Infection-associated Hemophagocytic Lymphohistiocytosis Research Articles

Critical risk factors analysis of infection-associated hemophagocytic lymphohistiocytosis in children.

To analyze the critical factors of infection-associated Hemophagocytic lymphohistiocytosis (HLH) in children, so as to provide theoretical basis for clinicians to evaluate the disease condition, formulate treatment plan and improve prognosis.This study is a retrospective analysis. 60 cases of children with infection-associated HLH were divided into critical and non-critical groups based on the presence of multiple organ dysfunction syndrome (MODS), and the clinical characteristics and laboratory data of the two groups of children were analyzed. A multifactor logistic regression analysis model was used to assess the independent risk factors affecting critical illness in children with infection-associated HLH, and the Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the predictive value of risk factors for critical illness in children with infection-associated HLH. Children in the critical group with HLH had a younger age at onset. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), D-dimer (DD), and triglycerides (TG) were significantly higher in the critical group, while albumin (ALB) was significantly lower, showing statistical significance (P < 0.05). Multifactorial logistic regression analysis of age, ALB, and TG showed that younger age and lower ALB were associated with a higher risk of MODS in children with infection-associated HLH, with age and ALB being independent risk factors for critical illness. ALB predicted the ROC area under the curve for critical children with infection-associated HLH was 0.765 (95% CI: 0.643-0.888, P = 0.011), with the optimal cut-off value being 32.50g/L (sensitivity = 68.3%, specificity = 84.2%); age predicted the ROC area under the curve for critical children with infection-associated HLH was 0.711 (95% CI: 0.570-0.851, P = 0.009), with the optimal cut-off value being 1.50 years (sensitivity = 70.7%, specificity = 68.4%). This study suggests that younger patients and those with hypoalbuminemia among infection-related HLH patients are more likely to develop MODS. In the future, verification will be required through large-scale, multi-center studies.

Clinical analysis of cytomegalovirus infection-associated hemophagocytic lymphohistiocytosis in five patients without underlying diseases

The clinical data of five patients [one male and four female; median age: 31 (21-65) years] with cytomegalovirus (CMV)-induced hemophagocytic lymphohistiocytosis (HLH) diagnosed and treated in the First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed from January 2011 to December 2020. None of the patients had any underlying disease, and all were immunocompetent. The main clinical presentations were fever in all five patients, splenomegaly in four, enlarged lymph nodes in two, liver enlargement in one, and rash in three. Pulmonary infection was found in three patients, two of whom developed respiratory failure. Two patients had jaundice. Central nervous system symptoms and gastrointestinal bleeding were observed in one case. All patients received glucocorticoids and antiviral therapy. One patient was treated with the COP (cyclophosphamide+vincristine+prednisone) chemotherapy regimen after antiviral therapy failed and he developed central nervous system symptoms. After treatment, four patients achieved remission, but the fifth pregnant patient eventually died of disease progression after delivery. CMV-associated HLH in an immunocompetent individual without underlying diseases is extremely rare, and most patients have favorable prognosis. Antiviral therapy is the cornerstone of CMV-HLH treatment.

A Retrospective Review of Secondary Hemophagocytic Lymphohistiocytosis (HLH) and Dengue-associated HLH from a Teaching Hospital in Singapore.

Real-world data on the outcome of Asian patients with secondary hemophagocytic lymphohistiocytosis (HLH), especially on dengue-associated HLH, are limited to small case series. This is a retrospective records review of adult patients with secondary HLH between 2015 and 2020. Thirty-two adult patients were followed up for a median of 6.6 months (range 0.1 - 75 months). 15 had underlying lymphomas, and 12 had viral infections. Hemophagocytosis was seen in 28 of 29 patients with a bone marrow biopsy. 100% and 76.5% of patients with and without an underlying malignancy required HLH-directed therapy and blood product transfusion. 12 of 15 patients with lymphomas were treated with additional chemotherapy. Patients with malignancy-associated HLH had poorer survival than non-malignancy-associated HLH (median overall survival (OS) 1.5 months versus not reached, p-value 0.003). The 1-year survival rates of patients with malignancy-associated HLH, HLH with unknown etiologies, and infection-associated HLH were 0.133 (95% CI: 0.036 - 0.484), 0.400 (95% CI: 0.137 - 1.000) and 0.833 (95% CI: 0.647 - 1.000), respectively. Malignancy significantly increased the risk of death compared to infection-associated HLH (HR 9.37, p-value 0.003). Eight patients were diagnosed with dengue-associated HLH with a median HSCORE of 240 (98-99% probability of HLH). Their mean ferritin was 34,740 ng/mL. Three patients required blood product transfusion, 5 required corticosteroids and/or etoposide, with a median duration of treatment of 31 days. Their overall survival rate was 87.5%. Our study highlights the stark contrast in the survival of secondary HLH patients with and without an underlying malignancy. We also present one of the world's most extensive case series of dengue-associated HLH.

