Diagnosis Of Hemophagocytic Lymphohistiocytosis Research Articles

MNGS helped diagnose scrub typhus-associated HLH in children: a report of two cases

BackgroundScrub typhus, caused by the Orientia tsutsugamushi (Ot), is a widespread vector-borne disease transmitted by chigger mites. Hemophagocytic lymphohistiocytosis (HLH) is considered to be one of the potentially severe complications. The diagnosis of scrub typhus-associated HLH may be overlooked due to the non-specific clinical characteristics and the absence of pathognomonic eschar.Case presentationWe obtained clinical data from two patients in the South of Sichuan, China. The first case involved a 6-year-old girl who exhibited an unexplained fever and was initially diagnosed with sepsis, HLH, and pulmonary infection. The other patient presented a more severe condition characterized by multiple organ dysfunction and was initially diagnosed with septic shock, sepsis, HLH, acute kidney injury (AKI), and pulmonary infection. At first, a specific examination for scrub typhus was not performed due to the absence of a characteristic eschar. Conventional peripheral blood cultures yielded negative results in both patients, and neither of them responded to routine antibiotics. Fortunately, the causative pathogen Orientia tsutsugamushi (Ot) was detected in the plasma samples of both patients using metagenomics next-generation sequencing (mNGS) and further confirmed by polymerase chain reaction. Subsequently, they both were treated with doxycycline and recovered quickly.ConclusionThe unbiased mNGS provided a clinically actionable diagnosis for an uncommon pathogen-associated infectious disease that had previously evaded conventional diagnostic approaches.

Clinical Characteristics, Prognostic Factors and Outcomes of Paediatric Patients with Haemophagocytic Lymphohistiocytosis

Objective: Haemophagocytic lymphohistiocytosis (HLH) is a multi-system autoimmune disorder. The objective of this study was to find out the clinical characteristics and prognosis of paediatric patients with Haemophagocytic Lymphohistiocytosis. Study Design and setting: Cross sectional study conducted at Pak Emirates Military Hospital, Rawalpindi from July 2021 to June 2023.   Methodology: Children with diagnosis of HLH were assessed by including patients who were aged = 13 years during hospitalization. All the patients who had not been diagnosed by using the HLH-2004 criteria were disqualified. Relevant findings were noted by evaluating records pertinent to physical examination, radiology and laboratory markers. Prognosis was assessed by determining the underlying clinical aetiology and whether patient-related factors modulated the overall life expectancy.   Results: A total of 32 patient records were evaluated. Mean age at diagnosis was 44.3 ± 39.1 months (Range: 1-132 months) with majority being males [n=23 (71.9%)]. The common clinical characteristics included fever [n=29 (90.6%)], lymphadenopathy [n=27 (84.4%)], splenomegaly [n=23 (71.9%)] and hepatomegaly [n=23 (71.9%)]. Serum ferritin, bilirubin, ALT, AST, and LDH were also raised. All patients were followed for a mean period of 12 months and 18 (56.3%) children failed to survive. Negative prognostic indicators included severe anaemia (p=0.001), neutropenia (p=0.007), thrombocytopenia (p=0.033), and hyperferritinemia (p<0.001). Elevation of liver enzymes (ALT: p<0.001; AST: p=0.031), serum bilirubin (p=0.037), and LDH (p<0.001) also indicated worse disease prognosis.   Conclusion: HLH in childhood is a potentially life-threatening disease and carries a significant association with deranged liver function

Novel Presentation of Major Histocompatibility Complex Class II Deficiency with Hemophagocytic Lymphohistiocytosis

PurposeMajor histocompatibility complex (MHC) class II deficiency is one of the combined immune deficiency disorders caused by defects in the MHC class II regulatory genes leading to abnormal T cells development and function. Therefore, patients mainly present with increased susceptibility to infections, diarrhea, and failure to thrive. In this report, we present one MHC class II deficient patient with a novel presentation with Hemophagocytic Lymphohistiocytosis (HLH).MethodsImmunophenotyping of lymphocyte subpopulations and HLA-DR expression was assess by flow cytometry. Gene mutational analysis was performed by whole exome and Sanger sequencing.ResultsWe reported a 7-year-old girl, who was diagnosed at age of 2 years with MHC class II deficiency by genetic testing and flow cytometry. Two years later, she developed disseminated BCGitis which was treated with proper antimicrobial agents. At the age of 7 years, she presented with clinical features fulfilling 6 diagnostic criteria of HLH including evidence of hemophagocytic activity in bone marrow aspiration. Accordingly, the diagnosis of HLH was established and the patient was started on IV Dexamethasone, Anakinra and IVIG. Eventually, patient started to improve and was discharged in good condition. Few months later, the patient was readmitted with severe pneumonia and sepsis leading to death.ConclusionPatients with MHC class II deficiency might present with disseminated BCGitis especially if the patient has severe T cell lymphopenia. Additionally, this immune defect might be added to the list of inborn errors of immunity that can be complicated with HLH.

Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients.

Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 μg/L) and underwent bone marrow biopsy during their ICU course. Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.

Histiocytic necrotizing lymphadenitis with hemophagocytic lymphohistiocytosis in adults: A single-center analysis of 5 cases.

