The ability of the neonatal immune response to handle SARS-CoV-2 infection
Authors: Florian Götzinger, Begoña Santiago-Garcia, Victòria Fumadó-Pérez, Folke Brinkmann, Marc Tebruegge
Journal: The Lancet Child & Adolescent Health (2021)

We read with interest the Article by Chris Gale and colleagues reporting data from active surveillance of neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first COVID-19 wave in the UK.1Gale C Quigley M Placzek A et al.Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance.Lancet Child Adolesc Health. 2020; (published online Nov 9.)https://doi.org/10.1016/S2352-4642(20)30342-4Summary Full Text Full Text PDF Scopus (176) Google Scholar The authors are to be commended for the detailed presentation of their data, and the overall carefully worded interpretation. However, the authors appear to contradict themselves in the Discussion section, initially stating that "neonatal SARS-CoV-2 infection led to severe disease in 42% of cases" and highlighting that 33% of babies required respiratory support. Contrasting with this, in the final paragraph the authors state that "most babies are only mildly affected in the neonatal period." We have previously published data from a multicentre study on SARS-CoV-2 infection, involving 82 health-care institutions in 25 European countries, which included 582 children with PCR-confirmed SARS-CoV-2 infection.2Goetzinger F Santiago-Garcia B Noguera-Julian A et al.COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.Lancet Child Adolesc Health. 2020; 4: 653-661Summary Full Text Full Text PDF PubMed Scopus (908) Google Scholar Prompted by the Article by Gale and colleagues, we did secondary data analyses that were focused on neonatal cases (aged <28 days) in our cohort. Our study population included 35 neonates, four (11%) of whom required mechanical ventilation (table), compared with 21 (4%) of 547 children older than 1 month (two-sided Fisher's exact test, p=0·0561). However, three of these neonates had substantial comorbidities, comprising cardiac anomalies (n=2) and prematurity (n=1), which might have caused the need for ventilatory support, rather than SARS-CoV-2. Considering this uncertainty, if the analysis is repeated with the only patient who required mechanical ventilation for SARS-CoV-2 infection alone, the proportion of neonates requiring ventilation would be similar to that observed in older children without pre-existing comorbidities in our cohort (one [3%] of 32 vs six [2%] of 299; p=0·5059]. An additional three neonates needed supplemental oxygen without requiring ventilation (one born prematurely); none of these neonates had evidence of acute respiratory distress syndrome on chest radiography. Only three of those seven neonates received medication aimed at treating SARS-CoV-2 infection. One baby received intravenous immunoglobulin; another hydroxychloroquine, which was a promising drug candidate at that time, but subsequently found to be ineffective;3Cavalcanti AB Zampieri FG Rosa RG et al.Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19.N Engl J Med. 2020; 383: 2041-2052Crossref PubMed Scopus (821) Google Scholar and one received remdesivir on a compassionate basis.TableNeonates included in the ptbnet COVID-19 study (n=35)n (%)Likely index caseParent29 (83%)Sibling1 (3%)Other (including potential nosocomial transmission)5 (14%)Presence of comorbidities at presentation*Comorbidities comprised prematurity (born <37 weeks of gestation; n=3); cardiac anomalies (n=3); gastro-oesophageal reflux disease (n=1); urogenital malformation (n=1); and red cell disorder (n=1).One comorbidity6 (17%)Two comorbidities0Three comorbidities1 (3%)No known comorbidities28 (80%)Symptoms related to COVID-19†Some neonates had more than one symptom.Pyrexia (>38·0°C)24 (69%)Upper respiratory tract infection symptoms18 (51%)Lower respiratory tract infection symptoms7 (20%)Gastrointestinal symptoms10 (29%)Asymptomatic6 (17%)Abnormal findings on chest radiography‡Only 12 neonates had a chest radiograph.Suggestive of lower respiratory tract infection (without ARDS)3 (9%)Suggestive of ARDS2 (6%)Intensive care unit (NICU or PICU) supportAdmitted to intensive care unit7 (20%)No intensive care unit support required28 (80%)Respiratory support required§Some neonates received more than one type of respiratory support.Invasive ventilation4 (11%)Continuous positive airway pressure5 (14%)Supplemental oxygen7 (20%)Extracorporeal membrane oxygenation0No respiratory support required28 (80%)ARDS=acute respiratory distress syndrome. NICU=neonatal intensive care unit. PICU=paediatric intensive care unit.* Comorbidities comprised prematurity (born <37 weeks of gestation; n=3); cardiac anomalies (n=3); gastro-oesophageal reflux disease (n=1); urogenital malformation (n=1); and red cell disorder (n=1).† Some neonates had more than one symptom.‡ Only 12 neonates had a chest radiograph.§ Some neonates received more than one type of respiratory support. Open table in a new tab ARDS=acute respiratory distress syndrome. NICU=neonatal intensive care unit. PICU=paediatric intensive care unit. The large majority (80%) of neonates did not require respiratory support at any stage, and almost one in five remained entirely asymptomatic (table). Importantly, all 35 neonates survived, and none had evidence of COVID-19-related sequelae at discharge. Our data indicate that the neonatal immune system, despite its inherent immaturity,4Kollmann TR Kampmann B Mazmanian SK Marchant A Levy O Protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny.Immunity. 2017; 46: 350-363Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 5Zimmermann P Curtis N Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections.Arch Dis Child. 2020; (published online Dec 1.)https://doi.org/10.1136/archdischild-2020-320338Crossref Scopus (300) Google Scholar is able to handle SARS-CoV-2 effectively, with most infected neonates either being asymptomatic or experiencing mild disease, which is concordant with the findings of two meta-analyses.6Walker KF O'Donoghue K Grace N et al.Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis.BJOG. 2020; 127: 1324-1336Crossref PubMed Scopus (187) Google Scholar, 7Raschetti R Vivanti AJ Vauloup-Fellous C Loi B Benachi A De Luca D Synthesis and systematic review of reported neonatal SARS-CoV-2 infections.Nat Commun. 2020; 115164Crossref PubMed Scopus (243) Google Scholar We declare no competing interests FG and MT conducted the secondary data analyses reported in this manuscript, and wrote the first draft. BS-G, VF-P, and FB interpreted the data, and reviewed and revised the manuscript. The remaining members of the ptbnet COVID-19 Study Group (appendix) also reviewed the manuscript, provided additional input, and approved the manuscript to be submitted for publication. The corresponding author had full access to all data and the final responsibility to submit for publication. Download .pdf (.12 MB) Help with pdf files Supplementary appendix The ability of the neonatal immune response to handle SARS-CoV-2 infection – Authors' replyWe thank Florian Götzinger and colleagues for their Correspondence. The additional analysis they report is welcome, and the points they raise in relation to this new disease and its severity are important. Full-Text PDF Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillanceNeonatal SARS-CoV-2 infection is uncommon in babies admitted to hospital. Infection with neonatal admission following birth to a mother with perinatal SARS-CoV-2 infection was unlikely, and possible vertical transmission rare, supporting international guidance to avoid separation of mother and baby. The high proportion of babies from Black, Asian, or minority ethnic groups requires investigation. Full-Text PDF Open Access