1.52; 95% CI, 1.18-1.96), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test-positive children vs 38.2% (95% CI, 38.1-38.4) among viral test-negative children, with an incidence proportion difference of 3.7% (95% CI, 3.2-4.2). A higher strength of association for PASC was identified in those cared for in the intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC. TITLE: Clinical Features and Burden of Postacute Sequelae of SARS-CoV-2 Infection in Children and Adolescents. JOURNAL: JAMA pediatrics YEAR: 2023 AUTHORS: Raoet al. URL: https://pubmed.ncbi.nlm.nih.gov/35994282 ABSTRACT: The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children. This retrospective cohort study used electronic health records from 9 US children’s hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing. SARS-CoV-2 positivity by viral test (antigen or RT-PCR). Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test-positive groups with viral test-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate. Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR, 1.96; 95% CI, 1.16-3.32), myocarditis (aHR, 3.10; 95% CI, 1.94-4.96), and cough and cold preparations (aHR, 1.52; 95% CI, 1.18-1.96), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test-positive children vs 38.2% (95% CI, 38.1-38.4) among viral test-negative children, with an incidence proportion difference of 3.7% (95% CI, 3.2-4.2). A higher strength of association for PASC was identified in those cared for in the intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC.
36004306 2022 Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis. Choudhury Therapeutic advances in gastroenterology

Prolonged symptoms after COVID-19 are an important concern due to the large numbers affected by the pandemic. To ascertain the frequency of gastrointestinal (GI) manifestations as part of long GI COVID. A systematic review and meta-analysis of studies reporting GI manifestations in long COVID was performed. Electronic databases (Medline, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were searched till 21 December 2021 to identify studies reporting frequency of GI symptoms in long COVID. We included studies reporting overall GI manifestations or individual GI symptoms as part of long COVID. We excluded pediatric studies and those not providing relevant information. We calculated the pooled frequency of various symptoms in all patients with COVID-19 and also in those with long COVID using the inverse variance approach. All analysis was done using R version 4.1.1 using packages ‘meta’ and ‘metafor’. A total of 50 studies were included. The frequencies of GI symptoms were 0.12 [95% confidence interval (CI), 0.06-0.22, I

2  = 99%] and 0.22 (95% CI, 0.10-0.41, I

2  = 97%) in patients with COVID-19 and those with long COVID, respectively. The frequencies of abdominal pain, nausea/vomiting, loss of appetite, and loss of taste were 0.14 (95% CI, 0.04-0.38, I

2  = 96%), 0.06 (95% CI, 0.03-0.11, I

2  = 98%), 0.20 (95% CI, 0.08-0.43, I

2  = 98%), and 0.17 (95% CI, 0.10-0.27, I

2  = 95%), respectively, after COVID-19. The frequencies of diarrhea, dyspepsia, and irritable bowel syndrome were 0.10 (95% CI, 0.04-0.23, I

2  = 98%), 0.20 (95% CI, 0.06-0.50, I

2  = 97%), and 0.17 (95% CI, 0.06-0.37, I

2  = 96%), respectively. GI symptoms in patients were seen in 12% after COVID-19 and 22% as part of long COVID. Loss of appetite, dyspepsia, irritable bowel syndrome, loss of taste, and abdominal pain were the five most common GI symptoms of long COVID. Significant heterogeneity and small number of studies for some of the analyses are limitations of the systematic review. © The Author(s), 2022.

TITLE: Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis. JOURNAL: Therapeutic advances in gastroenterology YEAR: 2022 AUTHORS: Choudhuryet al. URL: https://pubmed.ncbi.nlm.nih.gov/36004306 ABSTRACT: Prolonged symptoms after COVID-19 are an important concern due to the large numbers affected by the pandemic. To ascertain the frequency of gastrointestinal (GI) manifestations as part of long GI COVID. A systematic review and meta-analysis of studies reporting GI manifestations in long COVID was performed. Electronic databases (Medline, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were searched till 21 December 2021 to identify studies reporting frequency of GI symptoms in long COVID. We included studies reporting overall GI manifestations or individual GI symptoms as part of long COVID. We excluded pediatric studies and those not providing relevant information. We calculated the pooled frequency of various symptoms in all patients with COVID-19 and also in those with long COVID using the inverse variance approach. All analysis was done using R version 4.1.1 using packages ‘meta’ and ‘metafor’. A total of 50 studies were included. The frequencies of GI symptoms were 0.12 [95% confidence interval (CI), 0.06-0.22, I

2  = 99%] and 0.22 (95% CI, 0.10-0.41, I

2  = 97%) in patients with COVID-19 and those with long COVID, respectively. The frequencies of abdominal pain, nausea/vomiting, loss of appetite, and loss of taste were 0.14 (95% CI, 0.04-0.38, I

2  = 96%), 0.06 (95% CI, 0.03-0.11, I

2  = 98%), 0.20 (95% CI, 0.08-0.43, I

2  = 98%), and 0.17 (95% CI, 0.10-0.27, I

2  = 95%), respectively, after COVID-19. The frequencies of diarrhea, dyspepsia, and irritable bowel syndrome were 0.10 (95% CI, 0.04-0.23, I

