Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by uncontrolled immune activation. While traditionally associated with genetic mutations affecting cytotoxic function, recent advances have highlighted the prevalence and significance of HLH in adults, particularly in hematologic malignancies. This review focuses on malignancy-associated HLH (M-HLH), a complex and challenging condition with a poor prognosis. The review explores four main subtypes of M-HLH: (1) HLH as the initial presentation of malignancy, (2) Chemotherapy Associated HLH, (3) Cytokine Release Syndrome (CRS) Associated HLH-like Syndrome, and (4) immune effector cell-associated HLH-like syndrome. Diagnosis is complicated by overlap with cancer symptoms and limitations of existing criteria. The Optimized HLH Inflammatory (OHI) index shows promise in early identification of hyperinflammation in new-onset hematologic malignancies. Treatment approaches must balance controlling hyperinflammation with addressing the underlying malignancy. Emerging therapies, including targeted agents like anakinra, ruxolitinib, and emapalumab, offer new management possibilities. This review examines the current understanding of M-HLH pathophysiology, diagnostic approaches, and treatment strategies for each subtype. It underscores the critical need for further research to unravel underlying mechanisms and establish evidence-based treatment protocols. Given the complexity of M-HLH, international collaborative efforts are essential to advance knowledge and improve patient outcomes.

Macrophage activation syndrome (MAS) is a state of immune hyperactivation that can result in life-threatening multisystem end-organ dysfunction. Often termed a "cytokine storm," MAS occurs among the rheumatic diseases most typically in Still's disease but also in systemic lupus erythematosus and Kawasaki disease. MAS can also accompany infection, malignancy, and inborn errors of immunity. This review provides a practical, evidence-based guide to the understanding, recognition, and management of MAS in children and adults, with a primary focus on MAS complicating Still's disease.

A postpartum woman in her 40s, with a history of peripartum cardiomyopathy, developed neutropenic sepsis after a caesarean section and hysterectomy for placenta previa. She presented with high fever, respiratory distress, and splenomegaly, along with severe neutropenia (absolute neutrophil count <100 cells/mm³). Blood cultures showed coagulase-negative staphylococci, and viral tests were positive for cytomegalovirus (CMV). A suspected complication of haemophagocytic lymphohistiocytosis (HLH) following CMV infection was considered. Broad-spectrum antibiotics, corticosteroids, granulocyte-macrophage colony-stimulating factor and intravenous immunoglobulin were administered. There was marked improvement as the patient became afebrile, with the return of neutrophils and stabilisation of her vital parameters. Follow-up at 3 and 6 months post-admission showed that the patient remained clinically improved with no subsequent complications. This case highlights the challenging management of neutropenic sepsis complicated by HLH provoked by CMV in a postpartum woman.

Data on bone marrow (BM) findings in secondary hemophagocytic lymphohistiocytosis (sHLH) and their association with overall survival (OS) are limited.

This study aimed to develop a prognostic model incorporating BM findings and clinico-laboratory factors affecting OS.

We retrospectively evaluated 50 adults with sHLH and developed a clinicopathological prognostic model based on survival-associated factors.

Most patients demonstrated normocellular BM (46.3%) and mild hemophagocytic activity (44.2%). Factors associated with survival in multivariable analyses (MVA) were age above 70 years (hazard ratio [HR] 3.89, p = 0.016), infection-related (HR 4.62, p = 0.006), hemoglobin < 7 g/dL (HR 5.21, p < 0.001), and hypocellular marrow (HR 3.07, p = 0.04). A clinicopathological HLH risk model assigned 1 point to each MVA-identified survival factor, categorizing patients into low- (score 0-1), intermediate- (score 2-3), and high-risk (score 4) groups. The 6-month OS from bootstrapping internal validation among the low-, intermediate-, and high-risk groups were 84.2%, 55.6% (p < 0.001) and 7.7% (p < 0.001), respectively. The area under the receiver operating characteristic curve (AuROC) was 0.87.

This model stratified sHLH patients into three risk groups with distinct survival outcomes, potentially guiding future therapy.

Haemophagocytic lymphohistiocytosis (HLH) is a condition of uncontrolled immune activation caused by genetic defects or triggered by infections, malignancies, autoimmune diseases, drugs, pregnancy or post-transplant immunosuppression. This case describes a young man presenting with clinical jaundice and abnormal blood tests, including raised inflammatory markers, abnormal liver function, low haemoglobin (65 g/L) and a low white blood cell count (3.08×109/L). He met five out of eight HLH criteria and tested positive for Epstein-Barr virus (EBV) PCR (58 011 IU/mL). His bone marrow biopsy showed EBV-driven Hodgkin's lymphoma. He was initially treated with the HLH-94 protocol and later switched to ABVD chemotherapy (adriamycin, bleomycin, vinblastine and dacarbazine). He steadily recovered despite a prolonged hospital stay. He was discharged to complete his remaining cycles of chemotherapy as an outpatient with a plan of having a positron emission tomography (PET) scan after two cycles of chemotherapy.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of uncontrolled immune activation by macrophages, cytotoxic T cells and natural killer (NK) cells, marked by severe inflammation. It is often categorised as primary (genetic) or secondary (acquired). Here, a case of a young male with a history of stage IA seminoma in remission, who presented with persistent fevers, night sweats, weight loss and fatigue, is reported. He met ≥5 of 8 HLH-2004 criteria. Initial workup for secondary HLH, including infectious, autoimmune and malignancy, was negative. Bone marrow, sacral bone and splenic biopsies showed lymphohistiocytic infiltrates without malignancy. Genetic testing was unrevealing. With no identified aetiology and declining clinical status, the HLH-94 protocol was initiated. He improved initially, but fevers recurred, suggestive of HLH progression. A repeat positron emission tomography-CT (PET-CT) showed new hepatic hypermetabolic activity, leading to a biopsy diagnosing T-cell/histiocyte-rich large B-cell lymphoma. This case highlights the challenges in identifying the aetiologies of secondary HLH, particularly searching for an occult malignancy and ensuring prompt treatment is initiated.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal multi-systemic disorder. Patients with HLH are more prone to bleeding, which implies a poor outcome. The objective was to investigate the efficacy of recombinant activated factor VII (rFVIIa) in major intractable bleeding of HLH. A total of 20 patients with secondary HLH received at least one dose of rFVIIa. When bleeding occurs, 88.9% cases had a nadir platelet counts below 25*109/L. Median number of doses of rFVIIa was 3.5 (range, 1 to 78) with a mean dose of 76.45 µg/kg/dose. Total of 60% (12 of 20) patients obtained a response to rFVIIa therapy, however, in patients with a history of chronic active EBV infection (CAEBV), only 27.3% achieved a response. The mortality rate was 90% (18 of 20) in the cohort, none of the deaths were attributed to rFVIIa administration. Thromboembolism rate was low.