Etoposide Therapy of Cytokine Storm Syndromes.

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: an Under-recognized and Life-threatening Condition.

Diagnosis of hemophagocytic lymphohistiocytosis is a challenge in Nepal because of limited resources and the high prevalence of tropical febrile illness mimicking hemophagocytic lymphohistiocytosis. We retrospectively reviewed medical records of 21 patients who were diagnosed with hemophagocytic lymphohistiocytosis from 2010 to 2015 at a single center in Nepal. Two patients had a mutation in their perforin gene and underwent successful haploidentical stem cell transplantation. Marrow hemophagocytosis was found only in 57% of the patients. Five patients had hematological malignancy and were treated with disease-specific chemotherapy. Seven patients developed hemophagocytic lymphohistiocytosis secondary to an infection, including visceral leishmaniasis, scrub typhus, and Epstein Barr virus. EBV-associated hemophagocytic lymphohistiocytosis was refractory to hemophagocytic lymphohistiocytosis 94 protocol, including the addition of rituximab. Malignancy and infection-associated hemophagocytic lymphohistiocytosis was more common. The most common clinical presentations included fever, splenomegaly, hyponatremia, liver function derangement, hyperfibrinogenemia, hyperferritinemia, and cytopenia. With a mortality of 29% in our study cohort, hemophagocytic lymphohistiocytosis should be considered a lethal disease, and clinicians should maintain a high index of suspicion to diagnose this disease. Keywords: Hemophagocytic lymphohistiocytosis; infection; malignancy.

Postpartum Neonatal Disseminated Herpes Simplex Virus-1 Infection in Which Herpes Simplex Virus-1 Was Detected in Mother's Breast Milk.

A 17-d-old girl was diagnosed with disseminated herpes simplex virus-1 infection-associated hemophagocytic lymphohistiocytosis. The virus was detected in the neonate's blood and mandible. The neonate was treated with dexamethasone and acyclovir and discharged without neurological sequelae. The mother had no history of a herpes simplex virus-1 infection and did not have visible genital herpetic lesions; moreover, the neonate was delivered via an elective cesarean section. However, the day before the delivery, the mother had met with the neonate's grandmother, who had herpes labialis. Viral DNA was detected in bilateral breast milk samples; however, no superficial herpetic lesions were noted on both breasts. The authors speculated that the neonate may have acquired the infection via contaminated breast milk. Thus far, only one neonatal case of this infection contracted via breast milk has been reported. Further studies on breast milk as a transmission route for these infections are required.

Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH

AbstractCD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (HLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Peripheral blood mononuclear cells from children with inactive systemic juvenile idiopathic arthritis (sJIA, n = 17), active sJIA (n = 27), MAS in sJIA (n = 14), infection-associated HLH (n = 7), and with other forms of sHLH (n = 9) were analyzed by flow cytometry. Compared with patients with active sJIA, in patients with MAS and sHLH of different origins, beside a significant increase in the frequency of CD38high/HLA-DR+CD8+ T cells, we found a significant increase in the frequency of CD8+ T cells expressing the CD4 antigen (CD4dimCD8+ T cells). These cells expressed high levels of the activation markers CD38 and HLA-DR, suggesting they were a subset of CD38high/HLA-DR+CD8+ T cells, as well as of the activation/exhaustion markers CD25, PD1, CD95, and interferon-γ. The frequency of CD4dimCD8+ T cells strongly correlated with most of the laboratory parameters of MAS severity and with circulating levels of CXCL9 and interleukin-18. These findings were confirmed in a prospective replication cohort in which no expansion of any particular T-cell receptor Vβ family in CD3+ T cells of patients with sHLH was found. Finally, frequency of CD4dimCD8+, but not of CD38high/HLA-DR+CD8+ T cells, significantly correlated with a clinical severity score, further supporting the involvement of these cells in MAS/sHLH pathogenesis.

