Adult hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome triggered by various conditions. A nationwide study of the incidence and outcomes of HLH in Denmark over 23 years (2000-2023) was performed. Adults (≥18 years) with HLH and triggering diseases were identified in the Danish National Patient Registry and/or the Danish Pathology Registry. A total of 325 cases were identified. The incidence increased from 0.82 per 1 million person-years (1 M-PY) (95% CI 0.61-1.04) in 2000-2011 to 4.05 per 1 M-PY (95% CI 3.56-4.53) in 2012-2023. Hematologic malignancies were the triggering diagnosis in 46% of cases, mostly lymphomas (32%). There was no clear improvement in overall survival over time. However, survival differed markedly between subgroups, with the lowest 1-year overall survival of 31% for hematologic malignancy-associated HLH, compared with 75% for idiopathic HLH. In conclusion, HLH remains a rare syndrome with a dismal prognosis, especially when associated with hematologic malignancy.

Diagnostic Complexity of Pediatric Hemophagocytic Lymphohistiocytosis With Central Nervous System Involvement.

Lymphoma-associated haemophagocytic lymphohistiocytosis (HLH) represents a rare and life-threatening hyperinflammatory syndrome with a dismal prognosis, largely due to its poorly understood pathogenesis and unclear distinctions from non-lymphoma associated HLH (NLAHS). To elucidate these differences, we performed an integrated multiomics analysis on peripheral blood samples from patients with newly diagnosed lymphoma-associated HLH (LAHS), NLAHS and healthy controls (NC). Single-cell ribonucleic acid sequencing (scRNA-seq) analysis (4 LAHS, 3 NLAHS, 2 NC) revealed that LAHS is characterized by enhanced glycolytic activity in significantly expanded monocyte populations, notably within a distinct subset of pituitary tumor-transforming gene 1+ (PTTG1+) monocytes. Metabolomic profiling (21 LAHS, 11 NLAHS, 7 NC) further confirmed elevated levels of glycolytic products, such as lactate and pyruvate. Clinically, hyperlactataemia (>5.1 mmol/L, n = 84) emerged as a significant independent predictor of poor survival in LAHS, with a median overall survival of only 43.5 days (p < 0.001). Remission induced by treatment was associated with a reversal of this hypermetabolic phenotype. Cell communication analysis revealed upregulated thrombospondin signalling from PTTG1+ monocytes, linked to glycolytic activity. Our findings indicate that LAHS is characterized by a pronounced Warburg-like metabolic state, primarily involving glycolytic monocytes. Hyperlactataemia is associated with adverse outcomes and may guide the development of novel therapeutic strategies targeting immunometabolic pathways.

Organic acidemias (OAs) are a group of inherited disorders, most commonly caused by defects in mitochondrial enzymes involved in amino acid and fatty acid metabolism. While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine-specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID-19 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA-based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well-characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.

Two Cases of Epstein-Barr Virus (EBV)-Associated Secondary Hemophagocytic Lymphohistiocytosis (HLH) Following Bilateral Lung Transplantation

Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a rare but highly fatal complication after allogeneic hematopoietic cell transplantation (allo-HCT), frequently diagnosed under conditions of clinical uncertainty. We aimed to characterize post-transplant sHLH/MAS and to identify clinically accessible factors associated with early mortality. We retrospectively analyzed adult patients who developed sHLH/MAS after allo-HCT between 2018 and 2025. Inclusion required an HScore ≥ 169. Overall survival within 60 days from sHLH/MAS onset was the primary endpoint. Clinical and laboratory variables were evaluated using Cox proportional-hazards models, and patients were stratified according to the number of adverse prognostic factors identified. Seventy-two patients met inclusion criteria. Median time from allo-HCT to sHLH/MAS onset was 22 days. Sixty-day overall survival was poor. In univariable and multivariable analyses, vasopressor-dependent sepsis (HR 7.77, p < 0.001) and ferritin > 15 000 μg/L (HR 3.48, p = 0.002) were independently associated with early mortality. Stratification based on these two factors separated patients into low-, intermediate-, and high-risk groups with 60-day survival of 92%, 52%, and 9%, respectively (p < 0.001). Post-transplant sHLH/MAS is associated with extremely high early mortality. Vasopressor-dependent sepsis and extreme hyperferritinemia identify patients at particularly high risk. These findings require confirmation in independent cohorts.

