Sunday, March 1, 2020

Coronavirus COVID-19: Urgent need to explore the precision medicine component?

In cancer, we take it for granted that as few as 1-2 percent of patients may have distinct responses because of distinctive genomic patterns - such as lung cancer patients with ALK or ROS-1 driver mutations.

In SARS, we read that the mortality rate is around 1-2%.   The press is attributing this to generic cofactors - age, concurrent illness - but there is some risk this may be "satisficing" - stopping when we hear the first  reasonable explanation so we can move on to another question.  The first possible or even probable explanation isn't always right, however (for data on COVID-19 and age, here, here.)

According to Chen et al. in Lancet - who studied a hospital population, pre-selected for severity - of 99 patients observed for a month, 11 developed multi-organ failure and death (here).   WHO guidelines emphasize that terminal care may shift to the management of sepsis and septic shock (here).   In the earlier SARS crisis, reports of coinfections appeared (e.g. Gu & Korteweg, Am J Pathol 2007, 170:1136, here.)

It's been known since 2005 that respiratory coronaviruses can induce "hyperattack" immune responses which may be fatal - e.g. Perlman & Dandekar in Nature Rev Immun 5:917 (here).  Popular sources summarize this in 2020 as, "coronaviruses can spark a viral-induced fire through many of a person's organs" e.g. here.  An academic journal in 2020 remarks, "immunopathogenesis [in coronavirus] is associated with an immune response that is out of control" (e.g. Li et al., J Med Virol epub here.)

The facts that children are unlikely to get severe COVID-19 disease and men are more likely to die than women also suggests that subtleties of immune regulation and dysregulation are important.

Possible Precision Medicine Aspects of COVID-19: Things We Can Do Now

Molecular pathology can make many contributions to understanding the mortality pathways of the COVID-19 virus, besides access to rapid viral identification.

Do HLA or Other Innate Genomic Factors Raise the Odds of a Crisis Response?

Possibly.  Some review literature points in SARS to some reported high odds ratios (4 and higher) with some HLA genotypes (see Sun & Xi, 2014, book chapter, here).   An HLA receptor class 1 antigen can service as a receptor for some coronaviruses (Gralinski & Baric, J Pathol 2015 235:185, here.) although COVID-19 is thought to bind to the same angiotensin (ACE2) receptor as SARS-CoV (del Rio, JAMA 2/28, here).   In any case, we should also look beyond the main HLA associations and look at other genomic factors contributing to the dysfunctional immune response - we may find something much more specific than generic contributing factors like age or heart failure.

Genomics of Host Response

See an excellent open access paper by Gunsolus, Sweeney, et al., in J Clin Microbiol 2019 (here).   In a prior article (Sweeney et al., Crit Care Med 46:915, 2018, here), Sweeney and colleagues discovered and categorized three distinct molecular categories of host response to sepsis.  Each has different implications for etiology and novel immumodulatory interventions.   Potentially, patients developed a septic shock pattern after COVID-19 fall disproportionately into one of these categories, in a way that will be important to identify.

Do Coexisting Passive Infections Raise the Odds of a Crisis Response?

Another factor could be coexisting and otherwise passive infections.  (See assertions that healthcare workers do worse; here.)   One approach would be to sample the blood microbiome of patients with mild cases of SARS and looking for distinguishing associations with those who develop a fulminant COVID-19 syndrome with multiorgan failure and sepsis.   The blood microbiome can now be screened in non-selective (broad-band) ways by next-generation sequencing (e.g. one example is the commercialized Karius Test, Blauwkamp et al., 2019, here.)

Another approach would be to take patients already in multi-organ failure and sepsis and use blood microbiome screening to look for co-infections associated with death.   This lacks the predictive element but is more focused and still informative.


In a separate article, I discuss the severity of CMS policies for underfunding molecular virology (here).   CMS policies have to change quickly to meet the crisis.

However, venture capital and federal funding is flowing into this space.  Karius raised $165M in February 2020 (here), and Inflammatix (of which Sweeney is CEO; cited above) recently raised $32M (here) plus BARDA funding.