key: cord-0893105-wqu8dm15
authors: Lopez-Leon, S.; Wegman-Ostrosky, T.; Ayuzo del Valle, N. C.; Perelman, C.; Sepulveda, R.; Rebolledo, P. A.; Cuapio, A.; Villapol, S.
title: Long COVID in Children and Adolescents: A Systematic Review and Meta-analyses.
date: 2022-03-13
journal: nan
DOI: 10.1101/2022.03.10.22272237
sha: 0e8ddd4023d3570d0ce1514081cda845c0159878
doc_id: 893105
cord_uid: wqu8dm15

Objective: To estimate the prevalence of long COVID in children and adolescents and identify the full spectrum of signs and symptoms present after acute SARS-CoV-2 infection. Methods: Two independent investigators searched PubMed and Embase in order to identify observational studies that met the following criteria: 1) a minimum of 30 patients, 2) ages ranged from 0 to 18 years, 3) published in English, 4) published before February 10th, 2022, and 5) meets the National Institute for Healthcare Excellence (NICE) definition of long COVID, which consists of both ongoing (4 to 12 weeks) and post COVID 19 ([≥]12 weeks) symptoms. For COVID symptoms reported in two or more studies, random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence, and Review Manager (RevMan) software 5.4 was utilized to estimate the Odds Ratios (ORs) with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). Results: The literature search yielded 68 articles for long COVID in children and adolescents. After screening, 21 studies met the inclusion criteria and were included in the systematic review and meta-analyses. A total of 80,071 children and adolescents with COVID-19 were included. The prevalence of long COVID was 25.24% (95% CI 18.17-33.02), and the most prevalent clinical manifestations were mood symptoms (16.50%; 95% CI 7.37-28.15), fatigue (9.66%; 95% CI 4.45-16.46), and sleep disorders (8.42%; 95% CI 3.41-15.20). When compared to controls, children infected by SARS-CoV-2 had a higher risk of persistent dyspnea (OR 2.69 95%CI 2.30-3.14), anosmia/ageusia (OR 10.68, 95%CI 2.48, 46.03), and/or fever (OR 2.23, 95%CI 1.22-4.07). The main limitation of these meta-analyses is the probability of bias, which includes lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and the high level of heterogeneity. Conclusion: These meta-analyses provide an overview of the broad symptomatology of long COVID in minors, which may help improve management, rehabilitation programs, and future development of guidelines and therapeutic research for COVID-19.

It has been two years since the COVID-19 pandemic was first declared.

Consequently, millions of cases and thousands of deaths have been reported worldwide 1 .

Still, during this time, treatments have been developed rapidly and effective vaccines have been widely administered to the population, both children and adults, protecting millions from severe disease and death 2 . Until now, the focus was primarily aimed at the acute phase of the disease. However, once the acute phase of COVID-19 is over, many individuals experience months of debilitating COVID-19 symptoms that requires additional medical attention and follow-up.

Severe COVID-19 is less common in children than in adults 3 ; however, there are two long-term consequences that occur following SARS-CoV-2 infection in children: multisystem inflammatory syndrome (MIS-C) and long COVID. Both of these consequences can even appear in asymptomatic patients 4 . MIS-C is a condition where different body parts become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs 4 . It occurs in less than 0.01% of children with COVID-19 and requires intensive care support in 68% of cases 5 . Long COVID is a heterogeneous multisystemic condition for which there is still no precise definition and includes signs and symptoms that persist, develop, or fluctuate after SARS-CoV-2 infection. Until now, many authors have used the following terms interchangeably when referring to long COVID: long haulers, COVID-long, post-acute sequelae of COVID-19 (PASC), long run, post-COVID, COVID syndrome, and long COVID.

In this systematic review, we will refer to long-COVID. In addition, given that MIS-C is a severe disease which complications can persist for years, we will exclude MIS-C studies from this systematic review. In October 2021, the WHO proposed a clinical definition for post-COVID-19 through a Delphi consensus stating it generally occurs three months from the onset of COVID-19, with symptoms lasting at least two months and cannot be explained by an alternative diagnosis 6 . On February 2nd, 2022, the National Institute for Health and Care Excellence in the UK (NICE) published a guideline defining long-COVID as signs and symptoms that continue or develop after acute COVID 19, This includes both ongoing symptomatic COVID 19 (from 4 to 12 weeks) and post COVID 19 syndrome (12 weeks or more) 7 . Other organizations, such as the National Institutes of Health (NIH), also define long COVID as post-acute symptoms after 4 weeks 8 . In the present study, we will use the generic definition from NICE and NIH.

