RARE DISEASE
Familial hemophagocytic lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis
Synonyms: Familial HLH
Synonyms: Familial HLH
Synonyms: Familial HLH
Drug discovery
4
drugs
With orphan designations
Overview
Familial hemophagocytic lymphohistiocytosis (FHLH) is a life-threatening autosomal recessive immune dysregulation disorder caused by genetic defects in lymphocyte cytotoxicity pathways (PRF1, UNC13D, STX11, STXBP2). It triggers uncontrolled T-cell/macrophage activation, cytokine storms, and multi-organ damage. Diagnostic hallmarks include fever, cytopenias, hepatosplenomegaly, hyperferritinemia, and hemophagocytosis. Untreated mortality approaches 100% within months [1][2][6].
Therapies
Induction: HLH-94/2004 protocols with dexamethasone + etoposide ± cyclosporine (55-61% 5-year survival) [3][12]
Refractory disease: FDA-approved IFNγ inhibitor emapalumab (response rate 63-70%) [8][14]
Definitive cure: Allogeneic HSCT required for survival (66% 5-year post-transplant survival) [5][13]
Categories: rare genetic diseases, rare immunological diseases, rare neoplastic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
840 drug discovery papers about Familial hemophagocytic lymphohistiocytosis, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
840 drug discovery papers about Familial hemophagocytic lymphohistiocytosis, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-25 | Neonatal-onset familial hemophagocytic lymphohistiocytosis type 2: a case report
Background Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare autosomal recessive disorder primarily caused by mutations in the perforin-1 (PRF1) gene, leading to immune system hyperactivation and multi-organ dysfunction. FHL2 typically presents in infancy, with neonatal onset being extremely rare and particularly difficult to recognize early due to substantial clinical overlap with sepsis. Given its rapid progression, early detection is critical for effective diagnosis and management. Case summary This case report describes a neonate with FHL2 who presented on day 8 after birth with fever (peak 38.9 °C), abdominal distension, and dyspnea, accompanied by coagulation dysfunction, liver function abnormalities, and capillary leak syndrome. Despite intensive care, the patient's condition continued to deteriorate, with progression to disseminated intravascular coagulation (DIC), polyserositis, and multi-organ failure. Despite receiving intensive care and comprehensive treatment, the patient's condition continued to deteriorate. By day 7 of hospitalization, the patient was in a moribund state, and the family requested discharge against medical advice; the patient died after discharge. Postmortem genetic testing identified a homozygous c.145G > A mutation in the PRF1 gene, resulting in a substitution of aspartic acid to asparagine at position 49 of the encoded protein (p.Asp49Asn). This mutation has been documented as pathogenic in the Human Gene Mutation Database. Conclusion FHL2 may present in the neonatal period with complex and variable clinical manifestations, frequently leading to misdiagnosis as neonatal sepsis or DIC. When neonates present with unexplained persistent fever, cytopenia, coagulation dysfunction, and multi-organ dysfunction that fails to respond to conventional anti-infective therapy, HLH should be included in the differential diagnosis, and genetic testing should be performed promptly.
2026-09-17 | Syntaxin11 Deficiency Inhibits CRAC Channel Priming to Suppress Cytotoxicity and Gene Expression in T Lymphocytes Independent of Membrane Trafficking
Mutations in Syntaxin11, a Q-SNARE, result in a fatal immune disorder known as familial hemophagocytic lymphohistiocytosis 4 (FHLH4) in human patients. A key diagnostic feature of FHLH4 is defective T and natural killer (NK) cell cytotoxicity. Here we show that Syntaxin11 directly binds and regulates Orai1, the pore forming subunit of calcium release activated calcium (CRAC) channels. CRAC channels enable store-operated calcium entry (SOCE) from the extracellular space and are crucial for granule exocytosis and nuclear factor of activated T cell (NFAT) dependent gene expression in activated lymphocytes. Syntaxin11 depletion strongly inhibited SOCE, CRAC currents, NFAT activation, interleukin-2 gene expression and degranulation in FHLH4 patient T lymphocytes and cell lines without affecting membrane trafficking. Remarkably, defects of cytolytic granule exocytosis as well as interleukin-2 expression could be reversed by ionomycin in patient T lymphocytes and a constitutively active, H134S, mutant of Orai1 rescued calcium entry in Syntaxin11 depleted cells. Further analyses showed that Syntaxin11 ‘primes’ Orai1 for optimal on-site multimeric assembly which was Stim independent but required for gating. Priming of ion channel pore subunits is, therefore, a primary function of specific SNAREs which may have preceded their role in membrane trafficking and vesicle fusion.
2026-09-07 | [Mechanism and clinical progress of JAK inhibitors in hemophagocytic lymphohistiocytosis].
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by uncontrolled activation of lymphocytes and macrophages. Owing to its marked etiological heterogeneity, HLH is broadly classified into primary and secondary forms. Janus kinase (JAK) inhibitors, represented by ruxolitinib, exert therapeutic effects by blocking the JAK-STAT signaling pathway and suppressing the secretion of various cytokines, including interferon-γ. Accumulating evidence suggests that JAK inhibitors demonstrate unique therapeutic potential across diverse etiological backgrounds of HLH. This review summarizes the mechanisms and clinical research progress of JAK inhibitors in the treatment of HLH.
2026-09-04 | Hemophagocytic Lymphohistiocytosis Complicated With Reversible Cardiomyopathy and Severe Sinus Node Dysfunction.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome causing multiorgan failure. While cardiac involvement is recognized, associated conduction-system abnormalities are exceedingly rare and poorly described. A 60-year-old male presented with fever, pancytopenia, and progressive shock, meeting diagnostic criteria for HLH. His clinical course was acutely complicated by transient cardiomyopathy and frequent episodes of sinus arrest. Following the initiation of HLH-directed therapy, the patient experienced a complete recovery of both systolic function and sinus node conduction by day 10. This case identifies severe sinus node dysfunction as a reversible manifestation of HLH-related cytokine storm. Prompt initiation of immunosuppressive therapy led to complete recovery of left ventricular function and sinus node activity, highlighting the reversible nature of the HLH-related myocardial injury. This case highlights the importance of early identification of HLH-related cardiac involvement as it is critical to prevent irreversible damage and improve outcomes in these patients.
2026-09-03 | Hemophagocytic Lymphohistiocytosis As the Initial Presentation of Occult Diffuse Large B-cell Lymphoma: A Diagnostic Challenge.
Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome characterised by uncontrolled immune activation and cytokine release, resulting in multiorgan dysfunction and high mortality if not recognised and treated promptly. In adults, secondary HLH is frequently triggered by infection, autoimmune disease, or malignancy, with haematological malignancies carrying a particularly poor prognosis. The non-specific nature of its presentation often leads to diagnostic delay, as it can closely mimic sepsis and other inflammatory conditions. We present the case of a 76-year-old man who was admitted with a two-week history of progressive lethargy, exertional dyspnoea, anorexia, and headache after several months of constitutional symptoms. On presentation, he was hypotensive and tachycardic with atrial fibrillation and was initially managed for presumed sepsis with associated haemodynamic compromise. Despite supportive management, his clinical condition and biochemical profile deteriorated, with worsening cytopenias, deranged liver function tests, persistent hyperlactataemia, pyrexia, and escalating inflammatory markers. Further investigation demonstrated marked hyperferritinaemia exceeding 10,000 µg/L, hypertriglyceridaemia, hypofibrinogenaemia, elevated lactate dehydrogenase, and bicytopenia, producing an HScore of 220, which was highly suggestive of secondary HLH. Following multidisciplinary discussion with regional specialists, treatment with high-dose IV methylprednisolone and anakinra was commenced while an urgent search for the underlying trigger continued. Initial imaging failed to identify a clear source of malignancy or infection, and the patient showed only limited improvement with HLH-directed immunomodulatory therapy. Bone marrow biopsy subsequently demonstrated high-grade diffuse large B-cell lymphoma (DLBCL) with marrow involvement, establishing malignancy-associated HLH as the underlying diagnosis. The patient was transferred to a specialist haematology service and commenced on R-mini-CHOP chemotherapy, resulting in rapid clinical recovery and marked improvement in HLH parameters. Subsequent positron emission tomography imaging demonstrated a complete metabolic response after two treatment cycles, with the patient improving from a bedbound state to being independently ambulatory. This case highlights the significant diagnostic challenges associated with adult HLH and emphasises the importance of maintaining a high index of suspicion in patients presenting with unexplained fever, cytopenias, hyperferritinaemia, liver dysfunction, and multiorgan inflammation. It also demonstrates that, while immunosuppressive therapy may provide temporary disease control, successful management of malignancy-associated HLH depends on prompt identification and definitive treatment of the underlying haematological malignancy. Early multidisciplinary collaboration and timely bone marrow examination are critical to improving outcomes in this rapidly progressive and frequently fatal condition.
cell therapies
2026-09-03 | Use of Extracorporeal Membrane Oxygenation (ECMO) in Pediatric Patients With Hemophagocytic Lymphohistiocytosis: A Multicenter Sub-Analysis.