2  = 98%), 0.20 (95% CI, 0.06-0.50, I

2  = 97%), and 0.17 (95% CI, 0.06-0.37, I

2  = 96%), respectively. GI symptoms in patients were seen in 12% after COVID-19 and 22% as part of long COVID. Loss of appetite, dyspepsia, irritable bowel syndrome, loss of taste, and abdominal pain were the five most common GI symptoms of long COVID. Significant heterogeneity and small number of studies for some of the analyses are limitations of the systematic review. © The Author(s), 2022.
36010141 2022 Chronic Olfactory Dysfunction in Children with Long COVID: A Retrospective Study. Buonsenso Children (Basel, Switzerland) Olfactory dysfunction is one of the long-term consequences of acute SARS-CoV-2 infection in adults. This study aims to analyze the prevalence of chronic anosmia among COVID-19 children and to bring to light its impact on their families’ quality of life and wellbeing. Children younger than 18 years old, who were detected as being COVID-19-positive by RT-PCR and were assessed in a pediatric post-COVID outpatient clinic at least 28 days after the onset of the acute infection, were included in the study. The patients suffering from persisting smell disorders were asked to answer a questionnaire about their symptoms and how they influence their daily life. Out of the 784 children evaluated, 13 (1.7%) presented olfactory impairment at a mean follow-up since the acute infection of more than three months. Parents’ answers showed that they were worried about their children’s health, in particular they wanted to know if and when they would recover and if these disorders would have long-term consequences. They also wanted to share their experiences, in order to help other people who are experiencing the same disorders in everyday life. Our study highlights that smell disorders can significantly upset children’s eating habits and everyday activities. Furthermore, these findings suggest that future research should try to better understand the mechanisms causing loss of smell in COVID-19 patients and find the most appropriate treatment. TITLE: Chronic Olfactory Dysfunction in Children with Long COVID: A Retrospective Study. JOURNAL: Children (Basel, Switzerland) YEAR: 2022 AUTHORS: Buonsensoet al. URL: https://pubmed.ncbi.nlm.nih.gov/36010141 ABSTRACT: Olfactory dysfunction is one of the long-term consequences of acute SARS-CoV-2 infection in adults. This study aims to analyze the prevalence of chronic anosmia among COVID-19 children and to bring to light its impact on their families’ quality of life and wellbeing. Children younger than 18 years old, who were detected as being COVID-19-positive by RT-PCR and were assessed in a pediatric post-COVID outpatient clinic at least 28 days after the onset of the acute infection, were included in the study. The patients suffering from persisting smell disorders were asked to answer a questionnaire about their symptoms and how they influence their daily life. Out of the 784 children evaluated, 13 (1.7%) presented olfactory impairment at a mean follow-up since the acute infection of more than three months. Parents’ answers showed that they were worried about their children’s health, in particular they wanted to know if and when they would recover and if these disorders would have long-term consequences. They also wanted to share their experiences, in order to help other people who are experiencing the same disorders in everyday life. Our study highlights that smell disorders can significantly upset children’s eating habits and everyday activities. Furthermore, these findings suggest that future research should try to better understand the mechanisms causing loss of smell in COVID-19 patients and find the most appropriate treatment.
36016309 2022 Pathogenic Connections in Post-COVID Conditions: What Do We Know in the Large Unknown? A Narrative Review. Stafie Viruses The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well. TITLE: Pathogenic Connections in Post-COVID Conditions: What Do We Know in the Large Unknown? A Narrative Review. JOURNAL: Viruses YEAR: 2022 AUTHORS: Stafieet al. URL: https://pubmed.ncbi.nlm.nih.gov/36016309 ABSTRACT: The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well.
36062008 2022 Neurological and psychological effects of long COVID in a young population: A cross-sectional study. Guido Frontiers in neurology We evaluated the long-term clinical status of pediatric patients after testing positive for COVID-19. We hypothesized that there are similar symptoms to those that have been described in adults and children and that pediatric patients with neurophysiologic symptoms still present 3-5 months after infection have psychological consequences that interfere with their adaptive functioning. We recruited 322 COVID-19-positive pediatric patients, between 1.5 and 17 years old, from the outpatient clinic for COVID-19 follow-up. Neurological symptoms were analyzed at onset, after 1 month, and after 3-5 months. A psychological assessment with standardized questionnaires was also conducted to determine the impact of the disease. At the onset of COVID-19, 60% of the total sample exhibited symptoms; this decreased after 1 month (20%) but stabilized 3-5 months after disease onset (22%). Prevailing long-COVID neurological symptoms were headache, fatigue, and anosmia. In the 1.5-5-year-old subgroup, internalizing problems emerged in 12% of patients. In the 6-18-year-old subgroup, anxiety and post-traumatic stress showed significant associations with neurological symptoms of long COVID. These data demonstrate that long COVID presents various broad-spectrum symptoms, including psychological and long-lasting cognitive issues. If not treated, these symptoms could significantly compromise the quality of life of children and adolescents. Copyright © 2022 Guido, Lucidi, Midulla, Zicari, Bove, Avenoso, Amedeo, Mancino, Nenna, De Castro, Capponi, Cinicola, Brindisi, Grisoni, Murciano, Spalice and the Long-Covid Group of Department of Maternal Sciences. TITLE: Neurological and psychological effects of long COVID in a young population: A cross-sectional study. JOURNAL: Frontiers in neurology YEAR: 2022 AUTHORS: Guidoet al. URL: https://pubmed.ncbi.nlm.nih.gov/36062008 ABSTRACT: We evaluated the long-term clinical status of pediatric patients after testing positive for COVID-19. We hypothesized that there are similar symptoms to those that have been described in adults and children and that pediatric patients with neurophysiologic symptoms still present 3-5 months after infection have psychological consequences that interfere with their adaptive functioning. We recruited 322 COVID-19-positive pediatric patients, between 1.5 and 17 years old, from the outpatient clinic for COVID-19 follow-up. Neurological symptoms were analyzed at onset, after 1 month, and after 3-5 months. A psychological assessment with standardized questionnaires was also conducted to determine the impact of the disease. At the onset of COVID-19, 60% of the total sample exhibited symptoms; this decreased after 1 month (20%) but stabilized 3-5 months after disease onset (22%). Prevailing long-COVID neurological symptoms were headache, fatigue, and anosmia. In the 1.5-5-year-old subgroup, internalizing problems emerged in 12% of patients. In the 6-18-year-old subgroup, anxiety and post-traumatic stress showed significant associations with neurological symptoms of long COVID. These data demonstrate that long COVID presents various broad-spectrum symptoms, including psychological and long-lasting cognitive issues. If not treated, these symptoms could significantly compromise the quality of life of children and adolescents. Copyright © 2022 Guido, Lucidi, Midulla, Zicari, Bove, Avenoso, Amedeo, Mancino, Nenna, De Castro, Capponi, Cinicola, Brindisi, Grisoni, Murciano, Spalice and the Long-Covid Group of Department of Maternal Sciences.
36125379 2023 Pulmonary Dysfunction after Pediatric COVID-19. Heiss Radiology Background Long COVID occurs at a lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field-strength MRI may help identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma at low-field-strength MRI in children and adolescents with post-COVID-19 condition compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional clinical trial using low-field-strength MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes at MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive reverse transcriptase-polymerase chain reaction test result, and serologic parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants, and those with long COVID. Results A total of 54 participants after COVID-19 infection (mean age, 11 years ± 3 [SD]; 30 boys [56%]) and nine healthy controls (mean age, 10 years ± 3; seven boys [78%]) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (ventilation-perfusion [V/Q] match) was higher in healthy controls (81% ± 6.1) compared with the recovered group (62% ± 19; P = .006) and the group with long COVID (60% ± 20; P = .003). V/Q match was lower in patients with time from COVID-19 infection to study participation of less than 180 days (63% ± 20; P = .03), 180-360 days (63% ± 18; P = .03), and 360 days (41% ± 12; P < .001) as compared with the never-infected healthy controls (81% ± 6.1). Conclusion Low-field-strength MRI showed persistent pulmonary dysfunction in children and adolescents who recovered from COVID-19 and those with long COVID. Clinical trial registration no. NCT04990531 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Paltiel in this issue. TITLE: Pulmonary Dysfunction after Pediatric COVID-19. JOURNAL: Radiology YEAR: 2023 AUTHORS: Heisset al. URL: https://pubmed.ncbi.nlm.nih.gov/36125379 ABSTRACT: Background Long COVID occurs at a lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field-strength MRI may help identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma at low-field-strength MRI in children and adolescents with post-COVID-19 condition compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional clinical trial using low-field-strength MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes at MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive reverse transcriptase-polymerase chain reaction test result, and serologic parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants, and those with long COVID. Results A total of 54 participants after COVID-19 infection (mean age, 11 years ± 3 [SD]; 30 boys [56%]) and nine healthy controls (mean age, 10 years ± 3; seven boys [78%]) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (ventilation-perfusion [V/Q] match) was higher in healthy controls (81% ± 6.1) compared with the recovered group (62% ± 19; P = .006) and the group with long COVID (60% ± 20; P = .003). V/Q match was lower in patients with time from COVID-19 infection to study participation of less than 180 days (63% ± 20; P = .03), 180-360 days (63% ± 18; P = .03), and 360 days (41% ± 12; P < .001) as compared with the never-infected healthy controls (81% ± 6.1). Conclusion Low-field-strength MRI showed persistent pulmonary dysfunction in children and adolescents who recovered from COVID-19 and those with long COVID. Clinical trial registration no. NCT04990531 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Paltiel in this issue.
36166227 2022 Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany. Sorg JAMA network open During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures. To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents. This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years. Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays. Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue. Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2-seropositive (40.0%) and 158 of 534 SARS-CoV-2-seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS-related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue. These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic. TITLE: Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany. JOURNAL: JAMA network open YEAR: 2022 AUTHORS: Sorget al. URL: https://pubmed.ncbi.nlm.nih.gov/36166227 ABSTRACT: During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures. To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents. This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years. Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays. Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue. Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2-seropositive (40.0%) and 158 of 534 SARS-CoV-2-seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS-related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue. These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.
36203555 2022 Clinical Subphenotypes of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program. Rao medRxiv : the preprint server for health sciences Multi-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. We conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. We identified 1186 children hospitalized with MIS-C. The highest proportion of children (44·4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40·2%). Most (67·8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72·5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51·1% of children early in the pandemic, which decreased to 33·9% from the pre-delta period to the omicron period. MIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time. Evidence before this study: We searched PubMed and preprint articles from December 2019, to July 2022, for studies published in English that investigated the clinical subphenotypes of MIS-C using the terms “multi-system inflammatory syndrome in children” or “pediatric inflammatory multisystem syndrome” and “phenotypes”. Most previous research described the symptoms, clinical characteristics and risk factors associated with MIS-C and how these differ from acute COVID-19, Kawasaki Disease and Toxic Shock Syndrome. One single-center study of 63 patients conducted in 2020 divided patients into Kawasaki and non-Kawasaki disease subphenotypes. Another CDC study evaluated 3 subclasses of MIS-C in 570 children, with one class representing the highest number of organ systems, a second class with predominant respiratory system involvement, and a third class with features overlapping with Kawasaki Disease. However, this study evaluated cases from March to July 2020, during the early phase of the pandemic when misclassification of cases as Kawasaki disease or acute COVID-19 may have occurred. Therefore, it is not known from the existing literature whether the presentation of MIS-C has changed with newer variants such as delta and omicron. Added value of this study: PEDSnet provides one of the largest MIS-C cohorts described so far, providing sufficient power for detailed analyses on MIS-C subphenotypes. Our analyses span the entire length of the pandemic, including the more recent omicron wave, and provide an update on the presentations of MIS-C and its temporal dynamics. We found that children have a spectrum of illness that can be characterized as mild (lower inflammatory markers, fewer organ systems involved), moderate (4-6 organ involvement with clinical overlap with acute COVID-19) and severe (higher inflammatory markers, critically ill, more likely to have cardiac involvement, with hypotension/shock and need for vasopressors). Implications of all the available evidence: These results provide an update to the subphenotypes of MIS-C including the more recent delta and omicron periods and aid in the understanding of the various presentations of MIS-C. These and other findings provide a useful framework for clinicians in the recognition of MIS-C, identify factors associated with children at risk for increased severity, including the importance of laboratory parameters, for risk stratification, and to facilitate early evaluation, diagnosis and treatment. TITLE: Clinical Subphenotypes of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program. JOURNAL: medRxiv : the preprint server for health sciences YEAR: 2022 AUTHORS: Raoet al. URL: https://pubmed.ncbi.nlm.nih.gov/36203555 ABSTRACT: Multi-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. We conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. We identified 1186 children hospitalized with MIS-C. The highest proportion of children (44·4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40·2%). Most (67·8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72·5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51·1% of children early in the pandemic, which decreased to 33·9% from the pre-delta period to the omicron period. MIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time. Evidence before this study: We searched PubMed and preprint articles from December 2019, to July 2022, for studies published in English that investigated the clinical subphenotypes of MIS-C using the terms “multi-system inflammatory syndrome in children” or “pediatric inflammatory multisystem syndrome” and “phenotypes”. Most previous research described the symptoms, clinical characteristics and risk factors associated with MIS-C and how these differ from acute COVID-19, Kawasaki Disease and Toxic Shock Syndrome. One single-center study of 63 patients conducted in 2020 divided patients into Kawasaki and non-Kawasaki disease subphenotypes. Another CDC study evaluated 3 subclasses of MIS-C in 570 children, with one class representing the highest number of organ systems, a second class with predominant respiratory system involvement, and a third class with features overlapping with Kawasaki Disease. However, this study evaluated cases from March to July 2020, during the early phase of the pandemic when misclassification of cases as Kawasaki disease or acute COVID-19 may have occurred. Therefore, it is not known from the existing literature whether the presentation of MIS-C has changed with newer variants such as delta and omicron. Added value of this study: PEDSnet provides one of the largest MIS-C cohorts described so far, providing sufficient power for detailed analyses on MIS-C subphenotypes. Our analyses span the entire length of the pandemic, including the more recent omicron wave, and provide an update on the presentations of MIS-C and its temporal dynamics. We found that children have a spectrum of illness that can be characterized as mild (lower inflammatory markers, fewer organ systems involved), moderate (4-6 organ involvement with clinical overlap with acute COVID-19) and severe (higher inflammatory markers, critically ill, more likely to have cardiac involvement, with hypotension/shock and need for vasopressors). Implications of all the available evidence: These results provide an update to the subphenotypes of MIS-C including the more recent delta and omicron periods and aid in the understanding of the various presentations of MIS-C. These and other findings provide a useful framework for clinicians in the recognition of MIS-C, identify factors associated with children at risk for increased severity, including the importance of laboratory parameters, for risk stratification, and to facilitate early evaluation, diagnosis and treatment.
36222077 2023 Short-term complications and post-acute sequelae in hospitalized paediatric patients with COVID-19 and obesity: A multicenter cohort study. Valenzuela Pediatric obesity Obesity increases the severity of coronavirus disease 2019 illness in adults. The role of obesity in short-term complications and post-acute sequelae in children is not well defined. To evaluate the relationship between obesity and short-term complications and post-acute sequelae of SARS-CoV-2 infection in hospitalized paediatric patients. An observational study was conducted in three tertiary hospitals, including paediatric hospitalized patients with a confirmatory SARS-CoV-2 RT-PCR from March 2020 to December 2021. Obesity was defined according to WHO 2006 (0-2 years) and CDC 2000 (2-20 years) growth references. Short-term outcomes were intensive care unit admission, ventilatory support, superinfections, acute kidney injury, and mortality. Neurological, respiratory, and cardiological symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms were considered as post-acute sequalae. Adjusted linear, logistic regression and generalized estimating equations models were performed. A total of 216 individuals were included, and 67 (31.02%) of them had obesity. Obesity was associated with intensive care unit admission (aOR = 5.63, CI95% 2.90-10.94), oxygen requirement (aOR = 2.77, CI95% 1.36-5.63), non-invasive ventilatory support (aOR = 6.81, CI95% 2.11-22.04), overall superinfections (aOR = 3.02 CI95% 1.45-6.31), and suspected bacterial pneumonia (aOR = 3.00 CI95% 1.44-6.23). For post-acute sequalae, obesity was associated with dyspnea (aOR = 9.91 CI95% 1.92-51.10) and muscle weakness (aOR = 20.04 CI95% 2.50-160.65). In paediatric hospitalized patients with COVID-19, severe short-term outcomes and post-acute sequelae are associated with obesity. Recognizing obesity as a key comorbidity is essential to develop targeted strategies for prevention of COVID-19 complications in children. © 2022 World Obesity Federation. TITLE: Short-term complications and post-acute sequelae in hospitalized paediatric patients with COVID-19 and obesity: A multicenter cohort study. JOURNAL: Pediatric obesity YEAR: 2023 AUTHORS: Valenzuelaet al. URL: https://pubmed.ncbi.nlm.nih.gov/36222077 ABSTRACT: Obesity increases the severity of coronavirus disease 2019 illness in adults. The role of obesity in short-term complications and post-acute sequelae in children is not well defined. To evaluate the relationship between obesity and short-term complications and post-acute sequelae of SARS-CoV-2 infection in hospitalized paediatric patients. An observational study was conducted in three tertiary hospitals, including paediatric hospitalized patients with a confirmatory SARS-CoV-2 RT-PCR from March 2020 to December 2021. Obesity was defined according to WHO 2006 (0-2 years) and CDC 2000 (2-20 years) growth references. Short-term outcomes were intensive care unit admission, ventilatory support, superinfections, acute kidney injury, and mortality. Neurological, respiratory, and cardiological symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms were considered as post-acute sequalae. Adjusted linear, logistic regression and generalized estimating equations models were performed. A total of 216 individuals were included, and 67 (31.02%) of them had obesity. Obesity was associated with intensive care unit admission (aOR = 5.63, CI95% 2.90-10.94), oxygen requirement (aOR = 2.77, CI95% 1.36-5.63), non-invasive ventilatory support (aOR = 6.81, CI95% 2.11-22.04), overall superinfections (aOR = 3.02 CI95% 1.45-6.31), and suspected bacterial pneumonia (aOR = 3.00 CI95% 1.44-6.23). For post-acute sequalae, obesity was associated with dyspnea (aOR = 9.91 CI95% 1.92-51.10) and muscle weakness (aOR = 20.04 CI95% 2.50-160.65). In paediatric hospitalized patients with COVID-19, severe short-term outcomes and post-acute sequelae are associated with obesity. Recognizing obesity as a key comorbidity is essential to develop targeted strategies for prevention of COVID-19 complications in children. © 2022 World Obesity Federation.
36291381 2022 Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review. Morello Children (Basel, Switzerland) Long COVID is an emergent, heterogeneous, and multisystemic condition with an increasingly important impact also on the pediatric population. Among long COVID symptoms, patients can experience chronic gastrointestinal symptoms such as abdominal pain, constipation, diarrhea, vomiting, nausea, and dysphagia. Although there is no standard, agreed, and optimal diagnostic approach or treatment of long COVID in children, recently compounds containing multiple micronutrients and lactoferrin have been proposed as a possible treatment strategy, due to the long-standing experience gained from other gastrointestinal conditions. In particular, lactoferrin is a pleiotropic glycoprotein with antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory activities. Moreover, it seems to have several physiological functions to protect the gastrointestinal tract. In this regard, we described the resolution of symptoms after the start of therapy with high doses of oral lactoferrin in two patients referred to our post-COVID pediatric unit due to chronic gastrointestinal symptoms after SARS-CoV-2 infection. TITLE: Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review. JOURNAL: Children (Basel, Switzerland) YEAR: 2022 AUTHORS: Morelloet al. URL: https://pubmed.ncbi.nlm.nih.gov/36291381 ABSTRACT: Long COVID is an emergent, heterogeneous, and multisystemic condition with an increasingly important impact also on the pediatric population. Among long COVID symptoms, patients can experience chronic gastrointestinal symptoms such as abdominal pain, constipation, diarrhea, vomiting, nausea, and dysphagia. Although there is no standard, agreed, and optimal diagnostic approach or treatment of long COVID in children, recently compounds containing multiple micronutrients and lactoferrin have been proposed as a possible treatment strategy, due to the long-standing experience gained from other gastrointestinal conditions. In particular, lactoferrin is a pleiotropic glycoprotein with antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory activities. Moreover, it seems to have several physiological functions to protect the gastrointestinal tract. In this regard, we described the resolution of symptoms after the start of therapy with high doses of oral lactoferrin in two patients referred to our post-COVID pediatric unit due to chronic gastrointestinal symptoms after SARS-CoV-2 infection.
36293968 2023 Comparison of Long-Term Complications of COVID-19 Illness among a Diverse Sample of Children by MIS-C Status. Messiah International journal of environmental research and public health Most pediatric COVID-19 cases are asymptomatic; however, a small number of children are diagnosed with multisystem inflammatory syndrome in children (MIS-C), a rare but severe condition that is associated with SARS-CoV-2 infection. Persistent symptoms of COVID-19 illness in children diagnosed with/without MIS-C is largely unknown. A retrospective EHR review of patients with COVID-19 illness from one pediatric healthcare system to assess the presence of acute (<30 days) and chronic (≥30, 60-120, and >120 days) long-term COVID symptoms was conducted. Patients/caregivers completed a follow-up survey from March 2021 to January 2022 to assess the presence of long COVID. Results showed that non-MIS-C children ( n = 286; 54.49% Hispanic; 19.23% non-Hispanic Black; 5.77% other ethnicity; 79.49% government insurance) were younger (mean age 6.43 years [SD 5.95]) versus MIS-C ( n = 26) children (mean age 9.08 years, [SD 4.86]) ( p = 0.032). A share of 11.5% of children with MIS-C and 37.8% without MIS-C reported acute long COVID while 26.9% and 15.3% reported chronic long COVID, respectively. Females were almost twice as likely to report long symptoms versus males and those with private insurance were 66% less likely to report long symptoms versus those with government insurance. In conclusion, a substantial proportion of ethnically diverse children from low resource backgrounds with severe COVID illness are reporting long-term impacts. Findings can inform pediatric professionals about this vulnerable population in post-COVID-19 recovery efforts. TITLE: Comparison of Long-Term Complications of COVID-19 Illness among a Diverse Sample of Children by MIS-C Status. JOURNAL: International journal of environmental research and public health YEAR: 2023 AUTHORS: Messiahet al. URL: https://pubmed.ncbi.nlm.nih.gov/36293968 ABSTRACT: Most pediatric COVID-19 cases are asymptomatic; however, a small number of children are diagnosed with multisystem inflammatory syndrome in children (MIS-C), a rare but severe condition that is associated with SARS-CoV-2 infection. Persistent symptoms of COVID-19 illness in children diagnosed with/without MIS-C is largely unknown. A retrospective EHR review of patients with COVID-19 illness from one pediatric healthcare system to assess the presence of acute (<30 days) and chronic (≥30, 60-120, and >120 days) long-term COVID symptoms was conducted. Patients/caregivers completed a follow-up survey from March 2021 to January 2022 to assess the presence of long COVID. Results showed that non-MIS-C children ( n = 286; 54.49% Hispanic; 19.23% non-Hispanic Black; 5.77% other ethnicity; 79.49% government insurance) were younger (mean age 6.43 years [SD 5.95]) versus MIS-C ( n = 26) children (mean age 9.08 years, [SD 4.86]) ( p = 0.032). A share of 11.5% of children with MIS-C and 37.8% without MIS-C reported acute long COVID while 26.9% and 15.3% reported chronic long COVID, respectively. Females were almost twice as likely to report long symptoms versus males and those with private insurance were 66% less likely to report long symptoms versus those with government insurance. In conclusion, a substantial proportion of ethnically diverse children from low resource backgrounds with severe COVID illness are reporting long-term impacts. Findings can inform pediatric professionals about this vulnerable population in post-COVID-19 recovery efforts.
36319840 2022 Extended coagulation profile of children with Long Covid: a prospective study. Di Gennaro Scientific reports Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8-12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection. © 2022. The Author(s). TITLE: Extended coagulation profile of children with Long Covid: a prospective study. JOURNAL: Scientific reports YEAR: 2022 AUTHORS: Di Gennaroet al. URL: https://pubmed.ncbi.nlm.nih.gov/36319840 ABSTRACT: Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8-12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection. © 2022. The Author(s).
36343180 2022 Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology. Brugler Yonts Pediatric annals Although children have been largely spared the most severe consequences of acute infection with SARS-CoV-2 virus, it is estimated that up to one-quarter of the more than 14 million children diagnosed as having coronavirus disease 2019 (COVID-19) have developed persistent symptoms of fatigue, postexertional malaise, neurologic and cognitive symptoms, and other symptoms that interfere with activities of daily living for months after their initial illness. Pediatric postacute sequelae of COVID-19 (pPASC), or long-COVID, is a complex, heterogeneous, postviral condition involving multiple body systems and is likely attributable to several concurrent underlying physiologic processes, including damage from direct viral invasion, endovascular dysfunction and microthrombosis, viral persistence, and the development of autoimmunity. In this review, we explore the current state of the literature regarding definition, epidemiology, clinical presentation, and proposed pathophysiologic mechanisms of pPASC. [ Pediatr Ann . 2022;51(11):e416-e420.] . TITLE: Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology. JOURNAL: Pediatric annals YEAR: 2022 AUTHORS: Brugler Yontset al. URL: https://pubmed.ncbi.nlm.nih.gov/36343180 ABSTRACT: Although children have been largely spared the most severe consequences of acute infection with SARS-CoV-2 virus, it is estimated that up to one-quarter of the more than 14 million children diagnosed as having coronavirus disease 2019 (COVID-19) have developed persistent symptoms of fatigue, postexertional malaise, neurologic and cognitive symptoms, and other symptoms that interfere with activities of daily living for months after their initial illness. Pediatric postacute sequelae of COVID-19 (pPASC), or long-COVID, is a complex, heterogeneous, postviral condition involving multiple body systems and is likely attributable to several concurrent underlying physiologic processes, including damage from direct viral invasion, endovascular dysfunction and microthrombosis, viral persistence, and the development of autoimmunity. In this review, we explore the current state of the literature regarding definition, epidemiology, clinical presentation, and proposed pathophysiologic mechanisms of pPASC. [ Pediatr Ann . 2022;51(11):e416-e420.] .
36353967 2023 COVID-19 and pediatric pulmonology: Feedback from an expert center after the first year of the pandemic. Corvol Pediatric pulmonology The coronavirus disease 2019 (COVID-19) outbreak has evolved with different waves corresponding to subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations. While the most severe cases have been observed in the elderly and in individuals with underlying comorbidities, severe pediatric and young adult cases have been observed, as well as post-infectious inflammatory syndromes and persistent symptoms leading to long-COVID. This manuscript describes the experience of a pediatric respiratory unit during the first year of the pandemic and reviews the corresponding literature with a special emphasis on children and young people with underlying conditions, such as immunosuppression, sickle cell disease, and cystic fibrosis. © 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC. TITLE: COVID-19 and pediatric pulmonology: Feedback from an expert center after the first year of the pandemic. JOURNAL: Pediatric pulmonology YEAR: 2023 AUTHORS: Corvolet al. URL: https://pubmed.ncbi.nlm.nih.gov/36353967 ABSTRACT: The coronavirus disease 2019 (COVID-19) outbreak has evolved with different waves corresponding to subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations. While the most severe cases have been observed in the elderly and in individuals with underlying comorbidities, severe pediatric and young adult cases have been observed, as well as post-infectious inflammatory syndromes and persistent symptoms leading to long-COVID. This manuscript describes the experience of a pediatric respiratory unit during the first year of the pandemic and reviews the corresponding literature with a special emphasis on children and young people with underlying conditions, such as immunosuppression, sickle cell disease, and cystic fibrosis. © 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.
36474113 2022 Clinical assessment of children with long COVID syndrome. Garai Pediatric research There is a need for further understanding pediatric long COVID syndrome (LCS) to be able to create specific case definitions and guidelines for providing good clinical care. Medical records of all LCS patients who presented at our designated LC clinic were collected. We carried out descriptive analyses summarizing the history, clinical presentation, and findings of children, while doing a diagnosis of exclusion with multi-disciplinary medical examinations (physical, laboratory, and radiological examinations, specialist consultations, etc.) without a control group. Most children reported at least minor impairment to their quality of life, of which 17 (23%) had moderate or severe difficulties. Findings that could be directly connected to the linked complaint category were observed in an average of 18%, respiratory symptoms with objective alterations being the most frequent (37%). Despite our detecting mostly non-specific conditions, in a smaller number we identified well-described causes such as autoimmune thyroiditis (7%). The majority of children stated an impairment in their quality of life, while symptom-related conditions were detected only in a minority. Controlled studies are needed to separate the effect of the pandemic era from the infection itself. Evidence-based pediatric guidelines could aid to rationalize the list of recommended examinations. Long COVID syndrome is a complex entity with a great impact on children’s everyday lives. Still, there is no clear guidance for pediatric clinical management. Systematic, detailed studies with medical assessment findings could aid the process of creating evidence-based guidelines. We present validated systematic information collected during in-person medical assessments with detailed medical findings and quality of life changes. While making a diagnosis of exclusion, we could confirm symptom-related conditions only in a minority of children; however, the majority reported at least minor impairment to their quality of life. © 2022. The Author(s). TITLE: Clinical assessment of children with long COVID syndrome. JOURNAL: Pediatric research YEAR: 2022 AUTHORS: Garaiet al. URL: https://pubmed.ncbi.nlm.nih.gov/36474113 ABSTRACT: There is a need for further understanding pediatric long COVID syndrome (LCS) to be able to create specific case definitions and guidelines for providing good clinical care. Medical records of all LCS patients who presented at our designated LC clinic were collected. We carried out descriptive analyses summarizing the history, clinical presentation, and findings of children, while doing a diagnosis of exclusion with multi-disciplinary medical examinations (physical, laboratory, and radiological examinations, specialist consultations, etc.) without a control group. Most children reported at least minor impairment to their quality of life, of which 17 (23%) had moderate or severe difficulties. Findings that could be directly connected to the linked complaint category were observed in an average of 18%, respiratory symptoms with objective alterations being the most frequent (37%). Despite our detecting mostly non-specific conditions, in a smaller number we identified well-described causes such as autoimmune thyroiditis (7%). The majority of children stated an impairment in their quality of life, while symptom-related conditions were detected only in a minority. Controlled studies are needed to separate the effect of the pandemic era from the infection itself. Evidence-based pediatric guidelines could aid to rationalize the list of recommended examinations. Long COVID syndrome is a complex entity with a great impact on children’s everyday lives. Still, there is no clear guidance for pediatric clinical management. Systematic, detailed studies with medical assessment findings could aid the process of creating evidence-based guidelines. We present validated systematic information collected during in-person medical assessments with detailed medical findings and quality of life changes. While making a diagnosis of exclusion, we could confirm symptom-related conditions only in a minority of children; however, the majority reported at least minor impairment to their quality of life. © 2022. The Author(s).
36518782 2022 Development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction. Brasseler Frontiers in pediatrics Absent or abnormal senses of smell and taste have been frequently reported during both acute and long COVID in adult patients. In contrast, pediatric patients who test positive for SARS-CoV-2 are often asymptomatic and the loss of smell and/or taste has been infrequently reported. After observing several young patients with COVID-associated anosmia and ageusia at our clinic, we decided to investigate the incidence of subsequent eating disorders in these patients and in SARS-CoV-2 positive patients who did not experience anosmia and ageusia during the same period. A single-site retrospective cohort study of 84 pediatric patients with suspected long COVID who were treated in the Pediatric Infectious Diseases Outpatient Clinic at the University Hospital Essen were evaluated for persistent symptoms of COVID-19. Smell and taste dysfunction as well as eating behaviors were among the signs and symptoms analyzed in this study. 24 out of 84 children and adolescents described smell and taste dysfunction after confirmed or suspected SARS-CoV-2 infections. A large number of these patients (6 out of 24) demonstrated increased fixation on their eating behavior post-COVID and over time these patients developed anorexia nervosa. In this study we saw a possible association of long-lasting post-COVID smell and taste dysfunction with subsequent development of eating disorders. This observation is worrisome and merits further investigation by healthcare providers at multiple clinical sites. © 2022 Brasseler, Schönecker, Steindor, Della Marina, Bruns, Dogan, Felderhoff-Müser, Hebebrand, Dohna-Schwake and Goretzki. TITLE: Development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction. JOURNAL: Frontiers in pediatrics YEAR: 2022 AUTHORS: Brasseleret al. URL: https://pubmed.ncbi.nlm.nih.gov/36518782 ABSTRACT: Absent or abnormal senses of smell and taste have been frequently reported during both acute and long COVID in adult patients. In contrast, pediatric patients who test positive for SARS-CoV-2 are often asymptomatic and the loss of smell and/or taste has been infrequently reported. After observing several young patients with COVID-associated anosmia and ageusia at our clinic, we decided to investigate the incidence of subsequent eating disorders in these patients and in SARS-CoV-2 positive patients who did not experience anosmia and ageusia during the same period. A single-site retrospective cohort study of 84 pediatric patients with suspected long COVID who were treated in the Pediatric Infectious Diseases Outpatient Clinic at the University Hospital Essen were evaluated for persistent symptoms of COVID-19. Smell and taste dysfunction as well as eating behaviors were among the signs and symptoms analyzed in this study. 24 out of 84 children and adolescents described smell and taste dysfunction after confirmed or suspected SARS-CoV-2 infections. A large number of these patients (6 out of 24) demonstrated increased fixation on their eating behavior post-COVID and over time these patients developed anorexia nervosa. In this study we saw a possible association of long-lasting post-COVID smell and taste dysfunction with subsequent development of eating disorders. This observation is worrisome and merits further investigation by healthcare providers at multiple clinical sites. © 2022 Brasseler, Schönecker, Steindor, Della Marina, Bruns, Dogan, Felderhoff-Müser, Hebebrand, Dohna-Schwake and Goretzki.
36560907 2023 Post coronavirus disease 2019 condition in children at a children’s hospital in Japan. Horikoshi Pediatrics international : official journal of the Japan Pediatric Society Acute coronavirus disease 2019 (COVID-19) is associated with chronic symptoms. These have been termed the “post COVID-19 condition.” The data on this condition in children are still limited. We therefore aimed to elucidate the characteristics of this post COVID-19 condition. Children referred to a long COVID-19 clinic were included at Tokyo Metropolitan Children’s Medical Center between October 2021 and July 2022. Children with another diagnosis and those who failed to meet criteria for post COVID-19 condition were excluded. Demographic and clinical data were collected retrospectively. Of 33 referrals, nine were excluded, and 24 fulfilled the criteria for post COVID-19 condition. The median age and percentage of girls were 12.5 (IQR: 11-13) years and 29.2%, respectively. All the patients had mild, acute COVID-19. Dysgeusia and brain fog was observed more frequently during the Delta and Omicron variant periods, respectively. School absenteeism >4 weeks was observed in 41.6% of the patients. Common symptoms included malaise, headache, dysgeusia, and dysosmia. The median duration of post COVID-19 condition was 4.5 (IQR: 2.8-5.2) months. Pain management and counseling using the pacing approach were the most commonly offered treatments. Symptom resolution and improvement was observed in 29.2% and 54.2% of the patients, respectively. One third of the patients referred for long COVID did not fit the definition of the post COVID-19 condition. After a median follow up of 4.5 months, the majority of the cases resolved or improved. © 2023 Japan Pediatric Society. TITLE: Post coronavirus disease 2019 condition in children at a children’s hospital in Japan. JOURNAL: Pediatrics international : official journal of the Japan Pediatric Society YEAR: 2023 AUTHORS: Horikoshiet al. URL: https://pubmed.ncbi.nlm.nih.gov/36560907 ABSTRACT: Acute coronavirus disease 2019 (COVID-19) is associated with chronic symptoms. These have been termed the “post COVID-19 condition.” The data on this condition in children are still limited. We therefore aimed to elucidate the characteristics of this post COVID-19 condition. Children referred to a long COVID-19 clinic were included at Tokyo Metropolitan Children’s Medical Center between October 2021 and July 2022. Children with another diagnosis and those who failed to meet criteria for post COVID-19 condition were excluded. Demographic and clinical data were collected retrospectively. Of 33 referrals, nine were excluded, and 24 fulfilled the criteria for post COVID-19 condition. The median age and percentage of girls were 12.5 (IQR: 11-13) years and 29.2%, respectively. All the patients had mild, acute COVID-19. Dysgeusia and brain fog was observed more frequently during the Delta and Omicron variant periods, respectively. School absenteeism >4 weeks was observed in 41.6% of the patients. Common symptoms included malaise, headache, dysgeusia, and dysosmia. The median duration of post COVID-19 condition was 4.5 (IQR: 2.8-5.2) months. Pain management and counseling using the pacing approach were the most commonly offered treatments. Symptom resolution and improvement was observed in 29.2% and 54.2% of the patients, respectively. One third of the patients referred for long COVID did not fit the definition of the post COVID-19 condition. After a median follow up of 4.5 months, the majority of the cases resolved or improved. © 2023 Japan Pediatric Society.
36562653 2023 The outcomes of COVID-19 pneumonia in children-clinical, radiographic, and pulmonary function assessment. Bogusławski Pediatric pulmonology The goal of this study was to assess the pulmonary sequelae of COVID-19 pneumonia in children. Children (0-18 years old) diagnosed with COVID-19 pneumonia hospitalized between March 2020 and March 2021 were included in this observational study. All children underwent follow-up visits 3 months postdischarge, and if any abnormalities were stated, a second visit after the next 3 months was scheduled. Clinical assessment included medical history, physical examination, lung ultrasound (LUS) using a standardized protocol, and pulmonary function tests (PFTs). PFTs results were compared with healthy children. Forty-one patients with COVID-19 pneumonia (severe disease n = 3, mechanical ventilation, n = 0) were included in the study. Persistent symptoms were reported by seven (17.1%) children, the most common was decreased exercise tolerance (57.1%), dyspnea (42.9%), and cough (42.9%). The most prevalent abnormalities in LUS were coalescent B-lines (37%) and small subpleural consolidations (29%). The extent of LUS abnormalities was significantly greater at the first than at the second follow-up visit (p = 0.03). There were no significant differences in PFTs results neither between the study group and healthy children nor between the two follow-up visits in the study group. Our study shows that children might experience long-term sequelae following COVID-19 pneumonia. In the majority of cases, these are mild and resolve over time. © 2022 Wiley Periodicals LLC. TITLE: The outcomes of COVID-19 pneumonia in children-clinical, radiographic, and pulmonary function assessment. JOURNAL: Pediatric pulmonology YEAR: 2023 AUTHORS: Bogusławskiet al. URL: https://pubmed.ncbi.nlm.nih.gov/36562653 ABSTRACT: The goal of this study was to assess the pulmonary sequelae of COVID-19 pneumonia in children. Children (0-18 years old) diagnosed with COVID-19 pneumonia hospitalized between March 2020 and March 2021 were included in this observational study. All children underwent follow-up visits 3 months postdischarge, and if any abnormalities were stated, a second visit after the next 3 months was scheduled. Clinical assessment included medical history, physical examination, lung ultrasound (LUS) using a standardized protocol, and pulmonary function tests (PFTs). PFTs results were compared with healthy children. Forty-one patients with COVID-19 pneumonia (severe disease n = 3, mechanical ventilation, n = 0) were included in the study. Persistent symptoms were reported by seven (17.1%) children, the most common was decreased exercise tolerance (57.1%), dyspnea (42.9%), and cough (42.9%). The most prevalent abnormalities in LUS were coalescent B-lines (37%) and small subpleural consolidations (29%). The extent of LUS abnormalities was significantly greater at the first than at the second follow-up visit (p = 0.03). There were no significant differences in PFTs results neither between the study group and healthy children nor between the two follow-up visits in the study group. Our study shows that children might experience long-term sequelae following COVID-19 pneumonia. In the majority of cases, these are mild and resolve over time. © 2022 Wiley Periodicals LLC.
36599625 2023 Post-COVID-19 condition at 6 months and COVID-19 vaccination in non-hospitalised children and young people. Pinto Pereira Archives of disease in childhood To describe the physical and mental health of children and young people (CYP) 6 months after infection with SARS-CoV-2 and explore whether this varies by COVID-19 vaccination. A non-hospitalised, national cohort of people aged 11-17 years old with PCR-confirmed SARS-CoV-2 infection and PCR negatives matched at study invitation, by age, sex, region and date of testing who completed questionnaires 6 months after PCR testing. The questionnaire included 21 symptoms and standardised scales (eg, EQ-5D-Y and Chalder Fatigue Scale). 6407 test-positive and 6542 test-negative CYP completed the 6-month questionnaire: 60.9% of test-positive vs 43.2% of test-negative CYP reported at least one symptom 6 months post-test; 27.6% of test-positive vs 15.9% of test-negative CYP reported 3+ symptoms. Common symptoms at 6 months were tiredness and shortness of breath among both test-positive and test-negative CYP; however, the prevalence of both was higher in test-positive (38.4% and 22.8%, respectively) compared with test-negative CYP (26.7% and 10.9%, respectively). 24.5% test-positive vs 17.8% test-negative CYP met the Delphi research definition of long COVID. Mental health, well-being, fatigue and health-related quality of life scores were similar among test-positive and test-negative CYP 6 months post-test. Similarly, symptomatology was similar among COVID-19-vaccinated and COVID-19-unvaccinated test-positive and test-negative CYP. Six-months post-PCR testing, CYP who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but test-positive CYP had higher symptom prevalence. Mental health, well-being, fatigue and health-related quality of life were similar among test-positive and test-negative CYP, and symptoms at 6 months were similar in COVID-19 vaccinated and unvaccinated. ISRCTN 34804192. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. TITLE: Post-COVID-19 condition at 6 months and COVID-19 vaccination in non-hospitalised children and young people. JOURNAL: Archives of disease in childhood YEAR: 2023 AUTHORS: Pinto Pereiraet al. URL: https://pubmed.ncbi.nlm.nih.gov/36599625 ABSTRACT: To describe the physical and mental health of children and young people (CYP) 6 months after infection with SARS-CoV-2 and explore whether this varies by COVID-19 vaccination. A non-hospitalised, national cohort of people aged 11-17 years old with PCR-confirmed SARS-CoV-2 infection and PCR negatives matched at study invitation, by age, sex, region and date of testing who completed questionnaires 6 months after PCR testing. The questionnaire included 21 symptoms and standardised scales (eg, EQ-5D-Y and Chalder Fatigue Scale). 6407 test-positive and 6542 test-negative CYP completed the 6-month questionnaire: 60.9% of test-positive vs 43.2% of test-negative CYP reported at least one symptom 6 months post-test; 27.6% of test-positive vs 15.9% of test-negative CYP reported 3+ symptoms. Common symptoms at 6 months were tiredness and shortness of breath among both test-positive and test-negative CYP; however, the prevalence of both was higher in test-positive (38.4% and 22.8%, respectively) compared with test-negative CYP (26.7% and 10.9%, respectively). 24.5% test-positive vs 17.8% test-negative CYP met the Delphi research definition of long COVID. Mental health, well-being, fatigue and health-related quality of life scores were similar among test-positive and test-negative CYP 6 months post-test. Similarly, symptomatology was similar among COVID-19-vaccinated and COVID-19-unvaccinated test-positive and test-negative CYP. Six-months post-PCR testing, CYP who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but test-positive CYP had higher symptom prevalence. Mental health, well-being, fatigue and health-related quality of life were similar among test-positive and test-negative CYP, and symptoms at 6 months were similar in COVID-19 vaccinated and unvaccinated. ISRCTN 34804192. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
36636846 2023 [Long COVID in Children: A Pediatric Center Experience]. Demirbuğa Mikrobiyoloji bulteni Although COVID-19 (Coronavirus disease-2019) is observed to be milder in children, it has been observed that the symptoms continue for a long time in many people after the acute period of the disease, especially the multisystemic inflammatory syndrome (MISC) that developed after COVID-19 with the progression of the pandemic. Although it was first defined by different names such as long COVID and post COVID in adults, it has been observed in studies that similar complaints such as cough, fatigue and difficulty in concentrating continue for a long time in children, just as in adults. In our study, we aimed to evaluate the status of long COVID in childhood. Our study included patients aged from one month to 18 years with moderate and severe symptoms who were hospitalized and discharged for SARS-CoV-2 infection in İstanbul University Faculty of Medicine between November 1, 2020 and November 1, 2021. A questionnaire form was created to learn about the complaints of the patients and their ongoing complaints. The patients/parents were called by phone and their complaints were recorded in the questionnaire. The patients were classified according to the definitions in the guidelines published by NICE, RCGP and SIGN. In total, 116 patients were included; 57.8% (n= 64) male, 42.5% (n= 49) female; 53.4% (n= 62) 0-9, 46.6% (n= 54) 10-18 years old. Comorbid conditions were found in 64 (55.2%) patients. The mean follow-up period was 5.90 ± 3.61 [min-max (1-12)] months; longest symptom durations: decrease in effort loss/fatigue 19.25 ± 74.56 (0-365) days, concentration difficulties 11.12 ± 49.75 (0-365) days, fatigue 9.61 ± 34.96 (0-365) days and cough were 8.34 ± 35.37 (0-365) days. The percentage of the patients who met the definition of subacute/ongoing symptomatic COVID-19 was 37.9% (n= 44). The most common symptoms were the decrease of effort capacity/fatigue 12.1% (n= 14) and the concentration difficulties 10.3% (n= 12) in subacute symptomatic patients. The percentage of patients matching the definition of chronic/post COVID-19 was 11.2% (n= 13). In the first year of the disease, ongoing complaints such as fatigue and concentration difficulties were observed in eight patients. The rate of concentration difficulties in the 10-18 age group was statistically significantly higher than the 0-9 age group (p= 0.037). In terms of other symptoms, no significant difference was found according to age, gender and concomitant disease status. Out of these, one patient was diagnosed with Type 2 diabetes mellitus during the acute illness, and two patients were diagnosed with allergic rhinitis after COVID-19. A statistically significant difference was found in the rates of concentration disorders according to age groups with subacute/ongoing symptoms. Although only the hospitalized patients were included, fatigue and difficulty in concentration were among the most common ongoing symptoms in our study, similar to the literature, and they were seen to be more common in older children. It is important both for early diagnosis and awareness to follow up children with COVID-19 in terms of symptoms, not only in terms of prolonged symptoms but also in terms of new diseases. TITLE: [Long COVID in Children: A Pediatric Center Experience]. JOURNAL: Mikrobiyoloji bulteni YEAR: 2023 AUTHORS: Demirbuğaet al. URL: https://pubmed.ncbi.nlm.nih.gov/36636846 ABSTRACT: Although COVID-19 (Coronavirus disease-2019) is observed to be milder in children, it has been observed that the symptoms continue for a long time in many people after the acute period of the disease, especially the multisystemic inflammatory syndrome (MISC) that developed after COVID-19 with the progression of the pandemic. Although it was first defined by different names such as long COVID and post COVID in adults, it has been observed in studies that similar complaints such as cough, fatigue and difficulty in concentrating continue for a long time in children, just as in adults. In our study, we aimed to evaluate the status of long COVID in childhood. Our study included patients aged from one month to 18 years with moderate and severe symptoms who were hospitalized and discharged for SARS-CoV-2 infection in İstanbul University Faculty of Medicine between November 1, 2020 and November 1, 2021. A questionnaire form was created to learn about the complaints of the patients and their ongoing complaints. The patients/parents were called by phone and their complaints were recorded in the questionnaire. The patients were classified according to the definitions in the guidelines published by NICE, RCGP and SIGN. In total, 116 patients were included; 57.8% (n= 64) male, 42.5% (n= 49) female; 53.4% (n= 62) 0-9, 46.6% (n= 54) 10-18 years old. Comorbid conditions were found in 64 (55.2%) patients. The mean follow-up period was 5.90 ± 3.61 [min-max (1-12)] months; longest symptom durations: decrease in effort loss/fatigue 19.25 ± 74.56 (0-365) days, concentration difficulties 11.12 ± 49.75 (0-365) days, fatigue 9.61 ± 34.96 (0-365) days and cough were 8.34 ± 35.37 (0-365) days. The percentage of the patients who met the definition of subacute/ongoing symptomatic COVID-19 was 37.9% (n= 44). The most common symptoms were the decrease of effort capacity/fatigue 12.1% (n= 14) and the concentration difficulties 10.3% (n= 12) in subacute symptomatic patients. The percentage of patients matching the definition of chronic/post COVID-19 was 11.2% (n= 13). In the first year of the disease, ongoing complaints such as fatigue and concentration difficulties were observed in eight patients. The rate of concentration difficulties in the 10-18 age group was statistically significantly higher than the 0-9 age group (p= 0.037). In terms of other symptoms, no significant difference was found according to age, gender and concomitant disease status. Out of these, one patient was diagnosed with Type 2 diabetes mellitus during the acute illness, and two patients were diagnosed with allergic rhinitis after COVID-19. A statistically significant difference was found in the rates of concentration disorders according to age groups with subacute/ongoing symptoms. Although only the hospitalized patients were included, fatigue and difficulty in concentration were among the most common ongoing symptoms in our study, similar to the literature, and they were seen to be more common in older children. It is important both for early diagnosis and awareness to follow up children with COVID-19 in terms of symptoms, not only in terms of prolonged symptoms but also in terms of new diseases.
36646086 2023 Clinical Epidemiology of Pediatric Coronavirus Disease 2019 and its Postacute Sequelae. Habet Seminars in respiratory and critical care medicine The coronavirus disease 2019 (COVID-19) pandemic has affected individuals of all ages across. Although children generally experience a benign illness from COVID-19, the emergence of novel variants of the virus has resulted in significant changes in the morbidity and mortality rates for this age group. Currently, COVID-19 is the eighth leading cause of pediatric deaths in the United States. In addition to acute respiratory illness, some children can develop a severe postinfectious condition known as a multisystem inflammatory syndrome in children, which can progress to rapid-onset cardiogenic shock. Recovery from COVID-19 can also be slow for some children, resulting in persistent or reoccurring symptoms for months, commonly referred to as long COVID. These postinfectious sequelae are often distressing for children and their parents, can negatively impact the quality of life, and impose a considerable burden on the health care system. In this article, we review the clinical epidemiology of pediatric COVID-19 and outline the management considerations for its acute and postacute manifestations. Thieme. All rights reserved. TITLE: Clinical Epidemiology of Pediatric Coronavirus Disease 2019 and its Postacute Sequelae. JOURNAL: Seminars in respiratory and critical care medicine YEAR: 2023 AUTHORS: Habetet al. URL: https://pubmed.ncbi.nlm.nih.gov/36646086 ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic has affected individuals of all ages across. Although children generally experience a benign illness from COVID-19, the emergence of novel variants of the virus has resulted in significant changes in the morbidity and mortality rates for this age group. Currently, COVID-19 is the eighth leading cause of pediatric deaths in the United States. In addition to acute respiratory illness, some children can develop a severe postinfectious condition known as a multisystem inflammatory syndrome in children, which can progress to rapid-onset cardiogenic shock. Recovery from COVID-19 can also be slow for some children, resulting in persistent or reoccurring symptoms for months, commonly referred to as long COVID. These postinfectious sequelae are often distressing for children and their parents, can negatively impact the quality of life, and impose a considerable burden on the health care system. In this article, we review the clinical epidemiology of pediatric COVID-19 and outline the management considerations for its acute and postacute manifestations. Thieme. All rights reserved.
36674665 2023 COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes. Vasichkina International journal of molecular sciences In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated-post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events. TITLE: COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes. JOURNAL: International journal of molecular sciences YEAR: 2023 AUTHORS: Vasichkinaet al. URL: https://pubmed.ncbi.nlm.nih.gov/36674665 ABSTRACT: In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated-post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.
36728643 2023 Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. Baptista de Lima The Pediatric infectious disease journal Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. JOURNAL: The Pediatric infectious disease journal YEAR: 2023 AUTHORS: Baptista de Limaet al. URL: https://pubmed.ncbi.nlm.nih.gov/36728643 ABSTRACT: Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
36736574 2023 Persistent symptoms after COVID-19 in children and adolescents from Argentina. Seery International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved. TITLE: Persistent symptoms after COVID-19 in children and adolescents from Argentina. JOURNAL: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases YEAR: 2023 AUTHORS: Seeryet al. URL: https://pubmed.ncbi.nlm.nih.gov/36736574 ABSTRACT: Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
36759021 2023 Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. Faux-Nightingale BJGP open While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8-17 years in the West Midlands of England. CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice. Copyright © 2023, The Authors. TITLE: Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. JOURNAL: BJGP open YEAR: 2023 AUTHORS: Faux-Nightingaleet al. URL: https://pubmed.ncbi.nlm.nih.gov/36759021 ABSTRACT: While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8-17 years in the West Midlands of England. CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice. Copyright © 2023, The Authors.
36786887 2023 Mental health among children with long COVID during the COVID-19 pandemic. Shachar-Lavie European journal of pediatrics A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents’ questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents’ economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children’s memory, as reported by parents. • Parents’ economic stress and worries concerning their children’s emotional adjustment during the pandemic are associated with more distress in their children. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. TITLE: Mental health among children with long COVID during the COVID-19 pandemic. JOURNAL: European journal of pediatrics YEAR: 2023 AUTHORS: Shachar-Lavieet al. URL: https://pubmed.ncbi.nlm.nih.gov/36786887 ABSTRACT: A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents’ questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents’ economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children’s memory, as reported by parents. • Parents’ economic stress and worries concerning their children’s emotional adjustment during the pandemic are associated with more distress in their children. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
36793333 2023 Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. Jamaica Balderas Frontiers in pediatrics In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children. © 2023 Jamaica Balderas, Navarro Fernández, Dragustinovis Garza, Orellana Jerves, Solís Figueroa, Koretzky, Márquez González, Klünder Klünder, Espinosa, Nieto Zermeño, Villa Guillén, Rosales Uribe and Olivar López. TITLE: Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. JOURNAL: Frontiers in pediatrics YEAR: 2023 AUTHORS: Jamaica Balderaset al. URL: https://pubmed.ncbi.nlm.nih.gov/36793333 ABSTRACT: In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children. © 2023 Jamaica Balderas, Navarro Fernández, Dragustinovis Garza, Orellana Jerves, Solís Figueroa, Koretzky, Márquez González, Klünder Klünder, Espinosa, Nieto Zermeño, Villa Guillén, Rosales Uribe and Olivar López.
36795575 2023 Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. Ahn The Pediatric infectious disease journal Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. TITLE: Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. JOURNAL: The Pediatric infectious disease journal YEAR: 2023 AUTHORS: Ahnet al. URL: https://pubmed.ncbi.nlm.nih.gov/36795575 ABSTRACT: Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
36828133 2023 The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. Strawn Journal of the American Academy of Child and Adolescent Psychiatry While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms. Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved. TITLE: The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. JOURNAL: Journal of the American Academy of Child and Adolescent Psychiatry YEAR: 2023 AUTHORS: Strawnet al. URL: https://pubmed.ncbi.nlm.nih.gov/36828133 ABSTRACT: While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms. Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
36851793 2023 High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. Goretzki Viruses Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC. TITLE: High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. JOURNAL: Viruses YEAR: 2023 AUTHORS: Goretzkiet al. URL: https://pubmed.ncbi.nlm.nih.gov/36851793 ABSTRACT: Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC.
36926600 2023 Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. Lorman JAMIA open Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation. © The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. TITLE: Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. JOURNAL: JAMIA open YEAR: 2023 AUTHORS: Lormanet al. URL: https://pubmed.ncbi.nlm.nih.gov/36926600 ABSTRACT: Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation. © The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.

