key: cord-1042197-hit7rs6q
authors: Zhang, Linjie; Peres, Tyele G.; Silva, Marcus V. F.; Camargos, Paulo
title: What we know so far about Coronavirus Disease 2019 in children: A meta‐analysis of 551 laboratory‐confirmed cases
date: 2020-06-10
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.24869
sha: df4684271bd49f4bf63c0999750e15bd13cc12b7
doc_id: 1042197
cord_uid: hit7rs6q

AIM: To summarize what we know so far about coronavirus disease (COVID‐19) in children. METHOD: We searched PubMed, Scientific Electronic Library Online, and Latin American and Caribbean Center on Health Sciences Information from 1 January 2020 to 4 May 2020. We selected randomized trials, observational studies, case series or case reports, and research letters of children ages birth to 18 years with laboratory‐confirmed COVID‐19. We conducted random‐effects meta‐analyses to calculate the weighted mean prevalence and 95% confidence interval (CI) or the weighted average means and 95% CI. RESULT: Forty‐six articles reporting 551 cases of COVID‐19 in children (aged 1 day‐17.5 years) were included. Eighty‐seven percent (95% CI: 77%‐95%) of patients had household exposure to COVID‐19. The most common symptoms and signs were fever (53%, 95% CI: 45%‐61%), cough (39%, 95% CI: 30%‐47%), and sore throat/pharyngeal erythema (14%, 95% CI: 4%‐28%); however, 18% (95% CI: 11%‐27%) of cases were asymptomatic. The most common radiographic and computed tomography (CT) findings were patchy consolidations (33%, 95% CI: 23%‐43%) and ground glass opacities (28%, 95% CI: 18%‐39%), but 36% (95% CI: 28%‐45%) of patients had normal CT images. Antiviral agents were given to 74% of patients (95% CI: 52%‐92%). Six patients, all with major underlying medical conditions, needed invasive mechanical ventilation, and one of them died. CONCLUSION: Previously healthy children with COVID‐19 have mild symptoms. The diagnosis is generally suspected from history of household exposure to COVID‐19 case. Children with COVID‐19 and major underlying condition are more likely to have severe/critical disease and poor prognosis, even death.

The coronavirus disease 2019 (COVID- 19) is an emerging infectious disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was first reported in December 2019 in Wuhan, the capital of Hubei province, China. The World Health Organization declared COVID-19 a public health emergency of international concern on 30 January 2020, and recognized it as a pandemic on 11 March. As of 4 May, three and half million cases of COVID-19 have been reported in over 187 countries and regions, resulting in approximately 260 000 deaths. 1 COVID-19 appears to be less common in children than adults.

Early data from the Chinese Center for Disease Control (CDC) showed that 2.1% of 44.672 patients with laboratory-confirmed COVID-19 as of 11 February 2020, were children up to 10 years old. 2 As of 2 April, among the 149 760 laboratory-confirmed cases in the Unites States, 1.7 percent were children aged <18 years, which make up 22% of the U.S. population. 3 In Europe, children and adolescents made up a small proportion of the 266 393 cases reported to the European Surveillance System-European CDC (1.1%: <10 years, 2.5%: 10-19 years). 4 Since the first papers published on 24 January 2020, 2,5,6 there has been a growing number of publications related to However, the number of studies in children is still limited, and most of them were case series or case reports with a small number of patients. [7] [8] [9] A systematic and quantitative synthesis of data from such studies is needed to provide a more comprehensive and accurate overall picture of COVID-19 in children.

Three systematic reviews have been published to date to address COVID-19 in children. One review included 45 scientific papers or letters, 10 showing milder symptoms and better prognosis in children with COVID-19. However, the clinical picture of COVID-19 was narratively described, based on the data of 15 reports, mainly from two papers. Another review with 34 studies described clinical, radiological, and laboratorial characteristics of children with COVID- 19. 11 The authors used simple arithmetic means to estimate overall prevalence of clinical findings, and several duplicate publications were included in the review. The latest review 12 included 18 studies (16 primary studies and 2 secondary studies), and a qualitative synthesis of data was performed.

We conducted this systematic review and meta-analysis of currently available studies to summarize what we know so far about the epidemiological, clinical, radiological, and laboratory features, as well as therapeutic and prognostic aspects, of COVID-19 in children.

