COVID-19 has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other "respiratory" viruses, SARS-CoV-2 infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalisation of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5 days results in sustained downregulation of ACE2 protein expression, and that ACE2 is under negative-feedback regulation. We then expose openly-available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of interegulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer/promoters that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2 - and H2O2 (a "ROS storm"), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus for patients who fail to rapidly suppress viral replication, the newly-appreciated ACE2 co-regulated cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding which should help optimise therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.