While we could summarize all of these abstracts,2 we wouldn’t be able to fit all of the summaries into a prompt for the model to summarize overall. One common solution is to use sentence embeddings to associate each text with a high-dimensional vector that correlates well with semantic meaning. These can then be clustered or queried for similarity.

Embeddings are usually generated from specialized language models trained on different tasks, such as semantic search, Q&A, or more generalized tasks; the SentenceTransformers Python package provides easy access to these. We’ll use the 'allenai-specter' model, trained specifically for scientific citations and publications.3

specter_embed <- create_embedder(model_name = 'allenai-specter')

abstracts2 <- abstracts2 %>%
    mutate(specter_embedding = specter_embed(all_text))

str(abstracts2$specter_embedding, list.len = 5)
List of 66
 $ : num [1:768] 0.6883 1.1523 0.0632 -0.442 0.6676 ...
 $ : num [1:768] -0.271 0.864 0.249 -0.258 0.278 ...
 $ : num [1:768] -1.22389 0.13226 -0.00368 -0.351 -0.06432 ...
 $ : num [1:768] -0.5972 -0.1598 -0.2471 0.0661 0.1185 ...
 $ : num [1:768] 0.0888 0.3649 0.4317 0.3885 0.6272 ...
  [list output truncated]

From the first 5 embedding previews above, we can see that they are 768-dimensional vectors.

Let’s start with a k-nearest-neighbors method to link each abstract embedding to its 5 nearest neighbor embeddings. In the network below, edges are sized according to the cosine-similarity of the abstracts, and abstracts are sized according to their weighted PageRank in the network.4

abstracts_specter_graph <- gen_sim_graph(abstracts2[, ], embed_column = "specter_embedding", id_column = "pmid", k = 5) %>%
    activate(edges) %>%
    mutate(embedding_model = "specter")

#edgecolor_palette <- RColorBrewer::brewer.pal(2, "Set2")

toplot <- abstracts_specter_graph %>%
    activate(edges) %>%
    distinct() %>%
    activate(nodes) %>%
        mutate(journal = fct_infreq(journal)) %>% # fct_infreq orders the levels by occurrence count
        mutate(hovertext = "<div style='width: 400px; overflow-wrap: normal; white-space: normal'><b>" %+% title %+% "</b><br />" %+%
                                     first_author %+% "et al. " %+% year %+% ", " %+% journal %+% "<br />" %+%
                               "<a href=https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% " >
                                 https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% 
                               "</a></div>"
                        ) %>% 
        mutate(pagerank = page_rank(., 
                                                        directed = TRUE, 
                                                        weights = . %E>% pull(neighbor_dist))$vector %>% rescale(c(15, 40))
                     ) %>%
    activate(edges) %>%
        mutate(width = 0.5 + 11 * rescale(-1/log(neighbor_dist)), 0, 1)

node_df_umap <- add_umap_coords(toplot %N>% data.frame(), embedding_col = "specter_embedding")
V(toplot)$umap_1 <- node_df_umap$umap_1
V(toplot)$umap_2 <- node_df_umap$umap_2
coords <- node_df_umap %>% select(umap_1, umap_2) %>% as.matrix()

#pageranks <- toplot %N>% data.frame() %>% pull(pagerank)

visIgraph(toplot %N>% select(-title) %>% rename(size = pagerank, title = hovertext), 
                    layout = "layout.norm", type = "full", layoutMatrix = coords, physics = TRUE) %>%
#visIgraph(toplot, layout = "layout_with_fr", type = "full", physics = TRUE) %>%
    visOptions(highlightNearest = list(enabled = TRUE, hover = TRUE, algorithm = "hierarchical", degree = 1), collapse = TRUE) %>%
    visEdges(arrows = "to") %>%
  visPhysics(solver = "barnesHut",
            barnesHut = list(springConstant = 0.002, gravitationalConstant = -10000, damping = 0.8))

While PageRank provides one measure of “importance” of each abstract, we can also compute an embedding for our question, and compute its similarity to all of the abstracts. In the network below darker nodes are more similar to the query.

map_colors <- colorRamp(c("purple", "orange"), space = "Lab")

n_cols <- 101
pal <- colorRampPalette(brewer.pal(9, 'YlGnBu'))(n_cols)

match_percent <- 1.0

toplot2 <- toplot %>%
                        activate(nodes) %>%
                            mutate(query_sim = cosine(specter_embed(question), specter_embedding)) %>% 
                mutate(color_mix = (1 - match_percent) * pagerank + (match_percent) * query_sim) %>%
                        mutate(color_bin = findInterval(color_mix, 
                                                                                        seq(from = min(color_mix), to = max(color_mix), length.out = n_cols))) %>%
                        mutate(color = pal[color_bin]) %>%
                            mutate(hovertext = hovertext %+% "<br />Query cosine similarity: " %+% query_sim)

visIgraph(toplot2 %N>% select(-title) %>% rename(size = pagerank, title = hovertext), 
                    layout = "layout.norm", type = "full", layoutMatrix = coords, physics = TRUE) %>%
    visOptions(highlightNearest = list(enabled = TRUE, 
                                                                         hover = TRUE, 
                                                                         algorithm = "hierarchical", 
                                                                         degree = 1), 
                         collapse = TRUE) %>%
    visEdges(arrows = "to") %>%
  visPhysics(solver = "barnesHut",
            barnesHut = list(springConstant = 0.002, gravitationalConstant = -10000, damping = 0.8))

This gives us two measures we might use to pick abstracts to summarize, or we could mix them to more highly weight question similarity or network importance. In the following table we define an importance metric as the average of these two measures (after normalizing each to 0 mean and 1 sd).