Histiocytic necrotizing lymphadenitis (HNL) is a self-limited inflammatory disease of unknown pathogenesis. A very small fraction of patients with HNL could develop hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder. These patients are diagnosed as HNL with HLH (HNL-HLH). HNL-HLH in the pediatric population has been systemically studied, however, the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH remain to be explored. We aimed to explore the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH. We collected the clinical data of patients with HNL-HLH admitted to the First Affiliated Hospital of Nanjing Medical University from October 2010 to June 2015. All the patients underwent lymph node biopsy and have a pathological diagnosis of HNL. The age, gender, clinical presentation, lymph node signs, laboratory findings and imaging data, and pathological findings of the patients were collected. In this study, we reported five adult patients with HNL-HLH. All five patients showed enlarged lymph nodes and prolonged fever. Laboratory findings were consistent with the diagnosis of HLH. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed enlarged lymph nodes with increased FDG uptake and splenic hypermetabolism could be present. All the patients responded well to corticosteroids and had a good prognosis. Two of the five patients were diagnosed with systemic lupus erythematosus during the follow-up. Our study demonstrated that adult patients with HNL-HLH showed distinct clinical, laboratory, and radiological features. And the prognosis is good and patients could be managed with steroids and supportive care.

Infectious Diseases Evaluation of the Child With Suspected Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive and maladaptive inflammation. Classic clinical and laboratory features associated with the diagnosis of HLH, including fever, cytopenias, hyperferritinemia and splenomegaly, are not specific to HLH and can be caused by infections. Fulfillment of these clinical and laboratory criteria alone are not sufficient to diagnose HLH or initiate HLH-directed therapies. In this manuscript, we review the pathogenesis of HLH and HLH-like syndromes associated with infection. We offer a paradigm for evaluating patients with suspected HLH to identify key exposures, diagnose and treat infection before initiation of immunosuppression.

Prognostic factors of adult hemophagocytic lymphohistiocytosis and clinical utility of HLH-2004 diagnostic criteria and HScore: A real-world multicenter study from Thailand.

Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. This multicenter retrospective study investigated the etiologies, survival, and prognostic factors of HLH, including the utility of HLH-2004 criteria and HScore in real-life clinical practice. A total of 147 HLH patients were identified by using a combination of hemophagocytosis identification in bone marrow and the HLH-related international classification disease-10. A total of 116 (78.9%) patients fulfilled the HLH diagnosis by HScore, while 91 (61.9%) patients fulfilled 5 of 8 HLH-2004 criteria. In Thailand, the clinical application of HLH-2004 criteria needed to be reduced from 8 to 6 due to a lack of sCD25 and natural killer cell activity tests. Using the adapted HLH-2004 with a cutoff value of 4 resulted in 132 (89.9%) cases meeting the diagnostic criteria. Among these 132 confirmed HLH patients by using adapted HLH-2004, HLH was triggered by infection (29.5%), autoimmune disease (12.9%), malignancy (40.9%), and unknown cause (16.7%). Median overall survival of HLH patients was extremely short (67 days). Ferritin >6,000 μg/L, HLH from infection, malignancy, and unknown etiology were demonstrated as independent prognostic factors for inferior survival (hazard ratio (HR) 2.47; 95%CI 1.39-4.37, HR 4.69; 95%CI 1.38-15.92, HR 6.09; 95%CI 1.84-20.14, and HR 6.02; 95%CI 1.64-22.05, respectively). Ferritin is a helpful biomarker for HLH diagnosis and prognostic prediction. Autoimmune disease triggered HLH has favorable outcomes. Future prospective study is required to verify use of the adapted HLH-2004 criteria.

Clinical features of hepatic manifestations among adult patients with hemophagocytic lymphohistiocytosis: a retrospective study.

INTRODUCTION 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. METHODS A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury. RESULTS 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), 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). The CLIF-SOFA score was slightly better than the SOFA score (p = 0.068). CONCLUSION Patients with old age, elevated BUN and malignancy had inferior survival. CLIF-SOFA and SOFA enables a more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models.

A rare case of Disseminated Histoplasmosis with Hemophagocytic Lymphohistiocytosis mimicking a flare of Systemic Lupus Erythematosus in a middle-aged man: A Case Report

Abstract Introduction/Objective Disseminated histoplasmosis is a progressive granulomatous disease caused by Histoplasmosis capsulatum which is an intracellular dimorphic fungus endemic to Ohio and Mississippi River valleys in the United States. The progressive spread of the infection to organs is thought to be due to the failure of the activation of the T-cell mediated immune response. Hemophagocytic lymphohistiocytosis is a rare but potentially fatal condition in which histiocytes and lymphocytes build up in and damage organs and other blood cells. Diagnosing Disseminated Histoplasmosis with Hemophagocytic Lymphohistiocytosis in a patient with Systemic Lupus Erythematosus is diagnostically challenging due to the rare presentation. Hence, we are reporting this case to alert physicians to keep a high index of suspicion in such presentations. Methods/Case Report We present a 37-year-old man with a past medical history of Systemic Lupus Erythematosus complicated by Lupus Nephritis on immunosuppressive therapy who presented to the emergency department with hypotension and was admitted for acute kidney injury. Prior to the presentation, he had persistent fever, myalgias, cough, mild shortness of breath, and back pain. CT Chest shows “eggshell” calcification and further parasitology evaluation revealed a diagnosis of histoplasmosis using a blood sample where intracellular Histoplasma organisms were identified. A diagnosis of Hemophagocytic lymphohistiocytosis was made clinically after “Clinical and Testing Criteria” was evaluated. Despite further management, he developed coagulopathy and sepsis which led to his death. Results (if a Case Study enter NA) At autopsy, we found organomegaly of the liver, spleen, and kidneys. Microscopically, these enlarged organs show old fibrotic granulomas and granulomatous inflammation with suspected fungal organisms. Periodic Acid Schiff (Fungus) and Gomori's Methenamine Silver special stain confirm these fungal organisms to be consistent with Histoplasma species (3-5 micron budding yeasts). Conclusion This case report highlights that physicians should be aware of the diagnostic challenge that Disseminated Histoplasmosis with Hemophagocytic Lymphohistiocytosis could pose in patients with Systemic Lupus Erythematosus, especially those on immunosuppression. The clinical presentation could easily mimic a flare of Systemic Lupus Erythematosus, leading to more aggressive immunosuppression. Failure to recognize the infection promptly could lead to grievous complications and sometimes death.

