Hemophagocytic Syndrome and COVID-19: A Comprehensive Review

Abstract

Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory hyperferritinemic syndrome, is triggered by various etiologies and diseases and can lead to multiorgan dysfunction and death. There are two types of HLH: primary and secondary. Primary HLH (pHLH) is caused by a genetic mutation resulting in dysfunction in cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, hyperactivated immune cells, and hypercytokinemia. In secondary HLH (sHLH), an underlying etiology is the cause of the disease. Infections, malignancy, and autoimmune diseases are well-known triggers for sHLH. Infectious triggers for sHLH are most frequently viruses, where different mechanisms, including dysregulated CTLs and NK cell activity and persistent immune system stimulation, have been reported. Similarly, in severe coronavirus disease 2019 (COVID-19) patients, a hyperinflammatory mechanism leading to hypercytokinemia and hyperferritinemia has been demonstrated. A similar dysfunction in CTLs and NK cells, persistent immune system stimulation with increased cytokines production, and severe end-organ damage have been reported. Therefore, a significant overlap is present between the clinical and laboratory features seen in COVID-19 and sHLH. However, SARS-CoV-2, similar to other viruses, can trigger sHLH. Hence, a diagnostic approach is needed in severe COVID-19 patients presenting with multiorgan failure, in whom sHLH should be considered.

Keywords: covid-19; cytokine storm; haemophagocytic lymphohistiocytosis; haemophagocytic syndrome; immune system.

Figure 1. HLH variants and COVID-19

Note. This figure summarizes the different types of HLH. In addition, it shows the COVID-19 cytokine storm as a variant of HLH and the COVID-19-associated HLH as a part of the acquired HLH (infection-related HLH). HLH: hemophagocytic lymphohistiocytosis.

Figure 2. Pathogenesis of the COVID-19 cytokine storm

After binding to ACE2 receptors and entering the host cell, ssRNA is recognized by the innate immune system recognition receptors, including the toll-like receptors (TLRs). This results in the activation of NF-ĸB and the release of pro-inflammatory cytokines through different pathways (e.g., MYD and TRAF). The adaptive immune cells recognize pathogens and infected cells through MHC I and II present on cytotoxic T lymphocytes (CTLs) and CD4+ T cells, respectively. Activation of the adaptive immune system results in an amplified inflammatory reaction, which results in additional pro-inflammatory cytokines release. In addition, NK cells activated by the innate infected cells cytokines participate in the pathogenesis of the cytokine storm by the secretion of other regulatory cytokines that activate other immune pathways. ACE2: angiotensin-converting enzyme 2; ssRNA: single-stranded ribonucleic acid; MHC: molecular histocompatibility complex; NK: natural killer; NLRs: NOD-like receptors; APC: antigen-presenting cells. Note. This figure was created with BioRender.com.