abstracts3 <- toplot2 %>% 
    activate(nodes) %>%
    mutate(query_sim_norm = (query_sim - mean(query_sim))/sd(query_sim),
                 pagerank_norm = (pagerank - mean(pagerank))/sd(pagerank)) %>%
    mutate(importance = (query_sim_norm + pagerank_norm)/2) %>%
    arrange(desc(importance)) %>%
    data.frame()
    

abstracts3 %>%
    select(importance, query_sim_norm, pagerank_norm, pmid, year, title, first_author, journal, abstract) %>%
    kbl(escape = TRUE, table.attr = "class='dtable'", format = "html") %>%
     kable_styling(bootstrap_options = c("striped", "hover", "responsive"), 
                                full_width = TRUE
                                ) %>%
     column_spec(9, width_min = "800px") %>%
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1.9563544 1.5059543 2.4067545 36474113 2022 Clinical assessment of children with long COVID syndrome. Garai Pediatric research There is a need for further understanding pediatric long COVID syndrome (LCS) to be able to create specific case definitions and guidelines for providing good clinical care. Medical records of all LCS patients who presented at our designated LC clinic were collected. We carried out descriptive analyses summarizing the history, clinical presentation, and findings of children, while doing a diagnosis of exclusion with multi-disciplinary medical examinations (physical, laboratory, and radiological examinations, specialist consultations, etc.) without a control group. Most children reported at least minor impairment to their quality of life, of which 17 (23%) had moderate or severe difficulties. Findings that could be directly connected to the linked complaint category were observed in an average of 18%, respiratory symptoms with objective alterations being the most frequent (37%). Despite our detecting mostly non-specific conditions, in a smaller number we identified well-described causes such as autoimmune thyroiditis (7%). The majority of children stated an impairment in their quality of life, while symptom-related conditions were detected only in a minority. Controlled studies are needed to separate the effect of the pandemic era from the infection itself. Evidence-based pediatric guidelines could aid to rationalize the list of recommended examinations. Long COVID syndrome is a complex entity with a great impact on children’s everyday lives. Still, there is no clear guidance for pediatric clinical management. Systematic, detailed studies with medical assessment findings could aid the process of creating evidence-based guidelines. We present validated systematic information collected during in-person medical assessments with detailed medical findings and quality of life changes. While making a diagnosis of exclusion, we could confirm symptom-related conditions only in a minority of children; however, the majority reported at least minor impairment to their quality of life. © 2022. The Author(s).
1.9480188 0.8148918 3.0811458 36786887 2023 Mental health among children with long COVID during the COVID-19 pandemic. Shachar-Lavie European journal of pediatrics A growing number of studies report that persons of all ages, infected with SARS-CoV-2, may experience long-term persistent symptoms, known as long COVID (LC) or post COVID-19 condition. This is one of the first studies examining the consequences of LC on children’s mental health. In this case-control study, we compared select mental health aspects of 103 children diagnosed with LC to a control group of 113 children uninfected with SARS-COV-2; all 4-18 years old. Both groups were assessed via parents’ questionnaires. In comparison to the control group, children with LC exhibited more memory difficulties. However, no group differences emerged in other functional aspects (connection with friends and engagement in physical activities), problems with concentration, or levels of emotional-behavioral problems (externalizing, internalizing, ADHD, and PTSD symptoms). We also found that children with LC had greater exposure to COVID-19-related stressors. Higher levels of parental worries regarding their children’s functioning and economic difficulties at home significantly predicted higher levels of children’s emotional-behavioral problems and were better predictors than the child’s age, social functioning, or LC diagnosis.    Conclusion: LC was associated with impairments in some aspects of children’s memory which may relate to academic functioning, but not with higher rates of emotional-behavioral problems, thus warranting interventional programs addressing school functioning and cognitive abilities in this population. Additionally, parents’ economic stress and worries regarding their child’s emotional adjustment during the pandemic, are important factors affecting pandemic-related emotional-behavioral problems among children, regardless of COVID-19 infection, that should be addressed. What is Known: • Children may have long COVID (LC) after being infected with SARS-COV-2. What is New: • LC may be associated to impairments in some aspects of children’s memory, as reported by parents. • Parents’ economic stress and worries concerning their children’s emotional adjustment during the pandemic are associated with more distress in their children. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
1.6997243 1.7555701 1.6438786 36062008 2022 Neurological and psychological effects of long COVID in a young population: A cross-sectional study. Guido Frontiers in neurology We evaluated the long-term clinical status of pediatric patients after testing positive for COVID-19. We hypothesized that there are similar symptoms to those that have been described in adults and children and that pediatric patients with neurophysiologic symptoms still present 3-5 months after infection have psychological consequences that interfere with their adaptive functioning. We recruited 322 COVID-19-positive pediatric patients, between 1.5 and 17 years old, from the outpatient clinic for COVID-19 follow-up. Neurological symptoms were analyzed at onset, after 1 month, and after 3-5 months. A psychological assessment with standardized questionnaires was also conducted to determine the impact of the disease. At the onset of COVID-19, 60% of the total sample exhibited symptoms; this decreased after 1 month (20%) but stabilized 3-5 months after disease onset (22%). Prevailing long-COVID neurological symptoms were headache, fatigue, and anosmia. In the 1.5-5-year-old subgroup, internalizing problems emerged in 12% of patients. In the 6-18-year-old subgroup, anxiety and post-traumatic stress showed significant associations with neurological symptoms of long COVID. These data demonstrate that long COVID presents various broad-spectrum symptoms, including psychological and long-lasting cognitive issues. If not treated, these symptoms could significantly compromise the quality of life of children and adolescents. Copyright © 2022 Guido, Lucidi, Midulla, Zicari, Bove, Avenoso, Amedeo, Mancino, Nenna, De Castro, Capponi, Cinicola, Brindisi, Grisoni, Murciano, Spalice and the Long-Covid Group of Department of Maternal Sciences.
1.3026739 1.2553776 1.3499701 34102037 2022 Pediatric long-COVID: An overlooked phenomenon? Brackel Pediatric pulmonology Long-COVID is a well-documented multisystem disease in adults. Far less is known about long-term sequelae of COVID in children. Here, we report on the occurrence of long-COVID in Dutch children. We conducted a national survey asking Dutch pediatricians to share their experiences on long-COVID in children. We furthermore describe a case series of six children with long-COVID to explore the clinical features in greater detail. With a response rate of 78% of Dutch pediatric departments, we identified 89 children, aged 2-18 years, suspected of long-COVID with various complaints. Of these children, 36% experienced severe limitations in daily function. The most common complaints were fatigue, dyspnea, and concentration difficulties with 87%, 55%, and 45% respectively. Our case series emphasizes the nonspecific and broad clinical manifestations seen in post-COVID complaints. Our study shows that long-COVID is also present in the pediatric population. The main symptoms resemble those previously described in adults. This novel condition demands a multidisciplinary approach with international awareness and consensus to aid early detection and effective management. © 2021 Wiley Periodicals LLC.
1.2298439 1.0925971 1.3670907 35637934 2022 [Recommendation for standardized medical care for children and adolescents with long COVID]. Töpfner Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde This current consensus paper for long COVID complements the existing AWMF S1 guidelines for long COVID with a detailed overview on the various clinical aspects of long COVID in children and adolescents. Members of 19 different pediatric societies of the DGKJ convent and collaborating societies together provide expert-based recommendations for the clinical management of long COVID based on the currently available but limited academic evidence for long COVID in children and adolescents. It contains screening questions for long COVID and suggestions for a structured, standardized pediatric medical history and diagnostic evaluation for patients with suspected long COVID. A time and resource-saving questionnaire, which takes the clinical complexity of long COVID into account, is offered via the DGKJ and DGPI websites as well as additional questionnaires suggested for an advanced screening of specific neurocognitive and/or psychiatric symptoms including post-exertional malaise (PEM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). According to the individual medical history as well as clinical signs and symptoms a step by step diagnostic procedure and a multidisciplinary therapeutic approach are recommended. © The Author(s) 2022.
1.0901749 1.0290982 1.1512517 36636846 2023 [Long COVID in Children: A Pediatric Center Experience]. Demirbuğa Mikrobiyoloji bulteni Although COVID-19 (Coronavirus disease-2019) is observed to be milder in children, it has been observed that the symptoms continue for a long time in many people after the acute period of the disease, especially the multisystemic inflammatory syndrome (MISC) that developed after COVID-19 with the progression of the pandemic. Although it was first defined by different names such as long COVID and post COVID in adults, it has been observed in studies that similar complaints such as cough, fatigue and difficulty in concentrating continue for a long time in children, just as in adults. In our study, we aimed to evaluate the status of long COVID in childhood. Our study included patients aged from one month to 18 years with moderate and severe symptoms who were hospitalized and discharged for SARS-CoV-2 infection in İstanbul University Faculty of Medicine between November 1, 2020 and November 1, 2021. A questionnaire form was created to learn about the complaints of the patients and their ongoing complaints. The patients/parents were called by phone and their complaints were recorded in the questionnaire. The patients were classified according to the definitions in the guidelines published by NICE, RCGP and SIGN. In total, 116 patients were included; 57.8% (n= 64) male, 42.5% (n= 49) female; 53.4% (n= 62) 0-9, 46.6% (n= 54) 10-18 years old. Comorbid conditions were found in 64 (55.2%) patients. The mean follow-up period was 5.90 ± 3.61 [min-max (1-12)] months; longest symptom durations: decrease in effort loss/fatigue 19.25 ± 74.56 (0-365) days, concentration difficulties 11.12 ± 49.75 (0-365) days, fatigue 9.61 ± 34.96 (0-365) days and cough were 8.34 ± 35.37 (0-365) days. The percentage of the patients who met the definition of subacute/ongoing symptomatic COVID-19 was 37.9% (n= 44). The most common symptoms were the decrease of effort capacity/fatigue 12.1% (n= 14) and the concentration difficulties 10.3% (n= 12) in subacute symptomatic patients. The percentage of patients matching the definition of chronic/post COVID-19 was 11.2% (n= 13). In the first year of the disease, ongoing complaints such as fatigue and concentration difficulties were observed in eight patients. The rate of concentration difficulties in the 10-18 age group was statistically significantly higher than the 0-9 age group (p= 0.037). In terms of other symptoms, no significant difference was found according to age, gender and concomitant disease status. Out of these, one patient was diagnosed with Type 2 diabetes mellitus during the acute illness, and two patients were diagnosed with allergic rhinitis after COVID-19. A statistically significant difference was found in the rates of concentration disorders according to age groups with subacute/ongoing symptoms. Although only the hospitalized patients were included, fatigue and difficulty in concentration were among the most common ongoing symptoms in our study, similar to the literature, and they were seen to be more common in older children. It is important both for early diagnosis and awareness to follow up children with COVID-19 in terms of symptoms, not only in terms of prolonged symptoms but also in terms of new diseases.
0.9647958 1.0924602 0.8371313 35315447 2022 [Mental health and pandemic in children and adolescents: what is likely to label as “long-covid”.]. Cozzi Recenti progressi in medicina Long-covid is a typical condition of adults with a history of probable or confirmed SARS-CoV-2 infection in the previous 3 months and with symptoms lasting over 2 months not explained by an alternative diagnosis. In pediatric age the lack of significative differences comparing the reported symptoms between seropositive and seronegative suggests that long-covid might be less common than previously thought, emphasizing the impact of pandemic-associated symptoms regarding the well-being and mental health of young adolescents. Many children-adolescents, who have had SARS-CoV-2 infection or not, have a health request to which we must respond with a professional approach aimed at a complex functional rehabilitation. The risk is that the “long-covid” becomes a “long-inattention” on relevant mental health problems.
0.8321086 0.3912191 1.2729980 35598023 2022 Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population. Bloise Italian journal of pediatrics SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population. We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed. One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection. Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period. Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children’s mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures. © 2022. The Author(s).
0.5827713 -0.5306988 1.6962414 36599625 2023 Post-COVID-19 condition at 6 months and COVID-19 vaccination in non-hospitalised children and young people. Pinto Pereira Archives of disease in childhood To describe the physical and mental health of children and young people (CYP) 6 months after infection with SARS-CoV-2 and explore whether this varies by COVID-19 vaccination. A non-hospitalised, national cohort of people aged 11-17 years old with PCR-confirmed SARS-CoV-2 infection and PCR negatives matched at study invitation, by age, sex, region and date of testing who completed questionnaires 6 months after PCR testing. The questionnaire included 21 symptoms and standardised scales (eg, EQ-5D-Y and Chalder Fatigue Scale). 6407 test-positive and 6542 test-negative CYP completed the 6-month questionnaire: 60.9% of test-positive vs 43.2% of test-negative CYP reported at least one symptom 6 months post-test; 27.6% of test-positive vs 15.9% of test-negative CYP reported 3+ symptoms. Common symptoms at 6 months were tiredness and shortness of breath among both test-positive and test-negative CYP; however, the prevalence of both was higher in test-positive (38.4% and 22.8%, respectively) compared with test-negative CYP (26.7% and 10.9%, respectively). 24.5% test-positive vs 17.8% test-negative CYP met the Delphi research definition of long COVID. Mental health, well-being, fatigue and health-related quality of life scores were similar among test-positive and test-negative CYP 6 months post-test. Similarly, symptomatology was similar among COVID-19-vaccinated and COVID-19-unvaccinated test-positive and test-negative CYP. Six-months post-PCR testing, CYP who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but test-positive CYP had higher symptom prevalence. Mental health, well-being, fatigue and health-related quality of life were similar among test-positive and test-negative CYP, and symptoms at 6 months were similar in COVID-19 vaccinated and unvaccinated. ISRCTN 34804192. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
0.5182303 1.4572463 -0.4207857 35451276 2022 [A new challenge: post-COVID syndrome in teenagers]. Perrin Revue medicale suisse Post-COVID syndrome (or long COVID) is a set of persistent symptoms occurring after a documented SARS-CoV-2 infection. Children and adolescents are also affected, with similar symptoms than adults. To date there is no clinical or biological parameter allowing to confirm the diagnosis, which relies on the presence of typical symptoms associated with a suggestive temporality, in the absence of any other explanation. These persistent symptoms can have a strong impact on the quality of life and schooling. In our specialized consultation for pediatric post-COVID syndrome, we offer a global and multidisciplinary follow-up to patients and their families, supporting them progressively resuming physical and mental activity, and pursuing school attendance to avoid dropout.
0.5115832 0.7483581 0.2748083 36759021 2023 Symptom patterns and life with post-acute COVID-19 in children aged 8-17: a mixed methods studyprotocol. Faux-Nightingale BJGP open While there is a substantial body of knowledge about acute COVID-19, less is known about long-COVID, where symptoms continue beyond four weeks. This study aims to describe longer-term effects of COVID-19 infection in children and young people (CYP) and identify their needs in relation to long-COVID. This study comprises an observational prospective cohort study and a linked qualitative study, identifying participants aged 8-17 years in the West Midlands of England. CYP will be invited to complete online questionnairesto monitor incidences and symptoms of Covid-19 over a 12-month period. CYP who have experienced long-term effects of COVID will be invited to interview, and those currently experiencing symptoms will be asked to document their experiences in a diary. Professionals who work with CYP will be invited to explore the impact of long-COVID on the wider experiences of CYP, in a focus group. Descriptive statistics will be used to describe the incidence and rates of resolution of symptoms, and comparisons made between exposed and non-exposed groups. Logistic regression models will be used to estimate associations between candidate predictors and the development of long-COVID, and linear regression will be used to estimate associations between candidate predictors. Qualitative data will be analysed thematically using the constant comparison method. This study will describe features and symptoms of long-COVID and explore the impact of long-COVID within the lives of CYP and their families, to provide better understanding of long-COVID and inform clinical practice. Copyright © 2023, The Authors.
0.4594206 1.1868853 -0.2680441 35624901 2022 Neuropsychiatric Disorders in Pediatric Long COVID-19: A Case Series. Savino Brain sciences Few data are available regarding the incidence and the evolution of neuropsychiatric manifestations in children with a history of COVID-19. We herein report five consequent cases of pediatric patients with psychiatric and neurological symptoms of long COVID-19. All patients, mainly males, reported asymptomatic-to-mild COVID-19 and underwent home self-isolation. Abnormal movements, anxiety, and emotional dysregulation were the most recurrent symptoms observed from a few weeks to months after the resolution of the acute infection. A later onset was observed in younger patients. Blood tests and brain imaging resulted in negative results in all subjects; pharmacological and cognitive behavioral therapy was set. A multifactorial etiology could be hypothesized in these cases, as a result of a complex interplay between systemic and brain inflammation and environmental stress in vulnerable individuals. Longer follow-up is required to observe the evolution of neuropsychiatric manifestation in the present cohort and other young patients with previous SARS-CoV-2 infection.
0.4570882 -1.4085541 2.3227306 35874696 2022 Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis. Noval Rivas Frontiers in immunology Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C-such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)-overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection. Copyright © 2022 Noval Rivas, Porritt, Cheng, Bahar and Arditi.
0.4438741 -0.1426057 1.0303540 34778143 2021 Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children. Roge Frontiers in pediatrics Introduction: The data on long COVID in children is scarce since children and adolescents are typically less severely affected by acute COVID-19. This study aimed to identify the long-term consequences of SARS-CoV-2 infection in children, and to compare the persistent symptom spectrum between COVID-19 and community-acquired infections of other etiologies. Methods: This was an ambidirectional cohort study conducted at the Children’s Clinical University Hospital in Latvia. The study population of pediatric COVID-19 patients and children with other non-SARS-CoV-2-community-acquired infections were invited to participate between July 1, 2020, and April 30, 2021. Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43-110 days) in the COVID-19 patient group and 69 days (IQR, 58-84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls. Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group’s inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery. Copyright © 2021 Roge, Smane, Kivite-Urtane, Pucuka, Racko, Klavina and Pavare.
0.4336587 0.8616867 0.0056307 34852145 2022 Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital. Fink Clinics (Sao Paulo, Brazil) To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19). This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.
0.4323820 0.1408659 0.7238981 36560907 2023 Post coronavirus disease 2019 condition in children at a children’s hospital in Japan. Horikoshi Pediatrics international : official journal of the Japan Pediatric Society Acute coronavirus disease 2019 (COVID-19) is associated with chronic symptoms. These have been termed the “post COVID-19 condition.” The data on this condition in children are still limited. We therefore aimed to elucidate the characteristics of this post COVID-19 condition. Children referred to a long COVID-19 clinic were included at Tokyo Metropolitan Children’s Medical Center between October 2021 and July 2022. Children with another diagnosis and those who failed to meet criteria for post COVID-19 condition were excluded. Demographic and clinical data were collected retrospectively. Of 33 referrals, nine were excluded, and 24 fulfilled the criteria for post COVID-19 condition. The median age and percentage of girls were 12.5 (IQR: 11-13) years and 29.2%, respectively. All the patients had mild, acute COVID-19. Dysgeusia and brain fog was observed more frequently during the Delta and Omicron variant periods, respectively. School absenteeism >4 weeks was observed in 41.6% of the patients. Common symptoms included malaise, headache, dysgeusia, and dysosmia. The median duration of post COVID-19 condition was 4.5 (IQR: 2.8-5.2) months. Pain management and counseling using the pacing approach were the most commonly offered treatments. Symptom resolution and improvement was observed in 29.2% and 54.2% of the patients, respectively. One third of the patients referred for long COVID did not fit the definition of the post COVID-19 condition. After a median follow up of 4.5 months, the majority of the cases resolved or improved. © 2023 Japan Pediatric Society.
0.3560135 -0.0139990 0.7260260 36353967 2023 COVID-19 and pediatric pulmonology: Feedback from an expert center after the first year of the pandemic. Corvol Pediatric pulmonology The coronavirus disease 2019 (COVID-19) outbreak has evolved with different waves corresponding to subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations. While the most severe cases have been observed in the elderly and in individuals with underlying comorbidities, severe pediatric and young adult cases have been observed, as well as post-infectious inflammatory syndromes and persistent symptoms leading to long-COVID. This manuscript describes the experience of a pediatric respiratory unit during the first year of the pandemic and reviews the corresponding literature with a special emphasis on children and young people with underlying conditions, such as immunosuppression, sickle cell disease, and cystic fibrosis. © 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.
0.3550991 1.1263526 -0.4161545 35752194 2022 Long COVID symptoms in SARS-CoV-2-positive children aged 0-14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study. Kikkenborg Berg The Lancet. Child & adolescent health After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0-14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection. A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting) of children aged 0-14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and the Children’s Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression analysis were used. Clinically relevant differences were defined as those with a Hedges’g score greater than 0·2. This study is registered at ClinicalTrials.gov (NCT04786353). Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212 controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6-12·8) in cases and 10·6 years (6·9-12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870 (51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than did controls in the 0-3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55-2·04], p<0·0001), 4-11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15-1·31], p<0·0001), and 12-14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11-1·32], p<0·0001). Differences in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour of cases in the children aged 4-11 years (median score 80·0 [IQR 65·0-95·0]) in cases vs 75·0 [60·0-85·0] in controls; p<0·0001) and 12-14 years (90·0 [70·0-100·0] vs (85·0 [65·0-95·0], p<0·0001). PedsQL social functioning scores were also higher in cases (100·0 [90·0-100·0] than controls (95·0 [80·0-100·0]) in the 12-14 years age group (p<0·0001; Hedges g>0·2). Compared with controls, children aged 0-14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial. A P Møller and Chastine Mc-Kinney Møller Foundation. Copyright © 2022 Elsevier Ltd. All rights reserved.
0.3173902 1.4826032 -0.8478229 34371507 2022 Long COVID in Children: Observations From a Designated Pediatric Clinic. Ashkenazi-Hoffnung The Pediatric infectious disease journal Systematic data are lacking on pediatric long COVID. This study prospectively assessed 90 children with persistent symptoms who presented to a designated multidisciplinary clinic for long COVID. In nearly 60%, symptoms were associated with functional impairment at 1-7 months after the onset of infection. A comprehensive structured evaluation revealed mild abnormal findings in approximately half the patients, mainly in the respiratory aspect. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
0.2321457 -0.6949843 1.1592757 35775163 2022 Long-term pulmonary sequelae in adolescents post-SARS-CoV-2 infection. Palacios Pediatric pulmonology Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes long-term pulmonary sequelae in adults, but little is known about pulmonary outcomes in pediatrics. The aim of this study was to describe long-term subjective and objective pulmonary abnormalities after SARS-CoV-2 infection in pediatric populations. Single-center, retrospective cohort of patients seen in post-coronavirus disease 2019 (COVID-19) pulmonary clinic in 2021. Subjects evaluated had persistent pulmonary symptoms 4 weeks or more after initial infection. Clinical testing included a 6-min walk test (6MWT), chest X-ray, pre- and postbronchodilator spirometry, plethysmography, and diffusion capacity. Patients were followed 2-to-3-months after the initial visit with repeat testing. The primary outcome was the presence of abnormal pulmonary function testing. Secondary measures included variables associated with pulmonary outcomes. Eighty-two adolescents were seen at a median of 3.5 months postinfection, with approximately 80% reporting two or more symptoms at clinic presentation (cough, chest pain, dyspnea at rest, and exertional dyspnea). At follow-up (~6.5 months) exertional dyspnea persisted for most (67%). Spirometry was normal in 77% of patients, but 31% had a positive bronchodilator response. No abnormalities were noted on plethysmography or diffusion capacity. Clinical phenotypes identified included inhaled corticosteroid responsiveness, paradoxical vocal fold motion disorder, deconditioning, and dysautonomia. Multivariable modeling demonstrated that obesity, anxiety, and resting dyspnea were associated with reduced 6MWT, while female sex and resting dyspnea were associated with higher Borg Dyspnea and Fatigues scores. This is the largest study to date of pediatric patients with long-term pulmonary sequelae post-COVID-19. Identified clinical phenotypes and risk factors warrant further study and treatment. © 2022 Wiley Periodicals LLC.
0.2274861 1.1787425 -0.7237704 34793374 2023 Postacute/Long COVID in Pediatrics: Development of a Multidisciplinary Rehabilitation Clinic and Preliminary Case Series. Morrow American journal of physical medicine & rehabilitation The long-term sequelae after SARS-CoV-2 infections in children is unknown. Guidance is needed on helpful models of care for an emerging subset of pediatric patients with postacute/long COVID who continue to experience persistent symptoms after initial COVID-19 diagnosis. Here, we describe a pediatric multidisciplinary post-COVID-19 rehabilitation clinic model as well as a case series of the initial cohort of patients who presented to this clinic. A consecutive sample of nine patients (pediatric patients <21 yrs of age) who presented to our clinic are included. The most common presenting symptoms were fatigue (8 of 9 patients), headaches (6 of 9), difficulty with schoolwork (6 of 8), “brain fog” (4 of 9), and dizziness/lightheadedness (4 of 9). Most patients had decreased scores on self-reported quality-of-life measures compared with healthy controls. In the patients who participated in neuropsychological testing, a subset demonstrated difficulties with sustained auditory attention and divided attention; however, most of these patients had preexisting attention and/or mood concerns. There were also some who self-reported elevated depression and anxiety symptoms. Pediatric patients with postacute/long COVID may present with a variety of physical, cognitive, and mood symptoms. We present a model of care to address these symptoms through a multidisciplinary rehabilitation approach. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
0.2191584 0.6503737 -0.2120570 35264214 2022 Italian intersociety consensus on management of long covid in children. Esposito Italian journal of pediatrics Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed. Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type. Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue. © 2022. The Author(s).
0.1573486 0.4824606 -0.1677633 36736574 2023 Persistent symptoms after COVID-19 in children and adolescents from Argentina. Seery International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.
0.1311298 -0.6003518 0.8626114 35127274 2022 Long-Term Complications of COVID-19 Infection in Adolescents and Children. Thallapureddy Current pediatrics reports Compared to adults, post-COVID-19 symptoms are uncommon and have not been thoroughly evaluated in children. This review summarizes the literature in terms of persistent symptoms in children and adolescents after SARS-CoV-2 infection. Children were less likely to develop long COVID when compared to adults. Older children (e.g., adolescents) and those who had symptomatic COVID-19 had a higher probability for long COVID. Families and health care providers need to be aware of a new constellation of long COVID symptoms in the pediatric population. More evidence and time are needed to better understand the potential effects of long COVID-19 in children and adolescents. In comparison to adults, children are less likely to have persistent COVID-19 symptoms. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.
0.1056538 -0.4870093 0.6983169 36646086 2023 Clinical Epidemiology of Pediatric Coronavirus Disease 2019 and its Postacute Sequelae. Habet Seminars in respiratory and critical care medicine The coronavirus disease 2019 (COVID-19) pandemic has affected individuals of all ages across. Although children generally experience a benign illness from COVID-19, the emergence of novel variants of the virus has resulted in significant changes in the morbidity and mortality rates for this age group. Currently, COVID-19 is the eighth leading cause of pediatric deaths in the United States. In addition to acute respiratory illness, some children can develop a severe postinfectious condition known as a multisystem inflammatory syndrome in children, which can progress to rapid-onset cardiogenic shock. Recovery from COVID-19 can also be slow for some children, resulting in persistent or reoccurring symptoms for months, commonly referred to as long COVID. These postinfectious sequelae are often distressing for children and their parents, can negatively impact the quality of life, and impose a considerable burden on the health care system. In this article, we review the clinical epidemiology of pediatric COVID-19 and outline the management considerations for its acute and postacute manifestations. Thieme. All rights reserved.
0.1024192 -0.2376416 0.4424800 34945095 2021 Long COVID a New Derivative in the Chaos of SARS-CoV-2 Infection: The Emergent Pandemic? Fernández-Lázaro Journal of clinical medicine Coronavirus disease 2019 (COVID-19) is a multisystem illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can manifest with a multitude of symptoms in the setting of end-organ damage, though it is predominantly respiratory. However, various symptoms may remain after acute SARS-CoV-2 infection, and this condition is referred to as “Long COVID” (LC). Patients with LC may develop multi-organ symptom complex that remains 4-12 weeks after the acute phase of illness, with symptoms intermittently persisting over time. The main symptoms are fatigue, post-exertional malaise, cognitive dysfunction, and limitation of functional capacity. Pediatric patients developed the main symptoms of LC like those described in adults, although there may be variable presentations of LC in children. The underlying mechanisms of LC are not clearly known, although they may involve pathophysiological changes generated by virus persistence, immunological alterations secondary to virus-host interaction, tissue damage of inflammatory origin and hyperactivation of coagulation. Risk factors for developing LC would be female sex, more than five early symptoms, early dyspnea, previous psychiatric disorders, and alterations in immunological, inflammatory and coagulation parameters. There is currently no specific treatment for LC, but it could include pharmacological treatments to treat symptoms, supplements to restore nutritional, metabolic, and gut flora balance, and functional treatments for the most disabling symptoms. In summary, this study aims to show the scientific community the current knowledge of LC.