IntroductionHaemophagocytic lymphohistiocytosis (HLH) is a rare and serious immunological syndrome that involves a strong activation of cytotoxic T lymphocytes and macrophages. HLH determines a cytokine-mediated tissue injury with a contemporary multi-organ failure and a high fatality rate.Material and methodsA retrospective study was performed considering the medical records of paediatric patients who underwent a bone marrow aspirate for suspect HLH. The biomarkers evaluated were among those included in the HLH-2004. Lactate dehydrogenase (LD) was also evaluated. Haemophagocytosis was evaluated in bone marrow blood smear slides.ResultsEnrolled were 11 patients included in the HLH group and 8 patients as controls. Haemoglobin and fibrinogen resulted lower in HLH patients than in controls, while blood triglycerides, serum ferritin and LD resulted increased. Blood triglycerides and fibrinogen discriminated HLH cases perfectly, with a sensitivity and specificity of 100%. Ferritin had a sensitivity of 100% and a specificity of 83% (cut off ≥3,721 µg/L) and LD of 73% and of 100% (the cut off ≥1,903 U/L). Haemoglobin was found to have a sensitivity of 75% and a specificity of 100% (cut off ≤ 96 g/L). Total haemophagocytes cell counts were not different between patients and controls. Only the increased number of phagocytized nucleated red blood cells (NRBC) was found to be significantly increased in the patients. Erythrocytes phagocytosis (≥4/1,000 cells) only tended towards significance.ConclusionsThe blood biomarkers showed better diagnostic performance than the morphological evaluation. Among the different cell lineages engulfed by haemophagocytes, the best diagnostic performance was obtained by phagocytosed mature erythrocytes and immature nucleated erythrocytes.

Five fulfilled hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, and the HScore are widely used and recommended by international expert consensus to diagnose secondary HLH. Both diagnostic scores have never been validated in heterogeneous patient cohorts of secondary HLH patients. We aimed to systematically optimize and validate diagnostic criteria of secondary HLH using a multicenter approach.

We developed optimized criteria in our cohort of critically ill patients as a first step. We next validated these new criteria together with the original and modified HLH-2004 criteria as well as the HScore using original data of 13 published cohorts, which were identified by a systematic literature search.

The best performing HLH diagnostic criteria sets over all 13 validation cohorts were the original HLH-2004 criteria with a decreased cut-off (cut-off 4, mean sensitivity 86.5%, mean specificity 86.1%), followed by the revised HLH-2004 criteria (natural killer cell activity removed; cut-off 4, mean sensitivity 83.8%, mean specificity 87.8%) and the HScore (cut-off 169, mean sensitivity 82.4%, mean specificity 87.6%). Our newly developed HLH diagnostic criteria showed inferior performance. Ferritin ≥500 µg/L had 94.0% mean sensitivity over all cohorts.

In this first multicenter validation study, four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH, which will lead to rapid diagnosis and improved patient outcomes. Ferritin proved as a reliable HLH screening marker. Our results should be taken into account in clinical recommendations and in designing new studies.

Members of the RNA virus order Nidovirales infect hosts ranging from marine invertebrates to terrestrial mammals. As such, understanding the determinants of host range in this group of viruses, as well as their patterns of emergence and disease potential, is of clear importance. The Mesoniviridae are a recently documented family within the Nidovirales. To date, mesoniviruses have only been associated with the infection of arthropod species, particularly mosquitoes, and hence are regarded as insect-specific viruses (ISVs). Herein, we report the first detection of a mesonivirus-Alphamesonivirus-1 -in mammals. Specifically, we utilized genomic and histological techniques to identify Alphamesonivirus-1 in lung and lymph node tissues of two horses (a mare and its foal) from Italy that succumbed to an acute respiratory syndrome. The genome sequences of Alphamesonivirus-1 obtained from the two horses were closely related to each other and to those from a local Culex mosquito pool and an Alphamesonivirus-1 previously identified in Italy, indicative of ongoing local transmission. The discovery of Alphamesonivirus-1 in horse tissues prompts further investigation into the host range of mesoniviruses, the possible role of insect-specific viruses in mammalian disease processes, the determinants of and barriers to cross-species virus transmission, and the potential epizootic threats posed by understudied viral families.

