How Viruses Contribute to the Pathogenesis of Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory syndrome, characterized by the uncontrolled activation of macrophages and T cells, eliciting key symptoms such as persistent fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, hyperferritinemia, and coagulopathy. Viral infections are frequently implicated in the onset of active HLH episodes, both in primary, genetic HLH as in the secondary, acquired form. Infections with herpesviruses such as Epstein–Barr virus and cytomegalovirus are the most common. In autoimmune diseases, a link between viral infections and autoreactive immune responses has been recognized for a considerable time. However, the mechanisms by which viruses contribute to HLH pathogenesis remain to be clarified. In this viewpoint, different factors that may come into play are discussed. Viruses, particularly larger DNA viruses such as herpesviruses, are potent modulators of the immune response. By evading immune recognition, interfering with cytokine balances and inhibiting apoptotic pathways, viruses may increase the host’s susceptibility to HLH development. In particular cases, a direct connection between the viral infection and inhibition of natural killer cell or T cell cytotoxicity was reported, indicating that viruses may create immunological deficiencies reminiscent of primary HLH.

Rotavirus infection following post‐transplantation cyclophosphamide based haploidentical hematopoietic cell transplantation in children is associated with hemophagocytic syndrome and high mortality

“…The current report highlights the same syndrome of PTHPS occurring late after HCT, following treatment of gut GVHD, being triggered by rotavirus infection. However, we suspect that unlike early PTHPS, the late‐onset PTHPS following infections described in the current cohort might be related to the profound immunodeficiency resulting from prolonged immunosuppression with an abortive inflammatory cascade . Infection with a gut pathogen is intuitively expected to reinitiate the process of gut GVHD as described earlier .…”

“…The only patient (UPN 4) who survived was one without prior gut GVHD and was off all immunosuppression at the onset of rotavirus infection with a better immune reconstitution. The large body of data on virus associated HPS revolves around DNA viruses and points toward several pathways which impair cytotoxic T cells and NK cells and exaggerate the inflammatory milieu triggering macrophage activation . This combined with impaired apoptotic pathways result in ongoing macrophage activation along with continued and futile, yet unrelenting inflammatory cascade.…”

Hemophagocytic lymphohistiocytosis complicating invasive pneumococcal disease: a pediatric case report

“…Viruses are the most common cause of infectionassociated HLH, and the mechanisms by which viruses contribute to HLH pathogenesis remain to be clarified. However, it is thought that viruses can increase the host's susceptibility to HLH by modulating the host immune system via recognition by the innate or adaptive immune system, interfering with cytokine balances, and inhibiting apoptosis [18]. Serum inflammatory cytokines are known to be increased in the serum of viral HLH cases, particularly, IFN-γ, TNF-α, IL-6, IL-10, and IL-18 [19].…”

Coronavirus Epidemic and Extracorporeal Therapies in Intensive Care: si vis pacem para bellum

“…ECMO could have been a trigger or an amplifier of cytokine activation. The pathogenesis of VAHS involves excessive production of interferon gamma and interleukin-2 [16]. VAHS itself is a prototype of a cytokine storm syndrome.…”