More Clues on How COVID-19 Can Turn Immune System Against Us

Damian McNamara

August 25, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

A history of age-related macular degeneration or thrombocytopenia, thrombosis, or hemorrhage are associated with greater risk for COVID-19 morbidity and mortality, new evidence suggests.

The findings emerge from research aimed at uncovering specific ways immune dysregulation contributes to more severe COVID-19. This deeper dive into mechanisms lurking behind poorer clinical outcomes implicates differences in complement and coagulation components of the immune system — both of which are involved in inflammation.

Sagi Shapira, PhD

"In this case, it appears, at least in part, that SARS-CoV-2 engages the complement and coagulation cascades — the molecular details of which we have some hints to and are actively working on — which in turn leads to our immune system acting against us," co-senior author Sagi Shapira, PhD, assistant professor of systems biology (in microbiology and immunology) at Columbia University, New York City, told Medscape Medical News.

Lead author Vijendra Ramlall, from Columbia's Department of Biomedical Informatics and Department of Physiology & Cellular Biophysics, and colleagues published their findings online August 3 in Nature Medicine.

The researchers evaluated 11,116 patients with suspected SARS-CoV-2 infection in a retrospective, observational study. The patients presented to NewYork-Presbyterian/Columbia University Irving Medical Center between February 1 and April 25. A total of 6398 (58%) tested positive.

Participants' mean age was 52 years and 45% were male. Almost 27% had coronary artery disease, 13% had type 2 diabetes, and 12% were obese. A total of 88 patients had a history of macular degeneration, 4 had complement deficiency disorders, and 1179 had coagulation disorders. The investigators considered history of macular degeneration a proxy for complement-activation disorders.

Key Findings

Risks associated with macular degeneration and the coagulation disorders, including mechanical ventilation and death, were independent of age, sex, or history of smoking.

"Notably, we did not find evidence that smoking status (past or present) is a significant risk factor for either mechanical respiration or mortality," the researchers note.

Among participants with a history of macular degeneration, 14 patients were intubated and 22 died.

Shapira and colleagues also performed transcriptional genetic profiling. This analysis revealed type-1 interferon- and interleukin-6-mediated inflammatory responses involved in the complement and coagulation pathways.

The investigators also identified candidate genetic variants in these pathways associated with more severe COVID-19 infection. The genetic findings will require more research to confirm, they note.

A Bigger Picture?

This is not the first study to link dysregulation and genetic variation in complement and coagulation pathways with viral infection. For example, similar findings with dengue virus infection also correlate to more severe disease. This suggests, the authors note, that "complement and coagulatory disfunctions may represent risk factors for a broad range of pathogens."

"More broadly, I think we're poised to leverage the framework that we've developed — that combines structural biology, analytical approaches to electronic heath records, and genomics — to uncover fundamental biology as well as underlying pathophysiology [that] contribute to morbidity and mortality associated with other infectious diseases," Shapira said.

Despite the progress, Shapira cautioned that it remains too early to change clinical practice. "Though there are hints that existing complement and coagulation targeting therapies may hold promise for COVID-19 patients, those studies are in the early phases. Unfortunately, we are not at the point where the results should influence standard-of-care."

In the meantime, he added, "Physicians' biggest strength here is with prevention. In other words, be aware of their patient's comorbidities, talk with them, and encourage those with notable risk factors — including coagulopathies and complement dysfunctions — to be especially mindful."

"Once infected with SARS-CoV-2, those patients with histories of complement and coagulatory dysfunctions may be good candidates for immunotherapies," Shapira said.

Clinical trials are exploring the therapeutic potential of existing drugs that target the complement and coagulation pathways, Shapira said. "We are eager to see if we can convert what we've learned into valuable treatment."

Complementary Findings?

"I don't find it particularly impactful," Benjamin tenOever, PhD, professor of microbiology at Icahn School of Medicine at Mount Sinai in New York City, told Medscape Medical News when asked to comment on the study.

"All of these findings were reported well before this publication. We have known about complement and clotting in response to SARS-CoV-2 since May," added tenOever, senior author on a study published online May 28 in the journal Cell that addressed imbalanced host responses linked to development of COVID-19.

Shapira responded that although the peer-reviewed Nature Medicine report was published online August 3, a preprint of the study was published in early May. He also pointed out that the role of complement and coagulation functions in coronavirus infections was understood "well before this pandemic even started" in small animal studies and human research exploring SARS-1 and MERS infection.

Shapira and tenOever have disclosed no relevant financial relationships.

Nat Med. Published online August 3, 2020. Full text

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