Treatments and Outcomes of Lymphoma-Associated Hyperinflammation- a Report from the HLH in Adults Working Group for the Histiocyte Society

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome. Lymphoma is the most common cause of HLH in adults. Previous studies have indicated poor patient outcomes in lymphoma-associated HLH. The recently introduced optimized HLH inflammatory (OHI) index has improved prognostication and identification of the hyper-inflammatory phenotype of lymphoma; however, more comprehensive information on treatments and outcomes in a large cohort in the contemporary era is necessary. Our study aimed to investigate the clinical features, treatments, and outcomes of lymphoma-associated HLH through a multi-national effort by the HLH in Adults Working Group of the Histiocyte Society (NCT05898477). Methods: We conducted a multicenter, retrospective study evaluating patients diagnosed with lymphoma and hyperinflammation, defined by fulfilling 5/8 HLH diagnostic criteria or the OHI index from 2003-2022. Clinical characteristics were summarized using median and interquartile ranges (IQR). Survival analysis employed Kaplan-Meier curves and the log-rank test, considering HLH diagnosis as the zero time-point. Results: The analysis encompassed 181 patients with lymphoma: 55% had B-cell non-Hodgkin lymphoma (NHL), 35% had natural killer (NK) cell or T-cell lymphoma, and 10% had classical Hodgkin lymphoma. 35% of patients were from China, 21% from the USA, 17% from Israel, 16% from Europe, and 11% from Japan. Of the entire cohort, 157 (87%) patients met the HLH-2004 criteria, and 153 (83%) met the OHI index; The median age at HLH diagnosis was 60 years (IQR, 45-68), and 59% were males. 50% of patients presented with HLH before/at the time of lymphoma diagnosis (median time to lymphoma diagnosis 9 days), while 50% developed HLH after the initial lymphoma diagnosis (median time to HLH diagnosis 181 days). The median values of hemoglobin, absolute neutrophil count (ANC), and platelet count at HLH diagnosis were 8.6 g/dL, 2.1 K/microL, and 54.7 K/microL, respectively. The median values of triglycerides and fibrinogen were 241 mg/dL and 250 mg/dL, respectively. Interestingly, the median values for ANC, triglycerides, and fibrinogen fell outside the HLH-2004 diagnostic threshold. The median and interquartile ranges for ferritin and sCD25 (sIL-2r) were 3017 ng/mL (1337-8958) and 14098 U/mL (7894-39916), respectively. 48% of physicians altered their initial treatment approach due to the HLH diagnosis. Of these instances, 48% were treated with dexamethasone and etoposide outside of a formal treatment protocol, 11% with the HLH-94/2004 protocol, 24% with DEP regimen (liposomal doxorubicin, etoposide, and methylprednisolone), and 4% with DEP and ruxolitinib. Dexamethasone alone was used in 15% of the patients, while another 4% were treated with anakinra +/- steroids. After a median follow-up duration of 2.1y (range, 0.005-6.1), the median overall survival was 0.58 years. 46% of the patients died from multi-organ dysfunction/HLH, 17% from single-organ dysfunction, 16% from infection or septic shock, and 8% from bleeding. The risk of mortality among T-cell or NK cell lymphoma was higher than B-cell lymphoma (HR 1.7, 95% CI 1.16-2.61, Figure 1A). Finally, patients positive for the OHI index alone at diagnosis had a higher mortality risk (Figure 1B) compared to those positive for both the OHI index and HLH-2004 (HR 2.5; CI 1.26 - 4.8) or those positive for HLH-2004 alone (HR 3.72; CI- 1.62-8.58). Conclusions: Preliminary findings from this large multi-institutional study show that the overall survival for patients with lymphoma and HLH remains poor despite the institution of HLH-specific therapies. In nearly half of the cases, the physicians altered lymphoma treatment to control HLH, primarily through dexamethasone and etoposide-based or DEP regimens. Although B-cell lymphoma was our cohort's most common cause of HLH, overall survival was worse among those with T-cell or NK cell lymphoma, suggesting that the underlying lymphoma type might drive the prognosis even in cases with hyperinflammation. The most common causes of death included multi-organ dysfunction and infection. The OHI index-positive patients experienced higher mortality risk than those meeting the HLH-2004 criteria. The study is ongoing, and we plan to present data on the differential effects of treatment regimens at the meeting.

