小児のLong-CoVID: systematic review

2021年冬頃から「小児に対してmRNAワクチンを接種した方が良いのか」という質問をよく受けます。

まず、答えを先に言っておくと「どちらか選ぶなら接種した方が良い」という結論です。（2022/03/21時点）

＜打つことを推奨する理由＞

☆ Long-CoVIDが有意に減る。（これが、2022/03/21時点で最も有力なエビデンス）
☆ 感染率が下がる（が、短期間の可能性が高い。）
☆ 重症化率が下がる（が、元々小児の重症化率は低い。）
☆ 細胞障害性T cellを賦活化し、遺伝子組み換えを起こす。（mRNAでは無く、感染自体によって我々のT cellは組み換えを起こしている。）
☆ mRNAは自然感染より安全で、次の感染や重症化を防ぐ効果が高い。（これは過去のワクチンには無かった特性です。）
☆ 社会的意義がある。（献血と同じようなニュアンスです。）

＜打たなくても良い理由＞

★ 小児は軽症で済むことが多い。
★ 小児は免疫が成人と比べて持続しにくい。（強力に働くのは接種2週間後から2ヶ月後まで。半年後にはかなり減弱する。）
★ 待っていれば、もっと良いワクチンが出てくるだろう。

成人に比べると、見劣りする小児のmRNAワクチンですが、
1．初期免疫として、T cell を介した長期的効果が見込める可能性があること、
2．mRNAは歴史上、初めて自然感染を超えたワクチンであり、自然感染よりも心筋炎は1/10程度で、発熱も少ない(4万人の小児のうち13.4％。成人では37％で発熱する。ワクチンによる心筋炎は10万人当たり11名、COVIDでは100名以上が心筋炎になる。)
3．社会的意義があること（2022年1〜3月時点で小児がHubになって感染を繋いでいる）
という理由で接種を(弱めに)推奨しています。

なお、mRNAが体に蓄積するとか、将来、不妊の原因になるとかは荒唐無稽なデマです。
（おそらく大学で生化学を習ったことが無い無教養の人が書いていると思います。逆転写酵素はワクチンに含まれませんし、レトロウイルスにも含まれません。CoVはDNAウイルスでもありません。）

結果文献検索により、未成年のLong-COVIDに関する68の文献をスクリーニングした後、21の研究が選択基準を満たし、系統的レビューとメタアナリシスに含まれました。合計80,071人のCOVID-19の未成年が含まれていました。
Long-CoVIDの定義は1〜3ヶ月以上続く後遺症とされていて、文献によって差異があります。
基礎疾患を持つ子は解析から除外されています。

Long-COVIDの有病率は25.24％（95％CI 18.17-33.02%）であり、最も一般的な臨床症状は
★ 気分症状（16.50％; 95％CI 7.37-28.15％）
★ 倦怠感（9.66％; 95％CI 4.45-16.46％）
★ 睡眠障害（8.42％; 95％CI 3.41-15.20％）
★ 頭痛（7.84％; 95％CI 4.04-12.70％）
★ 呼吸器症状（7.62％; 95％CI 2.08-15.78％）
★ 認知症状；記憶障害･学習障害（6.27％; 95％CI 4.46-8.35％）
でした。
コントロールと比較した場合、SARS-CoV-2に感染した子どもは、
★ 持続性呼吸困難（OR 2.69、95％CI 2.30-3.14）
★ 無嗅覚症/味覚消失（OR 10.68、95％CI 2.48、46.03）
★ 発熱（OR 2.23、95％CI 1.22-4.07）
のリスクが2倍以上高かった。

これらのメタアナリシスの主な制限は、標準化された定義の欠如や誤分類、または追跡不能、および高レベルの不均一性を含むバイアスの可能性によるものです。

Long COVID in Children and Adolescents: A Systematic Review and Meta-analyses

Sandra Lopez-Leon, Talia Wegman-Ostrosky, Cipatli Ayuzo del Valle, Carol Perelman, Rosalinda Sepulveda, Paulina A Rebolledo, Angelica Cuapio, Sonia Villapol

https://www.medrxiv.org/content/10.1101/2022.03.10.22272237v1

ABSTRACT

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.

INTRODUCTION

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 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.

METHODS

Search strategy and selection criteria

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 (denominator). Titles, abstracts, and full texts of articles were independently screened by two authors (TWO and SLL). Each article was thoroughly reviewed by both authors in case there was a difference of opinion on the inclusion of a study based on title or abstract. Disagreement on including a full-text article was discussed among all the authors. The study was registered in PROSPERO [CRD42021275408] (https://www.crd.york.ac.uk/PROSPERO).

