key: cord-299544-r3cqvf0c
authors: de Souza, T. H.; Nadal, J. A.; Nogueira, R. J. N.; Pereira, R. M.; Brandao, M. B.
title: Clinical Manifestations of Children with COVID-19: a Systematic Review
date: 2020-04-03
journal: nan
DOI: 10.1101/2020.04.01.20049833
sha: 
doc_id: 299544
cord_uid: r3cqvf0c

Context: The coronavirus disease 2019 (COVID-19) outbreak is an unprecedented global public health challenge, leading to thousands of deaths every day worldwide. Despite the epidemiological importance, clinical patterns of children with COVID-19 remain unclear. Objective: To describe the clinical, laboratorial and radiological characteristics of children with COVID-19. Data Sources: The Medline database was searched between December 1st 2019 and March 30th 2020. Study Selection: Inclusion criteria were: (1) studied patients younger than 18 years old; (2) presented original data from cases of COVID-19 confirmed by reverse-transcription polymerase chain reaction; and (3) contained descriptions of clinical manifestations, laboratory tests or radiological examinations. Data Extraction: Number of cases, gender, age, clinical manifestations, laboratory tests, radiological examinations and outcomes. Results: A total of 34 studies (1,118 cases) were included. From all the cases, 1,111 had their severity classified: 14.3% were asymptomatic, 36.4% were mild, 46.0% were moderate, 2.2% were severe and 1.2% were critical. The most prevalent symptom was fever (16.3%), followed by cough (14.4%), nasal symptoms (3.6%), diarrhea (2.7%) and nausea/vomiting (2.5%). One hundred forty-five (12.9%) children were diagnosed with pneumonia and 43 (3.8%) upper airway infections were reported. Reduced lymphocyte count were reported in 13.1% of cases. Abnormalities on computed tomography was reported in 62.7% of cases. The most prevalent abnormalities reported were ground glass opacities, patchy shadows and consolidations. Only one death was reported. Conclusions: Clinical manifestations of children with COVID-19 differ widely from adults cases. Fever and respiratory symptoms should not be considered a hallmark of COVID-19 in children.

In late December 2019, Chinese authorities informed the World Health Organization (WHO) that, due to unknown cause, an outbreak of pneumonia emerged in Wuhan, Hubei province. On January 7, 2020, a new type of coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) was isolated and few days after the disease has been named "coronavirus disease 2019" (abbreviated "COVID-19"). The first death caused by COVID-19 was on January 9, 2020, in Wuhan and since then more than 370,000 cases and 16,000 deaths occurred worldwide. 1 Nowadays, the death toll in Italy has exceeded double the number registered in China and the United States became the new COVID-19 epicenter.

In spite of stepped-up efforts to contain the pandemic, the number of affected patients and the death toll continue to rise. Elderly patients infected with SARS-CoV-2 are at high risk to have severe acute respiratory syndrome, complications and death. 2 Due to unknown reasons, children with COVID-19 appear to have a milder clinical course compared to adults, and reports of death are scarce. 3, 4 However, pediatric population may play a major role in community spread of SARS-CoV-2. In addition to viral shedding in nasal secretions, there is evidence of fecal shedding for several weeks after diagnosis, which poses a challenge for infection control. 5 Despite the epidemiological importance, clinical patterns of children with COVID-19 remain unclear. The WHO recommends testing all suspected cases, however, . 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 peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04.01.20049833 doi: medRxiv preprint children infected with SARS-CoV-2 may not meet all the criteria required in the suspected case definition. 6 The objective of this study is to describe the clinical, laboratorial and radiological characteristics of children with COVID-19 reported in the literature.

This review was performed in accordance with the Preferred Reporting Items for Systematic and Meta-Analysis (PRISMA) statement. 7, 8 The Medline database was searched using the following search strategy: ((((covid-19) OR coronavirus) OR SARS-CoV-2)) AND (((((((pediatrics) OR children) OR neonates) OR child) OR neonate) OR infant) OR infants). No language restrictions were applied. Articles published between December 1 st 2019 and March 25 th 2020 were evaluated for inclusion. No attempts were made to contact the study authors for identifying missing and confusing data. A manual search of the references found in the selected articles and reviews was also performed.

Two authors (THS and JAN) screened the titles and abstracts independently and in duplicate for potential eligibility. They subsequently read the full texts to determine final eligibility. Discrepancies were resolved through discussion and consensus, and if necessary, the assistance of a third author (MBB) was sought.

. 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. 

A structured data extraction form was piloted and then used to extract data from the reports of all included studies in duplicate and independently by two authors (THS and JAN). Discrepancies in extracted data were resolved through discussion. The following data were extracted, when available, from each elected article: first author, publication year, study design, number of cases, gender, age, clinical manifestations, laboratory tests, radiological examinations and outcomes (discharged, still hospitalized or death).

When sufficient data was reported, the cases were classified into the following clinical types: 9 1. Asymptomatic infection: without any clinical symptoms and signs and the chest imaging is normal, while the SARS-CoV-2 nucleic acid test was positive or the serum-specific antibody was retrospectively diagnosed as infection. 3. Moderate: presented as pneumonia. Frequent fever and cough, mostly dry cough, followed by productive cough , some may have wheezing, but no . 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 . https://doi.org/10.1101/2020.04.01.20049833 doi: medRxiv preprint obvious hypoxemia such as shortness of breath, and lungs can hear sputum or dry snoring and / or wet snoring. Some cases may have no clinical signs and symptoms, but chest computed tomography (CT) shows lung lesions, which are subclinical. 4 . Severe: Early respiratory symptoms such as fever and cough, may be accompanied by gastrointestinal symptoms such as diarrhea. The disease usually progresses around 1 week, and dyspnea occurs, with central cyanosis.

