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.

Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders. Genetic defects affecting cellular cytotoxicity cause familial (primary) HLH. On the other hand, secondary HLH is more a pathophysiologic process common to many conditions, rather than a singular disease entity. Improved genetic, immunologic, and functional testing have changed not only the way we diagnose HLH, but also how we treat it. In 2004, there were few active agents and regimens. In 2024, there are multiple safe and effective targeted therapies. We have begun to understand that routine and immediate use of etoposide-based therapy in secondary HLH is likely not appropriate, and emerging cytokine-directed therapies may be more rational interventions. Moreover, it is recognized that identifying and treating the driver of secondary HLH is at least as important as treating the cytokine storm and immune dysregulation. Unfortunately, over-reliance on, and narrow interpretation of, the HLH- 2004 criteria can lead to overdiagnosis, misdiagnosis, and unneeded exposure to drugs that can be harmful. It is important that clinicians understand the limitations of the current diagnostic paradigms for secondary HLH, and the shortcomings of reflexive use of etoposide-based therapy. Herein we will discuss the pros and cons of the current paradigm for the recognition, diagnosis, and treatment of secondary HLH.

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.

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 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.

Tuberculosis-associated hemophagocytic lymphohistiocytosis (TB-HLH) presents significant challenges in diagnosis and treatment due to its complex interplay between TB and HLH. This systematic review aims to provide comprehensive insights into the epidemiology, clinical characteristics, and treatment outcomes of TB-HLH patients.

We performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Scopus, Web of Science, and Embase up to May 16, 2023, without language restrictions. We included case reports and cases series on patients with both TB and HLH with documented treatment outcomes. Data were analyzed using descriptive statistics, chi-square or Fisher's exact tests, t-tests, and mortality rates. Significant variables (p < 0.05) from univariate analysis and clinically relevant factors were used in binary logistic regression to determine odds ratios, 95% confidence intervals, and p-values.

A total of 185 articles involving 213 patients were included. The overall mortality rate was 39%. Age ≥ 44 years and comorbidities were identified as independent risk factors for increased mortality (p = 0.005). Anti-tuberculosis treatment (ATT) combined with HLH-specific therapies, was associated with reduced mortality compared to ATT alone (p < 0.05), especially IVIG (p = 0.04).

Integrating ATT with HLH-specific therapies significantly enhances survival in TB-HLH patients. Additionally, IVIG plays a key role in improving outcomes. Age ≥ 44 years and comorbidities are critical risk factors for increased mortality. Early and high suspicion of TB-HLH is essential, especially in high TB burden regions or recent travel contexts. Future research should focus on prospective multicenter studies to validate our findings and develop standardized treatment strategies on TB-HLH.

CRD42022364180.

Immunotherapy is a rapidly expanding cancer treatment strategy. Dostarlimab is administered as the first-line treatment for metastatic endometrial cancer in combination with chemotherapy. Herein, we describe the case of a 72-year-old female patient who developed hemophagocytic lymphohistiocytosis after receiving a single dose of 500 mg of dostarlimab. The patient's clinical outcome improved after treatment with ruxolitinib and corticosteroids. Oncological treatment was resumed in combination with chemotherapy alone.

Hemophagocytic Lymphohistiocytosis (HLH) carries a high mortality rate. Current existing risk-evaluation methodologies fall short and improved predictive methods are needed. This study aimed to forecast 30-day mortality in adult HLH patients using 11 distinct machine learning (ML) algorithms.

A retrospective analysis on 431 adult HLH patients from January 2015 to September 2021 was conducted. Feature selection was executed using the least absolute shrinkage and selection operator. We employed 11 ML algorithms to create prediction models. The area under the curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, F1 score, calibration curve and decision curve analysis were used to evaluate these models. We assessed feature importance using the SHapley Additive exPlanation (SHAP) approach.

Seven independent predictors emerged as the most valuable features. An AUC between 0.65 and 1.00 was noted among the eleven ML algorithms. The gradient boosting decision tree (GBDT) algorithms demonstrated the most optimal performance (1.00 in the training cohort and 0.80 in the validation cohort). By employing the SHAP method, we identified the variables that contributed to the model and their correlation with 30-day mortality. The AUC of the GBDT algorithms was the highest when using the top 4 (ferritin, UREA, age and thrombin time (TT)) features, reaching 0.99 in the training cohort and 0.83 in the validation cohort. Additionally, we developed a web-based calculator to estimate the risk of 30-day mortality.