0.0824690 0.9089782 -0.7440403 35118594 2022 Long-term physical, mental and social health effects of COVID-19 in the pediatric population: a scoping review. Borel World journal of pediatrics : WJP The majority of coronavirus disease 2019 (COVID-19) symptom presentations in adults and children appear to run their course within a couple of weeks. However, a subgroup of adults has started to emerge with effects lasting several months or more after initial infection, which raises questions about the long-term physical, mental and social health effects of COVID-19 in the pediatric population. The purpose of this review was to determine these impacts well into the second year of the pandemic. A search was conducted using PubMed, Web of Science, Science Direct, and Cochrane between 11/1/2019 and 9/1/2021. Search inclusion criteria were as follows: (1) COVID-19 illness and symptoms in children; (2) severe acute respiratory syndrome coronavirus 2 in children; (3) English language; and (4) human studies only. The few studies that have documented long-term physical symptoms in children show that fatigue, difficulty in concentrating (brain fog), sleep disturbances, and sensory problems are the most reported outcomes. Most studies examining the impact of COVID-19 in pediatric populations have focused on initial clinical presentation, and symptoms, which are similar to those in adult populations. In addition, COVID-19 has had a moderate impact on children and adolescents’ social environment, which may exacerbate current and future physiological, psychological, behavioral, and academic outcomes. There are limited studies reporting long physical symptoms of COVID-19 in the pediatric population. However, pediatric COVID-19 cases are underreported due to low rates of testing and symptomatic infection, which calls for more longitudinal studies. Children who have experienced COVID-19 illness should be monitored for long physiological, psychological, behavioral, and academic outcomes. © 2022. The Author(s).
0.0770559 -0.2467420 0.4008539 36793333 2023 Long COVID in children and adolescents: COVID-19 follow-up results in third-level pediatric hospital. Jamaica Balderas Frontiers in pediatrics In children, the manifestations of coronavirus disease 2019 (COVID-19) in the acute phase are considered mild compared with those in adults; however, some children experience a severe disease that requires hospitalization. This study was designed to present the operation and follow-up results of the Post-COVID-19 Detection and Monitoring Sequels Clinic of Hospital Infantil de Mexico Federico Gómez in managing children with a history of SARS-CoV-2 infection. This was a prospective study conducted from July 2020 to December 2021, which included 215 children aged 0-18 years who tested positive for SARS-CoV-2 on polymerase chain reaction and/or immunoglobulin G test. The follow-up was conducted in the pulmonology medical consultation; ambulatory and hospitalized patients were assessed at 2, 4, 6, and 12 months. The median age of the patients was 9.02 years, and neurological, endocrinological, pulmonary, oncological, and cardiological comorbidities were the most commonly observed among the patients. Moreover, 32.6% of the children had persistent symptoms at 2 months, 9.3% at 4 months, and 2.3% at 6 months, including dyspnea, dry cough, fatigue, and runny nose; the main acute complications were severe pneumonia, coagulopathy, nosocomial infections, acute renal injury, cardiac dysfunction, and pulmonary fibrosis. The more representative sequelae were alopecia, radiculopathy, perniosis, psoriasis, anxiety, and depression. This study showed that children experience persistent symptoms, such as dyspnea, dry cough, fatigue, and runny nose, although to a lesser extent than adults, with significant clinical improvement 6 months after the acute infection. These results indicate the importance of monitoring children with COVID-19 through face-to-face consultations or telemedicine, with the objective of offering multidisciplinary and individualized care to preserve the health and quality of life of these children. © 2023 Jamaica Balderas, Navarro Fernández, Dragustinovis Garza, Orellana Jerves, Solís Figueroa, Koretzky, Márquez González, Klünder Klünder, Espinosa, Nieto Zermeño, Villa Guillén, Rosales Uribe and Olivar López.
0.0755384 0.7809015 -0.6298247 36795575 2023 Non-neuropsychiatric Long COVID Symptoms in Children Visiting a Pediatric Infectious Disease Clinic After an Omicron Surge. Ahn The Pediatric infectious disease journal Although much interest has emerged regarding post-COVID conditions, data on children and adolescents are limited. The prevalence of long COVID and common symptoms were analyzed in this case-control study of 274 children. Prolonged non-neuropsychiatric symptoms were more frequent in the case group (17.0% and 4.8%, P = 0.004). Abdominal pain (6.6%) was the most common long COVID symptom. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
0.0564150 1.2128400 -1.1000101 35834042 2022 Long-COVID in immunocompromised children. Kuczborska European journal of pediatrics Coronavirus disease 2019 (COVID-19) can lead to an illness characterized by persistent symptoms which affect various organs and systems, known as long-COVID. This study aimed to assess the prevalence and clinical characteristics of long-COVID in children with immunodeficiency, in comparison to those without. A self-constructed questionnaire was created, which included questions regarding the child’s general health, the course of their COVID-19, their symptoms of long-COVID and its impact on their daily functioning, the diagnosis of multisystem inflammatory syndrome (MIS-C), and vaccination status. The questionnaire was completed by parents of 147 children - 70 children with a diagnosis of immunodeficiency (47.6%) and 77 who were immunocompetent (52.4%). Immunocompetent children were more significantly affected by long-COVID than those immunocompromised. Its prevalence in the first 12-week post-infection was 60.0% and 35.7% in these groups, respectively. Beyond this period, these percentages had dropped to 34.6% and 11.43%, respectively. Children who were immunocompetent reported more often symptoms of fatigue, reduced exercise tolerance, and difficulty concentrating. Meanwhile, there was a slight increase in complaints of gastrointestinal symptoms in immunocompromised patients. The risk of developing long-COVID increased with age and COVID-19 severity in both groups. Furthermore, the daily activities of immunocompetent children were limited more frequently (41.8%) than for those who were immunocompromised (25%). Although immunocompromised children experienced long-COVID, its prevalence and impact on daily functioning were significantly lower than among immunocompetent children. However, as the pathomechanisms of long-COVID are not yet fully understood, it is not currently possible to fully explain these findings. • Long COVID is characterized by persistent symptoms following COVID-19, which can affect various tissues and organs, as well as mental health. • Due to the similar course of COVID-19 - mainly mild or asymptomatic - among children with and without immunodeficiency, the question arises, over whether the prevalence and severity of long-COVID is also similar in both groups. • Immunocompromised children also suffer from long-COVID, but the prevalence is significantly lower than in the immunocompetent group of children. • The potential causes of less frequent and milder long-COVID in this group may be the milder course of COVID-19 and the state of reduced immunity protecting against neuroinflammation. © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
0.0458967 0.0377130 0.0540805 36926600 2023 Understanding pediatric long COVID using a tree-based scan statistic approach: an EHR-based cohort study from the RECOVER Program. Lorman JAMIA open Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC. We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) ( N  = 1309) to children with ( N  = 6545) and without ( N  = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls. We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise. Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes. We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation. © The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.
0.0334997 0.2268696 -0.1598702 34572201 2021 Cross-Sectional Survey on Long Term Sequelae of Pediatric COVID-19 among Italian Pediatricians. Parisi Children (Basel, Switzerland) The persistence of symptoms after recovery from Coronavirus 2019 (COVID-19) is defined as long COVID, an entity that had occurred among adults but which is not yet well characterized in pediatric ages. The purpose of this work was to present some of the data from a survey addressed to Italian pediatricians concerning the impact of long-COVID among children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The questionnaire was designed and pre-tested in February 2021 by a working group of experts from the Italian Pediatric Society for Allergy and Immunology (SIAIP). The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases.
0.0240175 0.6777200 -0.6296851 35659358 2023 Long COVID-19 in children: an Italian cohort study. Trapani Italian journal of pediatrics Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection. Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents. Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11-16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms. Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome. © 2022. The Author(s).
-0.0267503 1.0167693 -1.0702700 36728643 2023 Long COVID in Children and Adolescents: A Retrospective Study in a Pediatric Cohort. Baptista de Lima The Pediatric infectious disease journal Studies on long coronavirus disease (COVID) in children are scarce. We aimed to describe persistent symptoms and identify risk factors for its development. In our study population, 17.6% presented with long COVID, with respiratory symptoms more frequent in the first weeks and neuropsychiatric symptoms over time. Chronic conditions and obesity were risk factors, and adolescents were at a greater risk for long COVID. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
-0.0676617 -0.7238266 0.5885032 36166227 2022 Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany. Sorg JAMA network open During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures. To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents. This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years. Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays. Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue. Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2-seropositive (40.0%) and 158 of 534 SARS-CoV-2-seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS-related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue. These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.
-0.0694577 0.0729533 -0.2118688 36016309 2022 Pathogenic Connections in Post-COVID Conditions: What Do We Know in the Large Unknown? A Narrative Review. Stafie Viruses The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well.
-0.0914382 -0.6868960 0.5040196 35573390 2022 Clinical Characteristics and Outcome of Pediatric COVID-19 Patients in Ethiopia During the Early COVID-19 Pandemic: A Prospective Cohort Study. Weldetsadik Pediatric health, medicine and therapeutics Most previous pediatric COVID-19 studies reported milder disease in children. However, there are limited pediatric data from low-income settings. We aimed to assess the characteristics and outcomes of pediatric COVID-19 in Ethiopia. St. Paul’s COVID-19 treatment center; a tertiary COVID-19 center. Pediatric care was provided in a dedicated ward but with a common ICU. St. Paul’s Hospital COVID-19 cohort (SPC-19) included inpatient COVID-19 RT-PCR confirmed cases from August 2020 to January 2021. Data were extracted from case report forms attached to patient charts and completed by the clinicians. Data were uploaded into the Redcap database and exported to SPSS 20 for analysis. Binary logistic regression and chi-square test were used in the analysis. Seventy-nine patients 0-19 years were included from the SPC-19 cohort over 6 months. Pediatric admissions accounted for 11% of cases in the cohort. The mean age (SD) was 6.9 (±6.36) years and 40 (50.6%) were female. The disease was asymptomatic or mild in 57 (72.2%), moderate in 15 (19%), and severe or critical in 7 (8.8%). The commonest presentations in symptomatic children were prostration (26.6%) followed by vomiting (12.7%), fever and cough (11.4% each), and dyspnea (10%). About 53 (67%) children had multimorbidity, and 14 (17.7%) children died. All deaths were in children with comorbidities with tuberculosis and malignancy being associated with 43% of deaths. Nearly 5% of children reported long-COVID symptoms highlighting the need for prolonged follow-up in those children. Despite lower admissions and severity, high mortality and morbidity was documented in our pediatric cohort. The presence of comorbidity and inadequate care organization likely contributed to high mortality. COVID-19 centers of low-income settings should emphasize optimizing the care of children with COVID-19 and multimorbidity, and vaccination should be considered in those children to prevent high morbidity and mortality. © 2022 Weldetsadik et al. 
-0.1008593 0.7043767 -0.9060954 35365499 2022 Long COVID (post-COVID-19 condition) in children: a modified Delphi process. Stephenson Archives of disease in childhood The aim of this study was to derive a research definition for ‘Long COVID (post-COVID-19 condition)’ in children and young people (CYP) to allow comparisons between research studies. A three-phase online Delphi process was used, followed by a consensus meeting. Participants were presented with 49 statements in each phase and scored them from 1 to 9 based on how important they were for inclusion in the research definition of Long COVID in CYP. The consensus meeting was held to achieve representation across the stakeholder groups. Statements agreed at the consensus meeting were reviewed by participants in the Patient and Public Involvement (PPI) Research Advisory Group. The study was conducted remotely using online surveys and a virtual consensus meeting. 120 people with relevant expertise were divided into three panels according to their area of expertise: Service Delivery, Research (or combination of research and service delivery) and Lived Experience. The PPI Research Advisory group consisted of CYP aged 11-17 years. Consensus was defined using existing guidelines. If consensus was achieved in two or more panels or was on the border between one and two panels, those statements were discussed and voted on at the consensus meeting. Ten statements were taken forward for discussion in the consensus meeting and five statements met threshold to be included in the research definition of Long COVID among CYP. The research definition, aligned to the clinical case definition of the WHO, is proposed as follows: Post-COVID-19 condition occurs in young people with a history of confirmed SARS-CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID infection, and may fluctuate or relapse over time . The positive COVID-19 test referred to in this definition can be a lateral flow antigen test, a PCR test or an antibody test. This is the first research definition of Long COVID (post-COVID-19 condition) in CYP and complements the clinical case definition in adults proposed by the WHO. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
-0.1071062 -1.5168825 1.3026701 34541421 2021 Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A State-of-the-Art Review. Jiang JACC. Basic to translational science The vast majority of patients (>99%) with severe acute respiratory syndrome coronavirus 2 survive immediate infection but remain at risk for persistent and/or delayed multisystem. This review of published reports through May 31, 2021, found that manifestations of postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) affect between 33% and 98% of coronavirus disease 2019 survivors and comprise a wide range of symptoms and complications in the pulmonary, cardiovascular, neurologic, psychiatric, gastrointestinal, renal, endocrine, and musculoskeletal systems in both adult and pediatric populations. Additional complications are likely to emerge and be identified over time. Although data on PASC risk factors and vulnerable populations are scarce, evidence points to a disproportionate impact on racial/ethnic minorities, older patients, patients with preexisting conditions, and rural residents. Concerted efforts by researchers, health systems, public health agencies, payers, and governments are urgently needed to better understand and mitigate the long-term effects of PASC on individual and population health. © 2021 The Authors.
-0.1340670 0.6570021 -0.9251362 36851793 2023 High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID-A Single Center Cohort Study. Goretzki Viruses Long COVID (LC) is a diagnosis that requires exclusion of alternative somatic and mental diseases. The aim of this study was to examine the prevalence of differential diagnoses in suspected pediatric LC patients and assess whether adult LC symptom clusters are applicable to pediatric patients. Pediatric presentations at the Pediatric Infectious Diseases Department of the University Hospital Essen (Germany) were assessed retrospectively. The correlation of initial symptoms and final diagnoses (LC versus other diseases or unclarified) was assessed. The sensitivity, specificity, negative and positive predictive values of adult LC symptom clusters were calculated. Of 110 patients, 32 (29%) suffered from LC, 52 (47%) were diagnosed with alternative somatic/mental diseases, and 26 (23%) remained unclarified. Combined neurological and respiratory clusters displayed a sensitivity of 0.97 (95% CI 0.91-1.00) and a negative predictive value of 0.97 (0.92-1.00) for LC. The prevalence of alternative somatic and mental diseases in pediatric patients with suspected LC is high. The range of underlying diseases is wide, including chronic and potentially life-threatening conditions. Neurological and respiratory symptom clusters may help to identify patients that are unlikely to be suffering from LC.
-0.2194024 0.1616836 -0.6004884 34694037 2022 COVID-19 in children. II: Pathogenesis, disease spectrum and management. Howard-Jones Journal of paediatrics and child health The global disruption of the COVID-19 pandemic has impacted the life of every child either directly or indirectly. This review explores the pathophysiology, immune response, clinical presentation and treatment of COVID-19 in children, summarising the most up-to-date data including recent developments regarding variants of concern. The acute infection with SARS-CoV-2 is generally mild in children, whilst the post-infectious manifestations, including paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and ‘long COVID’ in children, are more complex. Given that most research on COVID-19 has focused on adult cohorts and that clinical manifestations, treatment availability and impacts differ markedly in children, research that specifically examines COVID-19 in children needs to be prioritised. © 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).
-0.2290040 0.4284335 -0.8864414 36343180 2022 Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology. Brugler Yonts Pediatric annals Although children have been largely spared the most severe consequences of acute infection with SARS-CoV-2 virus, it is estimated that up to one-quarter of the more than 14 million children diagnosed as having coronavirus disease 2019 (COVID-19) have developed persistent symptoms of fatigue, postexertional malaise, neurologic and cognitive symptoms, and other symptoms that interfere with activities of daily living for months after their initial illness. Pediatric postacute sequelae of COVID-19 (pPASC), or long-COVID, is a complex, heterogeneous, postviral condition involving multiple body systems and is likely attributable to several concurrent underlying physiologic processes, including damage from direct viral invasion, endovascular dysfunction and microthrombosis, viral persistence, and the development of autoimmunity. In this review, we explore the current state of the literature regarding definition, epidemiology, clinical presentation, and proposed pathophysiologic mechanisms of pPASC. [ Pediatr Ann . 2022;51(11):e416-e420.] .
-0.2495247 0.6494352 -1.1484846 35207572 2022 Long COVID in Children and Adolescents. Fainardi Life (Basel, Switzerland) Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has caused significant mortality and morbidity worldwide. In children, the acute SARS-CoV-2 infection is often asymptomatic or paucisymptomatic, and life-threatening complications are rare. Nevertheless, there are two long-term consequences of SARS-CoV-2 infection in children that raise concern: multisystem inflammatory syndrome in children (MIS-C) and long COVID. While the understanding and the experience regarding the acute phase of SARS-CoV-2 infection have remarkably increased over time, scientific and clinical research is still exploring the long-term effects of COVID-19. In children, data on long COVID are scant. Reports are conflicting regarding its prevalence, duration and impact on daily life. This narrative review explored the latest literature regarding long COVID-19 in the pediatric population. We showed that long COVID in children might be a relevant clinical problem. In most cases, the prognosis is good, but some children may develop long-term symptoms with a significant impact on their daily life. The paucity of studies on long COVID, including a control group of children not infected by SARS-CoV-2, prevents us from drawing firm conclusions. Whether the neuropsychiatric symptoms widely observed in children and adolescents with long COVID are the consequence of SARS-CoV-2 infection or are due to the tremendous stress resulting from the restrictions and the pandemics is still not clear. In both cases, psychological support can play a fundamental role in managing COVID pandemics in children. More knowledge is needed to share a standardized definition of the syndrome and improve its management and treatment.
-0.2927014 0.0574660 -0.6428688 36293968 2023 Comparison of Long-Term Complications of COVID-19 Illness among a Diverse Sample of Children by MIS-C Status. Messiah International journal of environmental research and public health Most pediatric COVID-19 cases are asymptomatic; however, a small number of children are diagnosed with multisystem inflammatory syndrome in children (MIS-C), a rare but severe condition that is associated with SARS-CoV-2 infection. Persistent symptoms of COVID-19 illness in children diagnosed with/without MIS-C is largely unknown. A retrospective EHR review of patients with COVID-19 illness from one pediatric healthcare system to assess the presence of acute (<30 days) and chronic (≥30, 60-120, and >120 days) long-term COVID symptoms was conducted. Patients/caregivers completed a follow-up survey from March 2021 to January 2022 to assess the presence of long COVID. Results showed that non-MIS-C children ( n = 286; 54.49% Hispanic; 19.23% non-Hispanic Black; 5.77% other ethnicity; 79.49% government insurance) were younger (mean age 6.43 years [SD 5.95]) versus MIS-C ( n = 26) children (mean age 9.08 years, [SD 4.86]) ( p = 0.032). A share of 11.5% of children with MIS-C and 37.8% without MIS-C reported acute long COVID while 26.9% and 15.3% reported chronic long COVID, respectively. Females were almost twice as likely to report long symptoms versus males and those with private insurance were 66% less likely to report long symptoms versus those with government insurance. In conclusion, a substantial proportion of ethnically diverse children from low resource backgrounds with severe COVID illness are reporting long-term impacts. Findings can inform pediatric professionals about this vulnerable population in post-COVID-19 recovery efforts.
-0.2990985 0.2923512 -0.8905481 33919537 2021 Long-COVID and Post-COVID Health Complications: An Up-to-Date Review on Clinical Conditions and Their Possible Molecular Mechanisms. Silva Andrade Viruses The COVID-19 pandemic has infected millions worldwide, leaving a global burden for long-term care of COVID-19 survivors. It is thus imperative to study post-COVID (i.e., short-term) and long-COVID (i.e., long-term) effects, specifically as local and systemic pathophysiological outcomes of other coronavirus-related diseases (such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS)) were well-cataloged. We conducted a comprehensive review of adverse post-COVID health outcomes and potential long-COVID effects. We observed that such adverse outcomes were not localized. Rather, they affected different human systems, including: (i) immune system (e.g., Guillain-Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation), (iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal, hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage), (viii) mental health (stress, depression and anxiety). We additionally hypothesized mechanisms of action by investigating possible molecular mechanisms associated with these disease outcomes/symptoms. Overall, the COVID-19 pathology is still characterized by cytokine storm that results to endothelial inflammation, microvascular thrombosis, and multiple organ failures.
-0.3306590 -0.3171928 -0.3441253 36010141 2022 Chronic Olfactory Dysfunction in Children with Long COVID: A Retrospective Study. Buonsenso Children (Basel, Switzerland) Olfactory dysfunction is one of the long-term consequences of acute SARS-CoV-2 infection in adults. This study aims to analyze the prevalence of chronic anosmia among COVID-19 children and to bring to light its impact on their families’ quality of life and wellbeing. Children younger than 18 years old, who were detected as being COVID-19-positive by RT-PCR and were assessed in a pediatric post-COVID outpatient clinic at least 28 days after the onset of the acute infection, were included in the study. The patients suffering from persisting smell disorders were asked to answer a questionnaire about their symptoms and how they influence their daily life. Out of the 784 children evaluated, 13 (1.7%) presented olfactory impairment at a mean follow-up since the acute infection of more than three months. Parents’ answers showed that they were worried about their children’s health, in particular they wanted to know if and when they would recover and if these disorders would have long-term consequences. They also wanted to share their experiences, in order to help other people who are experiencing the same disorders in everyday life. Our study highlights that smell disorders can significantly upset children’s eating habits and everyday activities. Furthermore, these findings suggest that future research should try to better understand the mechanisms causing loss of smell in COVID-19 patients and find the most appropriate treatment.
-0.3391024 -0.1229754 -0.5552294 36518782 2022 Development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction. Brasseler Frontiers in pediatrics Absent or abnormal senses of smell and taste have been frequently reported during both acute and long COVID in adult patients. In contrast, pediatric patients who test positive for SARS-CoV-2 are often asymptomatic and the loss of smell and/or taste has been infrequently reported. After observing several young patients with COVID-associated anosmia and ageusia at our clinic, we decided to investigate the incidence of subsequent eating disorders in these patients and in SARS-CoV-2 positive patients who did not experience anosmia and ageusia during the same period. A single-site retrospective cohort study of 84 pediatric patients with suspected long COVID who were treated in the Pediatric Infectious Diseases Outpatient Clinic at the University Hospital Essen were evaluated for persistent symptoms of COVID-19. Smell and taste dysfunction as well as eating behaviors were among the signs and symptoms analyzed in this study. 24 out of 84 children and adolescents described smell and taste dysfunction after confirmed or suspected SARS-CoV-2 infections. A large number of these patients (6 out of 24) demonstrated increased fixation on their eating behavior post-COVID and over time these patients developed anorexia nervosa. In this study we saw a possible association of long-lasting post-COVID smell and taste dysfunction with subsequent development of eating disorders. This observation is worrisome and merits further investigation by healthcare providers at multiple clinical sites. © 2022 Brasseler, Schönecker, Steindor, Della Marina, Bruns, Dogan, Felderhoff-Müser, Hebebrand, Dohna-Schwake and Goretzki.
-0.4675797 0.6817802 -1.6169396 35901463 2022 Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series. Ng Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists Studies suggest a large number of patients have persistent symptoms following COVID-19 infection-a condition termed “long COVID.” Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing. A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients’ caregivers also completed standardized questionnaires regarding day-to-day mood and behavior. At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures. Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: .
-0.4775452 -1.3256287 0.3705384 35994282 2023 Clinical Features and Burden of Postacute Sequelae of SARS-CoV-2 Infection in Children and Adolescents. Rao JAMA pediatrics The postacute sequelae of SARS-CoV-2 infection (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. To identify diagnosed symptoms, diagnosed health conditions, and medications associated with PASC in children. This retrospective cohort study used electronic health records from 9 US children’s hospitals for individuals younger than 21 years who underwent antigen or reverse transcriptase-polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020, and October 31, 2021, and had at least 1 encounter in the 3 years before testing. SARS-CoV-2 positivity by viral test (antigen or RT-PCR). Syndromic (symptoms), systemic (conditions), and medication PASC features were identified in the 28 to 179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting viral test-positive groups with viral test-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race and ethnicity, and time period of cohort entrance. The incidence proportion for any syndromic, systemic, or medication PASC feature was estimated in the 2 groups to obtain a burden of PASC estimate. Among 659 286 children in the study sample, 348 091 (52.8%) were male, and the mean (SD) age was 8.1 (5.7) years. A total of 59 893 (9.1%) tested positive by viral test for SARS-CoV-2, and 599 393 (90.9%) tested negative. Most were tested in outpatient testing facility settings (322 813 [50.3%]) or office settings (162 138 [24.6%]). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR, 1.96; 95% CI, 1.16-3.32), myocarditis (aHR, 3.10; 95% CI, 1.94-4.96), and cough and cold preparations (aHR, 1.52; 95% CI, 1.18-1.96), respectively. The incidence of at least 1 systemic, syndromic, or medication feature of PASC was 41.9% (95% CI, 41.4-42.4) among viral test-positive children vs 38.2% (95% CI, 38.1-38.4) among viral test-negative children, with an incidence proportion difference of 3.7% (95% CI, 3.2-4.2). A higher strength of association for PASC was identified in those cared for in the intensive care unit during the acute illness phase, children younger than 5 years, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC.
-0.4928178 0.2532418 -1.2388774 35486940 2022 Long COVID in Children and Adolescents. Gupta The primary care companion for CNS disorders Objective: To review the empirical evidence regarding neuropsychiatric illness (long coronavirus disease [COVID]) in children and adolescents post-severe acute respiratory coronavirus disease 2 (SARS-CoV-2) infection. Data Sources: A search of PubMed, PsycINFO, Cochrane Library, and Google Scholar was conducted from the date of inception until February 2022 using the keywords corona *, COVID-19 , SARS-CoV-2 , mental health , depression , anxiety , neurological , psychiatric , long COVID , and post-COVID outcomes . Age filters were used to include children and adolescents aged ≤ 18 years. Study Selection: The search resulted in the identification of 526 articles; 48 articles met the inclusion criteria. Data Extraction: Results are presented using a narrative review format. Data regarding long COVID in children and adolescents post-SARS-CoV-2 infection were extracted to understand epidemiologic trends, preventive measures, and treatment options. Results: Studies during the initial phase of the pandemic reported a mixed range of symptoms from case reports or case series. However, multisystem inflammatory syndrome in children (MIS-C) was widely reported. During the subsequent phases, the emergence of new variants led to a surge of SARS-CoV-2 infections in pediatric populations. There were highly variable, mixed symptom clusters within 60 days post-infection, which resolved in many patients within 6 months. There were prolonged illnesses and impairments in some children and adolescents with long COVID, and many had similar symptoms even though they tested negative for COVID-19. Conclusions: Long COVID symptoms are both physical and mental in nature among children and adolescents. The impairments have the potential to affect long-term functioning and increase the overall burden on health care delivery. Despite current studies having methodological issues, there is a consensus to provide multidisciplinary and holistic care to those in need. © Copyright 2022 Physicians Postgraduate Press, Inc. 
-0.4961919 -0.7332602 -0.2591236 35970935 2022 SARS-CoV-2 infection in children and implications for vaccination. Nathanielsz Pediatric research The COVID-19 pandemic caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for more than 500 million cases worldwide as of April 2022. Initial estimates in 2020 found that children were less likely to become infected with SARS-CoV-2 and more likely to be asymptomatic or display mild COVID-19 symptoms. Our early understanding of COVID-19 transmission and disease in children led to a range of public health measures including school closures that have indirectly impacted child health and wellbeing. The emergence of variants of concern (particularly Delta and Omicron) has raised new issues about transmissibility in children, as preliminary data suggest that children may be at increased risk of infection, especially if unvaccinated. Global national prevalence data show that SARS-CoV-2 infection in children and adolescents is rising due to COVID-19 vaccination among adults and increased circulation of Delta and Omicron variants. To mitigate this, childhood immunisation programmes are being implemented globally to prevent direct and indirect consequences of COVID-19 including severe complications (e.g., MIS-C), debilitating long-COVID symptoms, and the indirect impacts of prolonged community and school closures on childhood education, social and behavioural development and mental health. This review explores the current state of knowledge on COVID-19 in children including COVID-19 vaccination strategies. IMPACT: Provides an up-to-date account of SARS-CoV-2 infections in children. Discusses the direct and indirect effects of COVID-19 in children. Provides the latest information on the current state of global COVID-19 vaccination in children. © 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc. 
-0.5204539 -0.4971985 -0.5437094 36004306 2022 Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis. Choudhury Therapeutic advances in gastroenterology