A Fatal Case of Hemophagocytic Lymphohistiocytosis Triggered By Babesiosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by hyperactivation of macrophages and T lymphocytes. While HLH is primarily inherited in a recessive manner among children, in adults, it is more commonly associated with underlying infections, autoimmune disorders, and malignancies. However, the association between HLH and Babesia infection remains exceptionally uncommon, with only a few reported cases in the medical literature. In this report, we present a unique case of HLH in the context of babesiosis, shedding light on the crucial clinical features and risk factors. By raising awareness of this rare differential diagnosis, we aim to contribute to early recognition and timely treatment, potentially reducing mortality from this treatable illness. Case Presentation: A 77-year-old male with history of deep vein thrombosis (DVT), Parkinson's disease, and lumbar radiculopathy on chronic prednisone, presented for progressive generalized weakness, leg pain, and confusion. Initial labs showed normocytic anemia, thrombocytopenia, low fibrinogen and elevated INR and liver enzymes (Table 1). Multiple ischemic signs were noted including acute on chronic DVT, as well as findings of marked splenomegaly with wedge infarcts and periportal lymphadenopathy on abdominal ultrasound and CT (Figure 1). The underlying etiology of these findings was unclear and broad differential work up was pursued. Given the anemia and thrombocytopenia on presentation, the patient received multiple blood products including platelets, red blood cells, fresh frozen plasma and cryoprecipitate, in addition to vitamin K. No schistocytes were seen peripherally, and DIC/TTP workup was negative. Multidisciplinary teams evaluated the risk versus benefit of anticoagulation with heparin drip considering evidence of multi-organ ischemic damage. It was briefly initiated, but later held due to persistent thrombocytopenia and abnormal liver function. Further work up only revealed hemolysis with a low haptoglobin and elevated LDH (Table 1). However, the follow up Coombs test was negative, ruling out immune mediated hemolysis. While symptomatic management continued, blood parasite screen obtained on admission indicated Babesia microti infection. Upon repeat testing, no evidence of babesia was identified on labs or blood smear. However, this finding was skewed by the multiple transfusions the patient received. Unfortunately, the clinical course rapidly declined, and the patient's family elected a transition to comfort care measures whereby the patient expired within two days of presentation. Remaining work up resulted posthumously, with CD25 levels elevated at 38,354.0 pg/mL. Coupled with the previously established splenomegaly, pancytopenia, hypertriglyceridemia, and elevated ferritin, these findings indicate a diagnosis of HLH, likely triggered by Babesia microti infection. Conclusion: HLH should be strongly suspected in patients from endemic regions, especially with additional risk factors such as age, genetics, and immunosuppression. Tools such as the HScore and the HLH-2004 criteria can aid in further patient risk stratification. Urgent treatment with steroids and addressing underlying babesiosis with atovaquone, azithromycin, and potentially red blood cell exchange transfusion, remains crucial for preventing decompensation and improving outcomes.

The Clinical Significance and Prognostic Value of Serum Beta-2 Microglobulin in Adult Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: A Multicenter Analysis of 326 Patients

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by an excessive immune response. Beta-2 microglobulin (B2M) forms the light chain section of the major histocompatibility complex (MHC) class Ⅰ antigen. The prognostic role of B2M in lymphoma-associated HLH remains to be determined. This study was to investigate the prognostic role of serum B2M in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). Methods: The clinical and laboratory characteristics of adult patients in a multicenter cohort with lymphoma-associated HLH who had baseline serum B2M levels between August 2009 and June 2023 were retrospectively analyzed. The diagnosis of HLH was established according to the HLH-2004 criteria. Results: A total of 326 cases were included and the median serum B2M level was 5.19 mg/L. The most common subtype of lymphoma was T/NK cell lymphoma (51.8%, 169/326), followed by B-cell non-Hodgkin lymphoma (45.4%, 148/227) and Hodgkin lymphoma 8/326 (2.5). The optimal cut-off value of serum B2M for predicting overall survival was 8.73 mg/L (p &amp;lt; 0.0001). Patients were divided into two subgroups by the optimal cut-off value. The median survival was 21 days for the high level subgroup, and 236 days for the low level subgroup (Figure 1). The 6-month survival rates were 22% and 54%, respectively. The subgroup with B2M level &amp;gt; 8.73 mg/L was older and had a higher proportion of stage IV. Patients with higher levels of B2M showed lower levels of platelets, albumin, and fibrinogen, and high levels of creatinine. A moderate correlation between creatinine and serum B2M was found (Spearman's ρ = 0.417, p &amp;lt; 0.001). The multivariate analysis showed that the high levels of serum B2M (&amp;gt; 8.73 mg/L) and creatinine (≥ 133 μmol/L), decreased fibrinogen (≤ 1.5 g/L), agranulocytosis (&amp;lt; 0.5×10 9/L), severe thrombocytopenia (&amp;lt; 50×10 9/L), and increased Epstein-Barr virus DNA were found to have significant prognostic values in all patients. The high serum B2M level (&amp;gt; 8.73 mg/L), severe thrombocytopenia (&amp;lt; 50×10 9/L), agranulocytosis (&amp;lt; 0.5×10 9/L), and high Epstein-Barr virus DNA copy number were independent prognostic factors in patients with creatinine &amp;lt; 133 μmol/L. Finally, a prognostic scoring system was established based on serum B2M levels as well as five other independent prognostic factors and divided the patients into three groups with significant prognostic differences (median survival: low-risk [score ≤ 1] 428 days vs. intermediate-risk [score = 2] 102 days vs. high-risk [score ≥ 3] 18 days, P &amp;lt; 0.0001) (Figure 2). The 6-month survival rates were 67%, 46% and 14%, respectively. Conclusions: This study confirmed that the serum B2M level could be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival.

