Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome. In adults, HLH typically arises as a secondary condition (sHLH) triggered by infections, malignancies, or autoimmune/autoinflammatory diseases. Primary (familial) HLH (pHLH), caused by genetic mutations, usually presents in early childhood and is rarely described in adulthood.

Objectives: Investigate the prevalence, clinical features, management and outcomes of adults diagnosed with pHLH in a single-centre cohort.

Methods: This retrospective study included adult patients (≥18 years) diagnosed with HLH and admitted to a tertiary HLH centre between April 1, 2019, to January 1, 2025. Ethical approval was obtained. Demographic data, underlying triggers, treatment, and outcomes were extracted from electronic health records. Patients diagnosed with pHLH based on clinical findings and genetic testing were analysed.

Results: Of 138 patients diagnosed with HLH, 5 (3.6%) were identified as having pHLH, representing 12.8% (5/39) of cases in younger adults (age 18–30 years). The median age of presentation in pHLH patients was 22 years (IQR 19-24) compared to a median age of 43 (IQR 30-60) in patients with sHLH. 60% (3/5) were male and 60% (3/5) had a family history of consanguinity. The cohort included patients from the following backgrounds: Northern European, Chinese, Middle Eastern and South Asian (2 patients). All fulfilled HLH diagnostic criteria with HScores >169 (248 (184-284)). All presented with fevers. Other clinical features varied. One patient had profound neurological deficits and evidence of central nervous system HLH with diffuse, multifocal inflammatory brain lesions (CNS-HLH). Two patients had EBV viraemia . Cytopenias including bicytopenia (2/5) and pancytopenia (3/5) were present in all patients. All had elevated ferritin (13285 (7726-23000) ng/ml), soluble CD25 (12504 (5902 –15400) ng/L), alanine transaminase (160 (48-258) IU/L) and triglycerides (7.56 (3.3 -14) mmol/L). Of the four patients who had a bone marrow aspirate three had evidence of haemophagocytosis. Three patients had hepatomegaly and/or splenomegaly. One patient had a known history of immunodeficiency with homozygous loss of function mutations in TNFRSF9 associated with a history of primary CNS lymphoma followed by a T cell chronic active EBV. The other patients had screening assays for pHLH performed and subsequent whole genome sequencing (WGS). Two patients had perforin deficiency/absence with PRF1 gene mutations identified. One patient had an abnormal cytotoxic release assay indicating a defect in granule release pathway and a RAB27A gene mutation (Griscelli Syndrome – Type 2, patient noted to have partial albinism). One patient had a XIAP deficiency with XIAP gene mutation. Overall mortality was 40% (2/5). Despite treatment with corticosteroids, anakinra, IVIG and etoposide, four cases were refractory to these first-line therapies. Three patients subsequently received a JAK inhibitor (1 patient baricitinib, two patients ruxolitinib) with both patients receiving Ruxolitinib noted to have improvement in fevers and cytopenias. One patient continued ruxolitinib in combination with ciclosporin until undergoing allogeneic BMT 15 months after diagnosis. Three patients underwent allogeneic BMT (at 1, 4, and 15 months after HLH diagnosis). One patient was lost to follow-up 18 months after BMT, another experienced graft failure and is awaiting further allograft, and a third patient (with TNFRSF9-related disorder) died from post transplant disseminated fungaemia despite engrafting without delay. The patient with CNS-HLH, was deemed unfit for BMT, they were additionally managed with ruxolitinib, high-dose anakinra and intrathecal methotrexate but developed new inflammatory brain lesions and irreversible brain damage after their anakinra dose was weaned and were palliated. The patient with XIAP deficiency, who presented with EBV-related HLH, responded well to therapy with corticosteroids and rituximab, with no relapses. They receive monthly IVIG infusions and are being considered for future allogeneic BMT.

Conclusion: pHLH accounted for 3.6% of adult HLH cases, with higher prevalence (12.8%) in younger adults. This may be an underestimation of pHLH in our cohort, as genetic testing was only performed in those with a clinical suspicion of pHLH and there remains a population in our cohort with an unknown trigger as genetics were negative or they died prior to having genetics testing. Key clinical clues for suspecting pHLH in our cohort included younger age at presentation, consanguinity, CNS involvement, and concurrent EBV-related immunodeficiency. Treatment outcomes highlighted the limitations of standard therapies in refractory cases and the potential role of JAK inhibitors in managing resistant disease. Genetic testing via whole-genome sequencing (WGS) was critical for the diagnosis and treatment of adult primary hemophagocytic lymphohistiocytosis (HLH). Importantly, it identified mutations that guided the use of allogeneic bone marrow transplantation (BMT)—a crucial intervention in patients in our cohort whose disease was refractory to standard HLH therapies. Contrary to previous reports, our findings demonstrate that actionable results of genetic testing in adult HLH are not as rare as previously reported and can potentially improve outcomes. These results highlight the importance of early genetic testing in patients with suspected pHLH. Improving access to genetic testing and reducing turnaround times will be essential for enabling timely diagnosis and initiation of appropriate treatment. Furthermore, we believe further assessment of the optimal population to deploy this testing in is still required.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Amelia Holloway: None declared, Ben Carpenter: None declared. Sam Clark: None declared, Alexis Jones: None declared. Satyen Gohil Advisory board, Electra therapeutics, Aisling S Carr: None declared, Arian Laurence: None declared, Jessica Manson: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.