Prolonged symptoms after COVID-19 are an important concern due to the large numbers affected by the pandemic. To ascertain the frequency of gastrointestinal (GI) manifestations as part of long GI COVID. A systematic review and meta-analysis of studies reporting GI manifestations in long COVID was performed. Electronic databases (Medline, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were searched till 21 December 2021 to identify studies reporting frequency of GI symptoms in long COVID. We included studies reporting overall GI manifestations or individual GI symptoms as part of long COVID. We excluded pediatric studies and those not providing relevant information. We calculated the pooled frequency of various symptoms in all patients with COVID-19 and also in those with long COVID using the inverse variance approach. All analysis was done using R version 4.1.1 using packages ‘meta’ and ‘metafor’. A total of 50 studies were included. The frequencies of GI symptoms were 0.12 [95% confidence interval (CI), 0.06-0.22, I

2  = 99%] and 0.22 (95% CI, 0.10-0.41, I

2  = 97%) in patients with COVID-19 and those with long COVID, respectively. The frequencies of abdominal pain, nausea/vomiting, loss of appetite, and loss of taste were 0.14 (95% CI, 0.04-0.38, I

2  = 96%), 0.06 (95% CI, 0.03-0.11, I

2  = 98%), 0.20 (95% CI, 0.08-0.43, I

2  = 98%), and 0.17 (95% CI, 0.10-0.27, I

2  = 95%), respectively, after COVID-19. The frequencies of diarrhea, dyspepsia, and irritable bowel syndrome were 0.10 (95% CI, 0.04-0.23, I