With GBDT algorithms applied to laboratory data, accurate prediction of 30-day mortality is achievable. Integrating these algorithms into clinical practice could potentially improve 30-day outcomes.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, lifethreatening hyperinflammatory disorder characterized by dysfunction of NK cells and cytotoxic lymphocytes. We present a rare case of a patient diagnosed with HLH who presented with persistent fever during treatment for refractory T-cell/histiocyte-rich large B-cell lymphoma (TCHRLBCL), highlighting the challenges of managing HLH in the context of refractory lymphoma. According to our review of the literature, this is the first case of HLH that developed several months into treatment for refractory TCHRLBCL and not in close temporal relation to lymphoma diagnosis.

Hematological malignancies may require rapid-onset treatment because of their short doubling time, notably observed in acute leukemias and specific high-grade lymphomas. Furthermore, in targeted onco-hematological scenarios, chemotherapy is deemed necessary as an emergency measure when facing short-term, life-threatening complications associated with highly chemosensitive hematological malignancies. The risks inherent in the disease itself, or in the initiation of treatment, may then require admission to the intensive care unit (ICU) to optimize monitoring and initial management protocols. Hyperleukocytosis and leukostasis in acute leukemias, tumor lysis syndrome, and disseminated intravascular coagulation are the most frequent onco-hematological complications requiring the implementation of emergency chemotherapy in the ICU. Chemotherapy must also be started urgently in secondary hemophagocytic lymphohistiocytosis. Tumor-induced microangiopathic hemolytic anemia and plasma hyperviscosity due to malignant monoclonal gammopathy represent infrequent yet substantial indications for emergency chemotherapy. In all cases, the administration of emergency chemotherapy in the ICU requires close collaboration between intensivists and hematology specialists. In this review, we provide valuable insights that aid in the identification and treatment of patients requiring emergency chemotherapy in the ICU, offering diagnostic tools and guidance for their overall initial management.

There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL.

A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival.

With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT.

ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

Dengue's lack of specific treatments beyond supportive care prompts a focus on uncovering additional pathophysiological factors. Dengue-associated hemophagocytic lymphohistiocytosis (HLH), characterized by dysregulated macrophage activation and cytokine storm, remains underexplored despite its potential to worsen disease severity and mortality. While rare, dengue-associated HLH disproportionately affects severe cases, significantly impacting mortality rates. To mitigate high mortality, early identification and familiarity with dengue-associated HLH are imperative for prompt treatment by clinicians. This narrative review therefore aims to examine the current clinical and therapeutic knowledge on dengue-associated HLH, and act as a resource for clinicians to improve their management of HLH associated with severe dengue. Dengue-associated HLH should be considered for all cases of severe dengue and may be suspected based on the presence of prolonged or recurrent fever for >7 days, or anemia without intravascular hemolysis or massive bleeding. Diagnosis relies on fulfilling at least five of the eight HLH-2004 criteria. Treatment predominantly involves short courses (3-4 days) of high-dose steroids (e.g., dexamethasone 10 mg/m2), with additional therapies considered in more severe presentations. Notably, outcomes can be favorable with steroid therapy alone.

We aimed to examine the association between baseline platelet count (PLT) and the prognosis of adult secondary hemophagocytic lymphohistiocytosis (sHLH). Data from 292 patients with pretreatment platelet counts were retrospectively analysed from January 2016 to December 2020. We categorized platelet count into quartiles. Multivariable Cox proportional hazards models and restricted cubic splines (RCS) were used to evaluate the relationship between platelet count and mortality. During a median follow-up of 53 (interquartile ranges, 17-223) days, a total of 208 deaths occurred. After adjusting for multiple variables, a non-linear and inverse relationship was observed between platelet count and mortality in sHLH patient (P for nonlinearity=0.002). For non- lymphoma-associated haemophagocytic lymphohistiocytosis (non-LHLH), a similar curve was also observed (P for nonlinearity =0.028). Decreased PLT (PLT Q4) was associated with an increased risk of mortality (adjusted hazard ratio: 1.97; 95% confidence interval: 1.28-3.04; Ptrend =0.005). Similar results were observed in the LHLH subgroup (adjusted hazard ratio: 1.84; 95% confidence interval: 1.05-3.24; Ptrend =0.024) but not in the non-LHLH subgroup (Ptrend =0.266). Baseline platelet count demonstrated a nonlinear and inverse association with an increased risk of mortality among adult sHLH patients. This method is used to identify sHLH patients with inferior overall survival due to its low cost and universal availability.

