The UNC13D gene encodes Munc13-4, a key regulator of cytotoxic granule exocytosis in effector immune cells, enabling the release of perforin and granzymes that are essential for cytotoxic function and immune surveillance. Loss-of-function mutations in UNC13D result in immune dysregulation syndromes, most notably familial hemophagocytic lymphohistiocytosis (fHLH, also referred to as FHL). This review provides a comprehensive overview of UNC13D, including its structural characteristics, biological functions, and spectrum of pathogenic variants. We summarize the mechanistic roles of Munc13-4 in granule-mediated cytotoxicity and examine the clinical correlations between UNC13D mutations and fHLH type 3 (FHL3). Furthermore, we discuss emerging evidence linking UNC13D dysfunction to a broader range of diseases, highlighting its clinical relevance and potential as both a diagnostic biomarker and therapeutic target. Overall, this review aims to bridge the gap between molecular mechanisms and clinical translation in UNC13D-related disorders.

Third trimester hydrops fetalis as the presentation leads to prenatal diagnosis of familial hemophagocytic lymphohistiocytosis.

Even though tremendous effort has been undertaken within the past 40 years, both sepsis incidence and mortality remain high. The concept of various immune responses in sepsis, ranging from immune paralysis to severe hyperinflammation, has gained more and more attention. As such, the hyperinflammatory phenotype macrophage activation-like syndrome (MALS) became the cornerstone in the latest intervention trials. Our study sought to systematically investigate MALS patients, including their definitions, respective bone marrow markers and monocytic HLA-DR expressions. In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité - Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 μg/L) and sepsis, but no diagnosis of hemophagocytic lymphohistiocytosis. For diagnosis of MALS, we used the latest definition of ferritin ≥4420 µg/L. 1629 patients were included, of whom 322 were diagnosed with MALS (19.8%). In-hospital mortality was 62.4% in MALS patients compared to 30.5% in those without MALS. MALS patients had increased macrophage counts and higher rates of activated macrophages in bone marrow biopsies. HLA-DR expression did not differ significantly between the groups. In multivariable logistic regression analysis, MALS showed the highest odds ratio associated with in-hospital mortality. Different definitions of MALS identified largely distinct patient populations. MALS increased in-hospital mortality in sepsis patients. Our results underscore the urgent need for targeted research and therapeutic strategies. While promising insights into immune modulation have emerged, further studies are essential to refine treatment approaches and improve outcomes in this vulnerable patient population.

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome driven by uncontrolled immune activation. In adults, it is most commonly secondary to infections, autoimmune diseases, or hematologic malignancies. Case description In January 2020, a 55-year-old man was admitted to the hospital due to weight loss, weakness, and recurrent fevers lasting for about one month. Laboratory findings showed pancytopenia, while C-reactive protein was slightly elevated. A computed tomography (CT) scan revealed enlarged mediastinal lymph nodes and hepatosplenomegaly. Bone marrow biopsy immunophenotyping did not suggest lymphoma. Anti-nuclear antibodies at a titer of 1 : 160 (speckled pattern) and the presence of anti-RNP/Sm antibodies were found, causing a temporary transfer to the Rheumatology Department, where the extensive diagnostic process was inconclusive. Due to clinical features of HLH (6/8 HLH-2004 criteria), fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, ferritin at 9,000 ng/ml, and sIL-2R (sCD25) at 25,000 U/ml, i.v. dexamethasone was administered. Endobronchial ultrasound transbronchial needle aspiration, and the subcarinallymph node from mediastinoscopy did not show lymphoma infiltration. At that time, the histopathologic results of the initial bone marrow biopsy revealed infiltration by aggressive B-cell lymphoma, most likely diffuse large B-cell lymphoma. The patient received 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-based chemotherapy, initially without rituximab and including etoposide in the first 6 cycles (CHOEP), with subsequent modifications due to toxicities. After the first cycle of chemotherapy, the clinical symptoms of HLH began to subside, and after treatment, a complete metabolic response of lymphoma was observed on positron emission tomography/computed tomography (PET-CT). Patient remained in observation. In 2025, the patient presented with fever and, after examination, met 5 HLH-2004 criteria again. Although lymphoma relapse was suspected, it was not found in repeated biopsies (bone marrow, lymph node excision, liver) until the results of the spleen biopsy were obtained. The patient received second-line chemotherapy according to the R-ICE (rituximab, ifosfamide, carboplatin, etoposide) regimen. After 4 cycles, disease progression was detected on PET-CT. The patient is currently awaiting treatment with chimeric antigenreceptor T-cell (CAR-T) therapy. Conclusions Hemophagocytic lymphohistiocytosis in adult patients necessitates thorough evaluation for possible underlying malignancy, especially lymphoma. Repeated biopsies of different organs may be required. Glucocorticosteroid treatment, although life-saving, can obscure the diagnosis of occult lymphoma.