Scrub typhus can rapidly progress to severe disease with multi-organ dysfunction. Secondary hemophagocytic lymphohistiocytosis (HLH) is an increasingly recognized hyperinflammatory complication associated with high mortality, but adult data and simple admission-time risk tools remain limited. We conducted a single-center retrospective cohort study of hospitalized adults with scrub typhus at the First Affiliated Hospital of Guangzhou Medical University (May 2013-July 2025). Severe scrub typhus was defined by major organ involvement, shock, or in-hospital death. Variables available at admission were compared between severe and non-severe groups. Independent predictors were identified using multivariable logistic regression, and model performance was evaluated using ROC analysis. Among severe cases, HLH was identified according to standard diagnostic criteria, and clinical characteristics were compared between HLH and non-HLH patients. Among 135 patients, 44 (32.6%) developed severe scrub typhus and overall in-hospital mortality was 2.2% (3/135). Lower hemoglobin (Hb) (OR 0.965, 95% CI 0.947-0.982), higher serum creatinine (SCr) (OR 1.019, 95% CI 1.008-1.029), and lower fibrinogen (FIB) (OR 0.629, 95% CI 0.435-0.909) were independent predictors of severe disease. A parsimonious three-variable model showed good discrimination (AUC = 0.843). At the sensitivity-prioritized ROC threshold, sensitivity was 88%, specificity 46%, and the Youden index 0.34. HLH was identified in 6 patients overall, including 5 patients among the severe cases. Among severe patients, HLH cases showed higher observed in-hospital mortality than non-HLH cases (40.0% vs. 2.6%). They also had more severe thrombocytopenia and greater coagulation and organ-function abnormalities. A simple admission-time triad (Hb, SCr, and FIB) provides an interpretable tool for early identification of severe scrub typhus in hospitalized adults. HLH cases showed higher observed mortality and more severe thrombocytopenia/coagulation derangement; however, these findings should be interpreted descriptively due to the small number of cases.

