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
828 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:
828 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
2026-08-11 | Treating hematologic immune dysregulation in inborn errors of immunity: a real-life multicenter study.
Hematologic immune dysregulation (H-ID) - including autoimmune cytopenia (AIC), lymphoproliferation (LPD), and hemophagocytic lymphohistiocytosis (HLH) - is a potentially life-threatening manifestation of inborn errors of immunity (IEI). Despite the availability of targeted therapies, its management remains challenging, with no standardized treatment strategies established. To evaluate the efficacy and safety of the available treatments for H-ID, with a specific focus on the treatment indications and outcome differences between targeted versus non-targeted therapies. This multicentric retrospective study included 116 patients with IEI and H-ID across Italian tertiary care centers. Data included treatment indications, response rate, and incidence of adverse events (AEs). We included patients with autoimmune lymphoproliferative immunodeficiencies (ALPID, 37.1%), humoral immunodeficiencies (31%), syndromic IEI (8.6%), and combined immunodeficiencies (8.6%). H-ID consisted of AIC (67.2%), LPD (71.6%), and HLH (9.5%). 85.3% of patients received treatment, including on-demand therapies (37.9%), long-term treatments (LTT, 84.8%), and hematopoietic stem-cell transplantation (HSCT; 9.1%). LTT included sirolimus (42.9%), mycophenolate mofetil (34.5%), rituximab (29.8%), and targeted therapies (17.9%). Sirolimus showed a higher complete response (CR) rate (61.1%), especially in ALPID patients and those with lymphoproliferation (72%). CR rate was significantly higher in patients receiving targeted therapies (80% vs 43.4%, p < 0.05). AEs were reported in 13.3% of cases, leading to drug withdrawal in 3.6%. The indications for LTT and HSCT in H-ID are still heterogeneous. Response rates are variable and influenced by the underlying diagnosis. Targeted therapies are associated with an improved response, the suboptimal molecular diagnosis rate currently limits their use.
2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
2026-07-25 | Haemophagocytic lymphohistiocytosis: a life threatening complication of lymphoma.
Haemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome leading to organ damage and death, may arise as a complication of lymphomas (L-HLH). L-HLH diagnosis is challenging and optimal treatment strategies, influenced by factors such as timing of onset, lymphoma subtype and disease severity, remain ill-defined. This narrative review summarises recent evidence to support clinicians in navigating the competing priorities posed by L-HLH, including the urgent need to control inflammation, establish a diagnosis and initiate lymphoma-directed therapy, while minimising toxicity and avoiding unnecessary immunosuppression. While HLH-94 and H-score diagnostic criteria were not specifically designed for L-HLH, the optimised HLH inflammatory index (OHI) was developed in L-HLH patients and predicts the risk of multiorgan failure (MOF) but also benefit from etoposide. Recent evidence also highlights improved survival with early administration of lymphoma targeting drugs while, in critically unwell patients, non-myelosuppressive treatment with anakinra, ruxolitinib and intravenous immunoglobulins (IVIg) might offer a survival advantage. Finally, novel markers such as C-X-C motif chemokine ligand 9 (CXCL-9), recently shown to identify patients responding to interferon γ blockade, might become more widely available in the future. L-HLH encompasses a wide range of clinical presentations that force clinicians to balance competing priorities. Recent evidence improves patients stratification and supports early administration of lymphoma targeting drugs when feasible, etoposide in high risk patients and non-myelosuppressive regimens in critically unwell patients.
2026-07-17 | Long-term clinical trajectory of microvillus inclusion disease associated with STXBP2-related familial hemophagocytic lymphohistiocytosis type 5: A case report.
Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin-binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long-term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22-year-old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long-term follow-up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long-term extrahematopoietic phenotype of STXBP2-related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.
2026-07-15 | Simultaneous onset of familial hemophagocytic lymphohistiocytosis and T-cell large granular lymphocytic leukemia in an adult.