Clinical significance of cerebrospinal fluid soluble CD25 in pediatric hemophagocytic lymphohistiocytosis with central nervous system involvement.

To analyze the clinical significance of soluble CD25 (sCD25) levels in cerebrospinal fluid (CSF) in pediatric hemophagocytic lymphohistiocytosis (HLH) with central nervous system (CNS) involvement. All patients diagnosed with HLH admitted to Beijing Children's Hospital, Capital Medical University between January 1, 2017 and October 31, 2021 who received a measurement of their HLH-related parameters and CSF sCD25 levels at admission were enrolled in this study. CSF sCD25 levels in patients with primary HLH were higher than those in patients with Epstein-Barr virus infection-associated HLH, and the median level was 444pg/ml. The difference in CSF sCD25 levels between the non-CNS group and the CNS group was statistically significant (591 [259-33,643] pg/ml vs. 123 (36-437) pg/ml, p<.001). The best cutoff value of CSF sCD25 was 273.5pg/ml (AUC = 0.987, 95% CI: 0.972-1.000), with sensitivity, specificity, positive predictive values, and negative predictive values of 96.4%, 92.8%, 81.8%, and 98.7%, respectively. CSF sCD25 in the severe CNS involvement group was significantly higher than that in the nonsevere CNS involvement group (p=.014). The 3-year overall survival (OS) of patients with high CSF sCD25 levels was lower than that of patients with low CSF sCD25 levels(71.6% ± 8.1% vs. 93.3% ± 2.9%, hazard ratio [HR] = 3.637, p=.003). Increased CSF sCD25 levels in active disease can predict CNS-HLH. Primary HLH has a higher CSF sCD25 level than Epstein-Barr virus infection-associated HLH. Patients who are diagnosed with CNS-HLH with CSF sCD25 levels higher than 273.5pg/ml are more likely to develop severe CNS involvement, suggesting a poor prognosis.

Development of Laboratory Parameters-Based Formulas in Predicting Short Outcomes for Adult Hemophagocytic Lymphohistiocytosis Patients with Different Underlying Diseases.

Hemophagocytic lymphohistiocytosis (HLH) is a severe disease with high mortality. The purpose of this investigation was to build models to predict 30-day death in total and subgroup HLH patients based on available and cheap laboratory parameters. The research contained 431 adults HLH patients from January 2015 to September 2021 in the hospital. Logistic regression and receiver operating characteristic (ROC) were utilized to build models. Results suggested that age, ferritin, lymphocyte (LY), international normalized ratio (INR), thrombin time (TT), globulin, uric acid (UA), chloride, activated partial thromboplastin time (APTT), aspartate aminotransferase (AST), triglycerides (TG), total bilirubin (TB), and indirect bilirubin (IB) were independent factors in HLH and subgroups. Then, models adapted to patients with different underlying diseases were established based on these factors. Area under curve (AUC) of these models was excellent: HLH patients: 0.838 (p < 0.001); infection-associated HLH (I-HLH) patients: 0.913 (p < 0.001); malignancy-associated HLH (M-HLH): 0.921 (p < 0.001) and 0.809 (p < 0.001) for two or more different etiologies-associated HLH (Mix-HLH patients). In addition, UA, TT, and chloride were firstly confirmed as independent factors in adult HLH. Four models depending on biomarkers that available and affordable in clinical practice were built. With these models, high-risk patients with different underlying diseases could be easily identified.

Characteristic and prognosis of patients with non-EBV infection-associated hemophagocytic lymphohistiocytosis

