Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition. Primary HLH occurs early in life due to monogenic biallelic mutations affecting lymphocyte cytotoxicity. Secondary HLH occurs mostly in adults secondary to infections, lymphoma or rheumatic diseases. In this latter setting, lymphocyte cytotoxicity status is not known. We conducted a systematic evaluation of NK cell cytotoxicity in adult patients with secondary HLH. Adult patients with secondary HLH were prospectively studied ex vivo for total lymphocyte count and subtypes, NK cell phenotype, perforin expression and degranulation, natural or ADCC cytotoxicity, in comparison with patients affected by the same underlying diseases without HLH (disease controls, DC) and with healthy controls (HC). Screening for variants of cytotoxity genes was systematically performed. 68 patients were included in the HLH group, 34 in the DC and HC groups, respectively. In HLH patients, a severe and transient lymphopenia, an activated NK cell phenotype (increased CD69, ICAM-1, HLADR, CCR5 expression) and a decreased capacity of interferon gamma production were observed. Mean perforin expression was normal, degranulation tests and NK cell cytotoxicity were not different from DC. A monoallelic variant of uncertain significance affecting one of the lymphocyte cytotoxicity genes, or the perforin variant A91V, was observed in almost 50% of the patients. We detected no major intrinsic cytotoxicity dysfunction in secondary HLH compared to DC and no predicted pathogenic gene variant. The activated NK phenotype profile associated with decreased interferon gamma production appear similar to other hyperinflammatory diseases such as sepsis or systemic juvenile idiopathic arthritis.

Haemophagocytic syndrome and COVID-19

“…Clinically, HLH is a systemic disease characterised by persistent fever, progressive cytopenias and multi-organ dysfunction caused by an uncontrolled immune activation associated with excessive cytokine production [ 3 ]. Immunopathologically, HLH is characterised by a decreased capacity of interferon gamma production and an activated NK phenotype profile (increased CD69, ICAM-1, HLADR, CCR5 expression) similar to other hyperinflammatory diseases [ 4 ]. CD163 macrophages are involved in hyperferritinaemic syndromes given their role in reticuloendothelial iron signalling, hence sHLH is also known as macrophage activation syndrome (MAS) especially in paediatric literature [ 5 ].…”

Features of hemophagocytic lymphohistiocytosis in the intensive care unit (ICU) : a 260-patient retrospective analysis

“…Pediatric primary HLH is mostly caused by genetic mutations in genes involved in lymphocyte cytotoxicity [5][6][7][8]. In contrast, the analysis of adult HLH has highlighted the absence of a lymphocyte cytotoxicity defect [9].…”

“…Targeted therapy is based on the HLH-2004 protocol [18][19]. However, acquired adult HLH and primitive pediatric HLH are two different diseases, with non-comparable pathophysiology [9]. In addition, systematic immunosuppressive therapy on fragile ICU patients could aggravate their condition and expose them to a high risk of infection [20].…”

Perforin gene variant A91V in young patients with severe COVID-19.

“… 11 , 12 Previous studies reported higher prevalence of the A91V variant in HLH patients. 13 , 14 It is reasonable to think that perforin bearing the A91V change could be related to suboptimal activation and effector capacities of CD8 and/or natural killer (NK) cells. In the context of a viral infection, the correct function of these cells is required to contain the viral replication, clear the virus and overcome the infection.…”