To date, most of the published research on long COVID primarily focuses on adult populations. As a result, there is limited information on the long-term effects of COVID-19 in pediatric populations 9, 10 . One recent meta-analysis studied the persistent symptoms that occur following SARS-CoV-2 infection and examined their prevalence, risk factors, type, and duration. This meta-analysis included studies up to July 2021, encompassing 23, 141 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2022. ; https://doi.org/10.1101/2022.03.10.22272237 doi: medRxiv preprint children and young people 9 . The most common symptoms were fatigue 47% (95% CI 7-27), dyspnea 43% (95% CI 18-68), and headache 35% (95% CI 19-51). In addition, compared to controls, the prevalence of cognitive difficulties, headache, loss of smell, sore throat, and sore eyes was statistically higher 9 , however due to the lack of data this meta-analysis could only compute the pooled prevalence for 10 symptoms. To date, the potential range of signs and symptoms as well as their frequency of occurrence in children and adolescents remains unclear 11 . There is a need to create awareness among parents, physicians, and researchers on the afflictions following COVID-19 infection, and for the health system to better understand the sequelae in order to provide targeted medical attention and treatment.

This systematic review and meta-analyses aim to estimate the prevalence of long COVID in children and adolescents and to identify the full spectrum of signs and symptoms present after COVID-19.

This systematic review and meta-analyses examine the prevalence of long COVID signs and symptoms in children under the age of 18 with a diagnosed case of COVID-19 (confirmed via PCR, antigen test, or antibody test). To achieve this, two independent investigators searched PubMed and Embase to identify studies that met the following criteria: 1) a minimum of 30 patients with either ongoing symptomatic COVID 19 (from 4 to 12 weeks) or post COVID 19 syndrome (12 weeks or more) (i.e., patients who met the NICE definition of long COVID) (NICE 2022), 2) ages ranged from 0 to 18 years, 3) published in English, 4) published before February 10th, 2022, and 5) meets the National Institute for Healthcare Excellence (NICE) definition of long COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥12 weeks) symptoms, 6) excluding cohorts of children composed of exclusively pre-existing chronic diseases, or exclusively of MIS-C in children, and 7) excluding references of editorials, reviews, and commentaries.

The search terms used to identify publications discussing long COVID in children were: (COVID-19 OR COVID OR SARSCOV-2 OR coronavirus OR "long COVID" OR "post COVID") AND (PASC OR haulers OR lingering OR "post-acute" OR persistent OR convalescent OR convalescence OR sequelae OR post-viral) AND (pediatric OR kids OR young OR infant OR children OR adolescents). Given that MedLine was included in the PubMed search, we excluded articles from MedLine in the Embase search along with those not related to COVID-19. Observational studies, including cohorts and cross-sectional studies, were analyzed only when the cases (numerator) were part of a COVID-19 cohort . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2022 were removed, the search identified 68 papers after screening titles and abstracts. Of these, 21 were included after the exclusion criterium ( Figure 1 ).

Random-effects meta-analyses were performed for symptoms reported in two or more studies using MetaXL software to estimate the pooled prevalence, which uses a double arcsine transformation 12 . Prevalence (presented as percentages) with 95% confidence intervals (CIs) was estimated. Numerators represented the number of children with long COVID, and denominators described the total number of children with acute COVID-19 (with and without long-term effects). To compare cases and controls adjusted for confounders, we used the DerSimonian and Laird's random-effects model. Pooled Odds Ratios (ORs) and 95% CIs were calculated 13 . A p-value < 0.05 was considered statistically significant. Given the heterogeneity expected, a random-effects model was employed using the I² statistics.

Values of 25%, 50%, and 75% for I² represented low, medium, and high heterogeneity, respectively. The study's quality control was assessed using the Health States Quality-Controlled data. This index is described and recommended by the MetaXL Guidelines that evaluates the quality of studies assessing prevalence. In addition, the limitations of each study were listed, and they are reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The title and abstract of 8,373 publications were screened. Of these, 68 full publications were reviewed, and 47 were excluded because they did not fulfill the inclusion criteria. Thus, a total of 21 studies were selected for analysis (, Figure 1 ). The general study characteristics are shown in Table 1 . The majority of the studies assessed pre-specified symptoms included in a questionnaire. The process of study selection is presented in Figure 1 . There were 18 studies from Europe (e.g., Denmark, Russia, Italy, Germany, Tukey, Latvia, UK, France, Sweden, and Switzerland), 1 from Iran, 1 from Brazil, and 1 from Australia. The studies by Kikkenborg et. al. 14 and Borch et. al. 15 included an overlapping population (Denmark), as did the studies by Roge et. al. 16 and Smane et. al. 17 (Latvia). To ensure that no overlapping data were included, only the study with the largest sample size was included for the estimate of long COVID and for outcomes reported in both studies. Still, several outcomes were only presented in one of the studies, therefore both studies were included in the overall metaanalysis. Four studies included only hospitalized patients, and the rest included all COVID-19 severities (asymptomatic, mild, moderate, and severe). Due to a lack of stratification from all the studies, it was not possible to estimate the prevalence for the different severities. It was only possible to evaluate the prevalence of hospitalized patients. The number of patients included in the studies ranged from 53 to 57,763, and ages ranged from 0 to 18 years. A total of 80,071 children and adolescents with COVID-19 were included in the metaanalyses. We identified more than 40 long-term effects associated with COVID-19 in children and adolescents in the literature reviewed. Different authors have used the terms "Post-acute COVID", "long COVID," "Persistent COVID," "Persistent COVID Symptoms" as synonyms.