Haemophagocytic lymphohistiocytosis is a severe systemic hyperinflammatory syndrome characterised by dysregulation of immune cells and excessive production of cytokines, also known as a cytokine storm. It has distinctive clinical features with fever, hyperferritinaemia and falling blood counts. In adults, this usually occurs secondary to an underlying driver or trigger including infection, malignancy or rheumatic diseases. Prompt treatment with immunomodulatory therapy, including corticosteroids and the recombinant IL-1 receptor antagonist anakinra, is recommended to switch off the cytokine storm. Etoposide-based regimens are sometimes needed, and newer therapies such as emapalumab and JAK inhibitors are increasingly being used. The incidence of haemophagocytic lymphohistiocytosis has increased significantly over the last 20 years which may partly reflect increased awareness of the condition. Although relatively rare, haemophagocytic lymphohistiocytosis can be encountered by a broad range of hospital physicians, so knowing how to diagnose and treat this condition is essential. This article reviews the pathogenesis, clinical features, causes, diagnosis and treatment of haemophagocytic lymphohistiocytosis to improve physician recognition and management of this condition to improve future patient outcomes.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1-4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1-4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1-4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder characterized by extreme immune activation and excessive inflammation. It has been reported in patients with familial cases, immunodeficiencies, malignancies, stem cell transplants, and viral etiologies. This report describes acquired HLH associated with Human herpesvirus-6 (HHV-6) infection in a 76-year-old previously healthy male. The patient was admitted to the hospital due to fever, chills, and abdominal pain. The diagnostic workup revealed gallbladder wall thickening on imaging, concerning for cholecystitis. The patient was started on treatment for sepsis. Further clinical deterioration led to an extensive infectious workup. The patient was found to have elevated soluble IL-2Ra levels, and a bone marrow biopsy was performed, which revealed HLH. A positive HHV-6 polymerase chain reaction in the cerebrospinal fluid and serum confirmed the viral infection. Treatment involved the initiation of high-dose steroids, etoposide, and ganciclovir. Despite these interventions, the patient's clinical status worsened, leading to the implementation of comfort measures, and the patient eventually died. This case underscores the importance of considering HHV-6 as a potential cause of HLH in immunocompetent adults. From this case, we infer that a heightened level of vigilance is necessary to recognize and intervene in this challenging condition promptly.

Liver dysfunction is common in patients with hemophagocytic lymphohistiocytosis (HLH). However, whether the severity of liver injury is associated with the prognosis of patients with HLH remains to be determined. This study aims to assess the association of the severity of liver involvement with short-term prognosis among adult patients with HLH.

A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury.

The majority of our cohort suffered from mild to moderate hepatic damage, presenting with Child-Turcotte-Pugh (CTP) class A (55, 36.7%) or B (74, 49.3%). The prevalence of acute liver failure (ALF) was 9.3% in our cohort. The overall 30-day mortality rate was 49.3% among the study population. HLH patients with ALF showed an extremely adverse prognosis, with a mortality rate as high as 92.9%. In a multivariate analysis, age ≥60 years (p = 0.016), blood urea nitrogen (BUN) ≥7 μmol/L (p < 0.001), and malignancy-associated HLH (p < 0.001) at the diagnosis of HLH were identified as being strongly correlated with 30-day prognosis. An excellent predictive power was found. Among the predictive scores used to assess early death of HLH patients with liver injury, the prognostic efficiency of chronic liver failure-sequential organ failure assessment (CLIF-SOFA) (AUROC: 0.936 ± 0.0211) and SOFA score (0.901 ± 0.026) were significantly better than those of the APACHE II (p < 0.001), model for end-stage liver disease score (p < 0.001) and CTP scores (p < 0.001).

Patients with old age, elevated BUN, and malignancy had inferior survival. CLIF-SOFA and SOFA enable more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models.

Programmed cell death protein 1 (PD-1) checkpoint inhibitors such as pembrolizumab are novel therapeutics used to treat various advanced malignancies. Immune-related adverse events are common, among the most serious of these toxicities is hemophagocytic lymphohistiocytosis (HLH), which is a life-threatening disorder of unbridled immune activation but has not been properly established.

We have procured the first case of hemophagocytic lymphohistiocytosis as an aftermath of treatment with pembrolizumab from the Sir Run Run Shaw Hospital, Zhejiang University, China. In a pursuit to enhance the understanding of this condition, a comprehensive systematic review was performed encompassing all reported instances of ICI-associated Hemophagocytic lymphohistiocytosis within the realms of PubMed and Embase databases.