目的探讨非EB病毒病原体所致感染相关噬血细胞综合征（IAHLH）患者的临床特征及预后。方法收集2015年1月至2021年3月首都医科大学附属北京友谊医院确诊的48例非EB病毒病原体所致IAHLH患者的临床资料，对患者的临床特征、治疗、疗效及预后进行回顾性分析。结果共纳入48例患者，男28例，女20例，中位年龄34.5（2.0～74.0）岁，导致IAHLH的病原体中，病毒16例（33.3％），细菌17例（35.4％），寄生虫13例（27.1％），真菌2例（4.2％），患者发病至确诊噬血细胞综合征（HLH）的中位时间为40（10～160）d，发病至确诊为IAHLH的中位时间为67（23～270）d。患者起病时临床表现如下：发热48例（100％），脾大34例（70.8％），血细胞减低38例（79.1％），铁蛋白升高45例（93.8％），甘油三酯升高7例（14.6％），纤维蛋白原降低17例（35.4％），NK细胞活性减低26例（59.1％），可溶性CD25升高35例（74.5％）。25例（52.1％）患者起病时伴淋巴结肿大。明确导致HLH的病原体后尽快减停细胞毒药物及激素并应用有效的抗感染治疗，36例（75.0％）患者获得完全缓解，93.3％（14/15）的寄生虫及真菌所致IAHLH患者获得了病情缓解，细菌及病毒相关IAHLH仅有66.7％（22/33）的缓解率。患者5年预期总生存（OS）率为72.3％（95％ CI 50.3％～69.8％），多因素分析显示，总胆红素大于2倍正常上限（OR＝20.0，95％ CI 1.1～378.3，P＝0.046）及诱发HLH的病原体感染未控制（OR＝19.9，95％ CI 2.9～134.5，P＝0.002）为预后不良因素。结论非EB病毒病原体所致IAHLH预后较好，诊断后应尽快减停细胞毒药物及激素，有效控制病原体感染为关键性治疗。

Acute hepatitis A infection‐associated hemophagocytic lymphohistiocytosis in adult presenting as impending acute liver failure: A case report and literature review

Hemophagocytic lymphohistiocytosis has been reported as a severe complication of various viral infections but unusual for the hepatitis A virus. We report a case of 25‐year‐old man with hepatitis A infection‐associated hemophagocytic lymphohistiocytosis and impending acute liver failure to emphasize the importance of early diagnosis and treatment of this condition.

Multiple opportunistic infection-associated hemophagocytic lymphohistiocytosis in nephrotic syndrome

Multiple opportunistic coinfections during corticosteroid therapy for the nephrotic syndrome are uncommon. Infection-associated hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal multisystem disorder, manifesting as a state of hypercytokinemia in response to an infectious trigger. We describe a 4½-year-old boy with steroid-dependent nephrotic syndrome receiving high-dose steroids, who developed respiratory failure due to pulmonary tuberculosis, Cytomegalovirus, and Pneumocystis jirovecii coinfections; HLH complicated the course. Aggressive management of the underlying infections with antitubercular, antiviral, and antifungal therapy, prompt recognition of HLH, and immunomodulation with intravenous (IV) immunoglobulin and IV methylprednisolone enabled convalescence. This report emphasizes the serious risks of immunosuppression and the need for strict vigilance for rare opportunistic infections with multiple pathogens in patients receiving oral steroids for nephrotic syndrome. Clinical distinctions between severe sepsis and HLH may be ambiguous; a high level of suspicion is required for timely recognition and management.

High Mortality of HLH in ICU Regardless Etiology or Treatment.

Background: Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. Here, we report on a large cohort of adult HLH in the ICU (ICU-HLH). We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population.Methods: This retrospective study included adult patients diagnosed with HLH in four ICUs in Marseille, France between 2010 and 2020. Patients who fulfilled the HLH-2004 criteria (≥ 4/8) and/or had an HScore ≥ 169 were diagnosed with HLH. HLH was categorized into four groups according to etiology: sepsis-associated HLH, intracellular infection-associated HLH, malignancy-associated HLH, and idiopathic HLH.Results: Two hundred and sixty patients were included: 121 sepsis-associated HLH (47%), 84 intracellular infection-associated HLH (32%), 28 malignancy-associated HLH (11%), and 27 idiopathic HLH (10%). The ICU mortality rate reached 57% (n = 147/260) without a statistical difference between etiological groups. Independent factors associated with mortality in multivariate analysis included age (OR (5 years) = 1.31 [1.16–1.48], p < 0.0001), SOFA score at ICU admission (OR = 1.37 [1.21–1.56], p < 0.0001), degradation of the SOFA score between ICU arrival and HLH diagnosis (Delta SOFA) (OR = 1.47 [1.28–1.70], p < 0.0001), the presence of bone-marrow hemophagocytosis (OR = 5.27 [1.11–24.97], p = 0.04), highly severe anemia (OR = 1.44 [1.09–1.91], p = 0.01), and hypofibrinogenemia (OR = 1.21 [1.04–1.41], p = 0.02).Conclusions: In this large retrospective cohort study of critically ill patients, ICU-HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology or specific treatment. Factors independently associated with prognosis included age, presence of hemophagocytosis in bone-marrow aspirates, organ failure at admission, and worsening organ failure during the ICU stay. Whether a rapid diagnosis and the efficacy of specific therapy improve outcome is yet to be prospectively investigated.