Hemophagocytic lymphohistiocytosis (HLH) is a rare condition causing severe systemic inflammatory activation, cytokine storm, and multiorgan dysfunction for which extracorporeal membrane oxygenation (ECMO) may be required. There is a paucity of data to guide clinicians in the care of these patients; we aimed to address this need. From the Hematology and Oncology Pediatric Patients on ECMO (HOPPE) database, 30 patients diagnosed with HLH were identified from 13 of the 16 total participating centers between 2009 and 2021. Of those 30 patients, 63% survived to ECMO decannulation, 43% to ICU discharge, and 37% to hospital discharge. Among survivors, there was a median of 44.9 days between decannulation and hospital discharge. Half of the ECMO mortality occurred within the first 10 days on ECMO. Patients who survived to hospital discharge also had evidence of functional limitation and significant multiorgan dysfunction. A total of 90% of patients diagnosed with HLH on ECMO survived to decannulation vs. 50% of patients diagnosed before. Survival has improved in this patient population compared to previous literature but is still lower than the overall pediatric ECMO population. Clinical suspicion for HLH in these critically ill patients should not exclude them from escalation of support, including ECMO.
2026-09-03 | Spectrum of Primary Hemophagocytic Lymphohistiocytosis-Associated Gene Mutations in Chinese Patients.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by hyperinflammation. Primary HLH (primary HLH), resulting from genetic mutations, is a subtype of HLH. The mutation spectrum of primary HLH-associated genes has not been well determined in China. This study aimed to explore the mutation spectrum of 12 primary HLH-associated genes in a multicenter database. Medical records and gene sequencing data of 1224 HLH patients were retrieved from January 2014 to September 2024, and gene mutations were analyzed. Genetic variants were observed in 350 (28.59%) patients. Among them, 108 patients had a definitive genetic diagnosis, 227 patients carried single heterozygous variants, and 15 patients carried digenic/polygenic heterozygous variants. A total of 275 different variants were identified, and missense variants were most common. Variants in UNC13D were most common, followed by LYST and PRF1, while variants in MAGT1, ITK, and CD27 were rare. For UNC13D, LYST, and PRF1, variants c.2588G>A (p.Gly863Asp), c.368A>G (p.His123Arg), and c.1349C>T (p.Thr450Met) were most common, respectively. We described the mutation spectrum of primary HLH-associated genes in a largest Chinese cohort and found some mutation specificity for Chinese HLH patients. Our data might help design sequencing panels, interpret sequencing results, and understand genetic background of Chinese HLH patients.
2026-09-01 | Allogeneic Hematopoietic Stem Cell Transplantation in Hemophagocytic LymphohistiocytosisTwo Sides of the Locket: Trigger or Cure?
Allogeneic hematopoietic stem cell transplantation (alloHSCT) represents a paradoxical role in hemophagocytic lymphohistiocytosis (HLH): curative in primary disease yet potentially triggering secondary HLH in the posttransplant setting. We report two adult cases illustrating this duality. The first case developed life-threatening secondary HLH on day +40 following haploidentical alloHSCT, presenting with extreme hyperferritinemia and procalcitonin elevation mimicking septic shock, successfully treated with dexamethasone, ruxolitinib, and plasma exchange. The second case underwent alloHSCT as definitive therapy for familial HLH harboring a UNC13D variant, achieving complete remission despite posttransplant EBV reactivation and lymphoproliferative disorder. These cases highlight the diagnostic challenges and therapeutic complexity of HLH within the transplant continuum.
2026-08-04 | Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing.
The UNC13D gene encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in lymphocytes and the protein responsible for familial hemophagocytic lymphohistiocytosis (FHL). As an essential mediator of perforin release from cytotoxic T and NK cells, Munc13-4 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed "perforinopathy" manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13-4 deficiency, its association with autoimmune neuropathy remains largely unrecognized. We report two patients with a unique disease trajectory, presenting initially with autoimmune neuropathy before developing progressive FHL several years later. Both patients met the HLH-2004 diagnostic criteria, including fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. Genetic analysis revealed heterozygous UNC13D mutations: in Case 1, a nonsense (c.3193C>T; p.Arg1065*) and a missense (c.1135G>A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447 + 1G>A) and a paternal missense mutation (c.1241G>T; p.Arg414Leu). Case 1 underwent hematopoietic stem cell transplantation (HSCT), with significant recovery of weakness and numbness, and no recurrence of fever or lymphadenopathy at one year. Case 2 succumbed to disease progression after no timely, suitable allogeneic hematopoietic stem cell donor could be found. Our findings identify autoimmune neuropathy as a potential harbinger of FHL in perforinopathy, suggesting these neurological manifestations may be the initial phenotype of an underlying cytotoxic dysfunction. This temporal association mandates heightened clinical vigilance for immunodeficiency in patients with refractory neuropathy, particularly when accompanied by axonal degeneration or systemic inflammation. Recognizing this novel disease continuum has immediate diagnostic and therapeutic implications, as early genetic identification creates a critical window for potentially curative intervention with HSCT before irreversible multi-organ damage occurs. These cases expand the clinical spectrum of perforinopathy and challenge current diagnostic paradigms, emphasizing the need for an integrated neurological and immunological evaluation for unexplained autoimmune neuropathy.
2026-07-31 | Beyond Infections: Clinical and Genetic Spectrum of Pediatric Immune Dysregulation Disorders
Aim: Primary immune regulatory disorders represent a rapidly expanding subgroup of inborn errors of immunity.Unlike classical infectionpredominant immunodeficiencies, these disorders may initially present with autoimmunity, lymphoproliferation, cytopenias, dermatologic disease, allergy, enteropathy, hemophagocytic lymphohistiocytosis, or malignancy. Materials and Methods:We conducted a retrospective single-center observational cohort study of children with genetically confirmed diseases of immune dysregulation who had been followed at a tertiary pediatric immunology center between 2005 and 2025.Patients were included if their molecular diagnosis was classified under the International Union of Immunological Societies (IUIS) category of diseases of immune dysregulation.Demographic, clinical, genetic, therapeutic, transplant-related, and outcome data were extracted from the medical records and analyzed descriptively.Results: Twenty-one children were included.Parental consanguinity was frequent (71.4%), and more than half of the cohort had a family history of primary immunodeficiency (57.1%).A substantial diagnostic delay was observed, with a median delay of 28 months (interquartile range, 8-105.5).The most common IUIS subcategory was regulatory T-cell defects (52.4%), followed by familial hemophagocytic lymphohistiocytosis syndromes with hypopigmentation (19.0%), autoimmune lymphoproliferative syndrome (14.3%), susceptibility to Epstein-Barr virus and lymphoproliferative conditions (9.5%), and immune dysregulation with colitis (4.8%).The main clinical features were lymphoproliferation (76.2%), hematologic abnormalities (66.7%) and autoimmunity (52.4%).Notably, malignancy was documented in 2 patients (9.5%).Antimicrobial prophylaxis was administered in 90.5% of the patients, immunoglobulin replacement in 66.7%, conventional immunosuppressive therapy in 38.1%, and biological or targeted therapy in 33.3%.Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients (38.1%); immune reconstitution was achieved in all of the surviving transplant patients.Conclusion: Pediatric diseases of immune dysregulation frequently present with non-infectious manifestations, particularly lymphoproliferation, cytopenias, autoimmunity, and dermatologic findings.Recognition beyond infection-centered warning signs, the integration of genetic testing, and the individualized use of targeted therapies or HSCT may improve care for this heterogeneous group of disorders.
antibodies
2026-07-24 | Cytokine Release Syndrome Induced by Combination Therapy With Nivolumab and Ipilimumab in Lower Palpebral Conjunctival Melanoma: A Case Report.
Cytokine release syndrome (CRS) induced by immune checkpoint inhibitors (ICIs) is a potentially life-threatening immune-related adverse event (irAE). CRS has been recognized as a complication of chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engager (BiTE) therapy, but remains exceedingly rare as a complication of ICI therapy. Here, we report a case of CRS that developed after combination therapy with nivolumab and ipilimumab in a woman in her 60s with advanced conjunctival melanoma. The diagnosis was based on the clinical course and imaging findings together with characteristic laboratory abnormalities, including systemic inflammation, hepatic dysfunction, coagulopathy, and marked hyperferritinemia. This case highlights the importance of careful exclusion of infectious and neoplastic diseases for early diagnosis, demonstrates that ICI-related CRS can relapse after initial control, and shows that it may overlap with hemophagocytic lymphohistiocytosis (HLH)-like syndromes. Given the central role of interleukin-6 (IL-6) in CRS, early administration of tocilizumab may contribute to rapid control of inflammation and reduction of steroid exposure.
