Background to new treatments for COVID‐19, including its chronicity, through altering elements of the cytokine storm

Summary Anti‐tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL‐7 are of considerable interest in treating COVID‐19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well‐conducted human trials. Newer information with anti‐TNF biologicals has encouraged reintroducing this concept for treating COVID‐19. Viral models have had encouraging outcomes, as have the effects of anti‐TNF biologicals on community‐acquired COVID‐19 during their long‐term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL‐7Rα, the receptor for IL‐7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody‐based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL‐7‐ enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti‐TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL‐7, currently being trialed as a COVID‐19 therapeutic. The principles behind these COVID‐19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4‐positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.