We followed the preferred reporting items for systematic reviews and meta-analyses guidelines to conduct and report this review. The review protocol was registered on PROSPERO, an International Prospective Register of Systematic Reviews (CRD42020178178).

According to the Brazilian National Commission of Ethics in Research and the National Health Council, ethical approval is not required for literature review research (council resolution no. 510/2016).

We searched PubMed from 1 January 2020 to 4 May 2020, using the following search strategy: "Novel coronavirus" OR "Novel coronavirus 2019" OR "2019 nCoV" OR "COVID-19" OR "SARS-CoV-2." We also searched the Scientific Electronic Library Online (SciELO), the Latin American and Caribbean Health Sciences Literature (LILACS), and Google Scholar. We checked reference lists of retrieved articles for additional studies. There was no restriction in language.

To be included in this review, studies needed to meet the following criteria: (a) Study design: randomized trials, observational studies (cross-sectional, cohort and case-control), case series or case reports, and research letters; (b) Participants: children up to 18 years of age with laboratory-confirmed COVID-19; (c) Variables: epidemiological and demographic characteristics, clinical, radiological and laboratory findings, treatments, and prognosis. We excluded editorials, comments, and review articles. We also excluded studies reporting nationwide aggregated data and those reporting the same patients' data to avoid overlapping and duplicate publications.

Two authors (SMVF, PTG) independently assessed the titles and abstracts of all citations identified by the searches. We obtained the full articles when they met the inclusion criteria or there were insufficient data in the title and abstract for assessment of eligibility.

The definitive inclusion of studies was made after reviewing the full-text articles. Any disagreement between two reviewers was resolved by discussion with the third reviewer (ZL).

series, using the National Institutes of Health Study Quality Assessment Tools. 13

For dichotomous variables, we calculated the weighted mean prevalence and 95% CI whenever there were three or more studies with at least 50 patients. We aggregated the data of a single case report into a series of cases for meta-analysis because an individual case report has no denominator for any variables. We conducted sensitivity analysis excluding aggregated single cases from the analysis to assess the influence of such data management on the results of meta-analysis. For continuous variables, we calculated the weighted average means and 95% CI whenever there were three or more studies with at least 50 patients. We used random-effects model for meta-analyses.

We planned to perform subgroup analyses according to illness severity (mild/moderate vs severe/critical) and study countries (China vs others). However, the limited number of severe/critical cases and cases outside China did not allow us to conduct such subgroup analyses.

We assessed heterogeneity between studies using I 2 statistic which measures the percentage of observed total variation across studies that is due to real heterogeneity rather than chance. The heterogeneity was considered substantial if I 2 > 50%. We assessed publication bias using funnel plot with Egger's test for each variable whenever there were 10 or more studies. All meta-analyses were performed in Stata version 11.0 (Stata-Corp, College Station, TX).

The search strategy identified 8475 records (8058 from PubMed, 223 from LILACS, and 194 from SciELO). After screening the titles and abstracts, we retrieved 64 potentially relevant full text articles for further evaluation. Twenty-four articles were excluded, of which eight were duplicate publications of the patients' data from Wuhan Children's Hospital in the city of Wuhan, 14,15 the epicenter of SARS-CoV-2 outbreak (Figure 1 ). We also excluded another two Chinese nationwide reports of COVID-19 in children. 16, 17 We identified eight additional articles on Google Scholar. Thus, 46 articles [7] [8] [9] 14, 15, reporting 551 laboratory-confirmed cases of COVID-19 in children were included in the review (Figure 1 ). Thirty-five articles (429 cases) were from China, [7] [8] [9] 14, 15, and the remaining papers from Iran (one cases), 48, 49 Italy (109 case), [50] [51] [52] Korea (one case), 53 Malaysia (four cases), 54 Singapore (one case), 55 Spain (one case), 56 United States (one case), 57 and Vietnam (one case). 58 14, 15, 28, 34, 38, 44 epicenter of the outbreak. We included two studies from Wuhan Children's Hospital, 14, 15 but the larger one with 171 patients 14 had contributed the data to all but one category of variables (laboratory findings) for which we used the data from a subset of 82 patients. 15 Thirty-nine articles were case series or case reports, and six were research letters. 14, 22, 28, 36, 51, 56 We considered one observational cohort study 31 as a case series because this paper described clinical and epidemiological features of 36 cases, in which patients' data were retrospectively collected from electronic medical records. We rated the quality of 26 case series as poor (n = 2), fair (14) , and good (n = 10; Table S1 ). The characteristics of included studies and the main epidemiological and clinical findings of COVID-19 are summarized in Table 1 . The laboratory and radiological findings of COVID-19 are given in Table S2 .

