It is well established that a subset of patients infected with COVID-19 go on to exhibit cytokine storm syndrome (COVID-CSS). COVID-CSS is a cytokine release syndrome (CRS) thought to be due to a dysregulation of lymphocytes and macrophages, resulting in a hypersecretion of cytokines that produce massive systemic inflammation, rapid progression of pulmonary infiltrates, multi-organ failure, and often, death.
As this pandemic continues to evolve and the full spectrum of clinical manifestations of COVID-19 come to light, knowledge about the presentation and management of other hematological cytokine storm syndromes may help the pharmacist manage these critically ill patients during this pandemic.
Cytokine storm or hypercytokinemia has been associated with graft-versus-host disease (GVHD), viral infections including influenza, severe acute respiratory syndrome (SARS), autoimmune diseases such as systemic lupus erythematosus, systemic juvenile idiopathic arthritis, hematological conditions such as hemophagocytic lymphohistiocytosis (HLH) and drugs, such as the experimental agent TGN1412, an anti-CD28 monoclonal antibody or CAR (chimeric antigen receptor)-T cell therapy.
In a recent review, COVID-19 CSS was compared with hematological CSSs associated with secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicenter Castleman disease (iMCD), and CAR-T cell CRS, which represent three well-known CSSs.
Secondary sHLH occurs in adults following infections (Epstein-Barr virus, cytomegalovirus or HIV), lymphomas, macrophage activation syndrome-HLH subtype (MAS-HLH, a primary rheumatological condition), or the administration of drugs such as immune checkpoint inhibitors or lamotrigine. It is characterized by fever, cytopenia, multiorgan dysfunction, T-cell activation (as diagnosed by an increase in soluble interleukin-2 receptors), organomegaly, profound hyperferritinemia, and a coagulopathy. Unless sHLH results from MAS-HLH, which generally has a milder course, the mortality rate can be as high as 70%.
Pathophysiologically, all of these CSSs may share the same terminal pathway, although this may have been achieved via different mechanisms. Overlapping clinical findings shared among the various CSSs include marked elevations in IL-6, hyperferritinemia, and coagulopathy. COVID-CSS may result from delayed type 1 interferon signaling, which allows for a buildup of inflammatory macrophages. This manifests as markedly elevated cytokine levels, vascular leak, and impaired T-cell response. Other cytokines that are elevated in COVID-CSS include IL-2R, IL-10, and TNF cytokines. Based on autopsy results, it appears that SAR-CoV-2 infection leads to macrophage production of IL-6, which triggers immune dysregulation.
Therapies used in the management of sHLH include etoposide, dexamethasone, cyclosporine, emapalumab (monoclonal antibody [MAb] against interferon-gamma), ruxolitinib (JAK/STAT inhibitor), and anakinra (IL-1 receptor antagonist). CAR-T cell CRS is managed with corticosteroids and tocilizumab (MAb against IL-6). Drugs that have been employed in the management of mICD include siluximab and tocilizumab (both MAbs against IL-6), rituximab (MAb against CD20 antigen on B-lymphocytes), and sirolimus (mTOR inhibitor).
Since the CSSs share many similarities in disease presentation and immunological abnormalities, it is not surprising that medications used in managing other CSSs have also been tried in COVID-CSS. Among the therapeutic options being studied in COVID-CSS are corticosteroids, IL-6 blockers (tocilizumab, sarilumab, siltuiximab), IL-1 inhibition (anakinra), TNF inhibition, interferon-gamma inhibition (emapalumab), JAK inhibition (baricitinib, ruxolitinib, tofacitinib), complement inhibition, low molecular weight heparin (LMWH), and IV immune globulin (IVIG). (This review article lists published data on the use of these agents as of April 20, 2020.)
Drugs that have been incorporated into NIH treatment guidelines include corticosteroids, IL-6 blockade, IL-1 inhibitors, and JAK inhibitors. The NIH Panel recommended against the routine use of systemic corticosteroids in mechanically ventilated patients with COVID-19 who do not have acute respiratory distress syndrome (ARDS). For COVID-19 patients with ARDS, the Panel stated that there is insufficient evidence to recommend for or against the use of the glucocorticoids.
The therapeutic field in the management of COVID-CSS is rapidly evolving. Pharmacists need to stay abreast of the latest developments in order to optimally manage critically ill victims of this pandemic.
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