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome. The familial form (fHL), associated with specific genetic alterations, typically manifests in childhood, while secondary forms arise due to triggers such as malignancies or infections. We present the rare case of adult-onset fHL in a 30-year-old female concurrent with T-cell large granular lymphocytic leukemia (T-LGL). After presenting with symptoms of HLH, a bone marrow biopsy revealed T-cell lymphoma, leading to CHOEP treatment. This diagnosis was later revised to T-LGL, prompting a switch to methotrexate for T-LGL treatment. Further genetic testing uncovered an unexpected homozygous missense mutation in UNC13D (p.R414C), associated with fHL type 3. A detailed family history revealed a consanguineous marriage between her parents, which likely increased the risk of the homozygous mutation. Additionally, it was discovered that the patient's sister had undergone allogeneic stem cell transplantation during childhood for an unspecified lymphoproliferative disorder, with the patient herself serving as the donor. This case highlights the rare occurrence of adult-onset fHL, triggered by the evolution of T-LGL as a possible contributing factor. It underscores the importance of early diagnosis and illustrates how familial history and persistent symptoms can necessitate genetic testing.
cell therapies
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.
2026-07-06 | Familial Hemophagocytic Lymphohistiocytosis Type 3 - UNC13D mutation: A rare case report with comprehensive management and outcome
Abstract Background: Familial hemophagocytic lymphohistocytosis (FHL) is a rare autosomal recessive disease, resulting in an often-fatal presentation with persistent pyrexia, splenomegaly and cytopenia. The familial type of hemophagocytic lymphohistiocytosis is caused by mutations in several genes, including PRF1, STX11, STXBP2, Munc13-4, HPLH1, and UNC13D. We aimed to identify the genetically confirmed case of FHL and the pattern of presentation and outcome. Case presentation: We report a 4-month-old female patient who presented with typical signs and symptoms that fulfil HLH-2004 criteria. The UNC13D gene by whole exome sequences confirms a homozygous likely variant detected "c. 1828_1839del p(Arg610_Gln613del)". The HLH-2004 protocol was administered with excellent response. As a reason for delayed allogeneic hematopoietic stem cell transplantation (HSCT) after the protocol completion of 52 weeks, the patient has disease reactivation, which required re-induction of the protocol that ended successfully with HSCT. Conclusions: Our case aimed for a multifaceted presentation and clinical pattern in FHLH; remission can be achieved with immunosuppressive therapy and chemotherapy, but allo-HSCT is required for cure.
2026-07-06 | Critical care outcomes of hemophagocytic lymphohistiocytosis in children: a single centre retrospective observational study.
Hemophagocytic lymphohistiocytosis (HLH) is a challenging and potentially life-threatening condition characterized by an uncontrolled inflammatory response resulting from hyperactivation of T lymphocytes and macrophages, leading to excessive production of inflammatory cytokines. HLH can lead to multiple organ failure and death in a significant proportion of cases. It is challenging to differentiate HLH from sepsis. This study aims to describe the clinical characteristics, risk factors, and outcomes of a cohort of children admitted to a pediatric intensive care unit (PICU) with primary and secondary hemophagocytic lymphohistiocytosis (pHLH and sHLH). Retrospective observational analysis of all children with HLH admitted to the PICU between 2006 and 2019. Patients were evaluated at two time points: upon PICU admission (T1) and at the time of the highest ferritin level (T2). A total of 48 patients were included: 5 with pHLH, 37 with sHLH, and 6 with macrophage activation syndrome (MAS) in the context of systemic juvenile idiopathic arthritis (sJIA). The overall mortality rate in the PICU was 33.3%. Mortality rates within each group were: 60% for pHLH, 35.1% for sHLH, and nobody for MAS. The Pediatric Index of Mortality (PIM2) was higher among non-survivors. Splenomegaly and leukopenia at PICU admission were more common in non-survivors compared to survivors, as were the incidence of multiple organ failure and acute renal failure during the PICU stay. Platelet counts were significantly lower in patients who died, but only at T2. Ferritin levels remained consistently elevated in non-survivors throughout their PICU stay. In this cohort, mortality among children admitted to the PICU with HLH was high, particularly among those with primary or onco-hematological forms. Conversely, patients with MAS experienced more relapses but no mortality was observed in this sample. Early presence of splenomegaly, low platelet count, elevated ferritin levels, and PIM2 score at PICU admission appear to be indicators of poor prognosis. These findings may help to early identify patients at highest risk for complications and mortality.