The Identification and Characterization of Retrospective Cohorts of Secondary Hemophagocytic Lymphohistiocytosis (sHLH) Patients in the United States

Background:Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome induced by aberrantly activated myeloid and T cells. Primary or familial HLH (pHLH) is a genetic disorder that typically presents in young children. Secondary HLH (sHLH), which can occur at any age but is most common in adults, is triggered by infection, autoimmune disease, malignancy, or other conditions. Without treatment, HLH is universally fatal; even with existing etoposide-based regimens, survival remains low, particularly for malignancy-associated sHLH. There are no approved therapies specifically for sHLH, and most of our understanding of HLH diagnosis comes from studies of pHLH. The aim of this study is to assemble historical cohorts of sHLH patients from two, large US medical systems to better understand and refine the sHLH clinical definition, characterize demographic, clinical, and treatment characteristics, and compare survival and healthcare resource utilization (HRU) of the cohorts to matched comparison groups. Preliminary findings on the identification of sHLH patients at one US site were previously described [Broome et al., Blood (2022) 140 (Supplement 1): 5490-5491]. Data on sHLH patient identification at both sites are presented here. Methods: Two Electronic Medical Record (EMR) systems were queried to identify potential patients (site 1: 2009-May 2022 with no age restrictions and site 2: 2006-2022 patients &amp;gt;18 years of age). Three methods were developed for patient identification. Method 1 identified patients with any mention of an HLH-related ICD code (ICD-9 288.4; ICD-10 D76.1, D76.2, D76.3). Method 2 identified patients with combinations of an elevated ferritin value (1,000-10,000 ng/mL or &amp;gt;10,000 ng/mL) or a sCD25 test (predictive markers of malignancy-associated sHLH from the Optimized HLH Inflammatory [OHI] index). Method 3 identified patients with etoposide and dexamethasone treatment, removing patients receiving this treatment as part of a chemotherapy regimen. Full chart review of some cohorts was not logistically feasible because of their size (no ferritin &amp;gt;1,000 AND any sCD25 test, ferritin &amp;gt;10,000 AND no sCD25 test, and etoposide and dexamethasone treatment); in these instances, patient records were screened for a mention of HLH or MAS. At each site, one clinician reviewed all charts, and a second clinician reviewed a random sample. HLH diagnosis was assigned based on expert judgement, and all diagnostic conflicts were resolved between the two clinicians. Clinical and diagnostic data on sHLH patients were pulled from the EMR by the reviewing clinician. Results: 528 patients were identified at site 1 via the three methods and their charts were reviewed confirming 65 patients with sHLH. Likewise, among 714 charts reviewed at site 2, 188 patients were confirmed with sHLH. Among all patients with an ICD code (Method 1), 17% (56/327) were determined to have sHLH at site 1 and 33% (162/488) at site 2. Among patients reviewed with ferritin/sCD25 features (Method 2), 4% (9/200) were determined to have sHLH at site 1 and 11% (25/212) at site 2. Among patients reviewed with Method 3, 0% (0/1) were determined to have sHLH at site 1, and site 2 data were not available. (See Table 1) Additional analyses on clinical and treatment characteristics of the sHLH cohorts and survival/HRU comparisons will be presented. Conclusions: Since HLH is a rare, heterogeneous, and complex disease to diagnose and treat, HLH-related ICD codes may not accurately and sufficiently capture the spectrum of HLH patients in EMRs.Clinical indicators of disease were essential for identifying additional patients with this rare disorder. The general consistency of the findings between the two study sites supports the application of this patient identification algorithm across diverse medical centers.

Myelodysplastic Syndrome Associated Hemophagocytic Lymphohistiocytosis: A Retrospective Study of 15 Cases in a Single Center

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by excessive cytokine secretion, resulting in hyperinflammation and multiorgan dysfunction. It is classified into primary HLH, which is mainly caused by genetic defects, and secondary HLH, triggered by various underlying conditions. Malignancy-associated HLH (M-HLH) is a secondary form commonly observed in patients with hematological malignancies, such as lymphomas, T/NK-cell disorders, acute leukemias, lymphoproliferative diseases, and myelodysplastic syndrome (MDS). M-HLH can occur in up to 1% of patients with hematologic malignancies, with lymphoma being the most frequently associated malignancy. HLH initiated by MDS is a rare entity with only a few cases reported, leading to limited knowledge regarding its pathogenesis, diagnosis and optimal treatment strategies. Methods: In this retrospective study, we analyzed a consecutive series of MDS-HLH patients admitted to our center between March 1, 2019, and March 1, 2023. Bio-clinical data related with MDS and HLH were collected at diagnosis of MDS-HLH. Additional observational indicators encompassed the following: basic clinical characteristics of the patients (age at onset, gender, duration of MDS prior to HLH), correlation between the onset of HLH and MDS, treatment and response, and genetic defects associated with HLH and MDS. MDS risk classification was according to the Revised International Prognosis Scoring System (IPSS-R) and the WHO classification-based Prognosis Scoring System, while patients were categorized into two groups as higher-risk and lower-risk MDS-HLH group. The follow-up period started at the time of MDS-HLH diagnosis and ended at the date of death or last examination. Overall survival (OS) was calculated from the time of HLH diagnosis to the date of death from any cause. Results: A total of 15 patients diagnosed with MDS-HLH were included in the study, with a median age of 66 years (range, 33-83 years). The majority of patients (10/15, 67%) were over 60 years old. All patients exhibited typical features of aggressive HLH: fever, cytopenia and elevated serum ferritin in all patients, hepatomegaly/splenomegaly in 87% (13/15), hypofibrinogenemia/hypertriglyceridemia in 73% (11/15), hemophagocytosis in 73% (11/15), low NK-cell activity in 21% (3/14), and elevated levels of sCD25 in 93% of patients (14/15). Additionally, four patients (27%) had concurrent Epstein-Barr virus (EBV) infection. Further analysis comparing the lower-risk and higher-risk MDS-HLH groups revealed interesting findings. In the lower-risk group, all patients developed HLH concurrently with the diagnosis of MDS. However, in the higher-risk group, the majority of patients (6/8, 62.5%) experienced HLH onset during MDS progression or relapse (p=0.014). Among the 15 patients, 8 patients (53.3%) achieved remission of HLH. During the study period, 8 deaths occurred, all directly attributed to HLH or its complications. The majority of deaths (75%, 6/8) occurred within the first two months after HLH diagnosis. The median overall survival was 12.3 weeks (95%CI, 1.1-23.5). Patients who achieved complete or partial response had significantly prolonged overall survival compared to those who did not respond to treatment (p=0.002). In the multivariate analysis of prognosis, the remission status of HLH was the only factor which was significantly associated with survival (p=0.018, Exp(B)=0.003). Conclusion: This is the first comprehensive study focusing specifically on MDS-HLH, providing valuable insights into the clinical characteristics, treatment outcomes, and prognosis of MDS-HLH. The findings emphasize the need of considering revision of diagnostic criteria specially for MDS-HLH. The pathogenesis of HLH in MDS-HLH differs based on the risk classification of MDS, with higher-risk cases driven by malignancy and lower-risk cases associated with immune dysfunction. The prognosis of MDS-HLH is generally poor. Achieving remission of HLH is crucial for improving the prognosis of MDS-HLH patients. Conventional chemotherapy regimens, including etoposide, have shown limited efficacy and safety in this context. Chemotherapy-free regimens should be preferred considering the features of ineffective hematopoiesis in MDS. The role of EBV infection in MDS-HLH development should be recognized.

