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).