The prevalence of long COVID in children and adolescents, as defined by the presence of one or more symptoms more than 4 weeks following a SARS-CoV-2 infection, was 25 CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2022. ; https://doi.org/10.1101/2022.03.10.22272237 doi: medRxiv preprint hyposmia, anosmia, hyperosmia, parosmia, and phantom smell) (prevalence: 5.60%; 95% CI, 3.13-8.69). All other symptoms had less than 5.00% prevalence (Figure 2 and 3 ).

It was only possible to perform meta-analyses of ORs comparing cases and controls for 13 symptoms (Supplementary Figure 1 ). Cases were defined as patients that had a confirmed COVID infection, and controls as patients without COVID. When compared to controls, children with long COVID had a higher risk of persistent dyspnea (OR: 2.69; 95%CI, 2.30-3.14), anosmia/ageusia (OR: 10.68; 95% CI, 2.48, 46.03), and/or fever (OR: 2.23; 95% CI, 1.2-4.07). There was significant heterogeneity for 5 out of the 13 meta-analyses.

The controls were chosen in a very different way among studies, which might have introduced significant heterogeneity. The following were the different definitions of controls:

1) children with other infections (e.g., common cold, pharyngotonsillitis, gastrointestinal, urinary tract infections, pneumonia of bacteria or unknown origin) 16 ; 2) children with no antibodies testing 18 mixed with other children with other infections 16 ; 3) children with a negative antibody test 19 , 4) children with a negative PCR test that were symptomatic 20 ; and 5) children who did not have a positive test recorded in the database 14 .

The adjustments among studies also varied. Several studies adjusted their OR by age, sex, ethnicity, socioeconomic status, and comorbidities 20 . However age and sex 14 Figures 2 and 3 ).

The prevalence of symptoms over the course of long COVID for cases and controls is showed in Supplementary Table 1 . Given the heterogeneity in the definition of controls and the low number of subjects, no formal statistical comparison was done for the crude prevalence.

Symptoms that were presented in a single study and, therefore, unable to be incorporated into the meta-analyses included: orthostatic intolerance, cold hands/feet, chapped lips, adenopathy, fainting, twitching of fingers and toes, chills, swollen toes/fingers, and hallucinations. One study reported statistically significant differences between clinical cases and controls for systolic blood pressure, left ventricular ejection fraction, relative myocardial wall thickness, and tricuspid annular plane systolic excursion 21 . However, given that these variables were only evaluated in this study, we could not perform a meta-analysis for these outcomes.

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The copyright holder for this preprint this version posted March 13, 2022. ; https://doi.org/10.1101/2022.03.10.22272237 doi: medRxiv preprint Studies included in the meta-analyses evaluated whether certain variables increased the risk of long COVID-19 and found that age, sex, severe acute-COVID-19, obesity, allergic disease, and long-term health conditions were associated with high risk to develop long COVID-19 [22] [23] [24] [25] . Further, two of the studies evaluated the duration of symptoms. A study from Denmark reported that symptoms resolved in a minimum of 54-75% of children (varied with age) within 1-5 months 15 . Another, from England, which used the UK ZOE COVID Symptom Study app, reported that 4.4% of children still had symptoms four weeks after COVID-19 onset, which decreased to 1.8% at 8 or more weeks 24 .

Regarding the quality of studies, all had a score of 7 or more. Supplementary Table 1 presents a list of methodological strengths or, conversely, limitations for each study. All studies included laboratory-confirmed COVID-19 infection, PCR or antibody test. Two-thirds of the studies included over 100 children. Six meta-analyses had low heterogeneity (I 2 <25%) for the following symptoms: vomiting and nausea, nasal congestion, dysphonia, urinary problems, neurological abnormalities, and dysphagia. Three meta-analyses had medium heterogeneity for the following symptoms: abdominal pain, changes in menstruation, and speech disturbances. All other meta-analyses had high heterogeneity (I 2 >75%). It was not possible to stratify by any variable (e.g., age, sex, country, past comorbidities, or severity) to evaluate where the heterogeneity originated.

