2.1 Hemophagocytic lymphohistiocytosis
HLH, also called hemophagocytic syndrome, is a rare but potentially life-threatening aberrant hyperferritinemic condition (28). In a retrospective analysis, the 30-day mortality from clinical onset was 35% (45/129) in young patients and 58% (44/76) in patients older than 60 years (34). In adults, the clinical characteristics of HLH include fever, rash, hepatosplenomegaly, lymph node enlargement, potential bleeding diathesis, sepsis-like syndrome with or without variable degrees of neurologic symptoms and a possibly rapidly unexpected progress to multiple organ failure (35). Hyperferritinemia, liver dysfunction, cytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated D-dimer and lactate dehydrogenase are frequently observed (28). Interestingly, in a large single-centre case series, very high levels of ferritin (>50,000 µg/L) correlated with 30-day mortality (36) and the drop in ferritin level due to the treatment could have an important prognostic value (37).
As reported in the 2019 HLH recommendation, primary and secondary HLH, including MAS, have a “common terminal pathway but with different pathogenic roots” (38). The primary or familial form (FHLH) begins at an earlier age and tends to be more aggressive. It is due to different gene mutations (PRF1, UNC13-4, STX11, STXBP2, etc.) that lead to the dysregulation of the inflammasome (39, 40) and/or to the reduction in cytotoxic activity of T cytotoxic lymphocytes (CTL) and natural killer cells (NK); degranulation and the control of macrophages or cell apoptosis can be impaired (41, 42). Cytotoxic deficiency can lead to persistent antigen exposure of lymphocytes, inducing an over-production of various inflammatory cytokines, in particular IFN-γ, and consequently to CRS and uncontrolled activation of macrophages (43).
The secondary form (sHLH) can occur in different conditions among which viral infections are among the most frequent. Other infections include bacterial (44), parasitic and fungi (45, 46). Solid or blood malignancies represent other possible causes (40% to 70% of HLH cases in adults) followed by systemic autoinflammation and autoimmune diseases, in the which case sHLH is usually named MAS (47). Several rheumatologic diseases can develop MAS, such as systemic lupus erythematosus, RA, Sjögren’s syndrome, vasculitis and, most frequently, systemic juvenile idiopathic arthritis (sJIA), AOSD and cAPS. Finally, conditions of acquired immune deficiency occurring, for instance, after organ transplantation are rarer triggers of sHLH (38).
Virus infections are the main cause of sHLH, especially Epstein Barr Virus (EBV) (48), Herpes simplex virus (HSV) and Cytomegalovirus (CMV). How these viral agents are able to trigger HLH is not fully understood. It seems that they may suppress CTL and NK cell cytotoxicity, predisposing to the development of HLH. EBV latent membrane protein-1 (LMP1) can transcriptionally inhibit lymphocyte activation molecule (SLAM)–associated protein (SAP) leading to overt T-cell activation and cytokine production, especially IFN-γ (49). Recombinant hemagglutinin (H5) from H5N1, causing agent of avian influenza, may suppress the perforin expression and reduce cytotoxicity of human CTL in vitro . At the same time, it promotes an over production of IFN-γ that may play an important role in macrophages over-activation, cytokine storm and hemophagocytosis, all features observed in severe H5N1 infected patients (50). In addition, H1N1 influenza, directly infecting NK cells, reduced their number and their activity (51).
Nevertheless, these mechanisms cannot always explain the development of HLH. Infectious triggers are not always identified and defects in cytotoxic CTL may not be present (43). In other HLH models, a prominent role can be played directly by the innate immune pathways instead of the CTL and NK activity (43). Indeed, an excessive innate immune activation by IL-1 family cytokines, especially IL-18 and IL-33, seems to play the detrimental role (29, 52).Beside the main treatment of HLH based on HLH-94 protocol, consisting in corticosteroids, cyclosporine A, intrathecal therapy and etoposide (38, 53), the treatment of the specific trigger is essential because of the vast heterogeneity of the aetiology of HLH in adult patients. Sometimes, the specific treatment of the trigger agent can be able to control the HLH syndrome without the need of HLH-94 protocol, as in the case of autoimmune diseases including SLE (54). Interesting trials testing alternative therapeutic approaches have been promoted, such as those incorporating ruxolitinib (JAK1/2 inhibitor; ClinicalTrials.gov identifiers NCT02400463, NCT03795909, NCT03533790), anakinra (IL-1 blockade; NCT02780583), alemtuzumab (NCT02472054), and emapalumab (anti–IFN-g monoclonal antibody; NCT01818492).