To explore the efficacy of rituximab in treating patients with EB virus-related hemophagocytic syndrome (EBV-HLH) caused by B lymphocyte infection. A retrospective analysis was conducted on the data of patients diagnosed with EBV-HLH, without hematopoietic stem cell transplantation and receiving rituximab treatment at Beijing Friendship Hospital, Capital Medical University from November 2021 to January 2025. All patients received treatment with a regimen containing rituximab, such as the R-DEP regimen (rituximab+liposomal doxorubicin+etoposide+methylprednisolone), the R+HLH-94 regimen (rituximab+dexamethasone+etoposide+cyclosporine), the R regimen (rituximab), and the R+P-Gemox regimen (rituximab+gemcitabine+oxaliplatin). Follow-up was conducted until August 2025 or until the patients' death to analyze the related efficacy. A total of 20 patients with EBV-HLH who received rituximab-containing regimens were enrolled. There were 11 males and 9 females, with a median age of 40 (range 5-70) years. There were 12, 5, 2, and 1 cases receiving the R-DEP, R, R+HLH-94, and R+P-Gemox regimens, respectively. The median EBV-DNA load in peripheral blood mononuclear cells before treatment was 7 000 (range 590-240 000) copies/ml. The median follow-up time [M (Q1, Q3)] was 15 (6, 24) months, the median survival time was 19 (7, 27) months, and 18 patients survived. The overall disease remission rate after treatment was 95% (19/20), and EBV-DNA was negative in 17 patients. For patients with B lymphocyte infection-related EBV-HLH, early application of a regimen centered on rituximab can effectively eliminate the virus, induce clinical remission, and improve the survival prognosis of patients.

Intravascular large B-cell lymphoma is a rare type of extranodal lymphoma that has an aggressive and sometimes fatal course. Early diagnosis is necessary to improve the prognosis, but very few studies have reported random skin biopsies comparing positive and negative patients. A total of 161 patients with malignant lymphoma in the differential diagnosis underwent random skin biopsies. Their clinical presentations included fever, night sweats, and unintentional weight loss. Their laboratory and radiological findings were evaluated. Six patients were diagnosed with intravascular large B-cell lymphoma, 12 patients were diagnosed with other malignant lymphomas, and the remainder were diagnosed with other diseases. Patients who were diagnosed with intravascular large B-cell lymphoma had a tendency to have B symptoms (p = 0.046), include senile/cherry angioma(s) at the sites of random skin biopsies (p = 0.040), and have thrombocytopenia (p = 0.009). Patients with intravascular large B-cell lymphoma who have B symptoms and thrombocytopenia tend to be easily diagnosed. In cases with these manifestations, random skin biopsy is recommended, if the patients do not have hemophagocytic lymphohistiocytosis.

Efficacy of Emapalumab as Rescue Therapy in a Pediatric Case of Secondary Hemophagocytic Lymphohistiocytosis

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A 60-year-old woman with rheumatoid arthritis and an impaired consciousness was referred to our hospital. Prior to transfer, the patient underwent intensified immunosuppressive therapy under a diagnosis of rheumatoid vasculitis that had developed in her buttocks. Upon hospitalization, she developed severe multiorgan failure and hemophagocytic syndrome. Four days after admission, both blood cytomegalovirus (CMV) antigenemia and the DNA load were markedly elevated. Despite intensive care, the patient died. Later, a histopathological examination revealed that the cutaneous manifestation represented CMV disease, not rheumatoid vasculitis, as was initially suspected. Failure to identify CMV as the underlying cause may result in the inappropriate administration of immunosuppressive therapy, potentially worsening the patient's condition.