We detail the recovery of a cervical cancer patient with a history of psoriasis who developed HLH after combined pembrolizumab and bevacizumab treatment. Remarkably, tumor lesions exhibited substantial and sustained regression. From an analysis of 52 identified Immune Checkpoint Inhibitor (ICI)-related HLH cases, we discovered that HLH often occurred within the first two treatment cycles and approximately 20% of these patients had a history of autoimmune-related diseases. Despite a 15% mortality rate, the majority of patients experienced positive outcomes. Notably, in instances of recovery from HLH, 80% showed positive tumor outcomes. Even after discontinuation of ICI treatment, tumor control persisted in some cases.

We identified the first case of HLH caused by ICI treatment in cervical cancer and summarized the possible occurrence factors of these cases, the treatment outcomes of HLH, and the impact on tumor outcomes.

Hemophagocytic lymphohistiocytosis is a rare syndrome with a poor prognosis, characterized by an uncontrolled dysregulation of the immune system. The rarity of this disease makes it difficult to obtain large cohorts. In this study, we analyzed the data of 66 patients: the objective was to describe the epidemiological, clinical, biological and therapeutic characteristics and to compare our results with those already published.

We conducted a retrospective study at the University Hospital of Montpellier from 2015 to 2021. Patients were included when the diagnosis of HLH was mentioned on the hospitalization report and when the HSCORE was higher than 50% (169). Prognostic analyses were performed by comparing the patients who died from HMH to those who didn't.

The mean age the 66 patients included was 49.2 years, 62% were men. The percentage of deaths was 45.9%. Lymphoma was the main etiology, followed by infections, then autoimmune/autoinflammatory diseases. Fever, splenomegaly, hepatomegaly and organ failure were the main clinical manifestations. Pancytopenia was present in 62% of cases. Ferritin, triglycerides, LDH and AST were highly increased. Advanced age, associated lymphoma, and the severity of cytopenias were linked to a poor prognosis.

The study of the clinico-biological, epidemiological and survival data of the patients in our cohort allowed us to confirm previously published data but also to discuss some of them.

Hemophagocytic lymphohistiocytosis (HLH) has been described for decades in association with malignancies (M-HLH). While its mechanism is unknown, M-HLH has a poor prognosis, ranging from 10% to 30% overall survival. Mature T-cell lymphomas, diffuse large B-cell lymphoma, and Hodgkin lymphoma, with or without viral co-triggers such as Epstein-Barr virus, are among the most frequent underlying entities. Most M-HLH cases occur at the presentation of malignancy, but they may also occur during therapy as a result of immune compromise from chemotherapy (HLH in the context of immune compromise, IC-HLH) and (typically) disordered response to infection or after immune-activating therapies (Rx-HLH, also known as cytokine release syndrome, CRS). IC-HLH typically occurs months after diagnosis in the context of fungal, bacterial, or viral infection, though it may occur without an apparent trigger. Rx-HLH can be associated with checkpoint blockade, chimeric antigen receptor T-cell therapy, or bispecific T-cell engaging therapy. Until recently, M-HLH diagnosis and treatment strategies were extrapolated from familial HLH (F-HLH), though optimized diagnostic and therapeutic treatment strategies are emerging.

Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal adverse reaction to pembrolizumab. The clinical characteristics of pembrolizumab induced HLH are unknown. Exploring the clinical features of pembrolizumab induced HLH is crucial for the treatment and prevention of immune checkpoint inhibitor-induced HLH.

The literature related to pembrolizumab induced HLH was collected for retrospective analysis by searching the Chinese and English databases from inception until August 31, 2023.

A total of 24 patients were included, including 17 men (70.8%) with a median age of 61 years (41,80). The time between the last infusion and the start of HLH ranged from 2 to 46 days, with a median time of 14 days. Fever (100%) was the most common symptom, accompanied by splenomegaly (14 cases, 58.3%) and hepatomegaly (6 cases, 25.0%). Laboratory examination revealed revealed anemia (18 cases, 75.0%), leukopenia (12 cases, 50.0%), thrombocytopenia (20 cases, 83.3%), hypertriglyceridemia (11 cases, 45.8%), hypofibrinogenemia (11 cases, 45.8%). decreased natural killer cell function (7 cases, 29.2%), and elevated soluble CD25(15 cases, 62.5%). All patients developed hyperferriinemia, with a median of 30,808 ng/mL (range 1303 ~ 100,000). Bone marrow biopsy showed hemophagocytosis (15 cases, 62.5%). After discontinuation of pembrolizumab and treatment with steroids, etoposide, intravenous immunoglobulin, cytokine blocking, and immunosuppression, 17 patients recovered or improved, and 5 patients eventually died.

