key: cord-0736859-mn8q521a
authors: Buonaguro, Franco M.; Ascierto, Paolo A.; Morse, Gene D.; Buonaguro, Luigi; Puzanov, Igor; Tornesello, Maria Lina; Bréchot, Christian; Gallo, Robert C.
title: Covid‐19: Time for a paradigm change
date: 2020-07-03
journal: Rev Med Virol
DOI: 10.1002/rmv.2134
sha: 8f73f9f5730de6303008fa997be62c65b0a4a91a
doc_id: 736859
cord_uid: mn8q521a

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line coping with Covid-19 should focus on this reaction and give it the urgency they would afford to traditional cases of anaphylaxis.

Physicians are more familiar with IgE-mediated anaphylaxis, which represents the major mechanism underlying allergic anaphylaxis and is primarily mediated by histamine release (Figure 1 ). 9 The cytokine-release reaction, mainly related to IL6 (besides TNF-α and IL-1β), represents a hypersensitivity reaction (HSR), triggered by chimeric, humanized, and human mAbs and chemotherapeutic agents, including oxaliplatin. HSR mediators (ie, IL-6) activate monocytes, macrophages, mast cells, and other immune cells with the Fc gamma receptor (FcgR)-an essential player of many immune system effector functions, including the release of inflammatory mediators and antibodydependent cellular cytotoxicity. 9 Cytokine storm reactions are further characterized by activation of direct and indirect activation of the coagulation pathway. In particular the complement cascade generates anaphylatoxins, such as C3a and C5a, which bind to complement receptors resulting in the release of histamine, leukotrienes, and prostaglandins. 9 All such molecules contribute to the main symptoms such as flushing, hives, hypoxia, vasodilation, and hypotension. In patients infected with influenza A virus (eg, H5N1), the inflammatory cytokines such as IL-1β, IL-8, and IL-6 play a major role in mediating and amplifying acute lung injury (ALI) and ARDS by stimulating C5a chemotaxis.

The C5a induces innate immune cells including mast cells, neutrophils, and monocytes/macrophages to release proinflammatory cytokines such as IL-12, TNF-α, and macrophage inflammatory proteins-1α. In addition, C5a also stimulates adaptive immune cells such as T and B cells to release cytokines such as TNF-α, IL-1β, IL-6, and IL-8. The clinical condition caused by many cytokines triggered by highly pathogenic viruses like H5N1, has been called a "cytokine storm". Cytokines were rapidly induced at 24 hours post-infection with H5N1. The proinflammatory cytokines including IL-1β and TNF-α might contribute to the severity of disease by promoting maximal lung inflammation caused by H5N1 viral infection. 10 

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