Increased levels of serum interleukin-10 are associated with poor outcome in adult hemophagocytic lymphohistiocytosis patients

BackgroundInterleukin-10 (IL-10) is an independent factor for predicting adverse outcomes in pediatric patients with hemophagocytic lymphohistiocytosis (HLH). However, little is known about its prognostic value in adult patients.MethodsThis single center retrospective study was conducted to explore the prognostic value of IL-10 in 101 adults newly diagnosed with HLH. The serum interleukin levels were quantitatively determined by chemiluminescence using cytokine profiling kits.ResultsSerum IL-10 levels were significantly increased in adult HLH patients. Elevated IL-10 levels was correlated with lower concentrations of hemoglobin (r = − 0.279, P = 0.005). IL-10 levels were significantly lower in patients with macrophage activation syndrome (MAS) than in those with infection-associated HLH (IAHS) and malignancy-associated HLH (MAHS) (P = 0.033, P = 0.012). Patients with MAS had relatively longer survival than those with IAHS and MAHS (P < 0.001). Univariate analysis indicated that hemoglobin < 8.2 g/dL, platelets < 40 × 109/L, lactate dehydrogenase ≥ 700 IU/L, albumin < 28 g/L, post-treatment ferritin > 1050 µg/L and IL-10 ≥ 129 pg/mL were poor prognostic factors for survival. However, multivariate analysis revealed that only high serum IL-10 levels (≥ 129 pg/mL) at diagnosis and high post-treatment ferritin levels (> 1050 µg/L) were independent risk factors for poor overall survival in adult HLH patients (HR: 4.087, 95% CI 2.064–8.090, P < 0.001; HR 3.814, 95% CI 2.042–7.126, P < 0.001, respectively).ConclusionsOur results suggest that higher serum IL-10 levels might be a prognostic marker in adult HLH patients.

Non-EBV infection-associated hemophagocytic lymphohistiocytosis: a distinct subgroup where pathogen-directed therapy is essential and favorable outcomes are expected

EBV is the most prevalent cause of infection-associated hemophagocytic lymphohistiocytosis (IAHLH), non-EBV IAHLH is observed clinically but less documented. We conducted a retrospective research enrolled 36 cases from 1/1/2015 to 31/12/2019. Intriguingly, 92% cases were immunocompetent individuals prior to the onset of HLH. Clinically, the cardinal features were prolonged high fever, splenomegaly and hemophagocytosis. Bicytopenia occurred in most patients, besides, liver dysfunction was characterized by increased transaminase, bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (γ-GGT) and lactate dehydrogenase (LDH). Immunomodulatory agents should be added to control the overwhelming inflammatory storm without delay. Once a certain pathogen was identified as the causative factor of HLH, cytotoxic agents were withdrawn, specific pathogen-directed treatment was initiated. Further, glucocorticoids were tapered off when a stable state of HLH was achieved. After treatment, about 70% patients were fully recovered without relapse. All in all, non-EBV IAHLH is a special group of HLH with admirable outcome.

A retrospective analysis of etiology and outcomes of hemophagocytic lymphohistiocytosis in children and adults