Hemolytic uremic syndrome (HUS) in infancy may be difficult to classify because infection-associated HUS and genetic thrombotic microangiopathies (TMAs) can present with similar findings. We report a 7-month-old boy admitted with pneumonia, anemia, thrombocytopenia, and acute kidney injury. Radiologically confirmed pneumonia, elevated CRP levels, positive nasopharyngeal pneumococcal PCR testing initially suggested pneumococcal-associated HUS; however, microangiopathic hemolysis and anuria persisted despite infection control, dialysis, plasma exchange, and complement inhibition therapy. Genetic analysis subsequently revealed a homozygous DGKE mutation, establishing the diagnosis of complement-independent TMA. During follow-up, the course was further complicated by secondary hemophagocytic lymphohistiocytosis (HLH) triggered by severe inflammation and catheter-related sepsis. This case demonstrates that an apparent infectious trigger does not exclude an underlying genetic etiology in infants with TMA and highlights the importance of early genetic evaluation and awareness of hyperinflammatory complications such as HLH in patients with persistent disease activity.

Hemophagocytic lymphohistiocytosis (HLH) secondary to Pneumocystis jirovecii pneumonia (PJP) is extremely rare in children. We present the case of a 10-year-old girl with a history of idiopathic thrombocytopenic purpura (ITP) on long-term oral prednisone, who was admitted for progressive fever, cough, and dyspnea. Metagenomic next-generation sequencing of blood and bronchoalveolar lavage fluid confirmed PJP. Despite targeted antifungal therapy and respiratory support, she developed persistent high-grade fever, pancytopenia, hyperferritinemia, hypofibrinogenemia, and hemophagocytosis on bone marrow aspirate by day 10, meeting diagnostic criteria for HLH. Genetic testing was declined by the parents. Management included dexamethasone, continuous renal replacement therapy, and plasmapheresis. Unfortunately, her condition deteriorated, and she was discharged upon parental request on day 22, succumbing on the same day. To our knowledge, this is the first reported pediatric case of HLH secondary to PJP in China. This case highlights that in children with PJP—especially those on immunosuppressive therapy—the development of persistent fever and cytopenia should prompt immediate evaluation for secondary HLH to enable timely intervention.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a fulminant, hyperinflammatory syndrome increasingly recognized as a rare but devastating immune checkpoint inhibitors (ICI) toxicity. Given the lack of robust epidemiological data, a large-scale pharmacovigilance analysis was performed to characterize HLH reporting patterns across distinct ICI classes.MethodsThe FDA Adverse Events Reporting System (FAERS) was queried to identify HLH cases associated with FDA-approved PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors from Q4 2003 through Q3 2025. Disproportionality analysis was conducted to quantify safety signals relative to the full database.ResultsAll major ICI classes were associated with HLH, with PD-L1 inhibitors (particularly atezolizumab) and CTLA-4 inhibitors showing the strongest signals; no single agent class appeared to be spared. Among PD-1 inhibitors, pembrolizumab exhibited the highest burden (n = 120; ROR 9.51, 95% CI 7.93-11.40), while cemiplimab demonstrated a high point estimate (ROR 10.56). In the PD-L1 class, atezolizumab showed the strongest signal among widely used agents (n = 76; ROR 14.48, 95% CI 11.54-18.18). The CTLA-4 inhibitor ipilimumab yielded substantial disproportionality (n = 54; ROR 12.77, 95% CI 9.76-16.70), and the LAG-3 inhibitor relatlimab showed a comparable signal (ROR 12.64) despite limited case numbers.ConclusionsThis analysis confirms HLH as a significant class-wide toxicity of immune checkpoint blockade, with robust safety signals observed for pembrolizumab, atezolizumab, and ipilimumab. These findings underscore the critical need for heightened clinical vigilance and rapid diagnostic evaluation for HLH in patients presenting with hyperinflammatory symptoms during immunotherapy.