2026-07-09 | Advances in PD-1 monoclonal antibody therapy for hemophagocytic syndrome.
Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is a severe inflammatory condition, while the standard treatment still has limitations. With the conscious in-depth research on the pathogenesis, PD-1 (programmed cell death protein-1) monoclonal antibody has shown positive prospects in the treatment of HLH. This study retrospectively analyzed the clinical efficacy, and safety profile of PD-1 inhibitors in the treatment of HLH. A total of 15 studies was involved, covering with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and related malignancies. In pediatric patients with chronic active EBV infection (CAEBV) and refractory/relapsed EBV-HLH, sintilimab induced partial or complete clinical remission, and successfully served as a bridge therapy to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Retrospective studies on adult refractory/relapsed EBV-HLH showed that nivolumab treatment achieved an overall response rate (ORR) of 85.7% and a complete remission (CR) rate of 71.4% over 16 months. Sintilimab as salvage therapy also restored complete donor chimerism post-transplant and cleared viral loads. Furthermore, novel combinations with ruxolitinib, venetoclax, or thalidomide achieved rapid clinical remission in EBV-HLH. Safety assessments indicated that PD-1 blockade following HSCT was associated with a high risk of graft-versus-host disease (GVHD). Caution is warranted when using PD-1 monoclonal antibodies, as immune system stimulation is a double-edged sword. The optimal timing, dosage, and safety of PD-1 monoclonal antibodies in HLH treatment merit further clinical research and exploration.
2026-06-18 | The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and functionally resets CD33+ myeloid-derived suppressor cells in patients with metastatic cancer: a phase 2 single-arm, open-label trial.
We previously demonstrated that the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalized, and decreases those cells' viability. Treatment of MDSCs with GO restores T-cell proliferation in co-culture, overcomes M-MDSC suppression of CAR-T cell proliferation, and enhances target-cell killing. Gemtuzumab Ozogamicin Therapy in Hemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome (GOTHAM) is a phase 2 single-arm clinical trial for which patients were eligible if they had a diagnosis of solid cancer with radiological or clinical evidence of disease progression, or primary or secondary hemophagocytic lymphohistiocytosis, or macrophage activation syndrome disease relapsing or refractory to treatment at enrollment. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-d intervals: days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Using 2 schedules of GO, we could not convincingly demonstrate safe feasibility in patients with solid cancer, because of neutropenia. However, GO reproducibly and significantly reduced circulating MDSCs. Importantly, there is consistent preliminary evidence that, upon rebound, the monocyte population of CD33+ cells is replaced with nonsuppressive monocytes. These data support the phase 1b dose-escalation testing of GO up to 2 mg/m2 in combination with immune checkpoint blockade and other immunotherapies in patients with solid cancer to find a dose that depletes and repolarizes MDSCs without causing undue neutropenia, paving the way to use GO as an immune potentiator in this patient population. Trial registration: ISRCTN 89158144.
2026-01-26 | Hemophagocytic Lymphohistiocytosis as First Manifestation of Dual B-Cell Neoplasms: A Case Report of Co-Existing Multiple Myeloma and B-Cell Lymphoma.
Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder causing excessive inflammation and tissue damage. Lymphoma, especially T-cell lymphoma, is the most common cause of HLH, while Multiple Myeloma (MM) is rarely associated. We present a 61-year-old man with spiking fevers, fatigue, and unintentional weight loss. The HLH was driven by two distinct malignant clones in his bone marrow: plasma cell neoplasm and B-cell lymphoma. Patient failed initial therapy with steroids, anakinra, and chemotherapy. Tocilizumab use, on the other hand, led to an excellent clinical and laboratory response immediately. This is the first reported case of HLH associated with two hematological malignancies. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2025-12-19 | A Case of Severe Dengue With Hemophagocytic Lymphohistiocytosis (HLH) Successfully Managed With Tocilizumab and Dexamethasone.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition due to an uncontrolled hyperinflammatory response. While HLH can arise from various causes, it is most commonly triggered by infections. Dengue, a febrile viral illness prevalent in the tropics, can lead to HLH in rare cases. Dengue-associated HLH is particularly challenging to diagnose due to its clinical features overlapping with those of severe dengue. Unless immunosuppressive treatment is promptly initiated, the prognosis of dengue-associated HLH remains poor. A previously healthy 32-year-old female was admitted to a tertiary care hospital in Sri Lanka with high-grade intermittent fever, gastrointestinal symptoms, and severe dehydration. Initial blood investigations and a point-of-care ultrasound scan confirmed dengue hemorrhagic fever. Despite supportive therapy, the patient's condition deteriorated with persistent fever, severe bicytopenia, and liver impairment. She was diagnosed with HLH based on clinical and laboratory findings, including high ferritin levels and hemophagocytosis in the bone marrow. She was treated with intravenous dexamethasone and tocilizumab, leading to significant clinical improvement. Additionally, therapeutic plasma exchange was performed, contributing to recovery from severe liver dysfunction. This unique case highlights the importance of early recognition and integration of advanced immunosuppressive therapy in managing dengue-associated HLH. To the best of our knowledge, this is the first reported case where tocilizumab was successfully used in dengue-associated HLH, highlighting the potential of interleukin-6 (IL-6) receptor blockers in similar contexts. The coordinated efforts of hematology, gastroenterology, and general medical teams facilitated timely diagnosis and individualized management, demonstrating how interdisciplinary collaboration can enhance outcomes in complex cases.
proteins
2026-09-16 | Precision immunomodulation for pediatric hemophagocytic lymphohistiocytosis in intensive care.
Hemophagocytic lymphohistiocytosis (HLH) and related cytokine storm syndromes are life-threatening hyperinflammatory disorders that frequently intersect with pediatric critical care. Critically ill children may present with fever, shock, cytopenias, liver dysfunction, coagulopathy, hyperferritinemia, respiratory failure, neurologic deterioration, and multiple organ dysfunction, creating substantial overlap with severe sepsis. Traditional diagnostic criteria remain foundational but do not identify the dominant mechanism or optimal therapy for an individual child. In this review, precision immunomodulation is defined operationally as matching the suspected trigger and clinical phenotype with pathway-informed biomarkers when available, drug-delivery feasibility during organ failure, and the plan for definitive disease control. Interferon-gamma activity may be supported by CXCL9; interleukin (IL)-1/IL-18 biology may support anakinra in macrophage activation syndrome; broader cytokine signaling may support Janus kinase inhibition in selected refractory HLH; and IL-6-directed therapy is primarily syndrome- and grade-directed in immune effector cell cytokine release syndrome. These markers are supportive rather than validated treatment thresholds. Targeted therapy must proceed alongside antimicrobial therapy, source control, organ support, infection surveillance, and early hematopoietic stem cell transplantation planning when indicated. This review provides a bedside framework for phenotype assignment, biomarker interpretation, intensive care unit-focused targeted therapy, extracorporeal bridge strategies, and reassessment at 24-72 h.
2026-03-08 | Is a variant of uncertain significance always 'insignificant'? A systematic review on PRF1 A91V in Hemophagocytic Lymphohistocytosis and comparative analysis with Still's disease.
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that may arise secondary to rheumatic diseases such as Still’s disease, where macrophage activation syndrome (MAS) represents its clinical counterpart. The pathogenic significance of the PRF1 A91V variant remains uncertain, although functional data suggest partial perforin dysfunction and a possible contribution to late-onset or atypical HLH. This study aimed to clarify the clinical implications of the PRF1 A91V variant through a systematic review of published HLH and MAS cases and a comparative analysis with a single-center Still’s disease cohort. RESULTS: A total of 20 studies, including 38 individual HLH or MAS cases carrying the PRF1 A91V variant, were identified. The median age at diagnosis was 22 years, and 18.4% of patients were homozygous. Fever (82.6%), splenomegaly (57.9%), and hepatomegaly (36.8%) were the most frequent clinical findings. Anemia (57.1%) and thrombocytopenia (85.7%) were the predominant laboratory abnormalities, accompanied by marked hyperferritinemia (median 9319 ng/mL). Compared with 43 active Still’s disease cases, PRF1-mutated HLH patients showed significantly higher rates of cytopenias, hepatomegaly, and central nervous system involvement, together with substantially elevated ferritin levels (9,193 vs 800 ng/mL, p = 0.0023), whereas C-reactive protein levels were comparable. Receiver-operating characteristic analysis identified a ferritin cutoff of 7000 ng/mL (sensitivity 63.2%, specificity 84.6%) as the optimal discriminator for PRF1 A91V positivity. In multivariate regression, ferritin ≥ 7,000 ng/mL remained the only independent predictor (OR 17.3, 95% CI 2.0–146.3, p = 0.009). CONCLUSIONS: Patients carrying the PRF1 A91V variant represent a distinct subgroup within the spectrum of hyperinflammatory syndromes. Extreme hyperferritinemia combined with cytopenias should raise suspicion for perforin-related HLH rather than cytokine-driven MAS or classic Still’s disease. Recognition of this variant as a risk-modifying allele may guide early genetic testing and therapeutic decisions, including consideration of advanced interventions in selected cases.