Hemophagocytic Lymphohistiocytosis (HLH) in a Post-COVID-19 Infection: A Case Report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper inflammatory process caused by extensive immune activation and characterized by multi organ dysfunction. During COVID-19 pandemic secondary hemophagocytic lymphohistiocytosis has been reported in acute phase of COVID-19 infection, but HLH in recovered post-COVID-19 patients is rare. We report a case of HLH following of COVID infection. Case Description: 72-year-old female with well-controlled rheumatoid arthritis and COVID infection 2 months prior presented with progressive shortness of breath. She was diagnosed with acute on chronic heart failure, acute kidney injury, worsening anemia and thrombocytopenia. She progressively got worse during hospitalization and on day 9 developed fever and multiorgan failure (pancytopenia, acute liver injury, respiratory failure requiring mechanical ventilation, renal failure requiring hemodialysis). Labs included hemoglobin of 7.9 g/dL, platelets 50 Th/uL, ANC 1.38 Th/uL, LDH 6000 IU/L, ferritin &amp;gt;10,000 ng/ml, fibrinogen 136 mg/dL, triglycerides 656 mg/dL. HLH was suspected and a bone marrow biopsy showed occasional macrophages with hemophagocytosis without evidence of lymphoproliferative disorder (Figure 1). Interleukin-2 receptor soluble was elevated at 57026.9 pg/mL. HLH diagnosis was established, and patient was started on HLH-94 protocol with etoposide and dexamethasone. She improved quickly with treatment and was extubated in a few days. After 4 weeks, there was continued clinical improvement with improving liver function, LDH was down to 373, ferritin 3586 but she remained cytopenic needing transfusion support. By week 6, she was off dialysis and repeat Interleukin-2 receptor soluble was 2500 pg/ml and ferritin was 2500 ng/ml. A positron emission tomography (PET) scan did not show any evidence of lymphoma. Patient was not considered to be suitable candidate for stem cell transplant and was monitored. Within 6-8 weeks, she was noted to have worsening LDH, ferritin, liver function and patient was started on ruxolitinib 5 mg twice a day and dexamethasone 2 mg daily. Patient continued to have worsening anemia, thrombocytopenia, LDH and ferritin. Patient was readmitted around week 6 of ruxolitinib treatment with progressive shortness of breath. Patient was re-treated with dexamethasone and etoposide. On day 10 of 2nd hospitalization, she developed acute respiratory failure needing mechanical ventilation and was diagnosed with abdominal viscus perforation. After discussion with family, she was transitioned to best supportive care given poor prognosis. Discussion: Few cases of HLH in post-covid-19 patients have been reported in the literature, but this entity may be likely under diagnosed given the delayed presentation, absence of definitive clinical, laboratory, or histopathological criteria. Immune dysregulation and macrophage activation due to subclinical inflammation following post-COVID-19 infection is postulated to underlie the pathogenesis of HLH in post-COVID-19 patients. The hyperinflammatory situation results in multi-organ failure and high mortality rates. The HLH2004 has been recommended as the diagnostic criteria of choice for HLH among post-COVID-19 patients. Immunosuppressive therapies with steroids, and etoposide are the conventional first-line agents based on the HLH94 protocol; however, refractory cases have been shown to respond to other immunosuppressive agents and biologics including ruxolitinib, alemtuzumab, and emapalumab. Figure 1: A. Hemophagocytosis (Macrophage ingesting lymphocyte) B. Hemophagocytosis, more specifically-erythrophagocytosis (macrophage ingesting red blood cell).