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare but severe, life-threatening inflammatory condition if untreated. We aimed to investigate the etiologies, outcomes, and risk factors for death in children and adults with HLH.MethodsThe medical records of patients who met the HLH criteria of two regional university hospitals in Korea between January 2001 and December 2019 were retrospectively investigated.ResultsSixty patients with HLH (35 children and 25 adults) were included. The median age at diagnosis was 7.0 years (range, 0.1–83 years), and the median follow-up duration was 8.5 months (range, 0–204 months). Four patients had primary HLH, 48 patients had secondary HLH (20 infection-associated, 18 neoplasm-associated, and 10 autoimmune-associated HLH), and eight patients had HLH of unknown cause. Infection was the most common cause in children (14/35, 40.0%), whereas neoplasia was the most common cause in adults (13/25, 52.0%). Twenty-eight patients were treated with HLH-2004/94 immunochemotherapy. The 5-year overall survival (OS) rate for all HLH patients was 59.9%. The 5-year OS rates for patients with primary, infection-associated, neoplasm-associated, autoimmune-associated, and unknown cause HLH were 25.0%, 85.0%, 26.7%, 87.5%, and 62.5%, respectively. Using multivariate analysis, neoplasm-induced HLH (p=0.001) and a platelet count <50×109/L (p=0.008) were identified as independent risk factors for poor prognosis in patients with HLH.ConclusionInfection was the most common cause of HLH in children, while it was neoplasia in adults. The 5-year OS rate for all HLH patients was 59.9%. HLH caused by an underlying neoplasm or a low platelet count at the time of diagnosis were risk factors for poor prognosis.

Practice Patterns and Outcomes of Hemophagocytic Lymphohistiocytosis in Adults: A Two-Decade Provincial Retrospective Review

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by uncontrolled immune activation, resulting in multi-organ dysfunction and a high risk of death. Due to scarcity of data in adults, the diagnosis remains challenging and has been historically associated with a delayed time to diagnosis and heterogeneous practice patterns. We examined the processes of care measures and outcomes in a large cohort of adults with HLH. Methods: This multicenter, retrospective cohort study examined the epidemiology, management, and outcomes of adult inpatients (≥18 years) diagnosed with HLH in the province of Alberta, Canada from January 1999 to December 2019. Patients were identified via International Classification of Diseases (ICD) codes, and those who met the HLH-2004 diagnostic criteria were included. Chart reviews were performed to collect demographics, clinical and laboratory characteristics, process of care measures, and outcomes. Overall survival (OS) was defined as the time from hospital presentation to death. Survival analysis was performed using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Cox proportional hazards regression was used to assess the association between time to diagnosis and the hazard of death, adjusting for patient and disease characteristics. Results: 83 patients met the HLH-2004 diagnostic criteria; 1 had a clear alternative diagnosis, hence 82 were included in the final data analysis. The median age of the cohort was 47 (interquartile range, IQR 32-62) years; 57 (70%) were male. The etiologies of HLH were as follows: malignancy (38%), infection (35%), autoimmune disease (16%), and idiopathic/others (11%). The most common clinical and laboratory findings were hyperferritinemia (100%), fever (99%), cytopenias (94%), hypofibrinogenemia and/or hypertriglycermidemia (91%), and hemophagocytosis on biopsy (89%). The median H-score was 244, with no significant difference across HLH etiologies. Interim data analysis showed that sCD25, natural killer (NK) cell activity, and molecular studies were ordered in 69%, 36%, and 29% of cases. The median length of hospitalization was 33 days (IQR 16-62), with a 30-day mortality rate of 25.6%. A majority of patients (55%) required admission to the intensive care unit (ICU) (Table 1). The median OS was 8.5 months. Patients with malignancy-associated HLH had a significantly worse median OS compared with those with non-malignancy-associated HLH (2.1 vs 54.5 months, p=0.0004; Figure 1). There were no differences in the median OS between B-cell (n=11) and T/NK lymphoproliferative disorders (n=13), or between new cancer diagnosis (n=27) and active cancer receiving chemotherapy (n=4). Age (adjusted hazards ratio, aHR 1.06, 95% CI 1.01-1.10), Charlson comorbidity index (aHR 1.4, 95% CI 1.2-1.8), and ICU admission (aHR 4.1, 95% CI 1.4-12.2) were associated with increased hazards of death on multivariable Cox proportional hazards model. Malignancy was associated with increased hazard of death on univariate analysis (HR 2.8, 95% 1.5-4.9), but did not remain as an independent prognostic factor on multivariable analysis (aHR 1.0, 95% 0.4-2.6). Sex, delayed diagnosis, or peak ferritin level were not significant predictors of mortality. The median times from presentation to diagnosis and from presentation to therapy were 10 days (IQR 2-19) and 14 days (IQR 6-25), respectively. Practice patterns varied significantly between centers without differences in survival outcome (log-rank p=0.8). Most patients (83%) received corticosteroids, whereas etoposide, intravenous gammaglobulin, and cyclosporine were administered in 38%, 34%, and 18%, respectively. Twelve (15%) patients did not receive any HLH-specific treatment, mostly in infection-associated HLH (n=8). Of the 31 patients receiving steroids and etoposide, 21 (68%), 12 (39%), and 20 (65%) receivedpneumocystis jirovecii, antiviral, and antifungal prophylaxis, respectively. Conclusion: In our two-decade provincial study, we observed that delayed diagnosis and treatment heterogeneity were common. Older age, comorbidities, and ICU admission were independent predictors of poor survival, whereas delayed diagnosis and malignant HLH were not. Development of a standardized provincial diagnostic and treatment protocol has the potential to improve the quality of care in adult HLH. Disclosures Sun: Sanofi:Other: Advisory board;Octapharma:Other: Advisory board;Pfizer:Other: Advisory board;Octapharma:Research Funding;Novo Nordisk:Other: Advisory board.

