Role of RNAaemia and the Immunopathology of Moderate-to-Severe COVID

December 17, 2021

Viewpoint article published in The Lancet Rheumatology proposed that different presentations of COVID-19 may require varied approaches for treatment. Researchers shared that while mild COVID-19 may best be treated with antiviral cocktails, immunomodulatory therapy may benefit those with excessive innate immune responses in the lungs, including pulmonary immunothrombosis.

One hallmark sign of COVID-19 is the activation of cytokine storm with the release of pro-inflammatory cytokines. This aggressive inflammatory response may increase the risk of mortality. Tocilizumab, used to treat severe rheumatoid arthritis and juvenile arthritis, is an interleukin (IL)-6 receptor blocker, effective in treating cytokine storm syndromes.

While clinical studies have emerged using corticosteroids and IL-6 inhibitors, the use of therapies specifically targeted at mitigating cytokine storm syndromes has only recently been tested. Authors of this Viewpoint article shared that “immunotherapy would improve survival only in clinical settings in which excessive innate and adaptive immune responses (including autoimmune responses) occur in the context of rapid control of SARS-CoV-2 replication.” The benefits of corticosteroid or IL-6 receptor blockade in patients with COVID-19 have not been replicated consistently in controlled studies; this includes Tocilizumab. Moreover, distinguishing ongoing infections from excessive inflammatory responses and immunothrombosis, “could be useful to improve survival.”

Viral RNA can linger in the blood for weeks after initial infection, also persisting in the respiratory and gastrointestinal tracts for several weeks in some patients with more severe cases of COVID-19. Additionally, high serum cytokine concentrations can be linked to ongoing replication of SARS-CoV-2. “A key observation in patients with severe COVID-19 is that RNAaemia or detectible SARS-CoV-2 RNA in the blood, but not proven cultivable virus, is linked to serum concentrations of IL-6 up to 10 times higher than in patients without RNAaemia.” RNAaemia is the occurrence of COVID-19 pneumonia with the presence of viral RNA in the blood. Modest RNAaemia has been linked with high IL-6 concentrations and mortality in severe COVID-19 pneumonia patients.

Those in acquired immunodeficiency states with rheumatological conditions, including those with prolonged corticosteroid treatment, B-cell depleting therapy, and immunosuppressive drugs, have “marked effects” on T-cell function, and may lead to higher rates of COVID-19 mortality. Authors highlighted that these factors may contribute to ongoing viral replication, “which might be a major challenge in selecting patients for immunosuppression and means that consideration of early immunomodulatory therapy in patients with moderate-to-severe COVID-19 pneumonia needs careful re-evaluation.” That being said, some forms of immunotherapy actually seem to improve survival in severe cases of COVID-19. It is possible for cases where viral replication is controlled but a hyper-inflammatory response still occurs and creates immunothrombosis. In fact, pulmonary immunothrombosis occurs in over 90% of severe COVID-19 cases. Immunothrombosis involves the innate immune system to form blood clots. SARS-CoV-2 RNA in the blood of severe COVID-19 patients versus mild cases supports the idea that the blood-air barrier within the lungs breaks down, allowing viral RNA to spread and immunothrombosis to develop.

The authors point out that immunothrombosis without viral replication may help explain the benefits of immunomodulatory therapy when used in the post-viral replication phase of severe COVID-19 pneumonia cases. It was discovered in earlier research that heparin has not been seen to improve outcomes in patients with severe COVID-19. Additionally, the presence of viral RNA is “likely to result in temporary failure of immunological tolerance against many self-proteins, with emergency of multiple autoantibodies.” In mouse models, certain autoantibodies were shown to exacerbate disease. Immunotherapy may suppress these autoantibodies, including hyper T-cell responses.