Secondary hemophagocytic lymphohistiocytosis versus cytokine release syndrome in severe COVID-19 patients

Abstract

COVID-19 or SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome/pneumonia with features of cytokine storm reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH), which can be diagnosed by the calculated HScore. Recent reports have suggested favorable responses to the interleukin-1 receptor antagonist, anakinra in patients with COVID-19 associated secondary HLH. In our single institution study, we compared 14 COVID-19 cytokine storm patients with 10 secondary HLH patients seen immediately prior to the pandemic (non-COVID-19), to determine whether diagnostic features of secondary HLH were typically seen in COVID-19 patients presenting with cytokine storm. Although most of our COVID-19 patients did not fulfill diagnostic criteria for HLH, we hypothesize that identification of HLH may relate to the severity or timing of cytokine release. Based on our observations, we would suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria. Impact statement Severe COVID-19 associated pneumonia and acute respiratory distress syndrome has recently been described with life-threatening features of cytokine storm and loosely referred to as hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Although a recent report indicated favorable responses to the interleukin-1 receptor antagonist, anakinra in eight patients with COVID-19 secondary HLH diagnosed using the HScore calculation, others have suggested that the diagnosis of secondary HLH is uncommon and that the use of the HScore has limited value in guiding immunomodulatory therapy for COVID-19. Here, we provide additional perspective on this important controversy based upon comparisons between 14 COVID-19 cytokine storm patients and 10 secondary HLH patients seen immediately prior to the pandemic. We hypothesize that identification of HLH may relate to the severity or timing of cytokine release and suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

“…In children with MIS-C there was a significant reduction of lymphocytes and platelets as compared to the COVID-19 group. Notably lymphopenia and thrombocytopenia are also typical of the hyperinflammatory form of COVID-19 in adults (7,12). The analysis of the plasmatic levels of inflammatory chemokines and cytokines in patients with COVID-19 and MIS-C showed higher levels of IL-6, CXCL8, CCL2/MCP-1, CXCL9/MIG, and CXCL10/IP-10 in MIS-C, whereas CCL5 levels were significantly higher in the COVID-19 group.…”

“…COVID-19 adult patients, who develop the most severe disease, usually display a hyper-inflammatory state, resembling secondary hemophagocytic lymphohistiocytosis (sHLH) (6,7). There is also evidence that critically ill COVID-19 patients, as measured based on PaO2/FiO2 ratio (<200) (8,9), display higher plasmatic levels of chemokines (CXCL8, CXCL9, CXCL10), cytokines (IL-6, IL-10), and reactive oxygen species (ROS), bringing attention to the role of the host immune system in developing infection-related complications (10,11).…”

“…Cardinal features of sHLH include unremitting fever, cytopenias, hepatosplenomegaly with liver dysfunction, skin rash, coagulopathy, and hyperferritinaemia, and variable neurologic symptoms; pulmonary involvement (including ARDS) occurs in approximately 50% of patients (6). Thus, ferritin, D-dimer, lactate dehydrogenase (LDH), liver enzymes, and frequent monitoring of the blood cell count have been included in routine laboratory tests, confirming some features of sHLH in critical ill COVID-19 adult patients, although the classic HLH criteria are usually not satisfied (7,10,12). Zhou F and colleagues found that the factors associated with admission to the Intensive Care Unit (ICU) and death in a cohort of COVID-19 patients were older age, comorbidity conditions, and elevated body mass index, together with lymphopenia, elevated blood levels of liver enzymes, LDH, D-dimer, and ferritin (13).…”

Autoimmune and Rheumatic Manifestations Associated With COVID-19 in Adults: An Updated Systematic Review

“…Autopsy studies demonstrated a high percentage of hemophagocytosis in COVID-19 patients' bone marrow, pulmonary lymph nodes, or spleen, ranging from 75 to 94% (87,88). Using a validated hemophagocytic syndrome diagnostic score (HScore) cut-off point of 168 (89), we identified a total of 15 cases of COVID-19-associated HLH ( Table 3) (88,(90)(91)(92)(93)(94). However, the reported prevalence of HLH in severe COVID-19 patients was as low as 7% (93,94).…”

“…Using a validated hemophagocytic syndrome diagnostic score (HScore) cut-off point of 168 (89), we identified a total of 15 cases of COVID-19-associated HLH ( Table 3) (88,(90)(91)(92)(93)(94). However, the reported prevalence of HLH in severe COVID-19 patients was as low as 7% (93,94). Notably, routine examinations for serum triglycerides and fibrinogen, hepatosplenomegaly, or tissue hemophagocytosis were not always performed in these studies.…”