To characterise post-marketing adverse event (AE) reporting patterns associated with CD3×CD20 bispecific antibodies (BsAbs) using multi-method disproportionality analysis and to identify potential safety signals warranting further investigation. Retrospective pharmacovigilance study using disproportionality analysis with multiple complementary methods. Food and Drug Administration Adverse Event Reporting System database. A total of 2237 AE reports associated with CD3×CD20 BsAbs (1135 for epcoritamab, 673 for glofitamab and 429 for mosunetuzumab) were submitted from the fourth quarter of 2022 to the first quarter of 2025. Primary outcomes included identification of statistically significant AE signals using reporting odds ratio (ROR) and Bayesian confidence propagation neural network with information component as the principal signal detection methods, while proportional reporting ratio was only used as a supplementary measure to enhance the robustness of signal detection. Secondary outcomes included subgroup analyses by sex and age, analysis of fatal outcomes and time-to-onset patterns using Kaplan-Meier analysis and Weibull distribution. A total of 93 AE signals were identified for epcoritamab, 65 for glofitamab and 41 for mosunetuzumab. The three disproportionality methods showed near-complete agreement (>98% concordance) in signal detection. Signals were detected for several AEs not currently listed in product labelling. For epcoritamab, unlabelled signals included progressive multifocal leukoencephalopathy (ROR (95% CI) 13.28 (5.51 to 31.97)), haemophagocytic lymphohistiocytosis (ROR (95% CI) 18.19 (10.75 to 30.79)) and disseminated intravascular coagulation (ROR (95% CI) 8.76 (3.28 to 23.39)). For glofitamab, unlabelled signals included disseminated tuberculosis (ROR (95% CI) 53.30 (17.10 to 166.13)) and cerebral haemorrhage (ROR (95% CI) 6.08 (2.28 to 16.22)). For mosunetuzumab, tumour lysis syndrome (ROR (95% CI) 29.91 (11.19 to 79.97)) and uveitis (ROR (95% CI) 10.75 (3.46 to 33.41)) were detected. With respect to patient characteristics, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were more frequently reported in younger patients treated with epcoritamab, while pyrexia was more commonly reported among elderly patients receiving glofitamab or mosunetuzumab. Among reports with available dates, Kaplan-Meier analysis showed that most reported onset times fell within the first month following treatment initiation. In the indication-restricted sensitivity analysis, most signals remained detectable, whereas certain signals, including haemophagocytic lymphohistiocytosis with epcoritamab, were sensitive to comparator selection. This study provides a systematic characterisation of post-marketing AE reporting patterns for CD3×CD20 BsAbs, identifying several signals for AEs not currently listed in product labelling. However, disproportionality signals do not establish causality, and clinical correlation is essential. These findings may help inform post-marketing pharmacovigilance and prioritise signals for further clinical and epidemiological validation.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition. While few diagnostic scores are established, none exist to predict both clinical course and time-point specific outcome of sHLH patients so far. We present a machine learning (ML)-based tool to predict Initial Disease Severity (IDS; defined as admission to intensive care units (ICU) OR death < 90days without ICU admission) and mortality across different time points in sHLH patients. 167 adult sHLH patients from six study centers across three European countries were included retrospectively. Clinical and demographic features, course, survival, and laboratory data were assessed. Random forest models were trained with two sets of eight clinical and laboratory features: one to predict IDS, and five to predict mortality at distinct time points (30, 60, 90, 180 or 365days). After calibration, the models were tested against hold-out test sets containing n = 32 (IDS) or n = 43 (mortality) sHLH patients. Overall, the models demonstrated strong discriminatory ability, overall performance, and accurate prediction of risk. Serum levels of the soluble interleukin-2 receptor (sIL-2R) and albumin (for IDS) or sIL-2R and platelet counts (for mortality prediction) showed the strongest contributions to the models' predictions. The HLH-Risk-Calculator is an exploratory tool predicting the clinical course of sHLH. External validation is critical to assess its validity, applicability, and robustness for real-world use. To this end, the calculator is available at www.hlh-risk-calculator.com for research use only, and is currently not intended for clinical decision-making.

To establish a machine learning (ML) model for the early diagnosis of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) based on clinical features and to utilize the Shapley Additive Explanations (SHAP) method to interpret the ML model, thereby providing reliable factors for diagnosing EBV-HLH. We collected clinical data from 1,026 children with Epstein-Barr virus (EBV) infection who were hospitalized at Children's Hospital of Soochow University from October 2017 to September 2024. First, we compared the clinical data of Epstein-Barr virus-associated infectious mononucleosis (EBV-IM) and EBV-HLH through univariate analysis and least absolute shrinkage and selection operator (LASSO) regression to select key features for machine learning training. Subsequently, we applied six machine learning algorithms and logistic regression to build diagnostic models, and the optimal model was selected based on multiple evaluation metrics. Finally, we utilized the Shapley Additive Explanations (SHAP) algorithm to clarify the importance of variables in the model to facilitate its application in clinical settings. Among the six machine learning models and logistic regression evaluated, the Extreme Gradient Boosting (XGBoost) model demonstrated the strongest discrimination ability, with an area under the receiver operating characteristic curve (AUC) of 0.9775, sensitivity of 0.9461 and specificity of 0.9784. The SHAP analysis indicated that the most important predictors for EBV-HLH were D-dimer, cervical lymphadenopathy (CLA), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), and CD3 + CD4+ T cells. The XGBoost model demonstrated excellent predictive performance for the early identification of EBV-HLH in children. Compared with other models, it achieved higher sensitivity and may serve as a promising decision-support tool pending external validation. Not applicable.