Alphamesoniviruses, members of the family Mesoniviridaeare, are considered insect-specific RNA viruses with no known association with vertebrate hosts. Herein, we report the identification of Alphamesonivirus-1 in mammals. Using detailed molecular and histological analyses, we identified Alphamesonivirus-1 in lung and lymph node tissues of two horses that presented with an acute respiratory syndrome and that was phylogenetically related to virus sequences found in local Culex mosquitoes. Hence, Alphamesoniviruses may possess a broader host range than previously believed, prompting the investigation of their possible role in mammalian disease. This work highlights the need for increased surveillance of atypical viruses in association with unexplained respiratory illness, including those commonly assumed to be insect-specific, and may have implications for epizootic disease emergence.

Patients with fever of unknown origin (FUO) can sometimes be accompanied by haemophagocytic lymphohistiocytosis (HLH), a life-threatening disease. The prognostic model and specific markers for the early prognosis and the optimized treatment regimen are of considerable research interest.

A total of 135 FUO/HLH patients were enrolled and classified according to the 60-day outcomes following diagnosis. 79 patients (including 5 patients lost in follow-up) enrolled from 2007 to 2015 served as the derivation cohort, and 56 patients from 2016 to 2023 served as the validation cohort. In the derivation cohort, 27 patients (27/74, 36.5%) survived within 60 days and multivariate analyses showed that age > 67 years (P = 0.003), baseline PLT < 42 × 10^9/L (P = 0.012) and LDH > 1505 U/L (P = 0.002) were associated with a higher mortality rate in HLH patients. The external validation proved the reliability of the prediction model. In derivation cohort, the median alteration of PLT (△PLT) were + 78 × 10^9/L and - 17 × 10^9/L in the survival and non-survival groups, respectively (P < 0.001). The median △LDH was - 197.5U/L in the survival group, while in the non-survival group was + 119U/L (P < 0.001).

Age, baseline LDH and PLT levels may predict early mortality in secondary HLH patients and identify patients in critical conditions. △LDH and △PLT levels were of high value to monitor the efficacy of therapeutic regimen and the disease progression in HLH patients.

Hemophagocytic lymphohistiocytosis (HLH) is an excessive immune activation with cytokine storm und multi-organ dysfunction. It can occur secondarily, especially due to viral infections like COVID-19. Rapid treatment is crucial for favourable outcomes, but diagnosing HLH is challenging. The most common diagnostic instrument is the H-Score. However, the prognostic value of the H-score has not yet been assessed in detail in the spotlight of secondary HLH in severe COVID-19. COVID-19 patients treated between February 2020 and April 2021 at the intensive care unit (ICU) of the Department of Infectious Diseases and Tropical Medicine, Clinic Favoriten, Vienna, Austria, were included in this study. Data were assessed retrospectively by document review, and the follow-up period was at least 90 days. A total of 208 critically ill COVID-19 patients with an age of 61.8 ± 13.6 years were enrolled in this study. We found an average H-Score in the entire study collective of 94 ± 51 points, and 8.7% had a score ≥ 169 testing positive for HLH. A positive score was associated with increased mortality rates at 28 (66.7 vs. 26.3%, p < 0.001) and 90 days (72.2 vs. 27.9%, p < 0.001). In our cohort study, critically ill COVID-19 patients with an H-Score ≥ 169 during their ICU stay had increased mortality rates at 28 and 90 days. Thus, attention should be paid to individuals with rising or high scores. Therapeutic options and their impact on mortality for patients with COVID-19-associated secondary HLH should be evaluated in further studies.

We performed a thorough search of the literature published through December 2024 with no date exclusions on invasive fungal infection (IFI)-induced hemophagocytic lymphohistiocytosis (HLH) in non-human immunodeficiency virus (HIV) patients. The frequency of IFI-induced HLH reported across 16 articles was 9%. Of the 116 identified cases with available clinical information, 53% occurred in immunocompromised patients. IFIs were usually disseminated (76%), with Histoplasma capsulatum being the most common pathogen (51%). IFI and HLH were diagnosed simultaneously in most cases (78%). The 30-day survival rate was 64%. Reported cases had significant heterogeneity in patient characteristics, management strategies, and outcomes.

Haemophagocytic lymphohistiocytosis (HLH) is a serious condition characterised by uncontrolled hyperinflammation. Etoposide has been used as a treatment option in paediatric HLH; however, its effectiveness and the necessity for adult induction therapy remain unclear. This systematic review and meta-analysis aimed to assess the effectiveness of etoposide-based induction therapy in adult HLH, focusing on overall response (OR). A systematic literature search was conducted to identify relevant studies on 11 December 2023, resulting in the inclusion of seven studies in the analysis. The pooled data demonstrated a significant improvement in OR with etoposide-based therapy in adult patients with HLH (1.95, 95% CI 1.51-2.53), compared with non-etoposide-treated patients. Furthermore, overall survival improved with etoposide treatment (1.25, 95% CI 1.03-1.52). Our analysis revealed the potential benefit of etoposide-based therapy in adult patients with HLH. Therefore, etoposide should be considered as a timely and early therapeutic option for the management of adult HLH.

Hemophagocytic lymphohistiocytosis (HLH) is an immune deregulatory disorder resulting in severe inflammation and potentially fatal complications involving the bone marrow, liver, or brain; HLH can be considered primary. Secondary HLH is often associated with a specific trigger, including infectious trigger that could be bacterial, viral, fungal or parasitic. Histoplasmosis-associated HLH is a relatively rare but previously reported complication. This case report presents a patient with HLH caused by disseminated histoplasmosis who was treated with etoposide, rituximab, amphotericin B, and itraconazole. This case report aims to highlight the importance of keeping a broad differential for when patients present with fevers of unknown origin.

Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH.

REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH.

Fifteen of 105 patients (14.3%) had rheumatologic disease-associated HLH. Of these, nine (60.0%) had systemic juvenile idiopathic arthritis, and one (6.7%) had adult-onset Still disease. Median (range) age at HLH diagnosis was 5 (0.9-39) years. Most patients (9 of 15; 60.0%) initiated emapalumab in an intensive care unit. Emapalumab was most frequently initiated for treating refractory or recurrent (10 of 15; 66.7%) disease. Most patients received HLH-related therapies before (10 of 15; 66.7%) and concurrently with (15 of 15; 100.0%) emapalumab. Emapalumab-containing regimens stabilized or achieved physician-determined normalization of most laboratory parameters, including absolute neutrophil count and absolute lymphocyte count (13 of 14; 92.9%), chemokine ligand 9 (9 of 11; 81.8%), and platelets and alanine transaminase (11 of 14; 78.6%), and reduced glucocorticoid dose by 80%. Overall survival and 12-month survival probability from emapalumab initiation were 86.7%.

Emapalumab-containing regimens stabilized or normalized most key laboratory parameters, reduced glucocorticoid dose, and were associated with low disease-related mortality, thereby demonstrating potential benefits in patients with rheumatologic disease-associated HLH.

Macrophage activation syndrome (MAS) is a life-threatening form of secondary haemophagocytic lymphohistiocytosis (HLH) associated with rheumatic diseases, most commonly Still's disease. This study aimed to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model for emapalumab, a fully human monoclonal antibody that targets interferon-gamma (IFNγ), in patients with MAS associated with Still's disease. A two-compartment disposition model based on data from patients with primary HLH administered emapalumab (1 mg/kg every 3 days, with possible increases to 3, 6 or 10 mg/kg) was re-estimated for patients with MAS administered emapalumab (6 mg/kg, then 3 mg/kg every 3 days until day 15 and twice weekly until day 28). An exploratory population PK/PD analysis comprising patients' PD data for total IFNγ, chemokine C-X-C motif ligand 9 (CXCL9) and ferritin was performed. Emapalumab clearance was generally linear and independent of total IFNγ levels in patients with MAS (n = 14). Estimated baseline levels of CXCL9 (a marker of IFNγ activity), soluble interleukin-2 receptor α (sIL-2Rα; a marker of hyperinflammation) and ferritin (a clinical marker of MAS disease activity) were 8400, 6550 and 15,300 μg/L, respectively. All three PD markers responded rapidly to changes in emapalumab concentration. Emapalumab almost completely suppressed CXCL9, sIL2-Rα, and ferritin production (estimated reduction in synthesis rate: 98.3%, 87%, and 99.6%, respectively). Population PK/PD modeling indicated that emapalumab rapidly suppresses markers of hyperinflammation in patients with MAS associated with Still's disease. Emapalumab dosing regimen used in clinical trials in patients with MAS is unlikely to need adjustment.

The incidence of babesiosis is increasing and clinicians should have a high index of suspicion due to its diagnostic challenges and variable disease course, from asymptomatic infection to fulminant disease. We present a case of fatal secondary hemophagocytic lymphohistiocytosis (sHLH) due to acute babesiosis in a previously healthy adult. We also present a comprehensive review of previously reported sHLH cases triggered by babesiosis. Host factors, such as immunocompromising conditions or medications, appear to be a risk factor for developing sHLH while it is unclear if percent parasitemia of babesia correlates with development or outcomes of HLH. Increasing awareness to improve time to diagnosis is vital for treating both babesiosis and sHLH, while future studies should investigate the role for immunomodulator therapy in this setting.

Hemophagocytic lymphohistiocytosis (HLH) is a critical syndrome with a high mortality rate. In clinical practice, some patients with fever of unknown origin (FUO) can develop HLH, further complicating the diagnosis and treatment. However, studies on HLH in adults with FUO are limited. This study aimed to investigate the clinical characteristics of adult patients with FUO to facilitate the early identification of those at high risk of developing HLH.

We collected data from hospitalized patients with FUO between January 2014 and December 2020. Risk factors for HLH in adults with FUO were analyzed using univariate and multivariate analysis.

A total of 988 patients with FUO were included in the study. The incidence of HLH in adults with FUO was 6.4%, with hematological tumors being the primary cause. Multivariate analysis indicated that skin rash and elevated alanine aminotransferase, total bilirubin, triglycerides, lactate dehydrogenase, and ferritin levels were independent risk factors for HLH in adults with FUO.

This study revealed the incidence rate, etiology distribution, and risk factors for HLH in adults with FUO. Comprehensive assessment of clinical and laboratory data at admission can assist in the early identification of FUO patients at risk for HLH.

Pancytopenia in the setting of disseminated histoplasmosis is sparsely described in the literature. We investigated the underlying mechanisms of pancytopenia in disseminated histoplasmosis and highlighted clinical outcomes.

We conducted a scoping review of cases and series on disseminated histoplasmosis presenting with pancytopenia published between 2001 and 2024. PubMed database was used for the search. The search terms were (disseminated histoplasmosis) AND (pancytopenia OR haemophagocytic syndrome OR lymphohistiocytosis).