Scrub typhus is an acute febrile illness and often can present with multi-organ dysfunction. The primary objective of the study was to find out its clinical presentation and associated complications and secondary objectives for the response to therapy in relation to severity of disease and observe the mortality. This was a prospective observational study conducted in children, aged 1 - 18 years, with diagnosis of scrub typhus at a tertiary -care center. The diagnosis of Scrub typhus was based on compatible clinical presentation and positive specific IgM antibody titer. Seventy children with scrub typhus (males 67.1%), median age of 9 years (interquartile range 5 - 13) presented with fever (100%), abdominal pain (54.2%), vomiting (38.6%), cough (32.8%), and rash (22.8%). On examination, hepatomegaly (67.1%), pallor (61.4%), conjunctival congestion (60%) and splenomegaly (52.8%) were the predominant features. Nearly half of cases had fluid retention (45.7%), with respiratory distress (38.5%), myocarditis (31.4%), secondary hemophagocytic lymphohistiocytosis (28.6%), shock (25.7%), acute kidney injury (18.6%), and encephalitis (18.6%). Parenteral doxycycline was given along with supportive measures such as oxygen therapy, respiratory support, diuretic, and vasopressors. Patients having three or four of severe manifestations (fluid retention, myocarditis, shock and hemophagocytic lymphohistiocytos) had almost 17 - 18 times probability of late response to doxycycline in contrast to those who had two severe features (nearly 14 times, P = 0.001). Mortality was in 4.3% of cases. Scrub typhus is a serious infection presenting with multi-system involvement. Prompt therapy with Doxycycline along with supportive therapy help in better outcome.

Hemophagocytic lymphohistiocytosis (HLH) is a hereditary or acquired hyperinflammatory response syndrome. Diagnosis of HLH is challenging. We report a case of a 41-year-old male who was admitted to the hospital due to recurrent fever for 1 month and hematochezia for 2 days. Positron emission tomography/computed tomography (PET/CT) showed multiple intrahepatic high-uptake nodules, and B-mode ultrasound could not accurately localize them. Contrast-enhanced ultrasound (CEUS)-guided liver biopsy combined with flow cytometry confirmed the final diagnosis of natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome. Pathological confirmation was made with a lymph node biopsy. The patient received the gemcitabine-dexamethasone-cisplatin (GDP) regimen and symptomatic supportive treatments. Unfortunately, the patient experienced persistent disease progression and passed away. HLH is a hyperinflammatory response syndrome caused by immune dysfunction. Lymphoma-associated hemophagocytic syndrome is the most common type of HLH. Diagnosis can be confirmed through CEUS-guided biopsy, flow cytometry analysis, and relevant clinical information.

Splenic necrosis on contrast-enhanced ultrasound in a patient with MDS and hemophagocytic syndrome.

Objectives: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome increasingly reported with immune checkpoint inhibitors (ICIs). However, comparative real-world data across different ICI classes and treatment strategies are limited. This study aimed to characterize HLH reporting patterns associated with ICIs and to compare disproportionality signals among PD-1 inhibitors, PD-L1 inhibitors, and combination regimens using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: A retrospective pharmacovigilance analysis was performed using FAERS reports submitted between 2013 and 2025. HLH-related cases were identified using core Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms. Reporting odds ratios (RORs) with 95% confidence intervals (Cis) were calculated to assess disproportionality across ICI treatment strategies, with ICI monotherapy as the reference. Restricted analyses compared PD-1 inhibitors, PD-L1 inhibitors, and ICI plus CTLA-4 inhibitor therapy. Results: A total of 733 HLH-related reports associated with ICIs were identified. The median age was 65 years (range 1-92), and 54.9% of patients were male. Lung cancer (34.4%) and melanoma (16.0%) were the most frequently reported malignancies. ICI monotherapy accounted for 34.7% of cases, while combination regimens included ICI plus chemotherapy (31.6%), ICI plus targeted therapy (17.8%), and ICI plus CTLA-4 inhibitors (15.9%). All cases were classified as serious adverse events; hospitalization occurred in 69.2% and death in 25.1%. Compared with monotherapy, combination regimens showed higher reporting odds of HLH, with the strongest signal for ICI plus targeted therapy (ROR 2.17, 95% CI 1.72-2.73). PD-1 inhibitors demonstrated higher reporting odds than PD-L1 inhibitors (ROR 1.86, 95% CI 1.41-2.46). Conclusions: This large real-world pharmacovigilance analysis demonstrates differential HLH reporting patterns across ICI classes and treatment strategies. Higher reporting odds with combination regimens and PD-1 inhibitors highlight the need for heightened clinical vigilance, particularly in combination treatment settings.