The workshop on 'Reactive and therapy induced BM changes linked to systemic infectious and non-infectious disorders including MAS/HLH' of the 22nd meeting of the European Association for Haematopathology held in Dubrovnik, 2024, included 58 cases. These encompassed a broad range of infections, autoimmune disorders, malignancies and therapy-effects, or a combination of these factors, of which 28 had an associated Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage Activation Syndrome (MAS). Histoplasmosis, the infection mostly associated with HLH, showed a wide variability of BM changes, with or without focal lesions. Leishmaniasis, less often associated with HLH, induced BM changes that mimic myelodysplastic syndrome. BM changes after COVID-19 infection included myeloid and megakaryocytic hypoplasia, erythroid hyperplasia, dyserythropoiesis, hemophagocytosis, and possibly ring granulomas. Other infectious causes included viruses (HHV-8, EBV, Parvovirus B19), mycobacterial infections, and human granulocytic anaplasmosis. HLH may arise in association with the full spectrum of EBV-related disorders, including acute infection, systemic chronic active EBV disease, viral reactivation, and EBV-associated malignancies. BM changes associated with autoimmune diseases included plasmacytosis, myeloid hyperplasia and hemophagocytosis, with or without meeting the criteria of MAS/HLH, the latter often triggered by a secondary infection or exacerbation of the disease. Haematologic malignancies (EBV-positive and negative) with HLH encompassed B-cell, T-/NK-cell, and myeloid neoplasms. In addition, the workshop included therapy-induced BM changes, such as differentiation syndrome, lenalidomide-associated B-ALL, therapy-related dysplasia, gelatinous transformation, CAR-T-induced BM hypoplasia, and CAR-T-associated HLH. Finally, the workshop demonstrated the presence of T-cell expansions in a variety of conditions, which should not be misinterpreted as T-cell malignancy.

Retrospective study on allogeneic hematopoietic stem cell transplantation for the treatment of Hemophagocytic lymphohistiocytosis.

Chimeric antigen receptor-T cell therapy-induced cardiotoxicity: Pathophysiological mechanisms and pharmacological intervention strategies.

Inborn errors of immunity (IEIs), an expanding group of monogenic disorders with diverse clinical manifestations, are increasingly recognized to include neuroinflammatory disease. Examples of diseases included under this umbrella are Aicardi-Goutières syndrome, deficiency of adenosine deaminase 2, familial haemophagocytic lymphohistiocytosis, neonatal-onset multisystem inflammatory disease, and acute necrotizing encephalopathy, among others. Children with IEIs may develop encephalopathy, seizures, focal neurological deficits, aseptic meningitis, inflammatory lesions on magnetic resonance imaging, or other central or peripheral nervous system manifestations. While systemic features of autoinflammation or autoimmunity are often present and provide important clues that an underlying IEI may be present, neuroinflammation may be the presenting or sole manifestation in some children. Early recognition of neuroinflammatory presentations of IEIs is critical to prompt immunological and genetic investigations, enabling diagnosis and timely initiation of appropriate immunotherapies, and reducing the risk of long-term neurological outcomes. This review highlights paediatric-onset neuroinflammatory phenotypes associated with IEIs and provides practical frameworks for their recognition and investigation in clinical practice.

We previously demonstrated that the anti-CD33 antibody drug conjugate, gemtuzumab ozogamicin (GO) binds CD33-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), is internalised, and decreases their 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. GOTHAM is a phase II single arm trial. Patients with 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/refractory to treatment at enrolment were eligible. An initial regimen of 3 mg/m2 GO on days 1, 8, and 15 was tested, adjusted to 21-day intervals, days 1, 22, and 43. The primary outcome was the impact of GO therapy on peripheral CD33+ myeloid cells. Trial registration: ISRCTN 89158144. Using two schedules of GO, we could not convincingly demonstrate safe feasibility in patient with solid cancer because of neutropenia. However, GO reproducibly and significantly reduces circulating MDSCs. Importantly, there is consistent preliminary evidence that upon rebound the monocyte population of CD33+ cells is replaced with non-suppressive monocytes. These data support the phase Ib 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 repolarises MDSCs without causing undue neutropenia, paving the way to using GO as an immune potentiator in this patient population.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory condition that can be triggered by viral infections. However, influenza is not commonly recognized as a cause of HLH, and there is no comprehensive synthesis of influenza-associated HLH in the literature to guide clinicians. We conducted a systematic search of Pubmed and Embase to identify case reports and case series on influenza-associated HLH, and included 29 articles involving 47 patients. Their age ranged from 2 months to 72 years. 67% were males. Influenza A accounted for 91.3% of the cases, predominantly H1N1 (90.2%). All patients had fever, 60% had anemia, 69.7% had thrombocytopenia, 46.6% had leukopenia, 61.3% had splenomegaly, 71.4% had hypertriglyceridemia, and 94.7% had elevated ferritin levels. 97.6% had hemophagocytosis on biopsy. Antiviral therapy was administered in 89.5% of patients. HLH-directed therapy included corticosteroids (77%), intravenous immunoglobulin (36%), and etoposide (23.1%). Intensive care was required in 95.2% of cases. Overall survival was 53.2%. Survival rate was 50% among patients who received either antiviral therapy alone or HLH-directed therapy alone, compared with 65.4% among those who received both. Further studies are necessary to establish standardized diagnostic and therapeutic protocols for influenza-associated HLH.