We identified 72 cases. Forty-four (61.1%) cases were from the Americas, 18 (25.5%) from Asia, 8 (11.1%) from Europe, and 1(1.4%) each from Africa and Australia. Of the 72 cases, five cases (6.9%) were reported in children. The mean age was 41.9 ± 16.7 years with a range of 3 months to 78 years. Seven cases (9.7%) were immunocompetent, 27 (37.5%) had an underlying HIV infection and 45 (62.5%) were complicated with haemophagocytic lymphohistiocytosis syndrome. Histoplasma antigen assay (n = 29, 40.2%) was the major diagnostic method followed by bone marrow biopsy (n = 28, 38.9%). Fifty-three cases (73.6%) recovered, 15 (20.8%) died and outcomes were not stated in 4 cases (5.65%). The relationship between haemophagocytic lymphohistiocytosis and fatal outcomes was not statistically significant (P = 0.5). Likewise, HIV infection was not significantly associated with fatal outcomes (P = 0.6). Fatal outcomes were predominantly due to difficulty or delayed diagnosis of disseminated histoplasmosis and/or haemophagocytic lymphohistiocytosis (n = 5, 6.9%), multiple organ failure (n = 4, 5.6%) and late presentation (n = 2, 2.8%).

Pancytopenia in disseminated histoplasmosis is associated with poor outcomes. Such a hematologic finding should arouse the index of suspicion in the attending clinician for an invasive mycosis like disseminated histoplasmosis to avert fatal outcomes. Besides haemophagocytic lymphohistiocytosis, other factors associated with pancytopenia in disseminated histoplasmosis were the cooccurrence of viral and bacterial infections.

The objective of this review is to identify immunological pathways and markers of severity of illness associated with clinical outcomes that may represent potential therapeutic targets in the management of secondary hemophagocytic lymphohistiocytosis.

A broad range of immunomodulatory therapies is used to manage hemophagocytic lymphohistiocytosis, however, the supporting evidence for these therapies is scarce. Identifying patients likely to experience more severe disease or die is currently extremely difficult, if not impossible. The identification of implicated cytokines in secondary disease can provide further support for the identification of high-risk patients and the development of targeted therapies.

Studies reporting immune biomarker and cytokine measurement in adult patients (age ≥18 years) with secondary hemophagocytic lymphohistiocytosis will be considered for inclusion.

The proposed review will be conducted in line with the JBI methodology for scoping reviews. MEDLINE (Ovid) and Embase (Ovid) will be searched, without date limitations. Data will be extracted using a data extraction tool developed by the reviewers. Relevant sources will be retrieved, and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information.

Open Science Framework https://osf.io/9524e.

Hemophagocytic Lymphohistiocytosis (HLH) is a severe and potentially life-threatening condition characterized by an excessive and uncontrolled activation of the immune system. ICI-related hemophagocytic lymphohistiocytosis (irHLH) is a rare immune-related adverse event with an incidence of 0.03% to 0.4%. Although rare, it can be potentially lethal, with a high mortality rate of up to 50% in some cases. We present a patient with recurrent glioblastoma who developed Hemophagocytic Lymphohistiocytosis s a result of nivolumab treatment and was subsequently managed with cytokine-directed therapy (tocilizumab). Early diagnosis and treatment of Hemophagocytic Lymphohistiocytosis (HLH) associated with immune checkpoint inhibitors (ICIs) are indeed crucial due to the potentially life-threatening nature of the condition.Cytokine-based treatments (such as anti-IL-6) may be appropriate for patients who do not respond to high-dose steroids.

Melioidosis is an infectious disease caused by Burkholderia pseudomallei. People infected with B. pseudomallei experience fever and skin changes, pneumonia, abscesses, and septic shock that could cause death. Hemophagocytic lymphohistiocytosis is a severe inflammatory syndrome due to the excess activation of macrophages and T cells. We report a 50-year-old hypertensive and diabetic male patient presented with high-grade intermittent fever with loss of appetite and weight loss for two months and a history of jaundice, backache and swelling of both feet for 15 days. Blood and bone marrow culture grew Burkholderia pseudomallei. A liver biopsy revealed Kupffer cell hyperplasia and hemophagocytosis. The patient was treated with an injection of dexamethasone 4mg intravenous three times a day for five days and tapered over 15 days with ceftazidime 2 gm intravenous three times a day for six weeks. Early suspicion in the diagnosis of hemophagocytic lymphohistiocytosis in septicemia can prevent severe complications, even death.

Hemophagocytic lymphohistiocytosis is a potentially fatal multisystemic inflammatory syndrome that is better understood in the pediatric population. Consequently, the diagnostic criteria for adults still derives from studies conducted in the pediatric population. Several genetic mutations and secondary causes, including infections, autoimmunity, and malignancy, have been reported as significant actors in this condition, especially in adults. It is of the utmost importance to identify these triggers, as the treatment of this condition is largely dependent on addressing the underlying cause. Those who have undergone transplantation and whose immune response is already compromised are particularly susceptible to this condition. We present the case of a 74-year-old kidney transplant recipient who was admitted due to a persistent fever of unknown origin, pancytopenia, and splenomegaly. The patient was ultimately diagnosed with hemophagocytic lymphohistiocytosis in our hospital secondary to Epstein-Barr virus, aspergillosis, and leishmania infections. Targeted treatments for the aforementioned conditions led to the resolution of the syndrome and the recovery of the patient. Lymphohistiocytosis is a rare, albeit serious, condition that should be considered a differential diagnosis in the early stages of critical illness in transplant recipient patients. Doing so enables target treatments to be administered as soon as possible.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by uncontrolled immune activation, often associated with malignancy in adults. Early recognition and prompt initiation of treatment are crucial in managing this condition due to its rapid progression and poor prognosis. We report the case of a 75-year-old male with suspected lymphoproliferative disease who presented with clinical criteria compatible with HLH. Immediate treatment with dexamethasone led to rapid clinical improvement, and the patient was referred to hematology for continued management of the underlying disease. This case highlights the importance of constant clinical surveillance, early intervention, and the use of well-structured diagnostic tools in managing this syndrome in adults, where significant diagnostic and treatment challenges remain.

