The Resilient Child: Sex-Steroid Hormones and COVID-19 Incidence in Pediatric Patients

Abstract

COVID-19, a disease caused by the SARS-CoV-2 infection, has become an unprecedented global health emergency, with fatal outcomes among adults of all ages in the United States, and the highest incidence and mortality in adult males. As the pandemic evolves there is limited understanding of a potential association between symptomatic viral infection and age. To date, there is no knowledge of the role children (pre-pubescent, ages 9 to 13) play as “silent” vectors of the virus, with themselves being asymptomatic. Throughout different time frames and geographic locations, the current evidence on COVID-19 suggests that children are getting infected at a significantly lower rate than other age groups - as low as 1%. Androgens upregulate the protease TMPRSS2 (Type-II Transmembrane Serine Protease-2), which facilitates efficient virus-host cell fusion with the epithelium of the lungs, thus increasing susceptibility to SARS-CoV-2 infection and development of severe COVID-19. Due to low levels of steroid hormones, pre-pubertal children may have low expression of TMPRSS2, thereby limiting the viral entry into host cells. As the world anticipates a vaccine against SARS-CoV-2, the role of pre-pubescent children as vectors transmitting the virus must be interrogated to prepare for a potential resurgence of COVID-19. This review discusses the current evidence on the low incidence of COVID-19 in children and the effect of sex steroid hormones on SARS-CoV-2 viral infection and clinical outcomes of pediatric patients. Upon reopening society at large, schools will need to implement heightened health protocols, with the knowledge that children as the “silent” viral transmitters, can significantly impact the adult populations.

A retrospective cohort study of 12,306 pediatric COVID-19 patients in the United States

“…In the absence of patient-level data about prior infections, the role of empiric immunity in the prevention of infection and its clinical manifestation requires further investigation. There may be other factors that may contribute to the observed lower risk in children compared with adults, such as age-dependent expression of ACE2 receptor (SARS-CoV-2 binding receptor) and androgen levels [47][48][49] . We also observed relatively lower neutrophil levels in the hospitalized pediatric COVID-19 patients indicating a role of age-related neutrophil recruitment in the mild manifestation of the illness in children, as reported previously 50 .…”

Alert to US physicians: DHEA, widely used as an OTC androgen supplement, may exacerbate COVID-19

“…In vitro elimination of TMPRSS2 activity using a protease inhibitor blocks the ability of SARS-CoV-2 to infect human cells (Hoffmann et al 2020). The low morbidity and mortality of SARS-CoV-2 infection in very young children correlates with their pre-adrenarche developmental stage (see subsequently) (Mihalopoulos et al 2020).…”

A Review on Expression, Pathological Roles, and Inhibition of TMPRSS2, the Serine Protease Responsible for SARS-CoV-2 Spike Protein Activation

“…According to a recent study, this was due to the strong innate immune response of the children [52]. Another hypothesis was that children before puberty have lower levels of steroid hormones which are necessary for the upregulation of TMPRSS2 and thus are less susceptible to the severity of the disease [53].…”