The predictive value of cytokines (CK) for malignancy-associated adult hemophagocytic lymphohistiocytosis (M-HLHa) remains uncertain. We evaluated a cytokine-based Risk Score (RS) and the IL-10/IL-6 Ratio to predict M-HLHa. Adult patients (n = 112) from the French HLH cohort (NCT02113917) with complete data for nine key HLH related CK measured by Luminex were first analyzed. Logistic regression was performed, and a RS was subsequently derived and internally validated. In a post hoc analysis, the IL-10/IL-6 ratio obtained using the ELLA cytokine assay was evaluated in 75 patients, 54 of whom also had Luminex testing, plus 25 additional patients from the cohort. The RS and IL-10/IL-6 ratio were then jointly assessed in the 54 patients with results from both platforms. Among the 112 patients, 45 had M-HLHa and 67 non M-HLHa; median age was 48 years and 64 (57%) were male. Eight variables were associated with M-HLHa, of which four were retained in the logistic model: age > 48 years (2.9[1.12-7.33], p = 0.03), TNF-α ≤ 43 pg/mL (3.2[1.16-8.61], p = 0.02), IL-18 > 574 pg/mL (4.9[1.89-12.75], p = 0.001), and IL-10/IL-6 ≥ 1.5 (2.7[1.01-7.31], p = 0.04), with respective weights of 11, 12, 16, and 10. A RS ≥ 20 increased the odds of M-HLHa 17-fold (17.2 [5.4-54.5], p < 0.0001). The IL-10/IL-6 ratio alone (n = 75) showed good performance (AUC 0.83). In the 54 patients with both assays, the RS and IL-10/IL-6 ratio preserved their diagnostic performance (AUC 0.87 and 0.79, respectively). These data support the RS and IL-10/IL-6 Ratio as useful tools to improve the identification of M-HLHa in adults. Trial Registration: clinicaltrials.gov NCT02113917.

Neopterin Levels in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: A Potential Biomarker for Acute Graft-Versus-Host Disease?

Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency is a rare inborn error of immunity (IEI) involving defects in folate metabolism. It can present with combined immunodeficiency and variable phenotypic features, including recurrent bacterial infections, megaloblastic anemia, and failure to thrive. We describe 2 unrelated Kuwaiti children with MTHFD1 deficiency caused by a homozygous pathogenic variant [c.517C>T (Arg173Cys)]. Both cases presented with unexplained megaloblastic anemia, recurrent sinopulmonary infections, failure to thrive, and developmental delay. The first patient, a 10-year-old girl, was diagnosed with combined immunodeficiency and autoimmune thyroiditis. Treatment with folic acid resulted in significant clinical improvement. The second patient, a 3-year-old girl, presented with sepsis secondary to progressive lobar pneumonia and bone marrow failure. Despite intensive treatment, including broad-spectrum antibiotics, antifungals, IVIG, and dexamethasone for suspected hemophagocytic lymphohistiocytosis, she developed severe complications and passed away on day 18 of PICU admission. As there is no specific clinical or laboratory phenotype for most IEIs, we emphasize the importance of molecular diagnosis through urgent genetic testing in patients with suspected MTHFD1 deficiency. Precision therapy with prompt folate or folinic acid supplementation can significantly improve outcomes, as evidenced by the survival of one patient with minimal intervention.

Secondary Hemophagocytic Lymphohistiocytosis Triggered by Enteric Fever: A Case Series from a Resource-Limited Setting