Aims/Background Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare, rapidly progressive and highly lethal disease. This retrospective cohort study aims to analyze the factors influencing the mortality risk in adult patients with sHLH, which are instrumental to improving our understanding of the high mortality risks associated with sHLH. Methods This study included 85 patients diagnosed with sHLH who were admitted and treated in the Department of Emergency, Peking University People's Hospital between April 2015 and July 2023. Participants were classified based on prognosis into two groups: the death group and the survival group. We collected demographic data, routine blood tests, comprehensive biochemical profiles, coagulation analyses, serum ferritin levels, natural killer (NK) cell counts, soluble interleukin-2 receptor (sCD25) levels, and potential etiological factors upon admission. The mortality risk factors influencing the prognosis of sHLH were analyzed with univariate and multivariate COX regression. Additionally, a mortality risk prediction model was established, and its accuracy was validated and optimized using the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve, calibration curves and clinical decision curve analysis (DCA). Results A total of 85 patients were included in this study, the male-to-female ratio is 1:1.4. The median age at diagnosis of sHLH was 56.00 (33.00-69.00) years. Clinical symptoms were atypical, with fever being the most prevalent symptom (81 cases, 95.3%), followed by disturbance of consciousness (10 cases, 11.8%). Univariate COX analysis and Multivariate COX regression analysis revealed that age (hazard ratio (HR) [95% confidence interval (CI)], 1.098 [1.025-1.177], p = 0.008), Alanine transaminase (ALT) (HR [95% CI], 1.016 [1.001-1.031], p = 0.034), Aspartate transaminase (AST) (HR [95% CI], 1.005 [1.001-1.008], p = 0.004), and Troponin I (TNI) levels (HR [95% CI], 1.196 [1.011-1.414], p = 0.037) were independent risk factors affecting prognosis. Specifically, sHLH patients aged ≥63.5 years (sensitivity 82.8%, specificity 85.7%), with AST levels ≥111 U/L (sensitivity 82.8%, specificity 82.1%), ALT ≥41 U/L (sensitivity 58.6%, specificity 64.3%) and TNI levels ≥2.15 ng/mL (sensitivity 62.1%, specificity 100%), faced a higher risk of mortality. We established a mortality risk prediction model for sHLH patients, which yielded a C-index of 0.848 (0.773-0.901), indicating strong agreement between predicted and observed outcomes. The ROC curves of the 28-day, 60-day, and 90-day mortality risk prediction model for sHLH patients were drawn, and the results showed that the 28-day, 60-day, and 90-day area under the curve (AUC) were 0.900 (0.829-0.971), 0.940 (0.882-0.998), and 0.930 (0.874-0.986), respectively. The predictive effect of the prediction model is satisfactory. Additionally, the clinical decision curve analysis for 28, 60 and 90 days in sHLH patients indicated that the net benefit of the nomogram model was higher than that line of extremes models (treat all and treat none). Conclusion Patients with sHLH have frequently atypical clinical presentation, with early death risk and notably elevated mortality rate. Independent risk factors influencing mortality risk in sHLH patients include age ≥63.5 years, AST ≥111 U/L, ALT ≥41 U/L, and TNI ≥2.15 ng/mL. With high accuracy and efficacy, the risk prediction model constructed can facilitate timely identification of sHLH patients at elevated risk of mortality, which is critical for optimizing clinical interventions.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome fueled by uncontrolled mononuclear phagocyte activity, yet the innate immune mechanisms driving HLH pathogenesis remain elusive. Germline gain-of-function (GOF) mutations in CARD11, a pivotal regulator of lymphocyte antigen receptor signaling, cause the lymphoproliferative disease B-cell expansion with NF-κB and T-cell anergy, which is frequently associated with HLH development. Given that CARD11 is physiologically expressed not only in lymphocytes but also in dendritic cells (DCs), we explored whether enforced CARD11 signaling in DCs contributes to immunopathology. We demonstrated that exclusive DC-intrinsic expression of CARD11-GOF in mice was sufficient to induce a lethal autoinflammatory syndrome that mimicked human HLH. Mechanistically, DC-intrinsic CARD11-GOF signaling triggered cell-autonomous inflammatory cytokine production via MALT1 paracaspase engagement. Genetic deletion of Malt1 in CARD11-GOF-expressing animals reversed the hyperinflammatory phenotype. These results highlight the significant role of enforced CARD11/MALT1 signaling in DCs as a contributor to HLH pathology and suggest potential therapeutic strategies for HLH treatment.