2026-02-11 | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Bacillus Calmette-Guérin (BCG): A Steroid-Sparing Strategy in a Patient Awaiting Cardiac Surgery-A Case Report.
We report a case of hemophagocytic lymphohistiocytosis (HLH) secondary to disseminated Bacillus Calmette-Guérin (BCG) infection in an 80-year-old man treated with intravesical BCG for non-muscle-invasive bladder cancer. The patient presented with several weeks of constitutional symptoms including night sweats, fatigue, weight loss, confusion, and pancytopenia. Laboratory studies revealed profound inflammation, coagulopathy, and hepatocellular injury. HLH was suspected clinically and supported by a high H-score. Extensive infectious and autoimmune workup was negative. Mycobacterium bovis was subsequently isolated from urine and bone marrow cultures, which confirmed a diagnosis of disseminated BCG infection. The patient was treated with a combination of antimycobacterial therapy (isoniazid, rifampin, and ethambutol), intravenous immunoglobulin (IVIG), corticosteroids, and anakinra. Anakinra, an interleukin-1 receptor antagonist, was used both to minimize high-dose steroids, given the protracted inflammatory response anticipated with Mycobacterium infection, and to prevent steroid-related complications related to cardiac surgery. This therapeutic strategy was associated with improvement of cytopenias, normalization of inflammatory markers, and gradual clinical recovery. This case highlights the rare but serious complication of HLH triggered by disseminated BCG and suggests that targeted immunomodulation with anakinra may be a useful adjunct in selected, complex presentations of infection-associated HLH.
2026-01-30 | Hemophagocytic lymphohistiocytosis associated with extranodal NK/T cell lymphoma, nasal type or aggressive NK cell leukemia: a retrospective multicenter study of Jiangsu Cooperative Lymphoma Group (JCLG).
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95% CI, 1.08-3.83; P = 0.029), platelet count < 20 × 10⁹/L (HR, 2.70; 95% CI, 1.46-4.99; P = 0.002), and Epstein-Barr virus DNA (whole blood) > 33,850 copies/mL (HR, 1.97; 95% CI, 1.01-3.81; P = 0.045). ECOG performance status ≥ 2 (HR, 2.00; 95% CI, 1.24-3.23; P = 0.004) and platelet count < 20 × 10⁹/L (HR, 7.61; 95% CI, 2.14-27.09; P = 0.002) were independent risk factors for poor OS. Therefore, we recommend asparaginase-based regimens as first-line therapy for treatment-naive adult patients with HLH related to NK-cell malignancies. Future multicenter prospective studies are warranted to optimize asparaginase-containing regimens, evaluate novel combination strategies, and establish precision risk-prediction models to guide clinical practice.
2025-10-23 | Hemophagocytic Lymphohistiocytosis: A Life-Threatening Hyperinflammatory Syndrome.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome resulting from uncontrolled immune activation. It can be triggered by infections, malignancies, or autoimmune conditions and is difficult to diagnose due to its nonspecific clinical presentation. A male patient around 30 years old was admitted to the ICU in 2016 with severe diarrhea, vomiting, and abdominal pain. He developed pancytopenia requiring granulocyte colony-stimulating factor (G-CSF) support. Bone marrow aspiration and trephine revealed hemophagocytosis, with markedly elevated serum ferritin levels and a negative autoimmune workup apart from a positive anti-Ro antibody. The diagnosis of acquired HLH was established in the patient. Latent tuberculosis (TB) was treated empirically, and polymerase chain reaction (PCR) detected parvovirus B19. He was managed with high-dose dexamethasone after a hematology consultation and received intravenous immunoglobulin (IVIG). A few years later, in 2022, the patient was readmitted with acute respiratory distress and bilateral pulmonary consolidations. He was diagnosed with adult-onset Still's disease (AOSD) and secondary HLH. Imaging suggested fibrotic organizing pneumonia with a differential diagnosis of interstitial lung disease (ILD) or nonspecific interstitial pneumonitis (NSIP). Both episodes of HLH were successfully managed with interleukin-1 receptor antagonist therapy, i.e., anakinra. This case demonstrates the complexity of HLH in adults. The first episode was likely to be triggered by the latent TB and parvovirus infection, and the second one by the AOSD. Both episodes were treated with anakinra, showing that targeting specific immune system chemicals can help manage HLH. Clinicians should consider the possibility of HLH for patients who have low blood counts and widespread inflammation with an unclear cause, especially if they have known risk factors. Early recognition and prompt treatment with medicines that are targeted towards the immune system can save lives. It's also important to monitor these patients over time, as HLH can recur and may lead to long-term problems like lung damage.
other
2026-07-02 | Genome Editing for Familial Hemophagocytic Lymphohistiocytosis: Design Principles, Challenges, and Translational Perspectives.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by genetic defects in cytotoxic lymphocyte function. Current therapies can control disease activity, but transplantation of allogeneic hematopoietic stem and progenitor cells (HSPCs) remains the only curative option and is associated with substantial risks. These limitations have accelerated development of genome editing approaches enabling precise correction of disease-causing mutations in autologous cells. Familial HLH (FHL) represents a compelling target for genome editing, but successful and safe clinical translation has remained challenging. Preclinical studies demonstrate that targeted editing of key genes, such as PRF1 and UNC13D, can restore cytotoxic function in HSPCs and T cells. Translation to the clinic, however, depends on multiple factors, including the choice of target cell population, the level of functional correction required, and gene-specific constraints such as locus complexity and regulation of gene expression. In this review, we synthesize current progress in genome editing for FHL and highlight critical biological and technical barriers to clinical implementation. We propose a conceptual framework for designing genome editing strategies tailored to FHL, emphasizing the alignment of editing platform, gene architecture, and cellular context to enable effective and clinically translatable therapies.
2026-05-15 | Genotoxicity profiling reveals distinct platform-and cell type-specific effects in therapeutic gene editing for genetic hyperinflammation.
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62%-89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type-specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR-Cas9. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.
2026-02-10 | Context-Specific Genotoxicity in Therapeutic Base Editing for Genetic Hyperinflammation - Part 4
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform– and cell type–specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62–89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type–specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR–Cas9, particularly in HSCs. While off-target sequence edits persisted, CBE-induced chromosomal translocations largely resolved in vivo. These findings establish therapeutic base editing for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide clinical translation of genome editors.
2025-12-16 | Neonatal-onset familial hemophagocytic lymphohistiocytosis: a case report with genetic confirmation of PRF1 mutations.
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, inherited immune-dysregulation syndrome that can present in the neonatal period and progress rapidly without timely recognition. We report a full-term female who developed abdominal distension, fever, hepatosplenomegaly, and coagulopathy within hours of birth, with multiorgan failure leading to death on day 5 despite intensive care and broad antimicrobial coverage. This timing, essentially at birth with death on day 5, is exceptionally rare in FHL2 and clinically instructive for sepsis-like neonatal presentations. Postmortem whole-exome sequencing identified compound heterozygous PRF1 variants, c.1131C>A (p.Cys377Ter) and c.65delC (p.Pro22Argfs*29), confirming FHL type 2. The presentation closely mimicked culture-negative neonatal sepsis, underscoring the diagnostic challenge of distinguishing primary HLH from infectious and metabolic conditions in early life. This case highlights the need for early clinical suspicion and rapid genomic testing in neonates with fulminant, sepsis-like inflammation. While HLH-directed therapy followed by hematopoietic stem-cell transplantation remains the standard pathway to improve survival, the fulminant neonatal course can outpace therapeutic windows, emphasizing the value of streamlined access to urgent genetics and specialist input.
2025-03-10 | Gene therapy for inborn errors of immunity: Current clinical progress.