Differences in Outcomes of Hemophagocytic Lymphohistiocytosis (HLH) Based on Etiology: A Five Year Nationwide Analysis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, under-diagnosed, potentially lethal condition marked by dysregulated hyperinflammation and widespread multi-organ dysfunction. There is currently no literature describing the differences in HLH outcomes according to its commonly reported risk factors. Therefore, authors of this study aimed to identify potential differences in the outcomes of HLH among various etiologies as well as update literature on the prevalence of risk factors for HLH in the United States. Methods: Using weighted data from the Nationwide Inpatient Sample (NIS) database from 2016 to 2020, we assessed prevalence of known HLH risk factors (infection, malignancy, auto-immune, and inflammatory syndromes) and HLH outcomes (mortality, length of hospital stay, total healthcare charges, complications) stratified by HLH etiology (infection, malignancy, auto-immune, inflammatory). Baseline characteristics were analyzed using T-test for continuous variables and Chi-Square for categorical variables, and a multivariate regression analysis was used to estimate outcomes between races. Data analysis was performed using STATA® Version 17.0/SE Software, with statistical significance set at p &amp;lt; 0.05. Results: Among a total of 2,685 individuals admitted with a primary diagnosis of HLH, 52% (N=1,350) had an infection (27% bacterial, 28% viral,14% fungal, and 1% parasitic), 22% were with malignancy (N=525)(14% lymphoma, 2% leukemia, 3% plasma cell proliferation, 3% myeloproliferative disease, and 4% solid tumors), 16% had a history of autoimmune disease (N=380), and 7% had an inflammatory syndrome (N=175). 25% had no ICD-10 codes for common risk factors of HLH. Among patients with HLH and autoimmune disease, we noted a predominance of females (77%, p&amp;lt;0.001). Individuals with HLH and cancer had more comorbid conditions (Charlson index: 3 in 58%, p&amp;lt;0.001). Pertaining to outcomes, when compared to those with cancer, individuals with infection had a 3-fold increase in respiratory failure (adjusted Odds Ratio (aOR)=3.12, 95%CI: 1.13-8.61), while those with autoimmune disease had reduced odds of acute kidney injury (aOR=0.30, 95%CI: 0.10-0.87). There were no significant differences in the length of hospital stay, the total healthcare expenditures, mortality and the other complications (cardiac arrest, acute kidney injury, respiratory failure, disseminated intravascular coagulation, and acute liver failure) among HLH secondary to cancer versus other risk factors. Discussion: Our study findings demonstrate that infection is the most common trigger for secondary HLH in the U.S., followed by malignancy. This is consistent with existing literature. Individuals who develop HLH associated with the infection have a 3-fold higher odds of acute respiratory failure compared to those with HLH resulting from other cancer. This warrants increased vigilance, and the potential need for a lower threshold for mechanical ventilation to mitigate adverse outcomes in patients with HLH secondary to infection.

Granulocyte Colony-Stimulating Factor Use in Patients with Hemophagocytic Lymphohistiocytosis: A Single Center Experience

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome caused by activation of T cells that results in extreme inflammation. HLH is commonly associated with underlying conditions such as infection, autoimmune disease, or malignancy. HLH management includes treatment directed at the specific trigger, suppression of maladaptive cytokines, and inhibition of T cell and macrophage proliferation. Granulocyte colony-stimulating factor (GCSF) is a myeloid growth factor that stimulates the production, maturation, and activation of neutrophils. GCSF may theoretically promote production of inflammatory cytokines and enhance hemophagocytosis, thereby intensifying HLH. By contrast, GCSF could play a vital role in the treatment of granulocytopenia caused by HLH and thus limit the development of infections. There is a paucity of data examining the role of GCSF in patients with HLH. Current literature is limited to case reports of HLH exacerbated by GCSF administration. Practice patterns of GCSF use in HLH are highly variable, both within and between institutions. Aim: To compare the clinical course and overall survival of patients with HLH who received GCSF treatment and those who did not. Methods: We performed a retrospective, single-center cohort study of patients admitted with a diagnosis code of HLH from July 1997 through February 2023. Patients at least 18 years old with active HLH were included. Each case was reviewed to confirm the diagnosis of HLH based on available diagnostic evaluation and the final discharge diagnoses as documented by the primary treating team. In cases indeterminate for HLH, a second independent reviewer performed additional evaluation to reach consensus. The primary outcome was overall survival as determined by the Kaplan Meier method with statistical comparison using the log-rank test. Other examined outcomes included: incidence of infection, length of hospital stay (LOS), incidence of intensive care unit (ICU) admissions, length of ICU stay, incidence of 30-day re-admissions due to HLH, and time to first change in HLH-directed therapy. Results: Database analysis revealed 130 patients with a diagnosis code of HLH, of which 68 patients met inclusion criteria. The study cohort comprised 26 patients that received GCSF treatment and 42 patients that did not. The median follow-up time was 3.1 months (interquartile range [IQR] 0.6-29.4). The most common HLH triggers were infection (30.8% GCSF group vs 45.2% control, p=0.31) and malignancy (65.5% GCSF group vs 19% control, p&amp;lt;0.001). A median of 10 doses (IQR 6-16) of GCSF were administered per patient in the GCSF group, and the median time between diagnosis and the first administered dose was 6.5 days (IQR 2.25-18.75). Median overall survival in the GCSF group was 122.6 months compared to 1.5 months in the control group (p=0.02, Figure 1). There was a higher but statistically insignificant difference in infection rate in the GCSF arm (92.3%) compared to the control arm (71.4%, p=0.06). The median LOS was higher in the GCSF group (38 days vs 15 days, p&amp;lt;0.001). Rates of ICU admission (53.4% vs 62%, p=0.69), intubation and mechanical ventilation (34.6% vs 33.3%, p=1.0), and initiation of renal replacement therapy (23.1% vs 16.7%, p=0.74) were similar across the GCSF and control groups, respectively. Two patients in each group were re-admitted for HLH within 30 days of initial discharge. The median time to change in HLH-directed therapy was not reached in either group, and there was no significant difference in incidence of therapy change between groups at 1, 3, or 6 months (Figure 2). Conclusions: In this single center, retrospective cohort study of patients with HLH, treatment with GCSF was not associated with inferior overall survival. While over-representation of a malignancy-associated trigger in the GCSF group may confound interpretation of this result, it nevertheless reflects an important clinical finding that contradicts previously published case report-level evidence. This study highlights the need for further prospective investigation of GCSF administration in HLH.