2026-06-04 | A Hypomorphic UNC13D Variant Causes Pancytopenia in a 12-Year-Old Girl Without Systemic Inflammation
Background Familial hemophagocytic lymphohistiocytosis (FHL) is an immune dysregulation disorder in which most patients develop hemophagocytic lymphohistiocytosis (HLH) within the first year of life. Recently, an increasing number of patients with hypomorphic variants in FHL-related genes presenting with atypical features in late childhood or adulthood have been reported. Case A previously healthy 12-year-old girl presented with painful erythema at age 10. Laboratory tests revealed pancytopenia, and she was referred to our department. Although the erythema resolved spontaneously, splenomegaly was noted. Bone marrow examination showed hypocellularity without dysplasia or malignancy. Flow cytometry demonstrated TCRαβ+ double-negative T cells (DNTs) accounting for 2.5% of lymphocytes (3.3% of T cells). Cytokine analysis revealed markedly elevated IL-18 (5,804 pg/mL) and CXCL9 (8,688 pg/mL), while IL-6 was <3 pg/mL, and soluble TNF receptor II was 5,390 pg/mL. Based on these findings, an immune dysregulation disorder such as autoimmune lymphoproliferative syndrome (ALPS) was suspected. Genetic testing revealed compound heterozygous variants in UNC13D (c.2588G>A and c.1596+1G>C). Functional analysis showed mildly reduced Munc13-4 expression in platelets and impaired degranulation function in natural killer cells and cytotoxic T lymphocytes. Discussion Previous reports have described late-onset FHL and CLIPPERS syndrome in patients with missense variants in UNC13D or PRF1, most of which suggested these are hypomorphic variants. Variants in FHL-related genes can produce a broad clinical spectrum ranging from early-onset FHL to late-onset or atypical inflammatory phenotypes, depending on the degree of residual cytotoxic function. Conclusion We report a case of atypical cytopenia associated with hypomorphic UNC13D variants. Currently, pancytopenia is the only clinical manifestation, and the patient is receiving prophylactic trimethoprim–sulfamethoxazole. However, considering the risk of neurological sequelae with central nervous system involvement, hematopoietic stem cell transplantation is being considered.
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
2026-03-08 | 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.
2025-03-14 | Emergency admission with unremitting fever and lymphadenopathy: Kikuchi-Fujimoto disease causing haemophagocytic lymphohistiocytosis.
Haemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome. Over activation of histiocytes and lymphocytes can lead to multiorgan failure and death. The three key features are fever, raised ferritin and falling counts, that is, cytopenia (3Fs). Treatment is immunosuppression while identifying the driver. Our young female patient presented with high fever and extensive lymphadenopathy, raising the suspicion of HLH driven by lymphoma. Her H-score was consistent with HLH. Immunosuppression was commenced with intravenous steroids, followed by anakinra due to inadequate steroid response. She required intensive care unit (ICU) admission with input from haematology and rheumatology. A lymph node biopsy revealed likely Kikuchi-Fujimoto disease, a rare benign cause of painful lymphadenopathy that is usually self-limiting but is also reported as a cause of HLH. She responded rapidly to anakinra and was discharged home 1 week after leaving ICU. Regular clinic follow-up continues, immunosuppression has been weaned off and she remains in remission. Monitoring for later development of autoimmune disease continues. We discuss her management with reference to the recently published Getting it Right First Time guidelines on HLH.
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
2026-08-11 | Treating hematologic immune dysregulation in inborn errors of immunity: a real-life multicenter study.