Hematopoietic stem cell transplant has been the single curative treatment for inborn errors of immunity (IEI) and is recommended for the most severe IEI conditions, such as severe combined immunodeficiency. However, adverse outcomes primarily due to histocompatibility differences between the donor and the patient are still of concern. Progress in genetic and molecular mechanisms, including new technology to insert DNA sequences in cell genomes, has allowed the development of strategies to treat genetic diseases by correcting gene defect in patients' cells. This technology is named gene therapy. Gene therapy approaches being developed for IEI are mediated by gene insertion, using a retroviral vector, or by gene editing, using a combination of a nuclease and a DNA template. After the unexpected occurrence of oncogenesis associated with the initial retroviral vector designs, significant advances have led to successful gene therapy clinical trials for 3 forms of severe combined immunodeficiency, which demonstrated the safety and efficacy of this approach. Active preclinical and clinical studies are ongoing for diverse IEI, including chronic granulomatous disease, leukocyte adhesion deficiency, severe congenital neutropenia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and familial forms of hemophagocytic lymphohistiocytosis.
small molecules
2026-09-25 | Neonatal-onset familial hemophagocytic lymphohistiocytosis type 2: a case report
Background Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare autosomal recessive disorder primarily caused by mutations in the perforin-1 (PRF1) gene, leading to immune system hyperactivation and multi-organ dysfunction. FHL2 typically presents in infancy, with neonatal onset being extremely rare and particularly difficult to recognize early due to substantial clinical overlap with sepsis. Given its rapid progression, early detection is critical for effective diagnosis and management. Case summary This case report describes a neonate with FHL2 who presented on day 8 after birth with fever (peak 38.9 °C), abdominal distension, and dyspnea, accompanied by coagulation dysfunction, liver function abnormalities, and capillary leak syndrome. Despite intensive care, the patient's condition continued to deteriorate, with progression to disseminated intravascular coagulation (DIC), polyserositis, and multi-organ failure. Despite receiving intensive care and comprehensive treatment, the patient's condition continued to deteriorate. By day 7 of hospitalization, the patient was in a moribund state, and the family requested discharge against medical advice; the patient died after discharge. Postmortem genetic testing identified a homozygous c.145G > A mutation in the PRF1 gene, resulting in a substitution of aspartic acid to asparagine at position 49 of the encoded protein (p.Asp49Asn). This mutation has been documented as pathogenic in the Human Gene Mutation Database. Conclusion FHL2 may present in the neonatal period with complex and variable clinical manifestations, frequently leading to misdiagnosis as neonatal sepsis or DIC. When neonates present with unexplained persistent fever, cytopenia, coagulation dysfunction, and multi-organ dysfunction that fails to respond to conventional anti-infective therapy, HLH should be included in the differential diagnosis, and genetic testing should be performed promptly.
2026-09-17 | Syntaxin11 Deficiency Inhibits CRAC Channel Priming to Suppress Cytotoxicity and Gene Expression in T Lymphocytes Independent of Membrane Trafficking
Mutations in Syntaxin11, a Q-SNARE, result in a fatal immune disorder known as familial hemophagocytic lymphohistiocytosis 4 (FHLH4) in human patients. A key diagnostic feature of FHLH4 is defective T and natural killer (NK) cell cytotoxicity. Here we show that Syntaxin11 directly binds and regulates Orai1, the pore forming subunit of calcium release activated calcium (CRAC) channels. CRAC channels enable store-operated calcium entry (SOCE) from the extracellular space and are crucial for granule exocytosis and nuclear factor of activated T cell (NFAT) dependent gene expression in activated lymphocytes. Syntaxin11 depletion strongly inhibited SOCE, CRAC currents, NFAT activation, interleukin-2 gene expression and degranulation in FHLH4 patient T lymphocytes and cell lines without affecting membrane trafficking. Remarkably, defects of cytolytic granule exocytosis as well as interleukin-2 expression could be reversed by ionomycin in patient T lymphocytes and a constitutively active, H134S, mutant of Orai1 rescued calcium entry in Syntaxin11 depleted cells. Further analyses showed that Syntaxin11 ‘primes’ Orai1 for optimal on-site multimeric assembly which was Stim independent but required for gating. Priming of ion channel pore subunits is, therefore, a primary function of specific SNAREs which may have preceded their role in membrane trafficking and vesicle fusion.
2026-09-07 | [Mechanism and clinical progress of JAK inhibitors in hemophagocytic lymphohistiocytosis].
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by uncontrolled activation of lymphocytes and macrophages. Owing to its marked etiological heterogeneity, HLH is broadly classified into primary and secondary forms. Janus kinase (JAK) inhibitors, represented by ruxolitinib, exert therapeutic effects by blocking the JAK-STAT signaling pathway and suppressing the secretion of various cytokines, including interferon-γ. Accumulating evidence suggests that JAK inhibitors demonstrate unique therapeutic potential across diverse etiological backgrounds of HLH. This review summarizes the mechanisms and clinical research progress of JAK inhibitors in the treatment of HLH.
2026-09-04 | Hemophagocytic Lymphohistiocytosis Complicated With Reversible Cardiomyopathy and Severe Sinus Node Dysfunction.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammation syndrome causing multiorgan failure. While cardiac involvement is recognized, associated conduction-system abnormalities are exceedingly rare and poorly described. A 60-year-old male presented with fever, pancytopenia, and progressive shock, meeting diagnostic criteria for HLH. His clinical course was acutely complicated by transient cardiomyopathy and frequent episodes of sinus arrest. Following the initiation of HLH-directed therapy, the patient experienced a complete recovery of both systolic function and sinus node conduction by day 10. This case identifies severe sinus node dysfunction as a reversible manifestation of HLH-related cytokine storm. Prompt initiation of immunosuppressive therapy led to complete recovery of left ventricular function and sinus node activity, highlighting the reversible nature of the HLH-related myocardial injury. This case highlights the importance of early identification of HLH-related cardiac involvement as it is critical to prevent irreversible damage and improve outcomes in these patients.
2026-09-03 | Hemophagocytic Lymphohistiocytosis As the Initial Presentation of Occult Diffuse Large B-cell Lymphoma: A Diagnostic Challenge.
Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome characterised by uncontrolled immune activation and cytokine release, resulting in multiorgan dysfunction and high mortality if not recognised and treated promptly. In adults, secondary HLH is frequently triggered by infection, autoimmune disease, or malignancy, with haematological malignancies carrying a particularly poor prognosis. The non-specific nature of its presentation often leads to diagnostic delay, as it can closely mimic sepsis and other inflammatory conditions. We present the case of a 76-year-old man who was admitted with a two-week history of progressive lethargy, exertional dyspnoea, anorexia, and headache after several months of constitutional symptoms. On presentation, he was hypotensive and tachycardic with atrial fibrillation and was initially managed for presumed sepsis with associated haemodynamic compromise. Despite supportive management, his clinical condition and biochemical profile deteriorated, with worsening cytopenias, deranged liver function tests, persistent hyperlactataemia, pyrexia, and escalating inflammatory markers. Further investigation demonstrated marked hyperferritinaemia exceeding 10,000 µg/L, hypertriglyceridaemia, hypofibrinogenaemia, elevated lactate dehydrogenase, and bicytopenia, producing an HScore of 220, which was highly suggestive of secondary HLH. Following multidisciplinary discussion with regional specialists, treatment with high-dose IV methylprednisolone and anakinra was commenced while an urgent search for the underlying trigger continued. Initial imaging failed to identify a clear source of malignancy or infection, and the patient showed only limited improvement with HLH-directed immunomodulatory therapy. Bone marrow biopsy subsequently demonstrated high-grade diffuse large B-cell lymphoma (DLBCL) with marrow involvement, establishing malignancy-associated HLH as the underlying diagnosis. The patient was transferred to a specialist haematology service and commenced on R-mini-CHOP chemotherapy, resulting in rapid clinical recovery and marked improvement in HLH parameters. Subsequent positron emission tomography imaging demonstrated a complete metabolic response after two treatment cycles, with the patient improving from a bedbound state to being independently ambulatory. This case highlights the significant diagnostic challenges associated with adult HLH and emphasises the importance of maintaining a high index of suspicion in patients presenting with unexplained fever, cytopenias, hyperferritinaemia, liver dysfunction, and multiorgan inflammation. It also demonstrates that, while immunosuppressive therapy may provide temporary disease control, successful management of malignancy-associated HLH depends on prompt identification and definitive treatment of the underlying haematological malignancy. Early multidisciplinary collaboration and timely bone marrow examination are critical to improving outcomes in this rapidly progressive and frequently fatal condition.
cell therapies
2026-09-03 | Use of Extracorporeal Membrane Oxygenation (ECMO) in Pediatric Patients With Hemophagocytic Lymphohistiocytosis: A Multicenter Sub-Analysis.
Hemophagocytic lymphohistiocytosis (HLH) is a rare condition causing severe systemic inflammatory activation, cytokine storm, and multiorgan dysfunction for which extracorporeal membrane oxygenation (ECMO) may be required. There is a paucity of data to guide clinicians in the care of these patients; we aimed to address this need. From the Hematology and Oncology Pediatric Patients on ECMO (HOPPE) database, 30 patients diagnosed with HLH were identified from 13 of the 16 total participating centers between 2009 and 2021. Of those 30 patients, 63% survived to ECMO decannulation, 43% to ICU discharge, and 37% to hospital discharge. Among survivors, there was a median of 44.9 days between decannulation and hospital discharge. Half of the ECMO mortality occurred within the first 10 days on ECMO. Patients who survived to hospital discharge also had evidence of functional limitation and significant multiorgan dysfunction. A total of 90% of patients diagnosed with HLH on ECMO survived to decannulation vs. 50% of patients diagnosed before. Survival has improved in this patient population compared to previous literature but is still lower than the overall pediatric ECMO population. Clinical suspicion for HLH in these critically ill patients should not exclude them from escalation of support, including ECMO.