HLH should be suspected when unexplained fever, cytopenia, splenomegaly, and elevated aminotransferase occur in patients using pembrolizumab. Screening for risk factors before treatment with pembrolizumab may be necessary to prevent HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological hyperactivation-related disease with a high mortality rate. The purpose of this study was to examine the relationship between complete blood count parameters and the occurrence of acute kidney injury (AKI) and mortality in patients with HLH.

We included 585 adult patients with HLH. Logistic regression models for AKI and 28-day mortality were developed.

Multivariate logistic regression models revealed that hemoglobin (HB) ≤ 7.3 g/dl (adjusted OR, 1.651; 95% CI, 1.044-2.612), hemoglobin-to-red blood cell distribution width ratio (HRR) < 0.49 (adjusted OR, 1.692), neutrophil-to-lymphocyte ratio (NLR) ≥ 3.15 (adjusted OR, 1.697), and neutrophil-to-lymphocyte-platelet ratio (NLPR) ≥ 11.0 (adjusted OR, 1.608) were independent risk factors for the development of AKI. Moreover, lower platelet levels (31 × 109/L < platelets < 84 × 109/L, adjusted OR, 2.133; platelets ≤ 31 × 109/L, adjusted OR, 3.545) and higher red blood cell distribution width-to-platelet ratio (RPR) levels (0.20 < RPR < 0.54, adjusted OR, 2.595; RPR ≥ 0.54, adjusted OR, 4.307), lymphocytes ≤ 0.34 × 109/L (adjusted OR, 1.793), NLPR ≥ 11.0 (adjusted OR, 2.898), and the aggregate index of systemic inflammation (AISI) ≤ 7 (adjusted OR,1.778) were also independent risk factors for 28-day mortality. Furthermore, patients with AKI had a worse prognosis than those without AKI (P < 0.05).

In patients with HLH, hematological parameters are of great value for the early identification of patients at high risk of AKI and 28-day mortality.

Hemophagocytic lymphohistiocytosis (HLH) is a condition of immune dysregulation and hyperinflammation, leading to organ failure and death. Malignancy, autoimmune conditions, and infections, including Mycobacterium tuberculosis (TB), are all considered triggers of HLH. The aim of this study was to review all reported cases of TB-associated HLH in English literature, and to summarize the epidemiology, diagnostics, treatment, and mortality in patients with concomitant HLH and TB. A systematic review of described cases with TB-associated HLH, via a structured literature search in the medical database PubMed, is presented. Additional articles were included through cross-referencing with existing review articles. Articles were reviewed based on a predetermined set of criteria. A total of 116 patients with TB-associated HLH were identified with a male:female ratio of about 3:2. The age at presentation ranged from 12 days to 83 years. Malignancy, autoimmunity, and renal failure were the most common comorbid conditions. Most patients received both tuberculostatic and specific immunomodulating treatment, which was associated with a 66% (48/73) survival rate compared to 56% (15/27) in those receiving only tuberculostatic treatment, and 0% (0/13) in those receiving only immunomodulating treatment. The survival rate was 55% overall. The overlapping presentation between disseminated TB and HLH poses challenging diagnostics and may delay diagnosis and treatment, leading to increased mortality. TB should be considered as a potential trigger of HLH; clinicians' knowledge and awareness of this may result in the appropriate investigations needed to ensure diagnosis and proper treatment.

A 43-year-old Puerto Rican man with a kidney transplant presented to the ED with 2 weeks of flu-like symptoms, nausea, and vomiting. He had plasma exchange therapy 2 months before for acute transplant rejection and has been tolerating a heightened immunosuppressive regimen. CT scans characterized opacities as possibly early tree-in-bud opacities (Fig 1A). Patient remained stable throughout hospital stay with an unremarkable workup and was discharged with doxycycline for nonspecific pneumonia.

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.

The systemic inflammatory response seen in patients with severe COVID-19 shares many similarities with the changes observed in hemophagocytic lymphohistiocytosis (HLH); a disease characterized by excessive immune activation. Many patients with severe COVID qualify for a diagnosis of HLH. Etoposide, an inhibitor of topoisomerase II is used to control inflammation in HLH. This randomized, open-label, single center phase II trial attempted to determine whether etoposide can be used to blunt the inflammatory response in severe COVID. This trial was closed early after eight patients were randomized. This underpowered trial did not meet its primary endpoint of improvement in pulmonary status by two categories on an 8 point ordinal scale of respiratory function. There were not significant differences in secondary outcomes including overall survival at 30 days, cumulative incidence of grade 2 through 4 adverse events during hospitalization, duration of hospitalization, duration of ventilation and improvement in oxygenation or paO2/FIO2 ratio or improvement in inflammatory markers associated with cytokine storm. A high rate of grade 3 myelosuppression was noted in this critically ill population despite dose reduction, a toxicity which will limit future attempts to explore the utility of etoposide for virally-driven cytokine storm or HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with potentially fatal consequences that results from an excessive immune response caused by malfunctioning natural killer cells and cytotoxic T lymphocytes. Secondary HLH, which is the predominant type in adults, is associated with various medical conditions, including infections, malignancies, and autoimmune diseases. Secondary HLH associated with heat stroke has not been reported.