Exploratory study of PD-1 inhibitors with or without ruxolitinib for the treatment of adult EBV-associated hemophagocytic lymphohistiocytosis: a real-world data-based preliminary investigation.

To develop and validate a model for early risk stratification of secondary hemophagocytic lymphohistiocytosis (HLH) in patients with severe fever with thrombocytopenia syndrome (SFTS). This retrospective cohort included adults with laboratory-confirmed SFTS admitted to The First Affiliated Hospital with Nanjing Medical University between January 2019 and July 2024. Predictor variables were derived from clinical and laboratory data obtained within 3 days after virologic confirmation, corresponding to the predefined early-evaluation window of the study. HLH status (binary outcome) was defined using the entire-course HScore (≥170), calculated from the worst available values over the clinical course; HLH-2004 criteria and early-window HScore distributions were summarized descriptively to provide transparent outcome accounting. Twenty-eight candidate predictors entered LASSO with Boruta refinement, and retained variables were used to construct a multivariable logistic model and nomogram. Model performance was evaluated by discrimination, calibration, and decision-curve analysis in the derivation cohort, an internal validation set, and an external cohort of 60 patients from The First Affiliated Hospital with Anhui Medical University. Among 249 patients (152 non-HLH, 97 HLH), HLH was associated with higher peak temperature, longer fever, more lymphadenopathy/splenomegaly and neurological symptoms, and more severe thrombocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, higher viral load, elevated muscle/liver enzymes and LDH, and coagulopathy (all p < 0.05). LASSO-Boruta identified six routinely available predictors-peak temperature, splenomegaly, fever duration, triglycerides, fibrinogen, and ferritin. The model showed LR χ² = 214.82 (p < 0.0001), R² = 0.784, C-index = 0.962, Dxy = 0.923, with near-perfect calibration in derivation. In internal validation, discrimination remained near-perfect (AUC 0.997, 95% CI 0.989-1.000); mild miscalibration was corrected by intercept-and-slope recalibration, and decision curves showed net benefit across wide thresholds. External validation (n = 60) confirmed excellent discrimination (AUC 0.907, 95% CI 0.835-0.980), slight miscalibration resolved by recalibration, and preserved net benefit across most thresholds. A simple model based on early clinical and laboratory variables supports risk stratification for HLH in SFTS and may facilitate closer monitoring, repeated HLH assessment, and timely individualized management.

Hemophagocytic lymphohistiocytosis is a diagnostic and therapeutic emergency characterized by a cytokine storm. This hyperinflammation results from a complex interaction between innate immunoregulation and the environment. An etiological assessment must be conducted simultaneously with hyperinflammation treatment. No cause is found in nearly one-third of patients despite a thorough assessment. Anakinra limits interference with additional tests and provides a decisive time frame for identifying triggers. Treatment choices are largely based on expert opinion. This review summarizes recent advances regarding hemophagocytic lymphohistiocytosis in adults, proposes a diagnostic approach and stratified management according to severity and etiology.

Central Hypothyroidism Secondary to Pituitary Involvement in Hemophagocytic Lymphohistiocytosis