2026-09-03 | Spectrum of Primary Hemophagocytic Lymphohistiocytosis-Associated Gene Mutations in Chinese Patients.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by hyperinflammation. Primary HLH (primary HLH), resulting from genetic mutations, is a subtype of HLH. The mutation spectrum of primary HLH-associated genes has not been well determined in China. This study aimed to explore the mutation spectrum of 12 primary HLH-associated genes in a multicenter database. Medical records and gene sequencing data of 1224 HLH patients were retrieved from January 2014 to September 2024, and gene mutations were analyzed. Genetic variants were observed in 350 (28.59%) patients. Among them, 108 patients had a definitive genetic diagnosis, 227 patients carried single heterozygous variants, and 15 patients carried digenic/polygenic heterozygous variants. A total of 275 different variants were identified, and missense variants were most common. Variants in UNC13D were most common, followed by LYST and PRF1, while variants in MAGT1, ITK, and CD27 were rare. For UNC13D, LYST, and PRF1, variants c.2588G>A (p.Gly863Asp), c.368A>G (p.His123Arg), and c.1349C>T (p.Thr450Met) were most common, respectively. We described the mutation spectrum of primary HLH-associated genes in a largest Chinese cohort and found some mutation specificity for Chinese HLH patients. Our data might help design sequencing panels, interpret sequencing results, and understand genetic background of Chinese HLH patients.
2026-09-01 | Allogeneic Hematopoietic Stem Cell Transplantation in Hemophagocytic LymphohistiocytosisTwo Sides of the Locket: Trigger or Cure?
Allogeneic hematopoietic stem cell transplantation (alloHSCT) represents a paradoxical role in hemophagocytic lymphohistiocytosis (HLH): curative in primary disease yet potentially triggering secondary HLH in the posttransplant setting. We report two adult cases illustrating this duality. The first case developed life-threatening secondary HLH on day +40 following haploidentical alloHSCT, presenting with extreme hyperferritinemia and procalcitonin elevation mimicking septic shock, successfully treated with dexamethasone, ruxolitinib, and plasma exchange. The second case underwent alloHSCT as definitive therapy for familial HLH harboring a UNC13D variant, achieving complete remission despite posttransplant EBV reactivation and lymphoproliferative disorder. These cases highlight the diagnostic challenges and therapeutic complexity of HLH within the transplant continuum.
2026-08-04 | Case Report: Munc13-4 deficiency presenting with autoimmune neuropathy years before FLH: implications for early genetic screening and HSCT timing.
The UNC13D gene encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in lymphocytes and the protein responsible for familial hemophagocytic lymphohistiocytosis (FHL). As an essential mediator of perforin release from cytotoxic T and NK cells, Munc13-4 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed "perforinopathy" manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13-4 deficiency, its association with autoimmune neuropathy remains largely unrecognized. We report two patients with a unique disease trajectory, presenting initially with autoimmune neuropathy before developing progressive FHL several years later. Both patients met the HLH-2004 diagnostic criteria, including fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. Genetic analysis revealed heterozygous UNC13D mutations: in Case 1, a nonsense (c.3193C>T; p.Arg1065*) and a missense (c.1135G>A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447 + 1G>A) and a paternal missense mutation (c.1241G>T; p.Arg414Leu). Case 1 underwent hematopoietic stem cell transplantation (HSCT), with significant recovery of weakness and numbness, and no recurrence of fever or lymphadenopathy at one year. Case 2 succumbed to disease progression after no timely, suitable allogeneic hematopoietic stem cell donor could be found. Our findings identify autoimmune neuropathy as a potential harbinger of FHL in perforinopathy, suggesting these neurological manifestations may be the initial phenotype of an underlying cytotoxic dysfunction. This temporal association mandates heightened clinical vigilance for immunodeficiency in patients with refractory neuropathy, particularly when accompanied by axonal degeneration or systemic inflammation. Recognizing this novel disease continuum has immediate diagnostic and therapeutic implications, as early genetic identification creates a critical window for potentially curative intervention with HSCT before irreversible multi-organ damage occurs. These cases expand the clinical spectrum of perforinopathy and challenge current diagnostic paradigms, emphasizing the need for an integrated neurological and immunological evaluation for unexplained autoimmune neuropathy.
2026-07-31 | Beyond Infections: Clinical and Genetic Spectrum of Pediatric Immune Dysregulation Disorders
Aim: Primary immune regulatory disorders represent a rapidly expanding subgroup of inborn errors of immunity.Unlike classical infectionpredominant immunodeficiencies, these disorders may initially present with autoimmunity, lymphoproliferation, cytopenias, dermatologic disease, allergy, enteropathy, hemophagocytic lymphohistiocytosis, or malignancy. Materials and Methods:We conducted a retrospective single-center observational cohort study of children with genetically confirmed diseases of immune dysregulation who had been followed at a tertiary pediatric immunology center between 2005 and 2025.Patients were included if their molecular diagnosis was classified under the International Union of Immunological Societies (IUIS) category of diseases of immune dysregulation.Demographic, clinical, genetic, therapeutic, transplant-related, and outcome data were extracted from the medical records and analyzed descriptively.Results: Twenty-one children were included.Parental consanguinity was frequent (71.4%), and more than half of the cohort had a family history of primary immunodeficiency (57.1%).A substantial diagnostic delay was observed, with a median delay of 28 months (interquartile range, 8-105.5).The most common IUIS subcategory was regulatory T-cell defects (52.4%), followed by familial hemophagocytic lymphohistiocytosis syndromes with hypopigmentation (19.0%), autoimmune lymphoproliferative syndrome (14.3%), susceptibility to Epstein-Barr virus and lymphoproliferative conditions (9.5%), and immune dysregulation with colitis (4.8%).The main clinical features were lymphoproliferation (76.2%), hematologic abnormalities (66.7%) and autoimmunity (52.4%).Notably, malignancy was documented in 2 patients (9.5%).Antimicrobial prophylaxis was administered in 90.5% of the patients, immunoglobulin replacement in 66.7%, conventional immunosuppressive therapy in 38.1%, and biological or targeted therapy in 33.3%.Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients (38.1%); immune reconstitution was achieved in all of the surviving transplant patients.Conclusion: Pediatric diseases of immune dysregulation frequently present with non-infectious manifestations, particularly lymphoproliferation, cytopenias, autoimmunity, and dermatologic findings.Recognition beyond infection-centered warning signs, the integration of genetic testing, and the individualized use of targeted therapies or HSCT may improve care for this heterogeneous group of disorders.
antibodies
2026-07-24 | Cytokine Release Syndrome Induced by Combination Therapy With Nivolumab and Ipilimumab in Lower Palpebral Conjunctival Melanoma: A Case Report.
Cytokine release syndrome (CRS) induced by immune checkpoint inhibitors (ICIs) is a potentially life-threatening immune-related adverse event (irAE). CRS has been recognized as a complication of chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engager (BiTE) therapy, but remains exceedingly rare as a complication of ICI therapy. Here, we report a case of CRS that developed after combination therapy with nivolumab and ipilimumab in a woman in her 60s with advanced conjunctival melanoma. The diagnosis was based on the clinical course and imaging findings together with characteristic laboratory abnormalities, including systemic inflammation, hepatic dysfunction, coagulopathy, and marked hyperferritinemia. This case highlights the importance of careful exclusion of infectious and neoplastic diseases for early diagnosis, demonstrates that ICI-related CRS can relapse after initial control, and shows that it may overlap with hemophagocytic lymphohistiocytosis (HLH)-like syndromes. Given the central role of interleukin-6 (IL-6) in CRS, early administration of tocilizumab may contribute to rapid control of inflammation and reduction of steroid exposure.
2026-07-09 | Advances in PD-1 monoclonal antibody therapy for hemophagocytic syndrome.
Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is a severe inflammatory condition, while the standard treatment still has limitations. With the conscious in-depth research on the pathogenesis, PD-1 (programmed cell death protein-1) monoclonal antibody has shown positive prospects in the treatment of HLH. This study retrospectively analyzed the clinical efficacy, and safety profile of PD-1 inhibitors in the treatment of HLH. A total of 15 studies was involved, covering with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and related malignancies. In pediatric patients with chronic active EBV infection (CAEBV) and refractory/relapsed EBV-HLH, sintilimab induced partial or complete clinical remission, and successfully served as a bridge therapy to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Retrospective studies on adult refractory/relapsed EBV-HLH showed that nivolumab treatment achieved an overall response rate (ORR) of 85.7% and a complete remission (CR) rate of 71.4% over 16 months. Sintilimab as salvage therapy also restored complete donor chimerism post-transplant and cleared viral loads. Furthermore, novel combinations with ruxolitinib, venetoclax, or thalidomide achieved rapid clinical remission in EBV-HLH. Safety assessments indicated that PD-1 blockade following HSCT was associated with a high risk of graft-versus-host disease (GVHD). Caution is warranted when using PD-1 monoclonal antibodies, as immune system stimulation is a double-edged sword. The optimal timing, dosage, and safety of PD-1 monoclonal antibodies in HLH treatment merit further clinical research and exploration.