A 74-year-old male was admitted to the emergency department after being unconscious in a 42°C hot public bath. The patient was witnessed to be in the water for more than 4 hours. The patient's condition was complicated by rhabdomyolysis and septic shock, which were managed with mechanical ventilation, vasoactive agents, and continuous renal replacement therapy. The patient also showed evidence of diffuse cerebral dysfunction.

While the patient's condition initially improved, the patient developed a fever, anemia, thrombocytopenia, and an acute rise in total bilirubin, which, we suspected, was caused by HLH. Further investigations revealed elevated serum ferritin and soluble interleukin-2 receptor levels.

The patient received 2 cycles of serial therapeutic plasma exchange to lower the endotoxin burden. To manage HLH, high-dose glucocorticoid therapy was done.

Despite the best efforts, the patient did not recover and expired from progressive hepatic failure.

We report a novel case of secondary HLH associated with heat stroke. Diagnosing secondary HLH can be difficult since clinical manifestations of the underlying disease and HLH may present simultaneously. Early diagnosis and prompt initiation of treatment is required to improve the prognosis of the disease.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare life-threatening systemic disease. This study aimed to assess the prognostic value of pretreatment albumin-bilirubin (ALBI). We retrospectively analyzed 168 non-Hodgkin lymphoma-associated secondary hemophagocytic lymphohistiocytosis (NHL-sHLH) patients with hepatic injuries. Multivariable logistic/Cox models and restricted cubic spline models were conducted to evaluate the relationships between the ALBI score and short- and long-term survival. Among 168 adult NHL-sHLH patients, 82 (48.8%) patients died within 30 days after admission, and 144 (85.7%) patients died during the follow-up period. Multivariable logistic/Cox regression model indicated that ALBI grade could be an independent risk factor for predicting the prognosis of patients with 30-day mortality and overall survival (odds ratios [OR]_{30 days} 5.37, 95% confidence interval 2.41-12.64, P < 0.001; hazard ratios [HR]_OS 1.52, 95% confidence interval 1.06-2.18, P = 0.023), respectively. The restricted cubic spline curve displayed a linear and positive relationship between the ALBI score and risk of mortality (P for nonlinearity =0.503). Furthermore, receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) for predicting mortality by integrative analysis of the ALBI score and ferritin was significantly improved compared to the ALBI score (AUC _{30 days}: 0.820 vs 0.693, P = 0.001; AUC_{1 year}: 0.754 vs 0.681, P = 0.043) or ferritin (AUC_{30 days}: 0.820 vs 0.724, P = 0.005; AUC_{1 year}: 0.754 vs 0.658, P = 0.031) alone. The ALBI score could be a useful indicator of short and long-term survival for NHL-sHLH patients with hepatic injuries.

Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition characterized by hyperactivation of macrophages and cytotoxic lymphocytes, combining a series of non-specific clinical symptoms and laboratory disorders. Etiologies are multiple: infectious (mainly viral) but also oncologic, autoimmune or drug-induced. Immune checkpoint inhibitors (ICI) are recent anti-tumor agents associated with a novel profile of adverse events triggered by immune system over-activation. Here, we sought to provide a comprehensive description and analysis of HLH cases reported with ICI since 2014.

Disproportionality analyses were performed in order to further explore the association between ICI therapy and HLH. We selected 190 cases, 177 from the World Health Organization pharmacovigilance database and 13 from the literature. Detailed clinical characteristics were retrieved from the literature and from the French pharmacovigilance database.

The cases of HLH reported with ICI concerned men in 65% of cases with a median age of 64 years. HLH occurred in an average of 102 days after the initiation of ICI treatment and mostly concerned nivolumab, pembrolizumab and nivolumab/ipilimumab combination. All cases were considered serious. Most cases presented a favorable outcome (58.4%); however, death was reported for 15.3% of patients. Disproportionality analyses showed that HLH was seven times more frequently reported with ICI therapy than with other drugs and three times more than with other antineoplastic agents.