2  = 98%), 0.20 (95% CI, 0.06-0.50, I

2  = 97%), and 0.17 (95% CI, 0.06-0.37, I

2  = 96%), respectively. GI symptoms in patients were seen in 12% after COVID-19 and 22% as part of long COVID. Loss of appetite, dyspepsia, irritable bowel syndrome, loss of taste, and abdominal pain were the five most common GI symptoms of long COVID. Significant heterogeneity and small number of studies for some of the analyses are limitations of the systematic review. © The Author(s), 2022.
-0.5408222 0.0028472 -1.0844916 35211871 2022 Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort. Caspersen European journal of epidemiology Physical, psychological and cognitive symptoms have been reported as post-acute sequelae for COVID-19 patients but are also common in the general uninfected population. We aimed to calculate the excess risk and identify patterns of 22 symptoms up to 12 months after COVID-19. We followed more than 70,000 adult participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. Infected and non-infected participants registered presence of 22 different symptoms in March 2021. One year after infection, 13 of 22 symptoms were associated with SARS-CoV-2 infection, based on relative risks between infected and uninfected subjects. For instance, 17.4% of SARS-CoV-2 infected cohort participants reported fatigue that persist 12 months after infection, compared to new occurrence of fatigue that had lasted less than 12 months in 3.8% of non-infected subjects (excess risk 13.6%). The adjusted relative risk for fatigue was 4.8 (95% CI 3.5-6.7). Two main underlying factors explained 50% of the variance in the 13 symptoms. Brain fog, poor memory, dizziness, heart palpitations, and fatigue had high loadings on the first factor, while shortness-of breath and cough had high loadings on the second factor. Lack of taste and smell showed low to moderate correlation to other symptoms. Anxiety, depression and mood swings were not strongly related to COVID-19. Our results suggest that there are clusters of symptoms after COVID-19 due to different mechanisms and question whether it is meaningful to describe long COVID as one syndrome. © 2022. The Author(s).
-0.5573613 -1.3196298 0.2049073 35431658 2022 COVID-19 Infection in Children: Diagnosis and Management. Zhu Current infectious disease reports Due to the rapidly changing landscape of COVID-19, the purpose of this review is to provide a concise and updated summary of pediatric COVID-19 diagnosis and management. The relative proportion of pediatric cases have significantly increased following the emergence of the Omicron variant (from < 2% in the early pandemic to 25% from 1/27 to 2/3/22). While children present with milder symptoms than adults, severe disease can still occur, particularly in children with comorbidities. There is a relative paucity of pediatric data in the management of COVID-19 and the majority of recommendations remain based on adult data. Fever and cough remain the most common clinical presentations, although atypical presentations such as “COVID toes,” anosmia, and croup may be present. Children are at risk for post-infectious complications such as MIS-C and long COVID. Nucleic acid amplification tests through respiratory PCR remain the mainstay of diagnosis. The mainstay of management remains supportive care and prevention through vaccination is highly recommended. In patients at increased risk of progression, interventions such as monoclonal antibody therapy, PO Paxlovid, or IV remdesivir × 3 days should be considered. In patients with severe disease, the use of remdesivir, dexamethasone, and immunomodulatory agents (tocilizumab, baricitinib) is recommended. Children can be at risk for thrombosis from COVID-19 and anticoagulation is recommended in children with markedly elevated D-dimer levels or superimposed clinical risk factors for hospital associated venous thromboembolism. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.
-0.5645986 -0.5750642 -0.5541330 36828133 2023 The Impact of COVID-19 Infection and Characterization of Long COVID in Adolescents With Anxiety Disorders: A Prospective Longitudinal Study. Strawn Journal of the American Academy of Child and Adolescent Psychiatry While the coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted pediatric mental health, the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on youth with anxiety disorders has not been prospectively examined. Further, there are limited prospective data on post-acute sequelae COVID-19, including symptoms that constitute the long COVID neuropsychiatric syndrome. In December 2019, we began a longitudinal study of adolescents aged 12-17 years with DSM-5 primary anxiety disorders treated with either duloxetine or escitalopram. Assessments included all items from the Generalized Anxiety Disorder-7 (GAD-7) and Quick Inventory of Depressive Symptomatology (QIDS) scales at each week and a weekly clinician-rated Clinical Global Impressions-Severity (CGI-S) scale. We examined the longitudinal course of anxiety, including following laboratory-confirmed SARS-CoV-2 infection in affected adolescents. This prospective study of the longitudinal impact of COVID-19 in pediatric anxiety disorders reveals that COVID-19 is associated with worsening anxiety symptoms and a disquieting 33% worsening in syndromic severity. Further, these data raise the possibility that, in anxious youth, COVID-19 is associated with a surfeit of neuropsychiatric symptoms. Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
-0.6331631 -0.7689888 -0.4973373 36222077 2023 Short-term complications and post-acute sequelae in hospitalized paediatric patients with COVID-19 and obesity: A multicenter cohort study. Valenzuela Pediatric obesity Obesity increases the severity of coronavirus disease 2019 illness in adults. The role of obesity in short-term complications and post-acute sequelae in children is not well defined. To evaluate the relationship between obesity and short-term complications and post-acute sequelae of SARS-CoV-2 infection in hospitalized paediatric patients. An observational study was conducted in three tertiary hospitals, including paediatric hospitalized patients with a confirmatory SARS-CoV-2 RT-PCR from March 2020 to December 2021. Obesity was defined according to WHO 2006 (0-2 years) and CDC 2000 (2-20 years) growth references. Short-term outcomes were intensive care unit admission, ventilatory support, superinfections, acute kidney injury, and mortality. Neurological, respiratory, and cardiological symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms were considered as post-acute sequalae. Adjusted linear, logistic regression and generalized estimating equations models were performed. A total of 216 individuals were included, and 67 (31.02%) of them had obesity. Obesity was associated with intensive care unit admission (aOR = 5.63, CI95% 2.90-10.94), oxygen requirement (aOR = 2.77, CI95% 1.36-5.63), non-invasive ventilatory support (aOR = 6.81, CI95% 2.11-22.04), overall superinfections (aOR = 3.02 CI95% 1.45-6.31), and suspected bacterial pneumonia (aOR = 3.00 CI95% 1.44-6.23). For post-acute sequalae, obesity was associated with dyspnea (aOR = 9.91 CI95% 1.92-51.10) and muscle weakness (aOR = 20.04 CI95% 2.50-160.65). In paediatric hospitalized patients with COVID-19, severe short-term outcomes and post-acute sequelae are associated with obesity. Recognizing obesity as a key comorbidity is essential to develop targeted strategies for prevention of COVID-19 complications in children. © 2022 World Obesity Federation.
-0.6452284 -1.5357593 0.2453026 36674665 2023 COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes. Vasichkina International journal of molecular sciences In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated-post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.
-0.6542034 -0.8085242 -0.4998826 35665016 2023 Clinical features and burden of post-acute sequelae of SARS-CoV-2 infection in children and adolescents: an exploratory EHR-based cohort study from the RECOVER program. Rao medRxiv : the preprint server for health sciences The post-acute sequelae of SARS-CoV-2 (PASC) has emerged as a long-term complication in adults, but current understanding of the clinical presentation of PASC in children is limited. To identify diagnosed symptoms, diagnosed health conditions and medications associated with PASC in children. Retrospective cohort study using electronic health records from 9 US children’s hospitals for individuals <21 years-old who underwent reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 between March 1, 2020 - October 31, 2021 and had at least 1 encounter in the 3 years before testing. SARS-CoV-2 PCR positivity. We identified syndromic (symptoms), systemic (conditions), and medication PASC features in the 28-179 days following the initial test date. Adjusted hazard ratios (aHRs) were obtained for 151 clinically predicted PASC features by contrasting PCR-positive with PCR-negative groups using proportional hazards models, adjusting for site, age, sex, testing location, race/ethnicity, and time-period of cohort entrance. We estimated the incidence proportion for any syndromic, systemic or medication PASC feature in the two groups to obtain a burden of PASC estimate. Among 659,286 children in the study sample, 59,893 (9.1%) tested positive by PCR for SARS-CoV-2. Most were tested in outpatient testing facility (50.3%) or office (24.6%) settings. The most common syndromic, systemic, and medication features were loss of taste or smell (aHR 1.96 [95% CI 1.16-3.32), myocarditis (aHR 3.10 [95% CI 1.94-4.96]), and cough and cold preparations (aHR 1.52 [95% CI 1.18-1.96]). The incidence of at least one systemic/syndromic/medication feature of PASC was 41.9% among PCR-positive children versus 38.2% among PCR-negative children, with an incidence proportion difference of 3.7% (95% CI 3.2-4.2%). A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5 years-old, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of pediatric PASC that presented to health systems was low. Myocarditis was the most commonly diagnosed PASC-associated condition. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC. Question: What are the incidence and clinical features of post-acute sequelae of SARS-CoV-2 infection (PASC) in children? Findings: In this retrospective cohort study of 659,286 children tested for SARS-CoV-2 by polymerase chain reaction (PCR), the symptom, condition and medication with the strongest associations with SARS-CoV-2 infection were loss of taste/smell, myocarditis, and cough and cold preparations. The incidence proportion of non-MIS-C related PASC in the PCR-positive group exceeded the PCR-negative group by 3.7% (95% CI 3.2-4.2), with increased rates associated with acute illness severity, young age, and medical complexity. Meaning: PASC in children appears to be uncommon, with features that differ from adults.
-0.6995982 -0.3840364 -1.0151600 36203555 2022 Clinical Subphenotypes of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program. Rao medRxiv : the preprint server for health sciences Multi-system inflammatory syndrome in children (MIS-C) represents one of the most severe post-acute sequelae of SARS-CoV-2 infection in children, and there is a critical need to characterize its disease patterns for improved recognition and management. Our objective was to characterize subphenotypes of MIS-C based on presentation, demographics and laboratory parameters. We conducted a retrospective cohort study of children with MIS-C from March 1, 2020 - April 30, 2022 and cared for in 8 pediatric medical centers that participate in PEDSnet. We included demographics, symptoms, conditions, laboratory values, medications and outcomes (ICU admission, death), and grouped variables into eight categories according to organ system involvement. We used a heterogeneity-adaptive latent class analysis model to identify three clinically-relevant subphenotypes. We further characterized the sociodemographic and clinical characteristics of each subphenotype, and evaluated their temporal patterns. We identified 1186 children hospitalized with MIS-C. The highest proportion of children (44·4%) were aged between 5-11 years, with a male predominance (61.0%), and non- Hispanic white ethnicity (40·2%). Most (67·8%) children did not have a chronic condition. Class 1 represented children with a severe clinical phenotype, with 72·5% admitted to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 represented a moderate presentation, with 4-6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 represented a mild presentation, with fewer organ systems involved, lower CRP, troponin values and less cardiac involvement. Class 1 initially represented 51·1% of children early in the pandemic, which decreased to 33·9% from the pre-delta period to the omicron period. MIS-C has a spectrum of clinical severity, with degree of laboratory abnormalities rather than the number of organ systems involved providing more useful indicators of severity. The proportion of severe/critical MIS-C decreased over time. Evidence before this study: We searched PubMed and preprint articles from December 2019, to July 2022, for studies published in English that investigated the clinical subphenotypes of MIS-C using the terms “multi-system inflammatory syndrome in children” or “pediatric inflammatory multisystem syndrome” and “phenotypes”. Most previous research described the symptoms, clinical characteristics and risk factors associated with MIS-C and how these differ from acute COVID-19, Kawasaki Disease and Toxic Shock Syndrome. One single-center study of 63 patients conducted in 2020 divided patients into Kawasaki and non-Kawasaki disease subphenotypes. Another CDC study evaluated 3 subclasses of MIS-C in 570 children, with one class representing the highest number of organ systems, a second class with predominant respiratory system involvement, and a third class with features overlapping with Kawasaki Disease. However, this study evaluated cases from March to July 2020, during the early phase of the pandemic when misclassification of cases as Kawasaki disease or acute COVID-19 may have occurred. Therefore, it is not known from the existing literature whether the presentation of MIS-C has changed with newer variants such as delta and omicron. Added value of this study: PEDSnet provides one of the largest MIS-C cohorts described so far, providing sufficient power for detailed analyses on MIS-C subphenotypes. Our analyses span the entire length of the pandemic, including the more recent omicron wave, and provide an update on the presentations of MIS-C and its temporal dynamics. We found that children have a spectrum of illness that can be characterized as mild (lower inflammatory markers, fewer organ systems involved), moderate (4-6 organ involvement with clinical overlap with acute COVID-19) and severe (higher inflammatory markers, critically ill, more likely to have cardiac involvement, with hypotension/shock and need for vasopressors). Implications of all the available evidence: These results provide an update to the subphenotypes of MIS-C including the more recent delta and omicron periods and aid in the understanding of the various presentations of MIS-C. These and other findings provide a useful framework for clinicians in the recognition of MIS-C, identify factors associated with children at risk for increased severity, including the importance of laboratory parameters, for risk stratification, and to facilitate early evaluation, diagnosis and treatment.
-0.7232562 -0.5294624 -0.9170501 36291381 2022 Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review. Morello Children (Basel, Switzerland) Long COVID is an emergent, heterogeneous, and multisystemic condition with an increasingly important impact also on the pediatric population. Among long COVID symptoms, patients can experience chronic gastrointestinal symptoms such as abdominal pain, constipation, diarrhea, vomiting, nausea, and dysphagia. Although there is no standard, agreed, and optimal diagnostic approach or treatment of long COVID in children, recently compounds containing multiple micronutrients and lactoferrin have been proposed as a possible treatment strategy, due to the long-standing experience gained from other gastrointestinal conditions. In particular, lactoferrin is a pleiotropic glycoprotein with antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory activities. Moreover, it seems to have several physiological functions to protect the gastrointestinal tract. In this regard, we described the resolution of symptoms after the start of therapy with high doses of oral lactoferrin in two patients referred to our post-COVID pediatric unit due to chronic gastrointestinal symptoms after SARS-CoV-2 infection.
-0.7683668 -1.4780626 -0.0586711 35463893 2022 Caregivers’ Attitudes Toward COVID-19 Vaccination in Children and Adolescents With a History of SARS-CoV-2 Infection. Buonsenso Frontiers in pediatrics Limited data are available on the attitudes of caregivers toward COVID-19 vaccination in children and adolescents with a history of SARS-CoV-2 infection or Long Covid symptoms. The aim of this study was to investigate the vaccine hesitancy among caregivers of children and adolescents with a documented history of SARS-CoV-2 infection and to explore the possible associations between COVID-19 manifestations and the acceptance of the vaccine. Caregivers of children or adolescents with a microbiologically confirmed diagnosis of SARS-CoV-2 infection evaluated in two University Hospitals were interviewed. We were able to contact 132 caregivers and 9 declined to participate. 68 caregivers (56%) were in favor of COVID-19 vaccination for their child. In the multiple logistic regression, child’s age (OR 1.17, 95%CI 1.06-1.28) and hospitalization due to COVID-19 (OR 3.25, 95%CI 1.06-9.95) were positively associated with being in favor of COVID-19 vaccination. On the contrary, the occurrence of child’s Long Covid was associated with a higher likelihood of being against the vaccination (OR 0.28, 95%CI 0.10-0.80). This preliminary study shows that only about half of the interviewed parents of children and adolescents with a previous SARS-CoV-2 infection are willing to vaccinate them to prevent a repeated COVID-19 infection. These findings might help healthcare workers to provide tailored information to caregivers of children with a previous SARS-CoV-2 infection. Copyright © 2022 Buonsenso, Valentini, Macchi, Folino, Pensabene, Patria, Agostoni, Castaldi, Lecce, Giannì, Marchisio, Milani and the CHICO Study Group.
-0.9963558 -1.7711136 -0.2215981 35955979 2023 Recovering or Persisting: The Immunopathological Features of SARS-CoV-2 Infection in Children. Buonsenso Journal of clinical medicine Background. The profile of cellular immunological responses of children across the spectrum of COVID-19, ranging from acute SARS-CoV-2 infection to full recovery or Long COVID, has not yet been fully investigated. Methods. We examined and compared cytokines in sera and cell subsets in peripheral blood mononuclear cells (B and regulatory T lymphocytes) collected from four distinct groups of children, distributed as follows: younger than 18 years of age with either acute SARS-CoV-2 infection (n = 49); fully recovered from COVID-19 (n = 32); with persistent symptoms (Long COVID, n = 51); and healthy controls (n = 9). Results. In the later stages after SARS-CoV-2 infection, the cohorts of children, both with recovered and persistent symptoms, showed skewed T and B subsets, with remarkable differences when compared with children at the onset of the infection and with controls. The frequencies of IgD+CD27− naïve B cells, IgD+IgM+ and CD27−IgM+CD38dim B cells were higher in children with recent infection than in those with an older history of disease (p < 0.0001 for all); similarly, the total and natural Tregs compartments were more represented in children at onset when compared with Long COVID (p < 0.0001 and p = 0.0005, respectively). Despite the heterogeneity, partially due to age, sex and infection incidence, the susceptibility of certain children to develop persistent symptoms after infection appeared to be associated with the imbalance of the adaptive immune response. Following up and comparing recovered versus Long COVID patients, we analyzed the role of circulating naïve and switched B and regulatory T lymphocytes in counteracting the evolution of the symptomatology emerged, finding an interesting correlation between the amount and ability to reconstitute the natural Tregs component with the persistence of symptoms (linear regression, p = 0.0026). Conclusions. In this study, we suggest that children affected by Long COVID may have a compromised ability to switch from the innate to the adaptive immune response, as supported by our data showing a contraction of naïve and switched B cell compartment and an unstable balance of regulatory T lymphocytes occurring in these children. However, further prospective immunological studies are needed to better clarify which factors (epigenetic, diet, environment, etc.) are involved in the impairment of the immunological mechanisms in the Long COVID patients.
-1.2336225 -0.8967490 -1.5704960 36562653 2023 The outcomes of COVID-19 pneumonia in children-clinical, radiographic, and pulmonary function assessment. Bogusławski Pediatric pulmonology The goal of this study was to assess the pulmonary sequelae of COVID-19 pneumonia in children. Children (0-18 years old) diagnosed with COVID-19 pneumonia hospitalized between March 2020 and March 2021 were included in this observational study. All children underwent follow-up visits 3 months postdischarge, and if any abnormalities were stated, a second visit after the next 3 months was scheduled. Clinical assessment included medical history, physical examination, lung ultrasound (LUS) using a standardized protocol, and pulmonary function tests (PFTs). PFTs results were compared with healthy children. Forty-one patients with COVID-19 pneumonia (severe disease n = 3, mechanical ventilation, n = 0) were included in the study. Persistent symptoms were reported by seven (17.1%) children, the most common was decreased exercise tolerance (57.1%), dyspnea (42.9%), and cough (42.9%). The most prevalent abnormalities in LUS were coalescent B-lines (37%) and small subpleural consolidations (29%). The extent of LUS abnormalities was significantly greater at the first than at the second follow-up visit (p = 0.03). There were no significant differences in PFTs results neither between the study group and healthy children nor between the two follow-up visits in the study group. Our study shows that children might experience long-term sequelae following COVID-19 pneumonia. In the majority of cases, these are mild and resolve over time. © 2022 Wiley Periodicals LLC.
-1.3907269 -2.0307370 -0.7507169 36125379 2023 Pulmonary Dysfunction after Pediatric COVID-19. Heiss Radiology Background Long COVID occurs at a lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field-strength MRI may help identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma at low-field-strength MRI in children and adolescents with post-COVID-19 condition compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional clinical trial using low-field-strength MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes at MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive reverse transcriptase-polymerase chain reaction test result, and serologic parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants, and those with long COVID. Results A total of 54 participants after COVID-19 infection (mean age, 11 years ± 3 [SD]; 30 boys [56%]) and nine healthy controls (mean age, 10 years ± 3; seven boys [78%]) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (ventilation-perfusion [V/Q] match) was higher in healthy controls (81% ± 6.1) compared with the recovered group (62% ± 19; P = .006) and the group with long COVID (60% ± 20; P = .003). V/Q match was lower in patients with time from COVID-19 infection to study participation of less than 180 days (63% ± 20; P = .03), 180-360 days (63% ± 18; P = .03), and 360 days (41% ± 12; P < .001) as compared with the never-infected healthy controls (81% ± 6.1). Conclusion Low-field-strength MRI showed persistent pulmonary dysfunction in children and adolescents who recovered from COVID-19 and those with long COVID. Clinical trial registration no. NCT04990531 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Paltiel in this issue.
-1.4912958 -2.4220800 -0.5605116 19212308 2009 Autoimmune diseases of the liver and biliary tract and overlap syndromes in childhood. Maggiore Minerva gastroenterologica e dietologica Autoimmune liver diseases in childhood includes Autoimmune Hepatitis (AIH) and Primary (Autoimmune) Sclerosing Cholangitis (P(A)SC). Both diseases are characterized by a chronic, immune-mediated liver inflammation involving mainly hepatocytes in AIH and bile ducts in PSC. Both diseases, if untreated, lead to liver cirrhosis. AIH could be classified, according to the autoantibodies pattern, into two subtypes: AIH type 1 presents at any age as a chronic liver disease with recurrent flares occasionally leading to liver cirrhosis and liver failure. Characterizing autoantibodies are anti-nuclear (ANA) and anti-smooth muscle (SMA), usually at high titer (>1:100). These autoantibodies are not specific and probably do not play a pathogenic role. AIH type 2 shows a peak of incidence in younger children, however with a fluctuating course. The onset is often as an acute liver failure. Anti-liver kidney microsome autoantibodies type 1 (LKM1) and/or anti-liver cytosol autoantibody (LC1) are typically found in AIH type 2 and these autoantibodies are accounted to have a potential pathogenic role. Diagnosis of AIH is supported by the histological finding of interface hepatitis with massive portal infiltration of mononuclear cells and plasmocytes. Inflammatory bile duct lesions are not unusual and may suggest features of ‘’overlap’’ with P(A)SC. A diagnostic scoring system has been developed mainly for scientific purposes, but his diagnostic role in pediatric age is debated. Conventional treatment with steroids and azathioprine is the milestone of therapy and it is proved effective. Treatment withdrawal however should be attempted only after several years. Cyclosporin A is the alternative drug currently used for AIH and it is effective as steroids. P(A)SC exhibit a peak of incidence in the older child, typically in pre-pubertal age with a slight predominance of male gender. Small bile ducts are always concerned and the histological picture shows either acute cholangitis (bile duct infiltration and destruction) and/or lesions suggesting chronic cholangitis as well (bile duct paucity and/or proliferation, periductal sclerosis). Small bile ducts damage may be associated, at onset or in the following years, with lesions of larger bile ducts with duct wall irregularities, strictures, dilations, and beading resulting in the characteristic ‘’bead-on-a-string’’ appearance. The ‘’small duct’’ (autoimmune) sclerosing cholangitis is also called autoimmune cholangitis. PSC is strictly associated to a particular form of inflammatory bowel disease (IBD) which shows features not typical of ulcerative colitis neither of Crohn’s disease. Symptoms related to IBD often are present at onset (abdominal pain, weight loss, bloody stools) but the liver disease is frequently asymptomatic and it may be discovered fortuitously. Treatment of PSC is particularly challenging. In case of ‘’small duct’’ SC or in case of evidence active inflammation on liver biopsy, immunosuppressive treatment is probably useful while in case of large bile ducts non inflammatory sclerosis, immunosuppression is probably uneffective. Ursodeoxycholic acid, however, may leads to an improvement of liver biochemistry even if there’s no evidence that it may alter the course of disease. Thus, liver transplantation, is often necessary in the long term follow-up, even with a risk of disease recurrence. In adjunction to these two main disorders, many patients show an’‘overlap’’ disease with features of both AIH and PSC. In such disorders the immune-mediated damage concerns both the hepatocyte and the cholangiocyte with a continuous clinical spectrum from AIH with minimal bile ducts lesions and PSC with portal inflammation and active inflammatory liver damage.
-1.5514188 -2.2694513 -0.8333863 36319840 2022 Extended coagulation profile of children with Long Covid: a prospective study. Di Gennaro Scientific reports Emerging data suggests that endotheliopathy changes can be associated with post covid condition (PCC) in adults. Research on the matter in children is lacking. We analyzed an extended coagulation profile including biomarkers of endothelial damage in children with PCC and compared it with a control group of children that fully recovered post- SARS-CoV-2 infection. A case-control study enrolling children below 18 years of age with previous microbiologically confirmed SARS-CoV-2 infection in a pediatric post-covid unit in Italy ≥ 8 weeks after the initial infection. Samples were taken at 8 and 12 weeks after the SARS-CoV-2 diagnosis and analyzed for coagulation profiling (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). We compared coagulation profiles in samples from children identified with PCC (at least one, or three or more symptoms, which could not be explained by an alternative diagnosis, at the 8- and 12-week follow-up assessment using the pediatric Long Covid International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) survey. Seventy-five children were enrolled, 49.3% were females, the median age was 10.2 (IQR 4.9) years. Forty-six (61%) of the children had at least one persisting symptom at the eight weeks post-onset, (PCC8); 39/75 (52%) had persistent symptoms for more than 12 weeks (PCC12) and 15/75(32%) had at least three persisting symptoms (PCC ≥ 3) at 12 weeks. Children with PCC presented more frequently with abnormal D-Dimer levels above the reference range compared to children that had fully recovered at the 8-12 weeks (39.1% vs. 17.2%, p = 0.04), and 12 week follow up or more (41% vs. 17.2%, p = 0.05), and in children with three or more symptoms at 12 weeks follow up compared to those that had recovered (64.3% vs. 22.2%, p = 0.002). For the other coagulation profiles, there were abnormal values detected for VWF, FVIII, RC and Fibrinogen but no significant differences between children with PCC compared to controls. Although the majority of children in our cohort showed coagulation profile within or close to normal ranges, we found that a higher proportion of children with PCC, and specifically those with a more severe spectrum characterized with three or more persisting symptoms, had abnormal D-dimer levels compared to other children that fully recovered from an acute SARS-CoV-2 infection. © 2022. The Author(s).

Epilogue

We could continue to work with these data and refine, but I hope this gives a sense of potential and caveats for using Large Language Models. Regarding the above, the final summary prompt still needs work; the model occasionally omits the references section for example. Although we give it example output summaries, we don’t accompany those with example inputs, so it is not a true few-shot prompt. And while PageRank is a fun method, it’s not clear that it provides useful information beyond embedding-based question similarity for this task. There’s also peronalized PageRank, where nodes are initially weighted (e.g. by their query similarity), but in my experiments this didn’t perform as well as similarity ranking alone.

  1. GPT-4 has an 8k token limit by default, and 32k-token models are available at higher cost. Recent research suggests these limits will be less of a concern in the near future. Interestingly, modern LLM tokenization uses byte-pair encoding.↩︎

  2. The gpt-3.5-turbo models costs $0.002 per 1000 tokens. GPT-4 was released recently, which has significantly better reasoning ability, but as of March 2023 API use costs $0.03 per 1k prompt tokens and $0.06 per 1k response tokens. As mentioned in earlier footnote, GPT-4 also supports longer context windows at an even higher cost.↩︎

  3. OpenAI also have an embedding model available for $0.0004 / 1k tokens.↩︎

  4. The layout method here initially places nodes according to the first two UMAP dimensions, then applies force-based layout. Both methods also worked well individually.↩︎

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			margin-top: 1em;
			font-size: 1.5em;
		}		
		h2 {
			margin-top: 1em;
			font-size: 1.5em;
		}
		h1 {
			margin-top: 1em;
		  font-size: 2em;
		}

    .dt-top {vertical-align: top;}
    .dt-middle {vertical-align: middle;}
    .dt-bottom {vertical-align: bottom;}
    .vis-tooltip {
    	max-width: 200px;
    }
}
	</style>
</head>


```{r setup, include=FALSE}
library(crayon)
library(kableExtra)
library(openssl)
library(RColorBrewer)
library(forcats)
library(graphlayouts)
library(scales)

source("utils.R")

knitr::opts_chunk$set(echo = TRUE, 
											comment="")
options(crayon.enabled = TRUE)
old_hooks <- fansi::set_knit_hooks(knitr::knit_hooks, 
                                   which = c("output", "message", "error"))

```

*This vignette illustrates using Large Language Models (LLMs) and related technologies for PubMed literature search and summarization. We use OpenAI's `gpt-3.5-turbo` (ChatGPT) and `gpt-4` model, and sentence embeddings from the [SentenceTransformers](https://www.sbert.net/index.html) Python package. For a more sophisticated approach to this problem see [COVID-19 information retrieval with deep-learning based semantic search, question answering, and abstractive summarization](https://www.nature.com/articles/s41746-021-00437-0) by Esteva et al. The code demonstrated here makes calls to the OpenAI and PubMed APIs, but is not well-commented or robust to failures.*

## Some LLM examples

Let's consider a question like "What are the most common symptoms of Long-COVID in children?" We might ask a Large Language Model (LLM) like OpenAI's `gpt-3.5-turbo`, a.k.a ChatGPT.

```{r question, cache=FALSE}
question <- "What are the most common symptoms of Long-COVID in children?"
answer <- chatgpt(question, verbose = TRUE)
```

Notice in the above transcript that the input first started by giving the model a "system" command of `You are a helpful assistant`, followed by a "user" prompt of our question or request. ChatGPT is trained to work with conversational dialog, so a prompt may be a series of user/response text pairs. The system command is an additional feature of the model; here's what the OpenAI has to say about that:

> If adding instructions in the system message doesn't work, you can also try putting them into a user message. (In the near future, we will train our models to be much more steerable via the system message. But to date, we have trained only on a few system messages, so the models pay much more attention to user examples.)