Clinical Features and Outcomes of Hemophagocytic Lymphohistiocytosis Secondary to Lymphoma: Insights from a Tertiary Center in Saudi Arabia

Introduction: Lymphoma encompasses a prominent cause of secondary hemophagocytic lymphohistiocytosis (HLH), an aggressive hyperinflammatory syndrome characterized by immune dysregulation. The concurrence of lymphoma and HLH represents a challenging entity due to the ambiguity of clinical features and paucity of standardized treatment regimens. Limited data exists regarding the characteristics and outcomes of secondary HLH within the Middle East and Saudi Arabia. Moreover, the structure of the population within our region, characterized by a predominance of males and young adults, offers a unique perspective to the literature regarding secondary HLH. Herein, we evaluate the clinical features and outcomes of patients presenting with HLH secondary to lymphoma at a tertiary center in Saudi Arabia. Methods: We retrospectively reviewed the electronic medical records of patients diagnosed with lymphoma over the past ten years at our center to identify patients who developed secondary HLH. The Kaplan-Meier method was used to estimate median overall survival (OS). OS was defined as the incidence of death from any cause from the onset of HLH diagnosis until the end of follow-up. The Cox proportional hazards model was used to identify demographic, clinical, and treatment associated prognostic indicators which had a significant impact on OS. Results: A total of 1484 patients with lymphoma were identified, of which seventeen (1.1%) patients had concurrent HLH. Of the seventeen patients, the median age was 42 years (range 17-64) with 5 (29.4%) patients aged 50 and over. Interestingly, all 17 (100.0%) patients within our cohort were male. Regarding lymphoma subtypes, 10 (58.8%) patients had T and NK-cell lymphoma, 5 (29.4%) had B -cell lymphoma, and 2 (11.7%) had Hodgkin lymphoma. The median HScore was 272.0 (range 182-337) whereas the median HLH-2004 diagnostic criteria score was 6 out of 8 points (range 4-8). Hemophagocytic features in the bone marrow were present in 13 (76.5%) patients. Epstein-Barr virus infection was detected in 9 (52.9%) patients with a median quantitative PCR level of 37347.5 IU/mL (range 1960.0-402847.0). HLH therapy utilized in our patient sample included corticosteroids in 15 (88.2%) patients, etoposide in 8 (47.1%) patients, and intravenous immunoglobulin in 3 (17.6%) patients. Death occurred in 7 (41.2%) patients whilst the median OS of the cohort was 13.0 months (95% CI 0.0-27.4). Using the cox proportional hazards model, both age ≤50 years (P=0.04, hazard ratio=0.186) and etoposide administration (P=0.002, hazard ratio=0.011) were associated with significantly improved survival. Conclusions: To our knowledge, this is the first cohort study reporting the clinical features and outcomes of HLH secondary to lymphoma within our region. Our study highlights the significant disparities between our population and other countries across the globe as our cohort demonstrated a significant male predominance as well as a relatively young median age at diagnosis. Nonetheless, the survival outcomes of secondary HLH remain poor despite the advances in the diagnostication and recognition of the disease. Future efforts ought to explore both the pathophysiological mechanisms underlying lymphoma-associated HLH and the efficacy of different targeted therapeutic modalities.

Erythrophagocytosis is not a reproducible finding in liver biopsies, and is not associated with clinical diagnosis of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH. However, there are problems with this approach; in particular, we do not know whether this finding is reproducible or whether it is specific to HLH. Therefore, we conducted a multi-institutional study in which experienced liver pathologists reviewed images taken from liver biopsies from patients with normal liver, acute hepatitis, possible HLH, and clinical HLH to determine if there was agreement about the presence or absence of erythrophagocytosis, and to ascertain whether the finding corresponds to a clinical diagnosis of HLH. Twelve liver pathologists reviewed 141 images in isolation (i.e., no clinical information or diagnosis provided). These came from 32 patients (five normal, 17 acute hepatitis, six HLH, four possible HLH). The pathologists classified each image as negative, equivocal, or positive for erythrophagocytosis. Kappa was .08 (no agreement) for case-level and 0.1 for image-level (1.4% agreement, based on two images which were universally considered negative). There was no difference in the proportion of pathologists who diagnosed erythrophagocytosis among those with different diagnoses at case or image-level (p = 0.82 and p = 0.82, respectively). Thus, erythrophagocytosis is an entirely unreliable histologic parameter in liver, as it is irreproducible and not demonstrably associated with a clinical disease (namely, HLH). Unless and until more reliable guidelines can be established, pathologists should refrain from commenting on the presence or absence of erythrophagocytosis in liver biopsy.

Rapid Diagnosis of Hemophagocytic Lymphohistiocytosis Triggered by Disseminated BCG Infection in Infants With Severe Combined Immunodeficiency: Case Report.

Hemophagocytic lymphohistiocytosis triggered by disseminated Bacillus Calmette-Guerin infection is rare. Targeted next-generation sequencing for tuberculosis can rapidly identify different strains of Mycobacterium tuberculosis complex as well as drug resistance genes. Herein we report 2 cases of hemophagocytic lymphohistiocytosis in whom targeted next-generation sequencing rapidly identified Bacillus Calmette-Guerin as the infectious trigger.