The prevalence of long COVID in children and adolescents, following a COVID-19 infection was 25.24%. The five most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), sleep disorders (8.42%), headache (7.84%), and respiratory symptoms (7.62%). It was only possible to perform meta-analyses of ORs comparing cases and controls for 13 symptoms. When compared to controls, persons with COVID-19 had a higher risk of presenting persistent dyspnea, anosmia/ageusia, and/or fever.

The most frequent symptoms reported were related to mood. COVID-19 pandemic has initiated an explosion of future mental illnesses 26 , that is affecting both society as a whole as well as those who recover from COVID-19. Studies have shown that the pandemic has profoundly impacted society by affecting children's development through isolation, poverty, food insecurity, loss of parents and caregivers, loss of time in education, and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2022. ; https://doi.org/10.1101/2022.03.10.22272237 doi: medRxiv preprint increased stress 27 . The presence of these symptoms in the general population, regardless of COVID-19 status, has been coined long-Pandemic Syndrome 28 .

Interestingly, many of the symptoms identified in these meta-analyses, such as mood, fatigue, sleep disorders, orthostatic intolerance, decreased concentration, confusion, memory loss, balance problems, exercise intolerance, hyperhidrosis, blurred vision, body temperature dysregulation, dysfunction on heart, rate variability and palpitations, constipation or diarrhea, and dysphagia, are commonly present in dysautonomia 29 .

Dysautonomia is defined as a dysfunction of the sympathetic and/or parasympathetic . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2022. ; https://doi.org/10.1101/2022.03.10.22272237 doi: medRxiv preprint As with other meta-analyses, the strength of this study centers on the large sample size 40 which helps provide identify the signs and symptoms present after acute SARS-CoV-2 infection.. Further, there were some limitations to our meta-analyses. The quality of the meta-analyses results depends on the quality of the studies included. Table 3 contains a list of all the methodological aspects that future studies need to consider. We can observe that all studies had a high probability of bias, including lack of standardized definitions recall, selection, misclassification, nonresponse, and/or loss of follow-up. Additionally, the included studies have the limitations inherited in all observational studies, including bias due to residual and unmeasured confounding. Another limitation relates to the high level of heterogeneity. To account for heterogeneity, we used a random-effects model 41 . However, ideally one should stratify the meta-analysis to identify what is causing the heterogeneity.

This was not possible because most studies did not include data on different groups. The differences between studies were likely due to differences in study designs, settings, populations, follow-up time, symptom ascertainment methods, inconsistent terminology, little details on stratification on pre-existing comorbidities, and prior receipt of COVID-19 therapeutics and vaccines. Only four studies mentioned what percentage of the population was already vaccinated 14, 15, 23, 28 (Table 3) . It has been shown that vaccines reduce the risk of long COVID. A study in Israel compared the prevalence of symptoms of long COVID and found that fully vaccinated participants who had COVID-19 were 54% less likely to report headaches, 64% less likely to report fatigue, and 68% less likely to report muscle pain than were their unvaccinated control group 42 . More studies are needed to analyze the relationship between vaccines in children and long COVID.

Future prospective studies should include a control cohort and stratify and/or adjust their results by age, sex, race, severity of acute COVID-19 infection paired with clinical evaluation, vaccination status, preexisting medical conditions, and, if possible, SARS-CoV-2 variant. If we had analyzed these types of factors separately, we would have been able to discover the variations in the prevalence of long COVID. Retrospective studies using large population-based databases with historical controls and secondary data sources (e.g., claims and medical records) should also be used. The selection of controls will be difficult in the future because not all of the cases are recorded in databases (e.g., home tests), tests can be false negative or positive, or children can be asymptomatic. Proposed control groups for future studies include a negative N protein antibody test without vaccination, a negative antibody test with vaccination, or historical cohorts that include children who have neither been vaccinated nor exposed to the virus.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2022. ;  Protective measures are essential to prevent long COVID in children. We need to understand the long COVID pathophysiology and symptomatology in relation to other postinfectious syndromes to support clinical management systems, establish rehabilitation programs, and design guidelines and therapeutic research. Long COVID represents a significant public health concern, and there are no guidelines to address its diagnosis and management. Our meta-analyses further support the importance of continuously monitoring the impact of long COVID in children and adolescents, and the need to include all variables and appropriated control cohorts in studies to have a better knowledge of the real burden of pediatric long COVID.

All data relevant to the study are included in the article or uploaded as supplementary information. In addition, the datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

SLL is an employee of Novartis Pharmaceutical Company; the statements presented in the paper do not necessarily represent the position of the company. The remaining authors have no competing interests to declare.

This work was supported by funds from Houston Methodist Research Institute, Houston, TX. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2022. ;  13 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 13, 2022 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2022 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2022. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2022 Stratify by vaccination status 0 0 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 13, 2022. ; https://doi.org/10.1101/2022.03.10.22272237 doi: medRxiv preprint

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