Of 551 children with laboratory-confirmed COVID-19, 311 were males (57%, 95% CI: 53%-62%). The patients' age ranged from 1 day to 17.5 years old, and 216 (48%, 95% CI: 37%-58%) were children under 5 years of age. At least seven cases were neonates aged up to 28 days. All but three studies 26, 50, 57 provided data on exposure to COVID-19 case. Household exposure was most common, with a pooled mean prevalence of 87% (95% CI: 77%-95%) ( Table 2) . Thirtyfour patients (1%, 95% CI: 0%-4%) had unknown exposure information. Three small case series with a total of 26 patients reported the incubation period, with a median (range) of 7 days (2-10 days), 7 5 days (3-12 days), 21 and 7.5 days (1-16 days), 33 respectively.

All 551 children with laboratory-confirmed COVID-19 were hospitalized or treated in the emergency department (n = 100), of Oxygen therapy (n = 2), antiviral (n = 0), antibiotic (n = 0), glucocorticoids (n = 1) 

Ji et al, 24 China Case series (n = 2) Age: 15, 9 y; male/female: 2/0 Household (n = 2) Fever (n = 1), pharyngeal congestion (n = 1), diarrhea (n = 1), normal breath sounds (n = 2)

Symptomatic treatment (n = 2), probiotic (n = 1) China Case series (n = 5) Age: median of 3 y (range: 10 mo-6 y); male/female: 4/1

Household (n = 4) Community (n = 1) Asymptomatic (n = 4), fever (n = 1), cough Su et al, 35 China Case series (n = 9) Age: median of 3.6 y (range: 11 mo-9 y); male/female: 3/6 Household (n = 9) Fever (n = 2), cough (n = 1), asymptomatic (n = 6) Interferon (n = 9), ribavirin (n = 1) which 18% (95% CI: 11%-27%) were asymptomatic. The most common symptoms and signs were fever (53%, 95% CI: 45%-61%), cough (39%, 95% CI: 30%-47%), and sore throat or pharyngeal erythema (14%, 95% CI: 4%-28%). The less common symptoms and signs included tachypnea/dyspnea, nasal symptoms, diarrhea, vomiting, fatigue/weakness, and headache ( Table 2 ). The sensitivity analysis excluding series of 20 single cases yielded almost identical results.

Nine patients had severe/critical COVID-19, of which three were from one series of 171 cases, 14 two from one series of 25 cases, 44 two from one series of 100 cases, 51 one from a series of six cases, 28 and one from a single case report. 19 All but two patients had underlying medical conditions, such as hydronephrosis (n = 1), leukemia receiving maintenance chemotherapy (n = 1), intussusception (n = 1), encephalopathy (n = 1), and congenital heart diseases (n = 3).

Chest images were obtained in all but one patient, 52 and most of them (86%) were chest CT scans. The most common findings were patchy consolidations (33%, 95% CI: 23%-43%) and ground glass opacities associated or not with consolidations (28%, 95% CI: 18%-39%), 

SARS-CoV-2 was detected in nasopharyngeal and/or throat (NPT) specimens by reverse transcription-polymerase chain reaction (RT-PCR) testing in all 551 patients. Nine case series with a total of 92 patients reported duration of viral RNA shedding in NPT specimens. 7, 33, 35, 37, 39, 40, 43, 47, 54 The pooled average mean duration was 11.2 days (95% CI: 9.6-12.8 days, I 2 = 62). The range of shedding duration reported by nine case series was 6 to 22 days (n = 10), 7 9 to 20 days (n = 6), 33 7 to 16 days (n = 9), 35 7 to 23 days (n = 31), 37 10 to 15 days (n = 3), 39 3 to 16 days (n = 10), 40 three mycoplasma pneumoniae, and one bacteria). Six patients from a series of nine cases had testing, 45 and RSV was identified in one patient. No co-infection was found in three series of cases with a total of 28 patients. 7, 11, 40 The pooled prevalence of coinfections of SARS-CoV-2 with other respiratory pathogens was 10% (95% CI: 1%-24%, I 2 = 65).