Clinicians should be aware of the potential risk of ICI-related HLH to improve the early diagnosis of this rare immune-related adverse event.

Hemophagocytic lymphohistiocytosis (HLH) is a complex disease disorder that involves dysregulated activation of the immune system resulting in cytokine storm which can lead to widespread tissue injury. HLH is associated with a mortality rate of 41%. The diagnosis of HLH requires a median of 14 days to reach likely due to a varied range of symptoms and signs the disease can present with. Liver disease and HLH can have a significant overlap. Liver injury itself is frequently noticed in patients with HLH, with more than 50% of patients having elevated aspartate transaminase, alanine transaminase, and bilirubin levels. This case report describes a young individual who had developed intermittent fever, vomiting, fatigue, and weight loss with labs remarkable for elevated transaminases and bilirubin. His initial workup revealed an acute Epstein-Barr virus infection. The patient later presented again with similar signs and symptoms. He underwent a liver biopsy with histopathological features initially concerning for autoimmune hepatitis. However, by engaging a multidisciplinary team, a correct diagnosis was achieved. This case report serves to highlight the increased level of suspicion required to correctly diagnose HLH, especially in the presence of clinical features concerning for autoimmune hepatitis.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92-1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.

Red blood cell distribution width (RDW) is related to sepsis-related mortality. Hemophagocytic lymphohistiocytosis (HLH) is a syndrome caused by severe infection, tumors, or autoimmunity without a specific diagnosis.

To explore the correlation between RDW and mortality in patients with HLH.

A retrospective study conducted in a hospital in China.

A total of 101 inpatients with HLH from January 1, 2017 to December 31, 2021 were divided into non-survivor (n = 52) and survivor (n = 49) groups. A non-parametric test was used to analyze demographic, clinical, and laboratory data between groups. Independent variables with P < 0.05 were analyzed using binary logistic regression to screen out mortality-related variables. Selected variables were subjected to multivariate logistic regression analysis, and those with strong correlations were screened. Receiver operating characteristic (ROC) curves of strongly correlated variables and area under curve (AUC) values were obtained.

The APACHE II score, RDW, and platelet (PLT) and fibrinogen (FIB) levels (P < 0.05) different significantly. RDW, PLT, FIB were correlated with mortality. The AUC values of RDW, PLT, and FIB were 0.857, 0.797, and 0.726, respectively. RDW was associated with mortality in patients with HLH (P < 0.01, cut-off value: 16.9). The sensitivity and specificity of predicting mortality were 97.96% and 96.1%, respectively.

Logistic regression analysis showed a correlation between RDW and patients' mortality. Therefore, RDW can be used to predict mortality in patients with HLH.

Haemophagocytic lymphohistiocytosis (HLH) is a cytokine-driven inflammatory syndrome caused by uncontrolled hypersecretion of inflammatory cytokines. Conventional first-line treatment for HLH included HLH-94 and HLH-2004 regimens. However, quite a few patients do not respond to treatment or cannot tolerate intensive chemotherapy. We reported two cases of HLH, one caused by natural killer (NK)/T-cell lymphoma and another associated with missense variants in the perforin 1 gene. They both received the ruxolitinib plus dexamethasone protocol and had a rapid response to treatment without obvious adverse effects. Our report indicates that treatment with ruxolitinib plus dexamethasone might be a potential option for HLH, and clinical trials warrant further investigation. In addition, the detection of HLH-related genes is necessary for the identification of late-onset familial HLH in certain settings.

Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially life-threatening condition characterized by aberrant inflammation that can be related to genetic or sporadic forms. In both forms, triggering factors may be involved. Early detection of the underlying cause is crucial for therapeutic decision, while early intervention might be associated with better outcomes. The largest descriptions in the literature on HLH refer to pediatric cases. Adolescents and adults may also be affected, but there is scarce evidence regarding their diagnosis and management. We describe here the case of a 68-year-old Swiss woman with HLH, in whom an extensive search for underlying causes was performed, but neither trigger nor pathogenic variant was found. An early intervention first with dexamethasone and later with cyclosporine was performed. The patient showed a favorable response and did not require further hospitalization; however, one year after diagnosis, it was not possible to suspend cyclosporine due to recurrence of laboratory inflammation signs by drug tapering. The occurrence of HLH idiopathic forms represents a challenge; failure to identify the underlying triggering cause generates uncertainty, endless diagnostic investigations, and consequently additional delays in the treatment. This manuscript addresses the difficulties on this issue.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome with a high mortality rate. There is no biomarker to predict the early therapeutic response.Objective: Our study explores the significance of serum ferritin in predicting the response of induction therapy.Methods: We retrospectively analyzed the clinical data of 102 adult patients with HLH admitted to our hospital. These patients received HLH-94 regimen for induction therapy. The patients were divided into remission group and non-remission group according to the response of induction therapy. Results: Ferritin values between 1-4 weeks post induction were predictive of remission (p<.05), which were higher in the non-remission group than in the remission group. Ferritin obtained 2 weeks post-induction had the highest ROC for predicting remission, with a cut-off value of 1188.5 µg/L. And patients with ferritin lower than 1188.5 µg/L had better response of induction therapy.Conclusion: Our study suggests that serum ferritin is a good indicator to predict the efficacy of induction therapy for adult HLH. KEY MESSAGESSerum ferritin is a good indicator for predicting the efficacy of adult HLH induction therapy.Serum ferritin two weeks after treatment may be a better indicator to judge the early curative effect.Serum ferritin after treatment also had a predictive significance for the survival of HLH.

