Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

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.

Figure 1

Depicts individual’s clinical courses. Time from ICU-admission in days is displayed on the x-axis. Upward vertical movement indicates worsening of the clinical condition (up: intubation + positive pressure ventilation (PPV), requiring prone positioning, requiring sustained low efficiency dialysis (SLED), advanced organ support (ADVOS = dialysis + albumin-dialysis + CO2 removal) or extracorporeal membrane oxygenation (ECMO = oxygenation + CO2-removal). Downward vertical movement indicates reduced requirement of organ support, spontaneous breathing and discharge from ICU in good clinical condition.

Figure 2

Immunologic parameters, neutrophilia and IL-6 in relation to clinical course at time of ICU admission, at day 4–7 (median 6 days)—when patients were still intubated—and prior to extubation if applicable (median 10 days). The median of 10 days differs from the median intubation time of 8.5 days (see main manuscript) since not all patients were intubated within 24 h post admission. Data from the unfavourable group (no extubation possible) were matched accordingly to achieve equivalent median days post ICU admission. Abbreviations: C-reactive-protein (CRP), Interleukin-(IL)-6, neutrophile/lymphocyte-ratio (NLR). This analysis includes 17 patients who had undergone intubation (1 patient each from the favourable and the unfavourable group were excluded, see methods section). Each datapoint represents one patient. Statistical significance for independent t-test between groups: n.s. = not significant, * = p < 0.05, ***p < 0.001. Statistical significance for repeated measure ANOVA † = not significant, § = p < 0.05, §§ = p < 0.01, §§§ = p < 0.001.