Hematologic immune dysregulation (H-ID) - including autoimmune cytopenia (AIC), lymphoproliferation (LPD), and hemophagocytic lymphohistiocytosis (HLH) - is a potentially life-threatening manifestation of inborn errors of immunity (IEI). Despite the availability of targeted therapies, its management remains challenging, with no standardized treatment strategies established. To evaluate the efficacy and safety of the available treatments for H-ID, with a specific focus on the treatment indications and outcome differences between targeted versus non-targeted therapies. This multicentric retrospective study included 116 patients with IEI and H-ID across Italian tertiary care centers. Data included treatment indications, response rate, and incidence of adverse events (AEs). We included patients with autoimmune lymphoproliferative immunodeficiencies (ALPID, 37.1%), humoral immunodeficiencies (31%), syndromic IEI (8.6%), and combined immunodeficiencies (8.6%). H-ID consisted of AIC (67.2%), LPD (71.6%), and HLH (9.5%). 85.3% of patients received treatment, including on-demand therapies (37.9%), long-term treatments (LTT, 84.8%), and hematopoietic stem-cell transplantation (HSCT; 9.1%). LTT included sirolimus (42.9%), mycophenolate mofetil (34.5%), rituximab (29.8%), and targeted therapies (17.9%). Sirolimus showed a higher complete response (CR) rate (61.1%), especially in ALPID patients and those with lymphoproliferation (72%). CR rate was significantly higher in patients receiving targeted therapies (80% vs 43.4%, p < 0.05). AEs were reported in 13.3% of cases, leading to drug withdrawal in 3.6%. The indications for LTT and HSCT in H-ID are still heterogeneous. Response rates are variable and influenced by the underlying diagnosis. Targeted therapies are associated with an improved response, the suboptimal molecular diagnosis rate currently limits their use.
2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
2026-07-25 | Haemophagocytic lymphohistiocytosis: a life threatening complication of lymphoma.
Haemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome leading to organ damage and death, may arise as a complication of lymphomas (L-HLH). L-HLH diagnosis is challenging and optimal treatment strategies, influenced by factors such as timing of onset, lymphoma subtype and disease severity, remain ill-defined. This narrative review summarises recent evidence to support clinicians in navigating the competing priorities posed by L-HLH, including the urgent need to control inflammation, establish a diagnosis and initiate lymphoma-directed therapy, while minimising toxicity and avoiding unnecessary immunosuppression. While HLH-94 and H-score diagnostic criteria were not specifically designed for L-HLH, the optimised HLH inflammatory index (OHI) was developed in L-HLH patients and predicts the risk of multiorgan failure (MOF) but also benefit from etoposide. Recent evidence also highlights improved survival with early administration of lymphoma targeting drugs while, in critically unwell patients, non-myelosuppressive treatment with anakinra, ruxolitinib and intravenous immunoglobulins (IVIg) might offer a survival advantage. Finally, novel markers such as C-X-C motif chemokine ligand 9 (CXCL-9), recently shown to identify patients responding to interferon γ blockade, might become more widely available in the future. L-HLH encompasses a wide range of clinical presentations that force clinicians to balance competing priorities. Recent evidence improves patients stratification and supports early administration of lymphoma targeting drugs when feasible, etoposide in high risk patients and non-myelosuppressive regimens in critically unwell patients.
2026-07-17 | Long-term clinical trajectory of microvillus inclusion disease associated with STXBP2-related familial hemophagocytic lymphohistiocytosis type 5: A case report.
Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin-binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long-term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22-year-old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long-term follow-up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long-term extrahematopoietic phenotype of STXBP2-related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.
2026-07-15 | Simultaneous onset of familial hemophagocytic lymphohistiocytosis and T-cell large granular lymphocytic leukemia in an adult.
Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome. The familial form (fHL), associated with specific genetic alterations, typically manifests in childhood, while secondary forms arise due to triggers such as malignancies or infections. We present the rare case of adult-onset fHL in a 30-year-old female concurrent with T-cell large granular lymphocytic leukemia (T-LGL). After presenting with symptoms of HLH, a bone marrow biopsy revealed T-cell lymphoma, leading to CHOEP treatment. This diagnosis was later revised to T-LGL, prompting a switch to methotrexate for T-LGL treatment. Further genetic testing uncovered an unexpected homozygous missense mutation in UNC13D (p.R414C), associated with fHL type 3. A detailed family history revealed a consanguineous marriage between her parents, which likely increased the risk of the homozygous mutation. Additionally, it was discovered that the patient's sister had undergone allogeneic stem cell transplantation during childhood for an unspecified lymphoproliferative disorder, with the patient herself serving as the donor. This case highlights the rare occurrence of adult-onset fHL, triggered by the evolution of T-LGL as a possible contributing factor. It underscores the importance of early diagnosis and illustrates how familial history and persistent symptoms can necessitate genetic testing.
cell therapies
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.
2026-07-06 | Familial Hemophagocytic Lymphohistiocytosis Type 3 - UNC13D mutation: A rare case report with comprehensive management and outcome
Abstract Background: Familial hemophagocytic lymphohistocytosis (FHL) is a rare autosomal recessive disease, resulting in an often-fatal presentation with persistent pyrexia, splenomegaly and cytopenia. The familial type of hemophagocytic lymphohistiocytosis is caused by mutations in several genes, including PRF1, STX11, STXBP2, Munc13-4, HPLH1, and UNC13D. We aimed to identify the genetically confirmed case of FHL and the pattern of presentation and outcome. Case presentation: We report a 4-month-old female patient who presented with typical signs and symptoms that fulfil HLH-2004 criteria. The UNC13D gene by whole exome sequences confirms a homozygous likely variant detected "c. 1828_1839del p(Arg610_Gln613del)". The HLH-2004 protocol was administered with excellent response. As a reason for delayed allogeneic hematopoietic stem cell transplantation (HSCT) after the protocol completion of 52 weeks, the patient has disease reactivation, which required re-induction of the protocol that ended successfully with HSCT. Conclusions: Our case aimed for a multifaceted presentation and clinical pattern in FHLH; remission can be achieved with immunosuppressive therapy and chemotherapy, but allo-HSCT is required for cure.
2026-07-06 | Critical care outcomes of hemophagocytic lymphohistiocytosis in children: a single centre retrospective observational study.
Hemophagocytic lymphohistiocytosis (HLH) is a challenging and potentially life-threatening condition characterized by an uncontrolled inflammatory response resulting from hyperactivation of T lymphocytes and macrophages, leading to excessive production of inflammatory cytokines. HLH can lead to multiple organ failure and death in a significant proportion of cases. It is challenging to differentiate HLH from sepsis. This study aims to describe the clinical characteristics, risk factors, and outcomes of a cohort of children admitted to a pediatric intensive care unit (PICU) with primary and secondary hemophagocytic lymphohistiocytosis (pHLH and sHLH). Retrospective observational analysis of all children with HLH admitted to the PICU between 2006 and 2019. Patients were evaluated at two time points: upon PICU admission (T1) and at the time of the highest ferritin level (T2). A total of 48 patients were included: 5 with pHLH, 37 with sHLH, and 6 with macrophage activation syndrome (MAS) in the context of systemic juvenile idiopathic arthritis (sJIA). The overall mortality rate in the PICU was 33.3%. Mortality rates within each group were: 60% for pHLH, 35.1% for sHLH, and nobody for MAS. The Pediatric Index of Mortality (PIM2) was higher among non-survivors. Splenomegaly and leukopenia at PICU admission were more common in non-survivors compared to survivors, as were the incidence of multiple organ failure and acute renal failure during the PICU stay. Platelet counts were significantly lower in patients who died, but only at T2. Ferritin levels remained consistently elevated in non-survivors throughout their PICU stay. In this cohort, mortality among children admitted to the PICU with HLH was high, particularly among those with primary or onco-hematological forms. Conversely, patients with MAS experienced more relapses but no mortality was observed in this sample. Early presence of splenomegaly, low platelet count, elevated ferritin levels, and PIM2 score at PICU admission appear to be indicators of poor prognosis. These findings may help to early identify patients at highest risk for complications and mortality.