Etoposide remains the cornerstone of symptomatic management of critically ill patients with secondary hemophagocytic syndrome (sHS). Risk of healthcare-associated infections (HAIs) in this setting with etoposide has never been assessed. We sought to evaluate the association between etoposide administration, HAIs occurrence and survival in critically ill adult patients with sHS. In this retrospective single-center study conducted in a university hospital ICU between January 2007 and March 2020, all consecutive patients with sHS were included. HAIs were defined as any microbiologically documented infection throughout ICU stay. Competing risk survival analysis was performed to determine factors associated with HAIs. Propensity score-based overlap weighting was performed to adjust for factors associated with etoposide use.

168 patients with a median age of 49 [38, 59] were included. Forty-three (25.6%) patients presented with at least 1 microbiologically documented HAI throughout ICU stay. After adjustment, cumulative incidence of HAI was higher in patients receiving etoposide (p = 0.007), while survival was unaffected by etoposide status (p = 0.824). By multivariable analysis, etoposide treatment was associated with a higher incidence of HAIs (sHR 3.75 [1.05, 6.67]), whereas no association with survival (sHR 0.53 [0.20, 1.98]) was found. Other factors associated with increased mortality after adjustment included age, immunodepression, male sex, SOFA score > 13, and occurrence of HAI.

In patients with sHS, etoposide treatment is independently associated with increased occurrence of HAIs, whereas no association with survival was found. Intensivists should be aware of increased infectious risk, to promptly detect and treat infections in this specific setting. Studies to assess benefits from prophylactic anti-infectious agents in this setting are warranted and the lack of benefit of etoposide on survival needs to be interpreted cautiously.

Acute liver failure following COVID-19 infection and/or vaccination is very rare and can be secondary to hemophagocytic lymphohistiocytosis (HLH). Liver injury in such cases appears to be extrinsic and thus treatment hinges on prompt diagnosis and reversal of the primary disease. We describe a patient who developed acute liver failure secondary to HLH after receiving a second dose of the Pfizer COVID-19 vaccine. Persistently elevated liver function tests, fevers, and cytopenia following COVID-19 vaccination should prompt clinicians to calculate an H-score to evaluate for the presence of HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous, life-threatening clinical syndrome. There are scarce data on the quality of care in HLH or data comparing treatment patterns and outcomes between different triggers. We aimed to examine quality-of-care indicators and outcomes in adults with various HLH triggers. In this multi-centre retrospective cohort study of adult HLH in the province of Alberta, Canada (1999-2019), we examined quality indicators including diagnostic testing, time to diagnosis and treatment and trigger identification. We also compared treatment regimens and outcomes across HLH triggers. Logistic regression was used to identify predictors of etoposide use. Overall survival (OS) was estimated using the Kaplan-Meier method. We identified 97 patients; 66 (68%) were male. Triggers included malignancy (36%), infection (35%), autoimmune disease (21%) and idiopathic/others (8%). Specialized tests such as sCD25 (53%) and natural killer degranulation assay (19%) were under-performed, as were testing for infectious triggers. Etoposide was administered in only 33 (34%). Neutropenia, hyperbilirubinemia and hyperferritinemia, but not age, sex and comorbidities, were significant predictors of etoposide use. At median follow-up of 32 months, median OS was 18.8 months. Worse OS was seen in malignancy-associated and idiopathic HLH (log-rank P < 0.001). Our study showed low rates of specialized testing such as sCD25 and a low rate of etoposide use. Development of a standardized provincial protocol has the potential to improve quality of care in adult HLH.