Len and Cassie Calabrese COVID-19 Corner Issue #18

Len and Cassie Calabrese COVID-19 Corner Issue #18

Len and Cassie Calabrese COVID-19 Corner Issue #18

Genetics and COVID-19: A tectonic discovery!!

The past few weeks have witnessed several breakthroughs in understanding the underlying genetic risks for COVID-19 infection. This is particularly important in trying to make sense of mortality rates. Overall, the global fatality rate has been hard to reconcile since patient management has vastly improved from a mere 6 months ago. At the extremes, mortality has been estimated to be as low as 0.01% for children 1-9 yo and perhaps as high as 20% for patients over 80. It has been estimated that perhaps as many as 5% of previously healthy adults under the age of 50 present with severe disease. We assume that when young, healthy individuals without obvious comorbidities do poorly with COVID-19 it all comes down to fault lines in their integrated host defenses and the likely culprit could variably be some subtle (pre-clinical) inborn error of immunity (i.e. IEI).

We have known for some time that our immune health, which varies across age groups, cannot be totally explained by the exposome (Len’s favorite term, in case you need to wiki it- The exposome can be defined as the measure of all the exposures of an individual in a lifetime and how those exposures relate to health). As evidence for this is the well documented fact that some people do poorly in response to a variety of non-COVID-19 infections without classic co-morbid risk factors. This has been posited to explain up to 5-10% of cases of herpes simplex encephalitis, which represents a severe manifestation of an ubiquitous viral infection. It also has been demonstrated that among young and otherwise healthy adults who continue to succumb (rarely albeit) to influenza A, possibly  1 of 3  have been documented to harbor genes indicative of impaired defenses, particularly within interferon pathways which appears logical given their known role in viral defense (1).

We would like to now draw your attention to a series of studies which now appear to be pulling back the curtain on genetic risks in COVID-19 infection. Mind you that a quick search of PubMed reveals several hundred studies linking COVID-19 and whole genome or whole exome search terms and several thousand when paired with genetics, so this is not an understudied area. Having said that, remember that mere data is not information until it is cultivated and not knowledge until supported by data and consensus and not wisdom until applied in a thoughtful manner.  The two most tectonic studies are the work of the COVID Human Genetic Effort, an international consortium aiming to explore two important phenomenon namely (is/are) Monogenic inborn errors of immunity (IEI), rare or common, underlying severe forms of COVID-19 in previously healthy individuals and (ii) Monogenic variations, rare or common, which make certain individuals resistant to the infection by the SARS-CoV2 itself, despite repeated exposure.

The Human Genetic Effort is co-led by Jean Laurent Casanova of the Rockefeller (Dr. Casanova has keynoted one of our Biologic Summits at Cleveland Clinic in the past as his work has been enlightening in understanding why some IEIs manifest as auto inflammatory or autoimmune diseases) and Helen Su of NIH. The consortium has amassed samples on several thousand patients with COVID1-19 categorized as mild to severe as well as numerous other control populations of interest.

The first study  (https://science.sciencemag.org/content/early/2020/09/29/science.abd4570 ) utilized whole genome or whole exome scanning (as well as a lot of other functional assays) and found, not surprisingly to us, that 3.5% of individuals aged 17-77 with severe COVID harbored genetic defects in autosomal recessive genes associated with biologic loss of function in interferon pathways. Interestingly many of these same genes are ones previously associated with severe outcomes in influenza A though no subject had a history of severe/life threatening influenza in the past. These data, though, are more fuel to the theory that COVID-19 usurps interferon defenses and belies much of its clinical severity in young healthy individuals. Their lack of history of severe influenza illnesses suggests that COVID-19 is apparently a stronger stimulus (i.e. stronger than influenza) which is capable of exploiting this biologic weakness of harboring these saliently expressed genes.

The second study (https://pubmed.ncbi.nlm.nih.gov/32972996/ ), was to us the blockbuster, finding  that 101 of 987 patients (10.5% !!) with life threatening COVD-19 harbored neutralizing IgG antibodies directed against Type 1 interferon (its gets complicated from here as there are numerous subtypes of Type 1 IFN and not all antibodies reacted to all or even the same subtypes). This is particularly interesting however for in a few of these patients who had pre-infection samples to test it was found that these autoantibodies were already present at time of infection. They also clearly demonstrated ex vivo that SARS CoV-2 did not stimulate cells from such patients to make Type 1 interferon and again none of these patients had histories of severe/life threatening influenza illnesses in the past suggesting incomplete penetrance for flu. 

Where do these autoantibodies come from?! Well that’s a good question as anti-cytokine antibodies in general are quite rare particularly against interferons. They have been described in some rare IEIs like autoimmune polyglandular syndrome Type 1 (essentially a defect in T reg cell genetics) and in rare patients with SLE and not surprisingly in patients undergoing IFN therapy. Mind you we are talking about 10% of severely infected patients here with a previously undescribed immunologic disease?  We have no quick summary to give you more than the data and observations in this report have been hailed around the world by leaders in the field as being groundbreaking.

Implications? Well there are plenty. First, would many of you now want to get immune plasma for your COVID-19 infection if it was not screened for these autoantibodies? Second, it puts some pause on the design and interpretation of the multiple studies of Type 1 IFN therapeutic trials for COVID-19 (they will now need to stratify for autoantibodies post hoc of course). Finally, for us rheumatologists what does this mean for the fast track of research into drugs that neutralize interferon like anifrolumab (anifrolumab targets the Type1 receptor) which looks so promising for SLE. We can only imagine that the potential safety of this class is being carefully examined by the company and Data monitoring Committees conducting these trials.  At the minimum we now must work around the 10% of severe COVID-19 patients that may have or develop these antibodies in every way – both in research and care.  We now assume that the study group has already examined these samples for cross reactivity to IFN-beta (a Type 1 IFN) and interferon lambda (a type III interferon) which we both think promising as treatments for early Stage 1 COVID-19 and expect to hear much more on this soon.

Finally there were many other genetic/COVID-19 papers also published over this time period but we will save you the trouble of reading them other than to say: yes having blood group O is good if you get COVID-19 and having A or B groups not so much. The biology is interesting but the effect size is small and for now is like being old i.e. not much to do about it.

Have some topics you want us to dig into? Email us please

calabrl@ccf.org     @LCalabreseDO

calabrc@ccf.org   @CCalabreseDO

Len and Cassie

1 Zhang, S., Zhang, Q., Casanova, J. et al. Severe COVID-19 in the young and healthy: monogenic inborn errors of immunity?. Nat Rev Immunol 20, 455–456 (2020). https://doi.org/10.1038/s41577-020-0373-7 

2 Inborn errors of type I IFN immunity in patients with life-threatening COVID-19 – https://science.sciencemag.org/content/early/2020/09/29/science.abd4570

3  Auto-antibodies against type I IFNs in patients with life-threatening COVID-19 – https://science.sciencemag.org/content/early/2020/09/23/science.abd4585

Shout out with any questions or comments, or anything you’d like to read about in future issues of COVID-19 Corner