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

Study Overview
=================
Brief Summary
-----------------
The COVID-19 Androgen Sensitivity Test is a non-invasive In-Vitro Diagnostic device that utilizes Next Generation Sequencing Technology (NGS). The results of the test are used by a physician to assess the risk of developing severe symptoms following COVID-19 infection, The COVID-19 Androgen Sensitivity Test requires a health care professional to collect a DNA sample using an FDA cleared DNA sample collection kit.

Detailed Description
-----------------
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.

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

Conditions
-----------------
SARS-CoV 2, COVID, COVID-19, Androgenetic Alopecia, Androgen Receptor Abnormal, Androgen Deficiency

Intervention / Treatment
-----------------
* Diagnostic Test: CAG length <22
* Diagnostic Test: CAG length >=22


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male over the age of 18 First time present at the site Laboratory confirmed SARS-CoV-2 infection Able to give informed consent Exclusion Criteria: Unable to give informed consent Diagnosed with an additional respiratory co-infection XXY males

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| COVID-19 Male Patients<br>Males with laboratory confirmed SARS-CoV-2 infection | Diagnostic Test: CAG length <22<br>* CAG repeat length in exon 1 of AR gene<br>* Other names: Genetic Test - Short CAG Allele;Diagnostic Test: CAG length >=22<br>* CAG repeat length in exon 1 of AR gene<br>* Other names: Genetic Test - Long CAG Allele;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital-free days to Day 28 [ Time Frame: 28 days] | Defined as 28 days minus the number of days from randomization to discharge home. If a patient has not been discharged home prior to day 28 or dies prior to day 28, hospital free days will be zero. | 28 days | 
| 1. Severity of Disease | Defined as discharged, hospitalization, admission to intensive care unit [ICU] and death | Day 28 |