2026-06-18 | The anti-CD33 antibody drug conjugate gemtuzumab ozogamicin depletes and functionally resets CD33+ myeloid-derived suppressor cells in patients with metastatic cancer: a phase 2 single-arm, open-label trial.
We previously demonstrated that the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalized, and decreases those cells' viability. Treatment of MDSCs with GO restores T-cell proliferation in co-culture, overcomes M-MDSC suppression of CAR-T cell proliferation, and enhances target-cell killing. Gemtuzumab Ozogamicin Therapy in Hemophagocytic Lymphohistiocytosis or Macrophage Activation Syndrome (GOTHAM) is a phase 2 single-arm clinical trial for which patients were eligible if they had a diagnosis of solid cancer with radiological or clinical evidence of disease progression, or primary or secondary hemophagocytic lymphohistiocytosis, or macrophage activation syndrome disease relapsing or refractory to treatment at enrollment. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-d intervals: days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Using 2 schedules of GO, we could not convincingly demonstrate safe feasibility in patients with solid cancer, because of neutropenia. However, GO reproducibly and significantly reduced circulating MDSCs. Importantly, there is consistent preliminary evidence that, upon rebound, the monocyte population of CD33+ cells is replaced with nonsuppressive monocytes. These data support the phase 1b dose-escalation testing of GO up to 2 mg/m2 in combination with immune checkpoint blockade and other immunotherapies in patients with solid cancer to find a dose that depletes and repolarizes MDSCs without causing undue neutropenia, paving the way to use GO as an immune potentiator in this patient population. Trial registration: ISRCTN 89158144.
2026-01-26 | Hemophagocytic Lymphohistiocytosis as First Manifestation of Dual B-Cell Neoplasms: A Case Report of Co-Existing Multiple Myeloma and B-Cell Lymphoma.
Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder causing excessive inflammation and tissue damage. Lymphoma, especially T-cell lymphoma, is the most common cause of HLH, while Multiple Myeloma (MM) is rarely associated. We present a 61-year-old man with spiking fevers, fatigue, and unintentional weight loss. The HLH was driven by two distinct malignant clones in his bone marrow: plasma cell neoplasm and B-cell lymphoma. Patient failed initial therapy with steroids, anakinra, and chemotherapy. Tocilizumab use, on the other hand, led to an excellent clinical and laboratory response immediately. This is the first reported case of HLH associated with two hematological malignancies. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2025-12-19 | A Case of Severe Dengue With Hemophagocytic Lymphohistiocytosis (HLH) Successfully Managed With Tocilizumab and Dexamethasone.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition due to an uncontrolled hyperinflammatory response. While HLH can arise from various causes, it is most commonly triggered by infections. Dengue, a febrile viral illness prevalent in the tropics, can lead to HLH in rare cases. Dengue-associated HLH is particularly challenging to diagnose due to its clinical features overlapping with those of severe dengue. Unless immunosuppressive treatment is promptly initiated, the prognosis of dengue-associated HLH remains poor. A previously healthy 32-year-old female was admitted to a tertiary care hospital in Sri Lanka with high-grade intermittent fever, gastrointestinal symptoms, and severe dehydration. Initial blood investigations and a point-of-care ultrasound scan confirmed dengue hemorrhagic fever. Despite supportive therapy, the patient's condition deteriorated with persistent fever, severe bicytopenia, and liver impairment. She was diagnosed with HLH based on clinical and laboratory findings, including high ferritin levels and hemophagocytosis in the bone marrow. She was treated with intravenous dexamethasone and tocilizumab, leading to significant clinical improvement. Additionally, therapeutic plasma exchange was performed, contributing to recovery from severe liver dysfunction. This unique case highlights the importance of early recognition and integration of advanced immunosuppressive therapy in managing dengue-associated HLH. To the best of our knowledge, this is the first reported case where tocilizumab was successfully used in dengue-associated HLH, highlighting the potential of interleukin-6 (IL-6) receptor blockers in similar contexts. The coordinated efforts of hematology, gastroenterology, and general medical teams facilitated timely diagnosis and individualized management, demonstrating how interdisciplinary collaboration can enhance outcomes in complex cases.
proteins
2026-09-16 | Precision immunomodulation for pediatric hemophagocytic lymphohistiocytosis in intensive care.
Hemophagocytic lymphohistiocytosis (HLH) and related cytokine storm syndromes are life-threatening hyperinflammatory disorders that frequently intersect with pediatric critical care. Critically ill children may present with fever, shock, cytopenias, liver dysfunction, coagulopathy, hyperferritinemia, respiratory failure, neurologic deterioration, and multiple organ dysfunction, creating substantial overlap with severe sepsis. Traditional diagnostic criteria remain foundational but do not identify the dominant mechanism or optimal therapy for an individual child. In this review, precision immunomodulation is defined operationally as matching the suspected trigger and clinical phenotype with pathway-informed biomarkers when available, drug-delivery feasibility during organ failure, and the plan for definitive disease control. Interferon-gamma activity may be supported by CXCL9; interleukin (IL)-1/IL-18 biology may support anakinra in macrophage activation syndrome; broader cytokine signaling may support Janus kinase inhibition in selected refractory HLH; and IL-6-directed therapy is primarily syndrome- and grade-directed in immune effector cell cytokine release syndrome. These markers are supportive rather than validated treatment thresholds. Targeted therapy must proceed alongside antimicrobial therapy, source control, organ support, infection surveillance, and early hematopoietic stem cell transplantation planning when indicated. This review provides a bedside framework for phenotype assignment, biomarker interpretation, intensive care unit-focused targeted therapy, extracorporeal bridge strategies, and reassessment at 24-72 h.
2026-03-08 | Is a variant of uncertain significance always 'insignificant'? A systematic review on PRF1 A91V in Hemophagocytic Lymphohistocytosis and comparative analysis with Still's disease.
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that may arise secondary to rheumatic diseases such as Still’s disease, where macrophage activation syndrome (MAS) represents its clinical counterpart. The pathogenic significance of the PRF1 A91V variant remains uncertain, although functional data suggest partial perforin dysfunction and a possible contribution to late-onset or atypical HLH. This study aimed to clarify the clinical implications of the PRF1 A91V variant through a systematic review of published HLH and MAS cases and a comparative analysis with a single-center Still’s disease cohort. RESULTS: A total of 20 studies, including 38 individual HLH or MAS cases carrying the PRF1 A91V variant, were identified. The median age at diagnosis was 22 years, and 18.4% of patients were homozygous. Fever (82.6%), splenomegaly (57.9%), and hepatomegaly (36.8%) were the most frequent clinical findings. Anemia (57.1%) and thrombocytopenia (85.7%) were the predominant laboratory abnormalities, accompanied by marked hyperferritinemia (median 9319 ng/mL). Compared with 43 active Still’s disease cases, PRF1-mutated HLH patients showed significantly higher rates of cytopenias, hepatomegaly, and central nervous system involvement, together with substantially elevated ferritin levels (9,193 vs 800 ng/mL, p = 0.0023), whereas C-reactive protein levels were comparable. Receiver-operating characteristic analysis identified a ferritin cutoff of 7000 ng/mL (sensitivity 63.2%, specificity 84.6%) as the optimal discriminator for PRF1 A91V positivity. In multivariate regression, ferritin ≥ 7,000 ng/mL remained the only independent predictor (OR 17.3, 95% CI 2.0–146.3, p = 0.009). CONCLUSIONS: Patients carrying the PRF1 A91V variant represent a distinct subgroup within the spectrum of hyperinflammatory syndromes. Extreme hyperferritinemia combined with cytopenias should raise suspicion for perforin-related HLH rather than cytokine-driven MAS or classic Still’s disease. Recognition of this variant as a risk-modifying allele may guide early genetic testing and therapeutic decisions, including consideration of advanced interventions in selected cases.
2026-02-11 | Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Bacillus Calmette-Guérin (BCG): A Steroid-Sparing Strategy in a Patient Awaiting Cardiac Surgery-A Case Report.