Oxygen saturation is less than 92%, with other hypoxia manifestations. 5. Critical: Children can quickly progress to acute respiratory distress syndrome (ARDS) or respiratory failure, and may also have shock, encephalopathy, myocardial injury or heart failure, coagulation dysfunction, and acute kidney injury, including multiple organ dysfunction. Can be life threatening.

Of 205 potentially relevant articles identified by the search strategy, 34 met the inclusion criteria. A total of 1112 descriptions of pediatric cases 3,5,10-37 and 6 neonate cases 38-41 of COVID-19 were obtained, being that 639 were males 477 were females, and 2 were not disclosed. The flow diagram (Figure 1 ) summarizes the steps followed to identify the studies meeting the inclusion criteria.

Sixteen studies were case reports, 12 21 1 in Korea, 15 and 1 in Vietnam. 24 . 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 . https://doi.org/10.1101/2020.04.01.20049833 doi: medRxiv preprint

A total of 1111 cases had their severity classified based on the reported clinical data. One hundred fifty-nine (14.3%) cases were asymptomatic, 404 (36.4%) were mild, 511 (46.0%) were moderate, 24 (2.2%) were severe and 13 (1.2%) were critical cases. Table 1 summarizes the severity of illness reported in each included study.

The most prevalent symptom was fever, reported in 16.3% of the cases, followed by cough (14.4%), nasal symptoms (3.6%), diarrhea (2.7%), nausea/vomiting (2.5%), fatigue (1.8%) and respiratory distress (1.1%). One hundred forty-five (12.9%) children were diagnosed with pneumonia and 43 (3.8%) upper airway infections were reported.

Amongst the most common clinical signs described were pharyngeal erythema (7.1%), tachycardia (6.4%) and tachypnea (4.6%) on admission. All the clinical manifestations reported in the selected studies and their relative frequencies are described in Table 2 .

All clinical manifestations described in each study are presented in eTable 1 in the Supplement.

Twenty-five studies detailed the white blood cell count of 168 cases. 10 

Twenty-five studies reported 180 cases which underwent chest CT. 3, 10, 19, 22, 23, 25, [27] [28] [29] [31] [32] [33] 11, 34, [36] [37] [38] [39] [12] [13] [14] [15] [16] [17] [18] One hundred thirteen (62.7%) CT scans presented abnormalities. The . 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 . https://doi.org/10.1101/2020.04.01.20049833 doi: medRxiv preprint most prevalent abnormalities reported were ground glass opacities, patchy shadows and consolidations. In the study of Lu et al. involving 171 cases, ground glass opacities and patchy shadowings were observed in 32.7% and 31% of cases, respectively. 3 Pleural effusion was observed in a 2-month-old child with simultaneus RSV and SARS-CoV-2 infections. 11

Clinical outcomes of death, discharged or still hospitalized were described for 365 cases in 28 studies. 3, 5, 19, 21, 22, 24, [26] [27] [28] [29] [30] [31] 10, [32] [33] [34] [36] [37] [38] [39] 41, [12] [13] [14] [15] [16] [17] [18] Of these, 62 cases were still hospitalized when studies were submitted, 302 were discharged and 1 died.

In our study, we described the main clinical, laboratorial and radiological characteristics of children infected with SARS-CoV-2 reported in the literature. It was observed that only a small proportion of infected children became severely or critically ill. About half of the children with COVID-19 were asymptomatic or mild cases, and several were classified as moderate due to radiological abnormalities in spite of their mild clinical manifestations. The prognosis seems to be very good, with recovery described in the vast majority of reported cases. Only one death was reported in the included studies, a 10-month-old child with intussusception. 3 Since COVID-19 has a favorable clinical course in children, the importance of pediatric cases is mainly due to epidemiological issues. Despite being mild or asymptomatic cases, prolonged viral shedding in stool and nasal secretions made children facilitators of viral transmission. 5, 42 In the study of Xu et al., eight of ten children with SARS-CoV02 had persistently positive rectal swabs even after their nasopharyngeal tests . 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 . https://doi.org/10.1101/2020.04.01.20049833 doi: medRxiv preprint were negative. 42 . 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 . https://doi.org/10.1101/2020.04.01.20049833 doi: medRxiv preprint Our study has some limitations. Firstly, data from the same patient may have been presented in more than one included study. Secondly, the majority of data are from China, and may not be generalized for other populations. . 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 peer-reviewed) The copyright holder for this preprint 6 (0.6%) Sputum 6 (0.6%) Hypoxemia 5 (0.5%) Abdominal pain 2 (0.2%) Sneezing 2 (0.2%) Cyanosis 2 (0.2%) Lymphadenopathy 1(0.1%) * expressed in absolute number and percentage in relation to the total of cases described (n = 151).

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Thank you to Carolina Grotta Ramos Telio for her review of the manuscript.

* Values are expressed as N and relative frequencies. Studies that described asymptomatic cases were not included in this table.