Diverse Clinical Presentations of Primary Hemophagocytic Lymphohistiocytosis in Adulthood

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by pathologic T cell activation. Primary (pHLH) is caused by defects in cytotoxicity with 90% of cases presenting before two years of age. Rare cases in adolescents have been described; however, the prevalence and phenotypic spectrum of pHLH in adults is unknown.

We report on eight patients with pHLH evaluated between 2006 and 2024. The median age was 33 years (range: 17-50). Five (62.5%) were women and seven (87.5%) were White. Three patients had homozygous or compound heterozygous variants in PRF1, while one each had protein-altering variants in RAB27A, UNC13D, and STXBP2. One woman had a heterozygous XIAP variant with skewed lyonization (XIAP expression ∼10%) and one man had SAP deficiency with a somatic reversion in CD8 T cells (SAP expression ∼15% on CD8 T cells). Flow cytometry showed decreased perforin in patients with PRF1 variants and impaired CD107 degranulation in those with vesicle-trafficking defects. All individuals demonstrated classic HLH laboratory changes (cytopenias, liver injury, and increased sCD25). Ferritin was not markedly elevated (median: 538 ng/mL [IQR: 405-4856]), but CXCL9 (a surrogate for IFNγ) showed dramatic elevations (median: 69,720 pg/mL [IQR: 23,596-112,904]). Increases in activated T cells (CD38hiHLADR+) closely associated with disease activity. Four patients (x3-PRF1, x1-RAB27A) developed progressive, fulminant HLH. Two received successful hematopoietic stem cell transplant (HSCT) and two died prior to HSCT. The other four demonstrated a partial phenotype with chronic, smoldering HLH-like inflammation associated with acute flares triggered by infections. These flares responded to corticosteroids and a variety of steroid-sparing agents were trialed with variable success. These patients had a shared phenotype which included cytopenias (4/4), splenomegaly (4/4), migraines (3/4), and GI symptoms (3/4). Since their inflammatory syndromes have been controllable with immunomodulation, HSCT has not yet been pursued.

This series emphasizes the striking diversity of adults presenting with pHLH and highlights the substantial unknowns in terms of prevalence, pathogenesis, and long-term outcomes. Due to the atypical and sometimes subtle HLH phenotype, the current literature based on genetic testing of retrospective cohorts may substantially underestimate the burden of pHLH in adults. Our findings underscore the importance of recruiting prospective, longitudinal cohorts of adults with HLH and maintaining a low threshold to pursue genetic testing.