A battery of laboratory tests was performed in children with COVID-19. The more common laboratory abnormalities included lymphocytosis (35%, 95% CI: 14%-59%), increased lactate dehydrogenase (29%, 95% CI: 16%-43%), increased creatine kinase (21%, 95% CI: 8%-37%), and increased aspartate aminotransferase (18%, 95% CI: 9%-28%) ( Table 2) .

Four case series reported oxygen saturation. In one series of 36 cases, all had normal oxygen saturation. 31 One percent of patients in a series of 100 cases 51 and 2.3% of patients in another series of 171 cases 14 had oxygen saturation <92% during the period of hospitalization. In a series of three cases from Iran, 48 all had oxygen saturation below 92%. The pooled mean prevalence of oxygen saturation <92% was 4% (95% CI: 0%-17%, I 2 = 84).

Forty-two studies 7, 9, 14, 15, [18] [19] [20] [21] [22] [23] [24] [25] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [53] [54] [55] [56] [57] [58] with 381 cases of COVID-19 provided available data on treatments. All patients received symptomatic treatment. Antiviral agents were given in 227 patients (74%, 95% CI: 52%-92%). Inhaled interferon α (IFN-α) was the most commonly used antiviral drug. Other reported antivirals were ribavirin, oseltamivir, lopinavir, ritonavir, and litonavir. Antibiotics were used in 138 patients (40%, 95% CI: 19%-63%). Other treatments included intravenous immunoglobulin therapy (n = 15, 3%, 95% CI: 0%-10%), oxygen therapy (n = 30, 4%, 95% CI: 1%-10%), and systematic corticosteroids (n = 10, 1%, 95%

CI: 0%-3%). Six patients with severe/critical COVID-19 needed invasive mechanical ventilation.

Of 451 hospitalized children with COVID-19, 83% (95% CI:

67%-95%) were discharged as of the reporting date, with at least one negative RT-PCR testing for SARS-CoV-2 in nasopharyngeal/ throat specimens. The pooled average mean length of hospital stay was 12.5 days (95% CI: 11.1-14.0 days) among 182 discharged patients with available data. Of nine patients with severe/critical COVID, six needed intensive care with mechanical ventilation, 14, 44, 51 and all had major underlying medical conditions. One 10-month-old child with intussusception had multiple organ failure, and died 4 weeks after admission. 14 However, this is the best available evidence to date for a previously unknown disease. We used a comprehensive search strategy to identify larger number of relevant studies, and both visual inspection of the funnel plots and Egger's test did show substantial publication bias ( Figures S1,2) . We recognize, however, that some Chinese studies published in local medical journals might not be identified and included in the review.

In conclusion, children of all ages can get COVID-19, although they appear to be affected less commonly than adults. Mild-tomoderate fever and cough are the most common symptoms, but much less frequently than that reported in adults, and 18% of patients may be asymptomatic. Ground glass opacity and consolidation are the most common CT abnormalities in children with COVID-19.

The prevalence of such CT findings in pediatric cases is lower than that in adult patients, and 36% of children with laboratory-confirmed COVID-19 may have normal CT images. Previously healthy children with COVID-19 usually have mild symptoms and good prognosis.

However, children with COVID-19 and major underlying medical condition are more likely to have severe or critical disease, and poor prognosis, even death. To date, there is no approved treatment for COVID-19.

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The authors declare that there are no conflict of interests.

LZ conceptualized and designed the study, participated in trial selection, quality assessment, data collection, data analysis and interpretation, drafted the protocol and the review article, and approved the final manuscript as submitted. TGP and MVFS provided input for study conception and design, participated in trial selection, quality assessment and data collection, critically revised the manuscript, and approved the final manuscript as submitted. PC provided input for study conception and design, critically revised the manuscript, and approved the final manuscript as submitted.

http://orcid.org/0000-0001-5150-5840Paulo Camargos http://orcid.org/0000-0003-4731-291X