We report a case of hemophagocytic lymphohistiocytosis (HLH) secondary to disseminated Bacillus Calmette-Guérin (BCG) infection in an 80-year-old man treated with intravesical BCG for non-muscle-invasive bladder cancer. The patient presented with several weeks of constitutional symptoms including night sweats, fatigue, weight loss, confusion, and pancytopenia. Laboratory studies revealed profound inflammation, coagulopathy, and hepatocellular injury. HLH was suspected clinically and supported by a high H-score. Extensive infectious and autoimmune workup was negative. Mycobacterium bovis was subsequently isolated from urine and bone marrow cultures, which confirmed a diagnosis of disseminated BCG infection. The patient was treated with a combination of antimycobacterial therapy (isoniazid, rifampin, and ethambutol), intravenous immunoglobulin (IVIG), corticosteroids, and anakinra. Anakinra, an interleukin-1 receptor antagonist, was used both to minimize high-dose steroids, given the protracted inflammatory response anticipated with Mycobacterium infection, and to prevent steroid-related complications related to cardiac surgery. This therapeutic strategy was associated with improvement of cytopenias, normalization of inflammatory markers, and gradual clinical recovery. This case highlights the rare but serious complication of HLH triggered by disseminated BCG and suggests that targeted immunomodulation with anakinra may be a useful adjunct in selected, complex presentations of infection-associated HLH.
2026-01-30 | Hemophagocytic lymphohistiocytosis associated with extranodal NK/T cell lymphoma, nasal type or aggressive NK cell leukemia: a retrospective multicenter study of Jiangsu Cooperative Lymphoma Group (JCLG).
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95% CI, 1.08-3.83; P = 0.029), platelet count < 20 × 10⁹/L (HR, 2.70; 95% CI, 1.46-4.99; P = 0.002), and Epstein-Barr virus DNA (whole blood) > 33,850 copies/mL (HR, 1.97; 95% CI, 1.01-3.81; P = 0.045). ECOG performance status ≥ 2 (HR, 2.00; 95% CI, 1.24-3.23; P = 0.004) and platelet count < 20 × 10⁹/L (HR, 7.61; 95% CI, 2.14-27.09; P = 0.002) were independent risk factors for poor OS. Therefore, we recommend asparaginase-based regimens as first-line therapy for treatment-naive adult patients with HLH related to NK-cell malignancies. Future multicenter prospective studies are warranted to optimize asparaginase-containing regimens, evaluate novel combination strategies, and establish precision risk-prediction models to guide clinical practice.
2025-10-23 | Hemophagocytic Lymphohistiocytosis: A Life-Threatening Hyperinflammatory Syndrome.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome resulting from uncontrolled immune activation. It can be triggered by infections, malignancies, or autoimmune conditions and is difficult to diagnose due to its nonspecific clinical presentation. A male patient around 30 years old was admitted to the ICU in 2016 with severe diarrhea, vomiting, and abdominal pain. He developed pancytopenia requiring granulocyte colony-stimulating factor (G-CSF) support. Bone marrow aspiration and trephine revealed hemophagocytosis, with markedly elevated serum ferritin levels and a negative autoimmune workup apart from a positive anti-Ro antibody. The diagnosis of acquired HLH was established in the patient. Latent tuberculosis (TB) was treated empirically, and polymerase chain reaction (PCR) detected parvovirus B19. He was managed with high-dose dexamethasone after a hematology consultation and received intravenous immunoglobulin (IVIG). A few years later, in 2022, the patient was readmitted with acute respiratory distress and bilateral pulmonary consolidations. He was diagnosed with adult-onset Still's disease (AOSD) and secondary HLH. Imaging suggested fibrotic organizing pneumonia with a differential diagnosis of interstitial lung disease (ILD) or nonspecific interstitial pneumonitis (NSIP). Both episodes of HLH were successfully managed with interleukin-1 receptor antagonist therapy, i.e., anakinra. This case demonstrates the complexity of HLH in adults. The first episode was likely to be triggered by the latent TB and parvovirus infection, and the second one by the AOSD. Both episodes were treated with anakinra, showing that targeting specific immune system chemicals can help manage HLH. Clinicians should consider the possibility of HLH for patients who have low blood counts and widespread inflammation with an unclear cause, especially if they have known risk factors. Early recognition and prompt treatment with medicines that are targeted towards the immune system can save lives. It's also important to monitor these patients over time, as HLH can recur and may lead to long-term problems like lung damage.
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2026-07-02 | Genome Editing for Familial Hemophagocytic Lymphohistiocytosis: Design Principles, Challenges, and Translational Perspectives.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by genetic defects in cytotoxic lymphocyte function. Current therapies can control disease activity, but transplantation of allogeneic hematopoietic stem and progenitor cells (HSPCs) remains the only curative option and is associated with substantial risks. These limitations have accelerated development of genome editing approaches enabling precise correction of disease-causing mutations in autologous cells. Familial HLH (FHL) represents a compelling target for genome editing, but successful and safe clinical translation has remained challenging. Preclinical studies demonstrate that targeted editing of key genes, such as PRF1 and UNC13D, can restore cytotoxic function in HSPCs and T cells. Translation to the clinic, however, depends on multiple factors, including the choice of target cell population, the level of functional correction required, and gene-specific constraints such as locus complexity and regulation of gene expression. In this review, we synthesize current progress in genome editing for FHL and highlight critical biological and technical barriers to clinical implementation. We propose a conceptual framework for designing genome editing strategies tailored to FHL, emphasizing the alignment of editing platform, gene architecture, and cellular context to enable effective and clinically translatable therapies.
2026-05-15 | Genotoxicity profiling reveals distinct platform-and cell type-specific effects in therapeutic gene editing for genetic hyperinflammation.
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62%-89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type-specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR-Cas9. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.
2026-02-10 | Context-Specific Genotoxicity in Therapeutic Base Editing for Genetic Hyperinflammation - Part 4
Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform– and cell type–specific genotoxicities remain incompletely characterized. Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62–89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs. Comparative genotoxicity profiling revealed distinct platform- and cell type–specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR–Cas9, particularly in HSCs. While off-target sequence edits persisted, CBE-induced chromosomal translocations largely resolved in vivo. These findings establish therapeutic base editing for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide clinical translation of genome editors.
2025-12-16 | Neonatal-onset familial hemophagocytic lymphohistiocytosis: a case report with genetic confirmation of PRF1 mutations.
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, inherited immune-dysregulation syndrome that can present in the neonatal period and progress rapidly without timely recognition. We report a full-term female who developed abdominal distension, fever, hepatosplenomegaly, and coagulopathy within hours of birth, with multiorgan failure leading to death on day 5 despite intensive care and broad antimicrobial coverage. This timing, essentially at birth with death on day 5, is exceptionally rare in FHL2 and clinically instructive for sepsis-like neonatal presentations. Postmortem whole-exome sequencing identified compound heterozygous PRF1 variants, c.1131C>A (p.Cys377Ter) and c.65delC (p.Pro22Argfs*29), confirming FHL type 2. The presentation closely mimicked culture-negative neonatal sepsis, underscoring the diagnostic challenge of distinguishing primary HLH from infectious and metabolic conditions in early life. This case highlights the need for early clinical suspicion and rapid genomic testing in neonates with fulminant, sepsis-like inflammation. While HLH-directed therapy followed by hematopoietic stem-cell transplantation remains the standard pathway to improve survival, the fulminant neonatal course can outpace therapeutic windows, emphasizing the value of streamlined access to urgent genetics and specialist input.
2025-03-10 | Gene therapy for inborn errors of immunity: Current clinical progress.
Hematopoietic stem cell transplant has been the single curative treatment for inborn errors of immunity (IEI) and is recommended for the most severe IEI conditions, such as severe combined immunodeficiency. However, adverse outcomes primarily due to histocompatibility differences between the donor and the patient are still of concern. Progress in genetic and molecular mechanisms, including new technology to insert DNA sequences in cell genomes, has allowed the development of strategies to treat genetic diseases by correcting gene defect in patients' cells. This technology is named gene therapy. Gene therapy approaches being developed for IEI are mediated by gene insertion, using a retroviral vector, or by gene editing, using a combination of a nuclease and a DNA template. After the unexpected occurrence of oncogenesis associated with the initial retroviral vector designs, significant advances have led to successful gene therapy clinical trials for 3 forms of severe combined immunodeficiency, which demonstrated the safety and efficacy of this approach. Active preclinical and clinical studies are ongoing for diverse IEI, including chronic granulomatous disease, leukocyte adhesion deficiency, severe congenital neutropenia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and familial forms of hemophagocytic lymphohistiocytosis.
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Drug Discovery Landscape
4 orphan drug designations for Familial hemophagocytic lymphohistiocytosis, including 1 approved therapy.
4 orphan drug designations for Familial hemophagocytic lymphohistiocytosis, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
fully human IgG1 monoclonal antibody directed against human signal regulatory protein (SIRP)alpha, SIRPbeta1, and SIRPgamma | antibodies | FDA | Electra Therapeutics, Inc. | |
Tadekinig alfa | proteins | EMA | Yes Pharmaceutical Development Services GmbH | |
Recombinant human anti-interferon gamma monoclonal antibody | antibodies | EMA | Swedish Orphan Biovitrum AB (publ) | |
emapalumab-lzsg [Gamifant] | antibodies | FDA | Approved | Swedish Orphan Biovitrum AB |
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