Screening and data extraction

Data were extracted by four authors (AC, CA, PR, RS) and Quality-Controlled (QCed) by two authors (TWO, CP). Discrepancies were discussed with a third author. The descriptive variables extracted were country, study design, period of study, collection mode, follow-up time, severity of COVID-19, sample size, COVID-19 diagnosis, age, percentage of males, outcomes, and names used to describe the long-term effects of COVID-19. After duplicates were removed, the search identified 68 papers after screening titles and abstracts. Of these, 21 were included after the exclusion criterium (Figure 1).

Statistical analysis

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.

RESULTS

General characteristics of studies

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 meta-analysis. 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 meta-analyses. 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.

Meta-analyses of the prevalence of long-COVID

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 25.24% (95% CI, 18.17-33.02). For hospitalized patients, the prevalence of long COVID was 29.19% (95% CI, 17.83-41.98). The most common symptoms were mood symptoms (e.g., sadness, tension, anger, depression, and anxiety) (prevalence: 16.50%; 95% CI, 7.37-28.15), fatigue (prevalence: 9.66%; 95% CI, 4.45-16.46), sleep disorders (e.g., insomnia, hypersomnia, and poor sleep quality) (prevalence: 8.42%; 95% CI, 3.41-15.20); headache (prevalence: 7.84%; 95% CI, 4.04-12.70), respiratory symptoms (prevalence: 7.62%; 95% CI, 2.08-15.78), sputum production or nasal congestion (prevalence: 7.53%; 95% CI, 3.78-12.36), cognitive symptoms (e.g., less concentration, learning difficulties, confusion, and memory loss) (prevalence: 6.27%; 95% CI, 4.46-8.35), loss of appetite (prevalence: 6.07%; 95% CI, 3.95-8.59), exercise intolerance (prevalence: 5.73%; 95% CI, 0.00-19.38), and altered smell (e.g., 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).

Meta-analyses of ORs (cases vs. controls)

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 only adjusted for sex, only age ¹⁶ only adjusted for age, and Knoke et al did not adjust, or by OR without adjusting previous conditions ¹⁸ (Supplemental Figures 2 and 3).

Other Findings

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.

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 ^22-25. 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.

Quality of studies

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 (I²<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 (I²>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.

DISCUSSION

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 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 autonomic nervous system Postural orthostatic tachycardia syndrome, chronic fatigue syndrome (CFS), and myalgic encephalomyelitis (ME) are subclassifications of this condition³⁰. Moreover, the constellation of symptoms because of long COVID can vary from patient to patient, fluctuating in their frequency and severity ³¹. Several viruses have been shown to trigger ME/CFS, including the Epstein Barr Virus, Ross River virus, and earlier coronaviruses (e.g., SARS and MERS) ³². However, it remains unclear whether dysautonomia may occur as a direct result of the SARS-CoV-2 infection, interaction with other viruses, or due to immune-mediated processes such as cytokines, which are known mediators of the inflammatory response ^33-36.

Similar to adults, the following risk factors in the pediatric population were associated with long COVID: older age, female gender, severe COVID-19, overweight/obesity, comorbid allergic diseases, and other long-term co-morbidities. Protective factors leading to milder severity and duration of COVID-19, and possibly also long COVID, in children include fewer comorbidities, strong innate immune responses, reduced expression of ACE2 receptors, and active thymic function, which leads to the increased presence and decreased depletion of T cells which recognize viral proteins. Further protections include a range of environmental or non-inheritable factors such as vaccines, past infections, nutrition, and/or the gut microbiome ^22-25,37.

The prevalence of symptoms is highly dependent on how much time has passed after having acute COVID-19. The follow-up time in our meta-analyses varied between 1 to 13 months. Even though most symptoms improve with time ³⁸, there is evidence in adult studies that suggests some symptoms can persist one year after COVID-19 diagnosis ³⁹. It is important to understand which symptoms are associated with certain periods of time, so future studies should assess the prevalence of each symptom at different time points (e.g., 6 months, 12 months, 2 years) to determine which symptoms are associated with which time period.

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.

Protective measures are essential to prevent long COVID in children. We need to understand the long COVID pathophysiology and symptomatology in relation to other post-infectious 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.

Data Availability

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.

Data availability

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.

Conflict of interest statement

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.

Funding/Support

This work was supported by funds from Houston Methodist Research Institute, Houston, TX.

LEGENDS

Supplementary Figure 1. Prevalence of symptoms reported over the course of long COVID in children and adolescents who tested positive or negative for SARS-CoV-2 infection.

Supplementary Figure 2. Forest plots for individual long COVID-19 symptoms in children and adolescents (1-17). ORs and 95% CIs for the presence of any category of persistent symptoms for each long COVID study.

Supplementary Figure 3. Forest plots for individual long COVID-19 symptoms in children and adolescents (18-38). ORs and 95% CIs for the presence of any category of persistent symptoms for each long COVID study.

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