2026-06-04 | A Hypomorphic UNC13D Variant Causes Pancytopenia in a 12-Year-Old Girl Without Systemic Inflammation
Background Familial hemophagocytic lymphohistiocytosis (FHL) is an immune dysregulation disorder in which most patients develop hemophagocytic lymphohistiocytosis (HLH) within the first year of life. Recently, an increasing number of patients with hypomorphic variants in FHL-related genes presenting with atypical features in late childhood or adulthood have been reported. Case A previously healthy 12-year-old girl presented with painful erythema at age 10. Laboratory tests revealed pancytopenia, and she was referred to our department. Although the erythema resolved spontaneously, splenomegaly was noted. Bone marrow examination showed hypocellularity without dysplasia or malignancy. Flow cytometry demonstrated TCRαβ+ double-negative T cells (DNTs) accounting for 2.5% of lymphocytes (3.3% of T cells). Cytokine analysis revealed markedly elevated IL-18 (5,804 pg/mL) and CXCL9 (8,688 pg/mL), while IL-6 was <3 pg/mL, and soluble TNF receptor II was 5,390 pg/mL. Based on these findings, an immune dysregulation disorder such as autoimmune lymphoproliferative syndrome (ALPS) was suspected. Genetic testing revealed compound heterozygous variants in UNC13D (c.2588G>A and c.1596+1G>C). Functional analysis showed mildly reduced Munc13-4 expression in platelets and impaired degranulation function in natural killer cells and cytotoxic T lymphocytes. Discussion Previous reports have described late-onset FHL and CLIPPERS syndrome in patients with missense variants in UNC13D or PRF1, most of which suggested these are hypomorphic variants. Variants in FHL-related genes can produce a broad clinical spectrum ranging from early-onset FHL to late-onset or atypical inflammatory phenotypes, depending on the degree of residual cytotoxic function. Conclusion We report a case of atypical cytopenia associated with hypomorphic UNC13D variants. Currently, pancytopenia is the only clinical manifestation, and the patient is receiving prophylactic trimethoprim–sulfamethoxazole. However, considering the risk of neurological sequelae with central nervous system involvement, hematopoietic stem cell transplantation is being considered.
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.
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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.
2025-03-14 | Emergency admission with unremitting fever and lymphadenopathy: Kikuchi-Fujimoto disease causing haemophagocytic lymphohistiocytosis.
Haemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome. Over activation of histiocytes and lymphocytes can lead to multiorgan failure and death. The three key features are fever, raised ferritin and falling counts, that is, cytopenia (3Fs). Treatment is immunosuppression while identifying the driver. Our young female patient presented with high fever and extensive lymphadenopathy, raising the suspicion of HLH driven by lymphoma. Her H-score was consistent with HLH. Immunosuppression was commenced with intravenous steroids, followed by anakinra due to inadequate steroid response. She required intensive care unit (ICU) admission with input from haematology and rheumatology. A lymph node biopsy revealed likely Kikuchi-Fujimoto disease, a rare benign cause of painful lymphadenopathy that is usually self-limiting but is also reported as a cause of HLH. She responded rapidly to anakinra and was discharged home 1 week after leaving ICU. Regular clinic follow-up continues, immunosuppression has been weaned off and she remains in remission. Monitoring for later development of autoimmune disease continues. We discuss her management with reference to the recently published Getting it Right First Time guidelines on HLH.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
fully human IgG1 monoclonal antibody directed against human signal regulatory protein (SIRP)alpha, SIRPbeta1, and SIRPgamma | antibodies | FDA | 2024-10-02 | — | Electra Therapeutics, Inc. |
Tadekinig alfa | proteins | EMA | 2016-10-14 | — | Yes Pharmaceutical Development Services GmbH |
Recombinant human anti-interferon gamma monoclonal antibody | antibodies | EMA | 2010-06-09 | — | Swedish Orphan Biovitrum AB (publ) |
emapalumab-lzsg [Gamifant] | antibodies | FDA | 2010-03-26 | 2018-11-20 | Swedish Orphan Biovitrum AB |
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