Additional Concerns Regarding Children With Coronavirus Disease 2019—Reply

In Reply We much appreciated the interest aroused by our systematic review,¹ and we thank all the authors for their thoughtful comments about our work. In our analysis, available evidence showed that most children with coronavirus disease 2019 (COVID-19) presented with mild symptoms, if any, and recovered uneventfully. However, 1 infant had a severe presentation and was successfully treated with intensive care, and 1 death was reported.

The research occurred over a brief 3-month period (from December 1, 2019, to March 3, 2020), and the articles were observational designs and came mainly from Chinese reports because European and US studies in children with COVID-19 were not available at the time this review was conducted.

Despite these limitations, accumulating literature confirmed our main findings,² showing that children and adolescents appeared the least at-risk population for developing critical disease. Once infected, the risk for a child to develop severe disease requiring hospitalization is 25 times lower than in adults (0.1% vs 2.6%), and the risk of death is 500 times lower than in adults (0.001% vs 0.5%), as based on a French study.³ Hypotheses regarding the relative resistance of children to COVID-19 include (1) resistance to the infection, (2) more efficient control of the infection, (3) less intense immunopathologic reaction, and (4) better capacity of tissue repair.² Bunyavanich et al⁴ showed age-dependent nasal gene expression of angiotensin-converting enzyme 2, the receptor that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses for host entry.⁴ Lower angiotensin-converting enzyme 2 expression in children relative to adults may help explain why COVID-19 is less prevalent in children.

In addition to reported findings, the unprecedented global research effort to better characterize SARS-CoV-2 infection has shed new light on pediatric COVID-19, adding novel insights to initial evidence. As discussed by Chen and Chiu, Salvatore et al, and Zimmerman et al, although most children with COVID-19 present with mild symptoms, severe cases have been reported, and death can occur in all pediatric age ranges.⁵ Despite the fact that no definite risk groups have been identified in the pediatric population, comorbidities, including obesity, neurologic condition, chronic lung disease, cardiovascular disease, immunosuppression, and overall medical complexity, have been reported in children with severe COVID-19.⁵ Also, children younger than 1 year are overrepresented in pediatric COVID-19 cohorts, with a higher risk of fatality compared with children older than 1 year²; in this context, as discussed by He and Zhang, further studies need to analyze clinical outcomes in infected neonates.

Moreover, as a confirmation of the broad spectrum of disease caused by SARS-CoV-2, children presenting with a multisystem inflammatory syndrome associated with COVID-19 are also being reported.⁶ This syndrome, with features similar to Kawasaki disease, underscores the need for a better understanding of SARS-CoV-2 infection’s pathophysiology in children.

We are working on an updated systematic review of SARS-CoV-2 infection in children and adolescents (PROSPERO identifier: CRD42020181640) to fully characterize the clinical and immunologic features of pediatric COVID-19.

Corresponding Author: Amelia Licari, MD, Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Piazzale C. Golgi 19, 27100 Pavia, Italy (amelia.licari@unipv.it).

Published Online: October 26, 2020. doi:10.1001/jamapediatrics.2020.2940

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank Martina Votto, MD, and Ilaria Brambilla, MD, PhD, for their valuable inputs for the preparation of this response letter.