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.

Longitudinal prediction of hospital-acquired acute kidney injury in COVID-19: a two-center study

“…Increased levels in AST and ALT in COVID-19 are associated with the need for escalated care and higher rate of mortality [ 33 ]. Elevated ferritin is indicative of inflammation and cytokine storm, amongst others [ 34 ]. Lactate dehydrogenase is a marker of cell death and multi-organ failure [ 35 – 37 ].…”

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes)

“…At least 5 out of 8 symptoms (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia and hemophagocytosis, low/absent NK activity, hyperferritinemia, and high levels of sIL-2R/sCD25) are required to make a diagnosis according to the HLH-2004 criteria, of which only 6 are commonly available in clinical practice [ 158 ]. Meanwhile, an independent study of 19 severe COVID-19 cases with symptoms of hyperinflammation (neutrophil/lymphocyte ratio > 3.5) found that none of the patients met more than three HLH-2004 criteria [ 159 ]. For HLH/CSS verification and COVID-19 [ 160 ], the modified HLH-2009 criteria can be used.…”

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis

“…This is evident in COVID-19 patients, where although an excessive cytokine reaction is evident, many of them do not fulfill the HLH criteria. A prospective study by Lorenz et al assessed HScores and a modified HLH-2004 criterion in 19 severe COVID-19 patients admitted to ICU, found a median HScore of 122, in the absence of confirmed presence of hemophagocytosis on bone marrow aspirate and a median HScore of 157, if assumed positive bone marrow aspirate criterion [172]. Notably, Prilutskiy et al performed autopsies on four confirmed COVID-19 patients which showed evidence of hemophagocytosis within pulmonary hilar/mediastinal lymph nodes but none of these patients showed hemophagocytosis in the bone marrow [173].…”

“…Notably, Prilutskiy et al performed autopsies on four confirmed COVID-19 patients which showed evidence of hemophagocytosis within pulmonary hilar/mediastinal lymph nodes but none of these patients showed hemophagocytosis in the bone marrow [173]. Of the 19 patients studied by Lorenz et al, only one patient reached a threshold >169 in the absence of the bone marrow aspirate criterion and six patients reached a threshold >169 if the bone marrow aspirate criterion was assumed positive [172]. Clark et al retrospectively reviewed 152 patients with polymerase chain reaction confirmed COVID-19 patients and demonstrated a median HScore of 52, with the majority of patients not reaching sufficient thresholds for an HLH diagnosis, although notably, many variables were missing including 46 patients who did not have ferritin levels and no patients having bone marrow biopsies collected [174].…”