Abstract
Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.
Highlights
Severe COVID-19 associated respiratory failure, poses the one challenge of our days
In cases of serious COVID-19 with pneumonia and acute respiratory distress syndrome (ARDS), tocilizumab, a humanized monoclonal Interleukin-6-receptor antagonist, is administered in a phase II open label clinical trial (NCT04317092) to supress hyperinflammation that is assumed to cause fatal lung and multiorgan injury [6,7]. This is supported by cohort data from China, which report increased ferritin, and elevated TNF-α, IL-6 and IFN-γ levels in severe versus mild COVID-19-cases
Whether “virus-associated” cytokine release syndrome (CRS), secondary hemophagocytic lymphohistiocytosis (sHLH) or both are present in severe COVID-19 profoundly impacts our understanding of the disease and impacts on therapeutic strategies
Summary
Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. In cases of serious COVID-19 with pneumonia and acute respiratory distress syndrome (ARDS), tocilizumab, a humanized monoclonal Interleukin-6-receptor antagonist, is administered in a phase II open label clinical trial (NCT04317092) to supress hyperinflammation that is assumed to cause fatal lung and multiorgan injury [6,7] This is supported by cohort data from China, which report increased ferritin, and elevated TNF-α, IL-6 and IFN-γ levels in severe versus mild COVID-19-cases. Based on these preliminary data, cytokine release syndrome (CRS) or virus induced adult secondary hemophagocytic lymphohistocytosis (sHLH) have been proposed as underlying aetiology of severe COVID-19 7,8 The latter is a clinical syndrome, characterized by massive systemic inflammation, persistent fever flares, hepatosplenomegaly, and severe cytopenia, which is rooted in hemophagocytic activity in bone marrow. Charts were reviewed by two independent HLHexperienced clinicians to rule in or out actual sHLH
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