COVID toes led an international group of researchers to identify a previously unknown role of Immunoglobulin A (IgA) in severe COVID-19.
To date, over 50 million people have been affected by COVID-19 since the start of the pandemic. More than one million deaths have resulted from a range of virus-associated causes and complications, including acute respiratory distress syndrome and blood clots in the heart.
The initial connection between COVID toes and autoimmunity was made by Dr. Lukas Flatz, a professor of dermatology in Zurich and St. Gallen, and the senior author of a recent paper published in Clinical Infectious Diseases. “At the University Hospital Zurich, we wondered why patients with severe COVID-19 had multiple thromboses (blood clots), despite receiving preventive treatment,” says first author Dr. Omar Hasan Ali, a dermatologist from Zurich who recently joined LSI’s Penninger Lab following a research rotation with Dr. Flatz.
Flatz’s flash of inspiration was based on clinical experience with other autoimmune reactions, when the body attacks its own tissues. In this case, the blood clots and purplish toes reminded the Swiss team of patients with a condition known as antiphospholipid syndrome (APS).
“As clinicians, when we see multiple thromboses and purplish toes, we need to investigate for APS,” says Hasan Ali. “This is a rare phenomenon in which a trigger, usually an infection, makes the body develop antiphospholipid antibodies (aPL). These antibodies interfere with proteins that play an essential role in blood coagulation. When you mess with the coagulatory cascade, you can develop thromboses.”
There are many unknowns to APS, but it has been reported to be triggered by severe viral lung infections. APS leads to clots that can occlude larger vessels, as well as very small ones, which can stop the blood flow in hands and feet, resulting in blue toes and fingers.
“And so, when saw these blue toes and thromboses in severe COVID-19, we thought, what if the virus triggers APS?”
Flatz and Hasan Ali were further encouraged by a small case series with three stroke patients published in the New England Journal of Medicine. “All three patients had elevated aPL, suggesting APS,” says Hasan Ali. “The authors of this article found aPL based on the antibody IgA, and not so much the ‘typical’ IgG antibodies that we usually look for in APS. This was an important clue hinting to the novel coronavirus: IgA are at the forefront in protecting the mucus membranes and lung, where it hits first. We hypothesized that the virus causes the body to produce rare IgA-based aPL, resulting in thromboses. Other researchers investigated APS with IgM and IgG antibodies, and came up dry, but for us, it was clear. To show the association of IgA and COVID-19, we needed to asses them in patients with mild and severe COVID-19. And this was what we investigated.”
A retrospective international cohort study was launched with 64 patients, divided into three groups: one with mild COVID-19 from the Principality of Liechtenstein and two cohorts with severe COVID-19 from Switzerland. Measurements included clinical parameters, laboratory inflammation markers and two distinctive aPL.
“Obtaining theses samples was not easy, as Switzerland is a neighbor of Northern Italy and extra levels of security were put in place everywhere in anticipation of rising COVID-19 numbers,” recalls Hasan Ali. “There was a lot of pressure to obtain the samples safely in very little time, as I was working in parallel on my move to Vancouver for my postdoc. But with an incredibly dedicated collaborative effort with our partners in Buchs, Zurich, Vienna, Vaduz and Tel Aviv, we were able to meet that challenge just on the verge of my departure.”
“In APS, one can have antibodies based on IgM, IgG and IgA, so we had to measure all the three antibodies. When we completed our first results, we had a small Eureka moment. What we found was that there is a highly significant association with elevated IgA-aPL in patients with severe COVID-19, just as we suspected,” adds Hasan Ali. “In addition, total IgA antibodies were significantly higher as well, which may indicate a strong overall immune reaction in the mucosa in severe disease. There was no consistent correlation with IgG or IgM, which clearly suggests that IgA is a major factor.”
LSI’s tie in with the research extended beyond Hasan Ali’s new fellowship. “During data assessment, I presented our preliminary results to LSI Director Josef Penninger for guidance on potential mechanisms of action and data interpretation,” says Hasan Ali. “I was excited, as Josef Penninger is one of the most noted experts on SARS-CoV-2 to date.” Dr. Penninger made several key contributions to the paper, one of which was rooted in his research on SARS-CoV-1. His group demonstrated that SARS leads to a critical upregulation of Toll-like receptor 4 in the lung, which is known to enhance blood clotting. This showed that the SARS-COV-2 virus can promote blood clotting in various ways.
“At the moment, what we can say is that we see a novel significant association of severe COVID-19 with IgA and IgA-aPL, that may emerge from a strong response against SARS-CoV-2 in the lung. This may imply, that autoantibodies have a causal role in more severe COVID-19 and its many systemic complications, and further suggests that COVID-19 is a very potent inductor of autoimmunity,” emphasizes Hasan Ali. “We are currently working on follow-up studies investigating the triggers and potential mechanisms of these autoimmune responses. The Penninger Lab provides the profound expertise and tools to make this happen, and we already have preliminary results.”
Interest and receptivity in Vancouver’s clinical community will help drive the project forward. I am very, very excited about the road ahead,” concludes Hasan Ali.
The project has been supported by Swiss National Science Foundation (SNSF) grants to Drs. Hasan Ali and Lukas Flatz. Dr. Hasan Ali’s main research focus is on the clinical efficacy of checkpoint inhibitor therapies to combat metastatic skin cancer. He also explores autoimmune reactions in severe COVID-19.
Read the Paper
Hasan Ali O, Bomze D, Risch L, Brugger SD, Paprotny M, Weber M, Thiel S, Kern L, Albrich WC, Kohler P, Kahlert CR, Vernazza P, Bühler PK, Schüpbach RA, Gómez-Mejia A, Popa AM, Bergthaler A, Penninger JM, Flatz L. Severe COVID-19 is associated with elevated serum IgA and antiphospholipid IgA-antibodies. Clin Infect Dis. 2020 Sep 30:ciaa1496. doi: 10.1093/cid/ciaa1496. Epub ahead of print.