COVID–19 and Progesterone: Part 2. Unraveling High Severity, Immunity Patterns, Immunity grading, Progesterone and its potential clinical use

Severely ill COVID–19 (Corona Virus Disease of 2019) patients have a hyperinflammatory condition with a high concentration of pro-inflammatory cytokines termed the cytokine storm. This milieu is reported to cause acute lung injury, oxygen deprivation, multiorgan damage, critical illness, and often death. Post SARS–CoV–2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection, the fight between the invading virus and the host's immune system would either terminate in recovery, with eradication of the infection and regulation of the immune system; or there would be a continuation of immune attacks even after the virus has been cleared, leading to immune dysregulation and disease. This outcome is chiefly dependent on two factors: (1) the patient's immune response, and (2) sufficiency plus efficiency of the regulator(s). Concerning the first, the present research introduces a framework based on different types of immune responses to SARS–CoV–2 along with known disease examples, and how this relates to varying clinical outcomes and treatment needs for COVID–19 patients. About the second factor of ‘regulator(s)’, part 1 of the manuscript described in depth the regulatory role of progesterone in COVID–19. The present study investigates five immunity patterns and the status of the regulatory hormone progesterone with respect to the two established demographic risk factors for COVID–19 high-severity: male sex, and old age. The study evaluates the status of progesterone as a credible determinant of immune regulation and dysregulation. It duly relates the immunity patterns to clinical outcomes and evinces indications for clinical use of progesterone in COVID–19. It proposes a clear answer to the question: "why are males and old patients most likely to have critical illness due to COVID–19?" The study highlights clinical domains for the use of progesterone in COVID–19. Part 2 of this research introduces the concept of immunity patterns and immunity grading. These concepts herewith provided for the clinical course of COVID–19 also apply to other hyperinflammatory conditions. Possible clinical applications of progesterone to treat critically ill COVID–19 patients will open an avenue for hormonal treatments of infections and other immune-related diseases.