Cytomegalovirus (CMV) is a human herpes virus with a worldwide seroprevalence of 60-100%, mainly known to cause severe life-threatening disease in immunocompromised patients. In immunocompetent hosts (IMCh), CMV causes a self-limiting mononucleosis-like infection, and severe pictures are less recognized. We report a case of a previously healthy 62-year-old woman evaluated in the Internal Medicine outpatient clinic for 3 weeks of progressive fatigue, generalised inflammatory arthralgias, hypogastric discomfort and daily persistent fever. On first examination, paleness and hepatomegaly were noted. Further evaluation showed the presence of haemolytic anaemia; lymphocytosis and monocytosis; thrombocytosis; elevated C-reactive protein; hypertriglyceridemia and hyperferritinaemia; peripheral blood immunophenotyping with a 44% population of T cells and diminished CD4/CD8 ratio. Hemophagocytic lymphohistiocytosis (HLH) was suspected, with an Hscore of 190 points, giving a 70-80% probability. CMV serology was positive for acute infection (IgM positive/IgG negative), with a viral load of 4470 IU/ml. CMV primary infection was admitted, complicated with haemolytic anaemia, cholestatic hepatitis and possible HLH. Despite the laboratory frame exuberance, the patient remained stable and was discussed with Infectious Diseases, deciding not to initiate antiviral therapy. Over the next month, the fever, anaemia and hepatitis resolved, and the white blood cell count normalized. After two months, the CMV viral load was negative, and seroconversion was documented. Primary CMV infection is unusual in older patients. Additionally, in IMCh infection is usually mild, and severe infections are rare. In such cases, the use of antiviral therapy is not well established, and risk/benefit must be considered in a personalised approach. Altogether, the clinical and laboratory presentation of this case reinforces the need for high clinical suspicion.

Cytomegalovirus can have serious, and life-threatening manifestations in immunocompetent hosts and its incidence may be higher than previously thought.Despite its seroprevalence ranging near 100% in the global population, primary infection in the elderly immunocompetent hosts is uncommon, but not impossible.Antiviral treatment is not well established in non-life-threatening disease in immunocompetent hosts, and a personal and individual approach must be considered with risk/benefit consideration.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome marked by excessive immune activation. It can be triggered by various factors, including infections, malignancies, and autoimmune diseases, making the diagnosis challenging due to its overlap with other severe conditions.

We discuss two intensive care unit (ICU) cases illustrating the diverse manifestations of HLH and the critical importance of early recognition and treatment. The first case involves natural killer-cell leukaemia, and the second, a suspected viral trigger. Both highlight the necessity of a multidisciplinary approach in diagnosis and management, emphasizing the complexity of HLH in ICU settings.

High mortality rates, particularly in malignancy-associated HLH, underscore the importance of tailored treatment strategies based on the underlying aetiology.

Hemophagocytic lymphohistiocytosis (HLH) in adults can arise from a variety of triggers, including infections and malignancies, each influencing disease progression and prognosis differently. Recognizing these underlying aetiologies is crucial for tailoring management strategies and anticipating clinical outcomes.Due to its life-threatening nature, HLH requires prompt diagnosis and a coordinated, multidisciplinary approach. Early intervention, incorporating immunosuppressive therapies and supportive care, is essential to improve patient outcomes, particularly in intensive care unit settings where disease severity is often pronounced.Utilizing diagnostic tools such as the HScore and HLH-2004 criteria can facilitate early identification of HLH in critically ill patients with unexplained inflammatory symptoms. These tools, along with a high index of suspicion, help distinguish HLH from other hyperinflammatory conditions, enabling timely and appropriate therapeutic interventions.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease characterized by the uncontrolled activation of the immune system, resulting in a high clinical mortality rate. A 56-year-old Chinese female presented at the emergency room with symptoms including fever, fatigue, nausea, vomiting, cough, shortness of breath, and chest tightness. Laboratory investigations demonstrated decreased levels of white blood cells, hemoglobin, and platelets while interleukin-6 and ferritin exhibited significant elevations. She was subsequently admitted to the hematology department, where she was diagnosed with HLH caused by a Candida infection. Following treatment with antifungal agents, glucocorticoids, antiemetics, diuretics, and hepatoprotective therapy, the patient's condition has shown improvement. However, after being infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the patient experienced a reactivation of HLH, resulting in a more severe clinical presentation and complications compared to the initial onset. Although the patient's condition improved after the administration of antiviral drugs, etoposide, glucocorticoids, cyclosporin, and intravenous immunoglobulin, this case highlights the possibility of disease reactivation during the recovery phase of HLH. This should raise the attention of medical professionals.

An association exists between immune checkpoint inhibitors and hemophagocytic lymphohistiocytosis (HLH). Therefore, the main objective of this study was to collect data on this rare but potentially life-threatening immune-related adverse reaction to identify the medications that cause it, the clinical characteristics, and effective treatments.

Literature in English and Chinese on immune checkpoint inhibitors causing HLH published from August 2014 to March 2024 was analyzed. Immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome keywords were used to find the literature on China Knowledge Network, Wanfang, PubMed and Emabase Databases.

Twenty-four studies were included, with a total of 27 patients (18 males and 9 females) with a mean age of 58 years (range 26-86). The mean time to the onset of symptoms was 10.3 weeks (7 days-14 months). The main clinical characteristics were fever, cytopenia, splenomegaly, methemoglobinemia, hypofibrinogenemia, and bone marrow biopsy showed phagocytosis. Twenty-two patients improved after the treatment with steroids, cytokine blocking therapy and symptomatic treatment, four patients died, and one patient was not described.

HLH should be not underestimated as a potentially serious adverse effect of immune checkpoint inhibitors since appropriate treatments may save the life of patients.

Host immune dysfunction plays a crucial role in the onset, progression, and outcome of hemophagocytic lymphohistiocytosis (HLH). This study aimed to comprehensively evaluate the peripheral immune profiles in patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), and explore their predictive value for patient prognosis. A total of 77 patients with sHLH were enrolled in this study, with 31 of them experiencing mortality. Flow cytometry was used to assess the percentages, absolute numbers, and phenotypes of lymphocyte subsets. Simultaneously, cytokine levels and routine laboratory indicators were also collected. In sHLH patients, lymphocyte subset absolute numbers were significantly impaired, accompanied by T cell hyperactivation, B cell hyperactivation, and increased plasmablast proliferation. Prognostic analysis revealed that lower CD8+ T cell percentages, elevated APTT, IL-6, IL-10 levels, and increased CD4+CD28null T cell proportions were associated with poor patient outcomes. The study demonstrates dysregulation in the counts and phenotypes of lymphocyte subsets in sHLH patients. Several key factors, including IL-6, IL-10, APTT, and various T cell percentages, have potential as prognostic markers and therapeutic targets in sHLH.