Immunopathogenesis of Coronavirus-Induced Acute Respiratory Distress Syndrome (ARDS): Potential Infection-Associated Hemophagocytic Lymphohistiocytosis.

The outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, China, introduced the third highly pathogenic coronavirus into humans in the 21st century. Scientific advance after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic and Middle East respiratory syndrome coronavirus (MERS-CoV) emergence enabled clinicians to understand the epidemiology and pathophysiology of SARS-CoV-2. In this review, we summarize and discuss the epidemiology, clinical features, and virology of and host immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2 and the pathogenesis of coronavirus-induced acute respiratory distress syndrome (ARDS). We especially highlight that highly pathogenic coronaviruses might cause infection-associated hemophagocytic lymphohistiocytosis, which is involved in the immunopathogenesis of human coronavirus-induced ARDS, and also discuss the potential implication of hemophagocytic lymphohistiocytosis therapeutics for combating severe coronavirus infection.

A Case of EBV-Associated Hemophagocytic Lymphohistiocytosis in Adult: Lessons from the Treatment Process

Hemophagocytic lymphohistiocytosis (HLH), which was first described in 1939 by paediatricians Scott and Robb-Smith, is a life-threatening disease. HLH is characterized as cytokine release syndrome which is caused by excessive but non-malignant activation of macrophages and/or histiocytes in bone marrow and other reticuloendothelial systems. EBV-HLH is the most common type of infection-associated HLH, has a high mortality rate without prompt and effective treatment. A previous study showed that the one-year mortality rate of EBV-HLH patients is 75%. Here we report a case of EBV-associated hemophagocytic syndrome in adult, and the lessons from the treatment process. Through this case, we think that for EBV-related HLH, EBV-DNA should also be monitored in addition to hemophagocytosis-related indicators during treatment. In addition, DEP regimen may not be suitable for patients who have received at least partial response, because impaired immunological functioning may lead to EBV and hemophagocytic re-activity.

Hemophagocytic lymphohistiocytosis secondary to infectious diseases

Introduction:Secondary hemophagocytic lymphohistiocytosis (HLH) occurs in association with infections, autoimmune disorder or malignancy. Only few studies reported cases of infection-associated HLH (I-HLH). We aimed to study the clinical, laboratory and therapeutic features of I-HLH among children and adults.Material and methods:We conducted a retrospective study including all patients hospitalized in Pediatric and infectious diseases department with confirmed diagnosis of I-HLH between 2011 and 2017.Results:We enrolled 19 cases with I-HLH, among whom 11 cases were males (57.8%). We identified 15 children and 4 adults. The median age was 11 years [1-65 years]. Physical examination showed splenomegaly in 15 cases (78.9%) and hepatomegaly in 10 cases (52.6%). Regarding laboratory examinations, anemia and elevated ferritin levels were noted in all cases. Bone marrow aspiration showed images of haemophagocytosis in all cases. Bacterial infection was noted in 10 cases (52.6%) and parasitic infection in 5 cases (26.3%). All patients received symptomatic and/or etiological treatment. Specific treatment with corticosteroids and human immunoglobulins were used in 7 cases (36.8%). Ten patients were dead (52.6%) due to multiple organ failure.Conclusions:Hemophagocytic lymphohistiocytosis was a life-threatening disease. The prognosis depends on the underlying etiology, but remains poor. Prompt diagnosis and treatment are crucial in order to improve the outcome.