Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic

Abstract

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Infliximab can reduce mortality from 35 to 14% in critically ill patients with COVID-19: perhaps some potential confounders to consider

“…Other drugs such as infliximab may be life-saving in this group of patients. In conclusion, on the basis of the difference in ferritin levels between the two groups and the potential diagnosis of sHLH, the two groups in this study are not well matched [3]. A diagnosis of sHLH could explain the enormous cytokine storm responding so well to infliximab [1] and may also explain why dexamethasone is so effective in patients with severe COVID-19 [4].…”

“…Looking at the baseline characteristics of the patients, we can see that ferritin levels in the infliximab group were almost double those in the control group (2777.4 vs 1453 μg/L) [1]. It is possible that the patients in the treated group may have had secondary hemophagocytic lymphohistiocytosis (sHLH) syndrome induced by SARS-CoV-2 [3]. The HScore, one of the tools to diagnose HLH, assigns no points to a ferritin below 2000 μg/L, while a ferritin between 2000 and 6000 μg/L adds 35 points, showing that the limit of 2000 μg/L is really crucial [3].…”

“…It is possible that the patients in the treated group may have had secondary hemophagocytic lymphohistiocytosis (sHLH) syndrome induced by SARS-CoV-2 [3]. The HScore, one of the tools to diagnose HLH, assigns no points to a ferritin below 2000 μg/L, while a ferritin between 2000 and 6000 μg/L adds 35 points, showing that the limit of 2000 μg/L is really crucial [3]. Due to the massive cytokine release seen in patients with the condition, HLH is considered to be a cytokine storm syndrome [3].…”

“…The HScore, one of the tools to diagnose HLH, assigns no points to a ferritin below 2000 μg/L, while a ferritin between 2000 and 6000 μg/L adds 35 points, showing that the limit of 2000 μg/L is really crucial [3]. Due to the massive cytokine release seen in patients with the condition, HLH is considered to be a cytokine storm syndrome [3]. In potential sHLH, early use of high-dose steroids alone can be successful, consistent with the recent findings regarding the efficacy of dexamethasone in patients with severe COVID-19 receiving any form of respiratory support [4].…”

“…A diagnosis of sHLH could explain the enormous cytokine storm responding so well to infliximab [1] and may also explain why dexamethasone is so effective in patients with severe COVID-19 [4]. The sHLHcytokine storm may be the main reason for the rapid deterioration seen in patients with COVID-19 [3]. It is advisable to measure baseline ferritin before starting any immunological treatment in order to improve the efficacy [5].…”