In-vitro Diagnostic Test to Predict COVID-19 Mortality and Disease Severity

In late 2019, a novel coronavirus, subsequently named SARS-CoV-2 (COVID-19), was first
reported in Hubei province in China. Since it was first reported, a worldwide pandemic has
ensued affecting more than 450,000 individuals as of March 2020. In the midst of the
pandemic, epidemiological reports unveiled a disproportionate low rate of severe cases among
adult females compared to adult males, 42% and 58%, respectively. Similarly, the rate of
severe cases among pre-pubescent children was exceptionally low at 0.6%. An explanation for
the skewed prevalence of severe COVID-19 infection in adult males has yet to be elucidated.

In newborns, it has long been recognized that male infants are more susceptible to
respiratory distress syndrome and less likely to respond to prenatal glucocorticoid therapy
to protect against respiratory distress. Respiratory distress is intimately tied to the
production of pulmonary surfactant, e.g., pulmonary surfactant proteins have been
demonstrated to protect against influenza A. In animal studies, it was demonstrated that a
sexual dimorphism in fetal pulmonary surfactant production is influenced by the androgen
receptor (AR). For example, in rabbits, dihydrotestosterone was shown to inhibit fetal
pulmonary surfactant production in both males and females while an anti-androgen, flutamide,
was demonstrated to remove the sexual dimorphism in surfactant production. While severe
COVID-19 symptoms are primarily manifested in older adults, the similar sexual dimorphism in
the severity of respiratory disease is of interest. In addition, AR expression is low prior
to pubertal maturation and may contribute to the low incidence of severe COVID-19 infection
in children. As such, the investigators propose that the lower rate of severe COVID-19
infection in female patients may be attributed to lower androgen receptor expression.

Additional evidence to the possible implication of androgens in COVID-19 infection severity
is found in the molecular mechanism required for SARS-CoV-2 infectivity. SARS-CoV-2 is part
of the coronavirus family of viruses including SARS-CoV-1 and MERS-CoV. Coronavirus
predominantly infects type II pneumocytes in the human lung. Previously, it was demonstrated
that SARS-CoV-2 cell entry depends on priming of a viral spike surface protein by
transmembrane protease serine 2 (TMPRSS2) present in the host. In type II pneumocytes,
TMPRSS2 expression is associated with an increase in androgen receptor (AR) expression,
specifically connecting AR expression to SARS-CoV-2, due to AR-regulated TMPRSS2 gene
promoter. Moreover, angiotensin converting enzyme 2 (ACE2) has been recognized as the
attachment molecule to the viral spike surface protein, thus termed the "receptor of
SARS-CoV-2". Interestingly, ACE2 has been shown to have reduced activity by the decrease of
androgen hormones (experimental orchidectomy), possibly by decreased expression of ACE2.

A well known polymorphism of the androgen receptor is a CAG repeat in the first exon of AR
gene. The number of CAG repeats has been correlated with AR function and expression. The
primary purpose of this study is to evaluate the association of AR gene polymorphisms with
disease severity and mortality following COVID-19 infection. If an association can be
elucidated, it would imply novel treatment modalities. For example, the activation of AR can
be reduced by several classes of drugs including androgen receptor antagonists, androgen
synthesis inhibitors and antigonadotropins.