Sepsis represents a significant global health and hygiene challenge. Excessive activation of macrophages in sepsis can result in certain patients displaying characteristics akin to those observed in Macrophage Activation Syndrome (MAS). MAS represents a grave immune system disorder characterized by persistent and severe inflammation within the body. In the context of sepsis, MAS presents atypically, leading some researchers to refer to it as Macrophage Activation-Like Syndrome (MALS). However, there are currently no effective treatment measures for this situation. The purpose of this article is to explore potential treatment methods for sepsis-associated MALS.

The objective of this review is to synthesize the specific pathophysiological mechanisms and treatment strategies of MAS to investigate potential therapeutic approaches for sepsis-associated MALS.

We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing macrophage activation syndrome and sepsis up to Mar 2024 and combined with studies found in the reference lists of the included studies.

We have synthesized the underlying pathophysiological mechanism of MALS in sepsis, and then summarized the diagnostic criteria and the effects of various treatment modalities utilized in patients with MAS or MALS. In both scenarios, heterogeneous treatment responses resulting from identical treatment approaches were observed. The determination of whether the patient is genuinely experiencing MALS significantly impacts the ultimate outcomes of therapeutic efficacy. In order to tackle this concern, additional clinical trials and research endeavors are imperative.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of excessive immune activation, leading to severe inflammation and organ damage. While more common in infants, HLH can occur at any age and is often triggered by infections such as Epstein-Barr virus (EBV). In this case, a 38-year-old man presented with a three-week history of fevers, night sweats, poor appetite, and severe anemia. Investigations revealed hepatosplenomegaly, extremely elevated ferritin levels, triglycerides, and a positive EBV PCR. Despite treatment, his condition deteriorated, and a bone marrow biopsy confirmed HLH. He received immunosuppressive therapy but ultimately passed away after 64 days in the hospital. This case emphasizes the diagnostic challenges of HLH, particularly when triggered by the EBV. Early diagnosis and prompt treatment are vital, although prognosis can be poor in severe cases, underscoring the importance of clinical vigilance.

Dengue fever (DF), a significant global health issue, particularly impacts tropical and subtropical regions. Elevated serum ferritin levels are increasingly recognized as a biomarker for severe dengue infection. This review examines the role of serum ferritin in diagnosing and prognosticating dengue severity. It highlights how hyperferritinemia correlates with severe clinical outcomes, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). By integrating serum ferritin measurement into routine clinical practice, early identification and intervention for high-risk patients can be enhanced, potentially improving clinical outcomes. Further research should focus on standardizing ferritin level thresholds and exploring the mechanisms underlying ferritin elevation in dengue.

To analyze the current treatment status and prognostic regression of the chronic NK cell lymphoproliferative disorder (CLPD-NK).

We retrospectively analyzed the clinical features, treatment and prognosis of 18 patients with CLPD-NK who were treated at our Hospital between September 2016 and September 2022.

Eighteen patients were included: three patients were treated with chemotherapy, five patients underwent immune-related therapy, one patient was treated with glucocorticoids alone, five patients were administered granulocyte colony-stimulating factor, blood transfusion therapy, or anti-infection therapy, followed by observation and follow-up, and four patients were observed without treatment. Fifteen patients survived, including two patients who achieved complete remission (CR) and seven patients who achieved partial remission (PR), of whom one patient progressed to Aggressive NK-cell leukemia (ANKL) and sustained remission after multiple lines of treatment; three patients were not reviewed, of which one patient was still in active disease, three patients developed hemophagocytic syndrome during treatment and eventually died, one of them had positive Epstein-Barr virus (EBV) expression. The 5-years overall survival rate was 83%.

Most patients with CLPD-NK have inert progression and a good prognosis, whereas some patients have a poor prognosis after progressing to ANKL and combined with hemophagocytic syndrome. Abnormal NK cells invading the center suggest a high possibility of ANKL development, and immunosuppressants and hormones are effective treatments for this disease.

Hemophagocytic lymphohistiocytosis (HLH) is an acute, rapidly progressive systemic inflammatory disorder that often occurs secondary to hematological malignancies among other conditions in adults. Although the annual incidence of HLH is increasing, detailed epidemiological knowledge of HLH is still limited, especially in patients with hematological malignancies.

To analyze the impact of hematological malignancies on the epidemiology and outcomes of HLH.

Data from the National Readmission Database (NRD) from 2011 to 2020 were analyzed to explore the epidemiological trends and in-hospital outcomes of HLH patients, particularly those with hematological malignancies.

Our analysis included 7579 HLH hospitalizations, with hematological malignancies implicated in 24.01% of cases. Our findings reveal a steady increase in HLH diagnoses from 145 cases in 2011 to 1848 in 2020, with the proportion linked to hematological malignancies remaining consistent. Patients with hematological malignancies-associated HLH exhibited higher rates of in-hospital mortality (31.6%) than those without (14.4%), and a higher 30-day readmission rate, underscoring a critical need for early detection and treatment revision.

Despite the increasing awareness and diagnosis of HLH, the prognosis of patients with HLH associated with hematological malignancies remains poor, highlighting the urgent need for improved management strategies and therapeutic interventions.