How about an answer from a pirate, just for fun?:

```{r pirate_answer, cache=FALSE, cache.id=md5(question)}
system <- "You are an assistant pretending to be a drunken pirate. Miss-spell 
words to complete the effect. Arr!"

pirate_answer <- chatgpt(question, system_message = system, verbose = TRUE)
```

We may also compare the result to the `gpt-4` model, though we'll use this model selectively to reduce costs.

```{r gpt4_answer, cache=FALSE, cache.id=md5(question)}
question <- "What are the most common symptoms of Long-COVID in children?"
answer <- chatgpt(question, model = 'gpt-4', verbose = TRUE)
```


## JSON responses

Both `gpt-3.5-turbo` and `gpt-4` are trained on data through 2021 and are static. If we want to use them with more recent information we're going to need to grab it ourselves from APIs. In fact, we can treat the model as an API itself, by telling the model to produce JSON output so that we can parse it programmatically. This works well - JSON is a highly structured language and easy for LLMs to learn. The main thing is to keep the model from falling "out of character." (GPT-4 does better in this regard.)

The system message handles specifying JSON output, and the prompt requests keywords from the question in a specific JSON structure. We provide an example of the output we want, known as 'single shot' learning (providing multiple examples is 'few-shot'). Providing examples significantly improves and guides LLM output, at least for this model. 


```{r json1, cache=FALSE, cache.id=md5(question)}
system <- "You are processing system that responds to natural language text 
with valid JSON. If it is unclear how the output should be formatted, or the 
user has not provided enough information, simply respond in a 'message' field. 
If you are unable to do so, return a JSON structure with an 'error' field. Do 
not produce anything other than valid JSON responses." 

prompt <- "Generate keywords from the following question, storing the 
results in an array in an object with key 'keywords', for example {'keywords': 
['keyword1', 'keyword2', 'keyword3', ...]} 

Question: " %+% question %+% "

JSON:"

example <- chatgpt(prompt, system_message = system, verbose = TRUE)
```

The final `JSON:` part of the prompt is also helpful: these models are trained for text completion, so giving a prompt guiding the model where to start works well. 

We've wrapped these ideas up in a function `chatgpt_json()` that adds the system preamble and `Output JSON:` to the end of the query, and returns a parsed version for use in code:


```{r json2, cache=FALSE, cache.id=md5(question)}
prompt <- "Generate keywords from the following question, storing the results 
in an array in an object with key 'keywords': " %+% question

result <- chatgpt_json(prompt)
str(result)
```



## Try the impossible first

From here we could use the extracted keywords to build a query URL for the PubMed API. I tried this and several similar approaches, but the results were never satisfying, because the keywords need to be queried with appropriate logic and search parameters to be effective.

Instead, it often works better to simply ask the model for what we want--in this case a URL for searching PubMed. 


>a weird thing (for me at least) that happens with playing with LLMs and similar is that I have to keep making sure I a pushing it's limits. a lot of the constraints are just my own inertia assuming incorrectly something wouldn't work
>
>i literally have a post-it note for play time that says "try the impossible first" on my desk because it kept happening
>
>-- <cite>@generativeist (Twitter)</cite>

With some experimenting I found that it would frequently use boolean expressions, and occasionally in [conjunctive normal form](https://en.wikipedia.org/wiki/Conjunctive_normal_form) to group synonyms. Asking for this makes the behavior consistent. Another useful trick, in what is now known as ['prompt engineering'](https://github.com/dair-ai/Prompt-Engineering-Guide), is to ask the model to work out a solution step-by-step (which we don't do here). Much like our `Output JSON:` prompt end above, we end with the first part of the output we want: the URL up to and including the `?`. The model knows the PubMed API well enough that we can specify specific features like JSON output and the `usehistory` feature required for fetching the matched abstracts.


```{r pubmed_search_gen, cache=FALSE, cache.id=md5(question)}
prompt <- "Consider the following question: " %+% question %+% '

Generate an Entrez e-search URL query that would search for article abstracts 
most likely to answer the question, using usehistory and returning JSON. Use 
conjunctive normal form to group synonyms.

https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi?'

url_query <- chatgpt(prompt, verbose = TRUE)
```

Now let's fetch the top 10 abstracts for this query:

```{r pubmed_search}
abstracts <- pubmed_esearch_abstracts(url_query, retmax = 10)
```

```{r kable_abstracts1, echo=FALSE}
kbl(abstracts, escape = TRUE) %>%
 kable_styling(bootstrap_options = c("striped", "hover", "responsive"), 
 							full_width = TRUE
 							) %>%
 column_spec(6, width_min = "800px") %>%
 scroll_box(height = "400px")

```

## Token limits

Ideally would include all of these abstracts in a prompt and ask the model to summarize them. We can't really do this, because the total length of a prompt and its response must be less than 4096 "tokens", which in normal text represents about 3000 words, though scientific literature tends to use more tokens per word.^[GPT-4 has an 8k token limit by default, and 32k-token models are available at higher cost. [Recent research](https://arxiv.org/abs/2112.05682) suggests these limits will be less of a concern in the near future. Interestingly, modern LLM tokenization uses [byte-pair](https://towardsdatascience.com/byte-pair-encoding-the-dark-horse-of-modern-nlp-eb36c7df4f10) encoding.]

```{r count_tokens}
get_tokens("Anterior knee pain was found in 5.7% of...")
```

To work around this limit, let's ask the model to first summarize each abstract (with respect to our question), and then concatenate the summaries and ask the model to summarize those!

First we need to bring each abstracts' title, journal, author, year, and text together into a single string. We add line breaks with `\n` to structure the text a bit, and use the `pmid` column to create a PubMed URL for each as well. We'll print just the first to demonstrate.

```{r gen_all_text, class.source = 'fold-hide'}
abstracts <- abstracts %>%
	mutate(all_text = 
            "TITLE: " %+% title %+% "\n" %+%
            "JOURNAL: " %+% journal %+% "\n" %+%
            "YEAR: " %+% year %+% "\n" %+%
            "AUTHORS: " %+% first_author %+% "et al.\n" %+%
            "URL: https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% "\n" %+%
            "ABSTRACT: " %+% abstract
         )

abstracts$all_text[1] %>% cat()
```

Now we'll build a series of prompts, each an individual summary request (which we accomplish with R vectorization). We'll also setup a system message setting the stage. This step takes a little bit to run, because we are making 10 individual requests of the model, and we'll print just the first result.

```{r sub_summaries, cache=FALSE, cache.id=md5(question, paste(abstracts, collapse=""))}
system_message <- "You are an expert in summarizing scientific literature."

prompts <- "As an expert in summarizing scientific literature, consider the
following question: " %+% question %+% "\n\n" %+%

"Generate a two or three sentence summary of the following paper, with special 
attention to any information relevant to the question: \n" %+% abstracts$all_text

summaries <- chatgpt(user_message = prompts, system_message = system_message)

# print the first
summaries[1]
```

Excellent! Now we can ask the model to summarise this list of summaries, but first let's add the title, year, and URL information back to the summaries for future use; here's the first one again.

```{r gen_summaries_meta, class.source = 'fold-hide'}
abstracts <- abstracts %>%
	mutate(summary_text = 
            "TITLE: " %+% title %+% "\n" %+%
            "JOURNAL: " %+% journal %+% "\n" %+%
            "YEAR: " %+% year %+% "\n" %+%
            "AUTHORS: " %+% first_author %+% "et al.\n" %+%
            "URL: https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% "\n" %+%
            "SUMMARY: " %+% summaries
         )

abstracts$summary_text[1] %>% cat()
```
Now we can build a prompt that asks the model to summarize all of this information, using the journal, author, and year information to add citations. We use few-shot prompting by providing examples of summaries, and prompt the model to complete the final `Summary:`.

```{r final_summary, cache=FALSE, cache.id=md5(question, paste(abstracts, collapse=""))}
system_message <- "You are an expert in summarizing scientific literature."

prompt <- "As an expert in summarizing scientific literature, consider the
following question: " %+% question %+% "\n\n

We want to answer this question by summarizing the following article
information:\n" %+% paste(abstracts$summary_text, collapse = "\n\n") %+%

"Now, summarize the information above, paying special attention to any 
information relevant to the question. Be detailed and comprehensive, including 
references for each sentence. Also include a list of authors, years, titles, 
and URLs at the end, based on the example format below. Only include information 
provided above, and do not guess. 

Summary:
Regular exercise has been shown to have positive effects on mental health 
outcomes (Johnson et al., 2018; Smith et al., 2020). In a randomized controlled 
trial, Johnson and colleagues found that participants who engaged in regular 
exercise for 12 weeks showed significant improvements in symptoms of depression 
and anxiety compared to a control group. Similarly, Smith and colleagues 
conducted a meta-analysis of 20 studies and found consistent evidence that 
exercise can reduce symptoms of depression and anxiety in individuals with 
mental health disorders. Other studies have also demonstrated the positive 
effects of exercise on mental health, including research on the impact of 
exercise on stress reduction (Gomes et al., 2021) and the benefits of exercise 
in the treatment of post-traumatic stress disorder (Rosenbaum et al., 2019).

References:
- Gomes et al. 2021: Physical exercise as a tool for stress reduction: A 
    systematic review. https://pubmed.ncbi.nlm.nih.gov/33857535/
- Johnson et al. 2018: The effects of exercise on mental health. 
    https://pubmed.ncbi.nlm.nih.gov/29589555/
- Rosenbaum et al. 2019: Exercise augmentation compared with usual care for 
    post-traumatic stress disorder: A randomized controlled trial. 
    https://pubmed.ncbi.nlm.nih.gov/30666600/
- Smith et al. 2020: Exercise and mental health: A meta-analysis. 
    https://pubmed.ncbi.nlm.nih.gov/32223299/

Summary:
Research has shown that meditation can have positive effects on stress and 
anxiety levels (Brown et al., 2019; Smith & Jones, 2020). In a randomized 
controlled trial, Brown and colleagues found that participants who practiced 
mindfulness meditation for 8 weeks reported significant reductions in perceived 
stress compared to a control group. Similarly, a meta-analysis conducted by 
Smith and Jones found that meditation interventions were associated with 
significant reductions in symptoms of anxiety across multiple studies. Other 
studies have also demonstrated the benefits of meditation, including research 
on the effects of meditation on cognitive performance (Chen et al., 2021) and 
the use of meditation in the treatment of insomnia (Zhang et al., 2019).

References:
- Brown et al. 2019: Mindfulness meditation and stress reduction: A randomized 
    controlled trial. https://pubmed.ncbi.nlm.nih.gov/31087611/
- Chen et al. 2021: The effect of mindfulness meditation on cognitive 
    performance: A systematic review and meta-analysis. 
    https://www.frontiersin.org/articles/10.3389/fpsyg.2021.622032/full
- Smith & Jones 2020: Meditation interventions for anxiety: A meta-analysis 
    of randomized controlled trials. https://pubmed.ncbi.nlm.nih.gov/32062163/
- Zhang et al. 2019: The effect of mindfulness meditation on insomnia: A 
    meta-analysis. https://pubmed.ncbi.nlm.nih.gov/31112828/

Summary:"
```

Before we send this to the model, we should make sure that the number of tokens and the length of our desired output is less than 4096, the maximum number of tokens. Let's see how many tokens this request will be.

```{r count_final_summary_tokens}
message_tokens <- length(get_tokens(system_message %+% prompt))
message_tokens
```

These tokens, along with the number of tokens in the response, must sum to less than 4096. We can ensure
this is the case by specifying the `max_tokens` parameter, which controls the maximum number of tokens the response should
have - anything beyond this will be truncated rather than producing an error. There's some overhead for the "role" information
that is also sent, so we use 4000 rather than 4096.

```{r get_final_summary, cache=FALSE, cache.id=md5(prompt, system_message)}
result <- chatgpt(user_message = prompt, 
                  system_message = system_message, 
                  max_tokens = 4000 - message_tokens)
result %>% cat()
```

Here's the list of abstracts again for comparison:

```{r abstracts_summary_compare, class.source = 'fold-hide'}
kbl(abstracts, escape = TRUE) %>%
 kable_styling(bootstrap_options = c("striped", "hover", "responsive"), 
 							full_width = TRUE
 							) %>%
 column_spec(6:8, width_min = "800px") %>%
 scroll_box(height = "400px")
```

For this relatively complex task of summarizing a field of literature, GPT-4's improved reasoning abilities and larger 8k context window may be worth paying for. 2,349 tokens at \$0.03 per 1024 prompt tokens comes to just under 7 cents; we also pay \$0.06 for response tokens for maybe another 3 cents. The ChatGPT model on the other hand is only \$0.002 / 1k tokens, for a total of \$0.0065. 

```{r get_final_summary_gpt4, cache=FALSE, cache.id=md5(prompt, system_message)}
result <- chatgpt(user_message = prompt, 
                  system_message = system_message, 
                  max_tokens = 8000 - message_tokens,
									model = 'gpt-4')
result %>% cat()
```

### Errors and Security

This LLM model (`gpt-3.5-turbo`) can take a `temperature` parameter, with values between 0 and 1 influencing the amount of
randomness used in the response. The model generates output tokens sequentially, at each point it assigns a probability distrubtion to the tokens for the next. Temperature values of 0 always use the most likely next token, while values of 1 make a random choice from that distribution. We've used `temperature = 0` for all
of the above for reproducibility and output likelihood maximization.

Even so, the model is inherently stochastic, and will return different outputs for the same input. And as we've seen, it can be difficult to guarantee a specific output type or format for all possible inputs. As a result, there are many failure modes to be accounted for. What if we asked for JSON output, but the result can't be parsed? What if the API went down temporarily? What if we try to generate a prompt that is too long? And so on. These issues become more prevalent when many calls are made, as in our summary generation above.

In a production use case, we should also think about "prompt injection attacks." If we pass user input to the model, they may include additional requests, for example to generate a URL to a malware site. For applications that search the web, we must additionally be careful that prompt injections are not crawled and included from search results. [This paper](https://arxiv.org/pdf/2302.12173.pdf) by Greshake et al. provides a summary of potential attack vectors.

## Searching wider

Let's try to search wider by pulling the top 100 PubMed abstracts. As before we'll generate an `all_text` column.

```{r search_100, class.source = 'fold-hide'}

abstracts2 <- pubmed_esearch_abstracts(url_query, retmax = 100)

abstracts2 <- abstracts2 %>%
	mutate(all_text =
            "TITLE: " %+% title %+% "\n" %+%
            "JOURNAL: " %+% journal %+% "\n" %+%
            "YEAR: " %+% year %+% "\n" %+%
            "AUTHORS: " %+% first_author %+% "et al.\n" %+%
            "URL: https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% "\n" %+%
            "ABSTRACT: " %+% abstract
         )

kbl(abstracts2, escape = TRUE) %>%
 kable_styling(bootstrap_options = c("striped", "hover", "responsive"),
 							full_width = TRUE
 							) %>%
 column_spec(6:7, width_min = "800px") %>%
 scroll_box(height = "400px")
```

While we could summarize all of these abstracts,^[The `gpt-3.5-turbo` models costs \$0.002 per 1000 tokens. GPT-4 was released recently, which has significantly better reasoning ability, but as of March 2023 API use costs \$0.03 per 1k prompt tokens and \$0.06 per 1k response tokens. As mentioned in earlier footnote, GPT-4 also supports longer context windows at an even higher cost.] we wouldn't be able to fit all of the summaries into a prompt for the model to summarize overall. One common solution is to use [sentence embeddings](https://www.taus.net/resources/blog/what-are-sentence-embeddings-and-their-applications) to associate each text with a high-dimensional vector that correlates well with semantic meaning. These can then be clustered or queried for similarity.

Embeddings are usually generated from specialized language models trained on different tasks, such as semantic search, Q&A, or more generalized tasks; the [SentenceTransformers](https://www.sbert.net/) Python package provides easy access to these. We'll use the `'allenai-specter'` model, trained specifically for scientific citations and publications.^[OpenAI also have an embedding model available for $0.0004 / 1k tokens.]

```{r embed_specter, cache=FALSE, cache.id=md5(as.character(abstracts2)), cache.extra=3}
specter_embed <- create_embedder(model_name = 'allenai-specter')

abstracts2 <- abstracts2 %>%
	mutate(specter_embedding = specter_embed(all_text))

str(abstracts2$specter_embedding, list.len = 5)
```

From the first 5 embedding previews above, we can see that they are 768-dimensional vectors. 

Let's start with a k-nearest-neighbors method to link each abstract embedding to its 5 nearest neighbor embeddings. In the network below, edges are sized according to the cosine-similarity of the abstracts, and abstracts are sized according to their weighted PageRank in the network.^[The layout method here initially places nodes according to the first two UMAP dimensions, then applies force-based layout. Both methods also worked well individually.]


```{r visnetwork1, class.source = 'fold-hide'}
abstracts_specter_graph <- gen_sim_graph(abstracts2[, ], embed_column = "specter_embedding", id_column = "pmid", k = 5) %>%
	activate(edges) %>%
	mutate(embedding_model = "specter")

#edgecolor_palette <- RColorBrewer::brewer.pal(2, "Set2")

toplot <- abstracts_specter_graph %>%
	activate(edges) %>%
	distinct() %>%
	activate(nodes) %>%
		mutate(journal = fct_infreq(journal)) %>% # fct_infreq orders the levels by occurrence count
		mutate(hovertext = "<div style='width: 400px; overflow-wrap: normal; white-space: normal'><b>" %+% title %+% "</b><br />" %+%
					 				 first_author %+% "et al. " %+% year %+% ", " %+% journal %+% "<br />" %+%
					 	       "<a href=https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% " >
					             https://pubmed.ncbi.nlm.nih.gov/" %+% pmid %+% 
					 	       "</a></div>"
					 	) %>% 
		mutate(pagerank = page_rank(., 
														directed = TRUE, 
														weights = . %E>% pull(neighbor_dist))$vector %>% rescale(c(15, 40))
					 ) %>%
	activate(edges) %>%
		mutate(width = 0.5 + 11 * rescale(-1/log(neighbor_dist)), 0, 1)

node_df_umap <- add_umap_coords(toplot %N>% data.frame(), embedding_col = "specter_embedding")
V(toplot)$umap_1 <- node_df_umap$umap_1
V(toplot)$umap_2 <- node_df_umap$umap_2
coords <- node_df_umap %>% select(umap_1, umap_2) %>% as.matrix()

#pageranks <- toplot %N>% data.frame() %>% pull(pagerank)

visIgraph(toplot %N>% select(-title) %>% rename(size = pagerank, title = hovertext), 
					layout = "layout.norm", type = "full", layoutMatrix = coords, physics = TRUE) %>%
#visIgraph(toplot, layout = "layout_with_fr", type = "full", physics = TRUE) %>%
	visOptions(highlightNearest = list(enabled = TRUE, hover = TRUE, algorithm = "hierarchical", degree = 1), collapse = TRUE) %>%
	visEdges(arrows = "to") %>%
  visPhysics(solver = "barnesHut",
            barnesHut = list(springConstant = 0.002, gravitationalConstant = -10000, damping = 0.8)) 


```

While PageRank provides one measure of "importance" of each abstract, we can also compute an embedding for our question, and compute its similarity to all of the abstracts. In the network below darker nodes are more similar to the query.


```{r visnetwork2, visnetwork2, class.source = 'fold-hide'}
map_colors <- colorRamp(c("purple", "orange"), space = "Lab")

n_cols <- 101
pal <- colorRampPalette(brewer.pal(9, 'YlGnBu'))(n_cols)

match_percent <- 1.0

toplot2 <- toplot %>%
						activate(nodes) %>%
							mutate(query_sim = cosine(specter_embed(question), specter_embedding)) %>% 
	            mutate(color_mix = (1 - match_percent) * pagerank + (match_percent) * query_sim) %>%
  						mutate(color_bin = findInterval(color_mix, 
  																						seq(from = min(color_mix), to = max(color_mix), length.out = n_cols))) %>%
  						mutate(color = pal[color_bin]) %>%
							mutate(hovertext = hovertext %+% "<br />Query cosine similarity: " %+% query_sim)

visIgraph(toplot2 %N>% select(-title) %>% rename(size = pagerank, title = hovertext), 
					layout = "layout.norm", type = "full", layoutMatrix = coords, physics = TRUE) %>%
	visOptions(highlightNearest = list(enabled = TRUE, 
																		 hover = TRUE, 
																		 algorithm = "hierarchical", 
																		 degree = 1), 
						 collapse = TRUE) %>%
	visEdges(arrows = "to") %>%
  visPhysics(solver = "barnesHut",
            barnesHut = list(springConstant = 0.002, gravitationalConstant = -10000, damping = 0.8)) 


```


This gives us two measures we might use to pick abstracts to summarize, or we could mix them to more highly weight question similarity or network importance. In the following table we define an `importance` metric as the average of these two measures (after normalizing each to 0 mean and 1 sd).


```{r importance, class.source = 'fold-hide'}
abstracts3 <- toplot2 %>% 
	activate(nodes) %>%
	mutate(query_sim_norm = (query_sim - mean(query_sim))/sd(query_sim),
				 pagerank_norm = (pagerank - mean(pagerank))/sd(pagerank)) %>%
	mutate(importance = (query_sim_norm + pagerank_norm)/2) %>%
	arrange(desc(importance)) %>%
	data.frame()
	

abstracts3 %>%
	select(importance, query_sim_norm, pagerank_norm, pmid, year, title, first_author, journal, abstract) %>%
	kbl(escape = TRUE, table.attr = "class='dtable'", format = "html") %>%
	 kable_styling(bootstrap_options = c("striped", "hover", "responsive"), 
	 							full_width = TRUE
	 							) %>%
	 column_spec(9, width_min = "800px") %>%
	 scroll_box(height = "400px")
```


## Epilogue

We could continue to work with these data and refine, but I hope this gives a sense of potential and caveats for using Large Language Models. Regarding the above, the final summary prompt still needs work; the model occasionally omits the references section for example. Although we give it example output summaries, we don't accompany those with example inputs, so it is not a true few-shot prompt. And while PageRank is a fun method, it's not clear that it provides useful information beyond embedding-based question similarity for this task. There's also [peronalized PageRank](https://www.r-bloggers.com/2014/04/from-random-walks-to-personalized-pagerank/), where nodes are initially weighted (e.g. by their query similarity), but in my experiments this didn't perform as well as similarity ranking alone.






