Trigger Of Hemophagocytic Lymphohistiocytosis Research Articles

Real-World Treatment Patterns and Outcomes Among Patients with Secondary Hemophagocytic Lymphohistiocytosis Treated with Emapalumab in the United States: The Real-HLH Study

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome caused by the overproduction of proinflammatory cytokines, such as interferon gamma (IFNγ). Secondary HLH (sHLH) occurs in the context of an underlying disease (malignancy, rheumatologic, or metabolic disease) and/or an infection. Emapalumab is a fully human anti-IFNγ monoclonal antibody approved by the FDA in 2018 for refractory, recurrent, or progressive primary HLH (pHLH), or intolerance with conventional therapy. Since its approval, there are limited data on emapalumab use in a real-world setting. The REAL-HLH study assessed real-world treatment patterns and outcomes among patients with HLH treated with emapalumab. Methods: A retrospective medical chart review conducted across 33 US hospitals identified patients treated with ≥1 dose of emapalumab between November 20, 2018, and October 31, 2021. Data were extracted from time of emapalumab initiation to end of data availability, death, or study end (December 31, 2021). Results are presented for the subgroup of patients with sHLH treated off-label with emapalumab. Results: Overall, 105 patients were included in this chart review of which 98 (93.3%) were reportedly treated for HLH-related conditions. Of these, 51/98 (52%) did not meet the pHLH classification criteria (Table 1) and were categorized as presenting with sHLH. These patients (n=51) were grouped based on the underlying disease (i.e., rheumatologic, n=14; malignancy, n=17; and others, n=20). The “others” category comprised a miscellaneous group of patients with underlying diseases and/or HLH triggers that could not be categorized as rheumatologic or malignant disease. Median (range) age at sHLH diagnosis was 9 (0.1-39) years. Baseline demographics and clinical characteristics are presented in Table 1. More than half (32/50; 64%) of these patients were critically ill and received emapalumab in an intensive care unit. Emapalumab was primarily initiated to treat refractory (20/51; 39.2%), progressive (15/51; 29.4%), or recurrent (8/51; 15.7%) disease. The median (range) time from sHLH diagnosis to emapalumab initiation and emapalumab treatment duration are presented in Table 2. Median (range) starting, maximum single, cumulative, and number of administered doses of emapalumab are presented in Table 2. Among patients who achieved normalization of key laboratory parameters (i.e., platelets, absolute lymphocyte count, absolute neutrophil count, alanine transaminase, sCD25, ferritin, and fibrinogen [ Table 2]), the median time to first normalization of all these laboratory parameters ranged from 7-38.5 days for those with underlying rheumatologic disease; 7-38 days for those with underlying malignancy; and 7-11 days among patients in the “others” category. The 12-month survival probability following emapalumab initiation was 85.7% for patients with underlying rheumatologic disease, 23.5% for those with underlying malignancy, and 55% for patients in the “others” category. Conclusion: This is the first study to report real-world treatment patterns with emapalumab across a diverse patient population with sHLH. A phase 3 clinical trial of emapalumab in patients with sHLH/macrophage activating syndrome (MAS) and underlying rheumatologic disease is ongoing (NCT05001737).

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<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<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.

Hemophagocytic lymphohistiocytosis secondary to unrecognized Bartonella henselae infection: a case report

BackgroundBartonella henselae is a species of intracellular bacteria transmitted to humans through animal bites and scratches contaminated with the feces of arthropod vectors, and are most commonly associated with cat exposure although transmission from other mammals has been reported. Bartonella henselae infection has a spectrum of clinical manifestations and has rarely been reported as cause of hemophagocytic lymphohistiocytosis (HLH) in immunocompromised hosts.Case presentationWe present a report of Bartonella henselae infection progressing to HLH in an immunocompetent patient. The patient initially presented with regional lymphadenopathy but the diagnosis was not suspected as the patient reported no exposure to cats. On further history, he did report a scratch from a dog prior to development of symptoms. The patient was treated with methylprednisolone, intravenous immunoglobulin and anakinra for the HLH and three months of Doxycycline for Bartonella infection, with complete resolution of symptoms.ConclusionsAlthough commonly associated with cat exposure, Bartonella henselae transmission can occur after exposure to other animals and vectors including dogs and clinicians need to maintain an index of suspicion for timely diagnosis. Bartonella henselae is associated with a spectrum of clinical manifestations which can include disseminated infection with severe complications such as hemophagocytic lymphohistiocytosis. Prompt initiation of Bartonella treatment is essential when thought to be the trigger for hemophagocytic lymphohistiocytosis although the optimal treatment regimen is unclear.

Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: A Review of Current Literature.

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.

Disparity Analysis of Clinical Features and Prognostic Evaluation of Hemophagocytic Lymphohistiocytosis in Pediatric and Adult Patients: A Retrospective Multicenter Study of 525 Cases in HHLWG

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare immune disorder with rapid progression and high mortality. There have been few large cohort study comparisons of pediatric and adult HLH until now. This study was designed to explore the disparity of clinical presentations and evaluate the prognosis in pediatric and adult HLH patients. Methods: Totally, 525 newly diagnosed HLH patients were included and divided into 4 groups according to age: <6, 6–18, 18–60, and >60 years (geriatric patients). Mann-Whitney U test, Kruskal-Wallis test, χ² test, and Bonferroni’s adjustment were used to explore the difference between age groups. Overall survival (OS) was estimated by using Kaplan-Meier method. The Cox proportional hazard model was used to analyze the univariable and multivariable association between prognostic factors and OS. Results: Geriatric patients had the lowest levels of hemoglobin, platelet, albumin, and the highest level of creatinine, while patients <6 years of age had the lowest values of fibrinogen, IgA, IgM and highest values of triglyceride. The trigger of HLH in patients <18 years of age was mainly EBV infection. However, lymphoma and non-EBV-driven infection were the more frequent drivers in patients aged 18–60 and >60 years, respectively. Geriatric patients were associated with highest mortality (58.8%), and 5-year OS was 43%. By contrast, 5-year OS of patients <6, 6–18, and 18–60 years was 86.1%, 74%, and 58.9%, respectively. Additionally, among patients with different etiologies (EBV, non-EBV-driven infection, and uncertain causes) and treatment regimens (HLH-04, HLH-94, and glucocorticoid regimen), geriatric patients showed lowest 5-year OS. Multivariate analysis revealed that creatinine and alanine aminotransferase were independent risk factors affecting the survival of patients aged 0–6 years, while albumin and IgG were independent factors affecting survival of geriatric patients. Conclusion: Our study showed a wide heterogeneity of clinical presentations, etiology distribution, prognostic factors, and survival outcomes in pediatric and adult HLH patients.

Quotidian Fever in Secondary Hemophagocytic Lymphohistiocytosis Due to Diffuse Large B-Cell Lymphoma: A Case Report

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal syndrome characterized by excessive abnormal activation of the immune system. Fever is the most encountered clinical feature and is found in 100% of HLH cases (Al-Samkari & Berliner, 2018) Fever patterns can be an important clinical clue in certain diseases but have not been described in HLH. We report a 74-year-old Caucasian female patient who presented with fever, fatigue, and dyspnea on exertion of 2 months duration. On examination, she was found to be febrile, hypoxic, and disoriented. Initial laboratory workup was significant for normocytic anemia (6.3 g/dl) with severely elevated Ferritin (1501 µg/dL). Infectious and autoimmune workup was negative. Full body CT scan was negative for malignancy or lymphadenopathy but showed mild splenomegaly. The hospital course was complicated by worsening respiratory status despite empiric antibiotic treatment. She was noted to have persistent daily fever spikes in the early hours of the morning. This prompted workup for HLH which revealed rising serum ferritin, hypertriglyceridemia, elevated soluble IL-2 and low NK cell activity receptors, fulfilling the criteria of HLH. Bone marrow aspirate revealed clonal CD20 positive lymphocyte diagnostic of DLBCL as the trigger for HLH. The patient was started on HLH protocol and mini R-CHOP protocol with marked improvement in her symptoms and anemia. Little is known about the patterns of fever in HLH patients. Before this case, two other case reports described quotidian fever in HLH (Kouides et al., 2021; Henter et al., 2007). interestingly both were cases of secondary HLH. This case illustrates the possible association between HLH and quotidian fever and proposes the possibility of quotidian fever being a clinically important clue to secondary causes of HLH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PATIENT WITH COVID-19 AND HERPES SIMPLEX VIRUS (HSV): A CASE REPORT

SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PATIENT WITH COVID-19 AND HERPES SIMPLEX VIRUS (HSV): A CASE REPORT

SEVERE COVID-19 COMPLICATED WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A CASE REPORT

SEVERE COVID-19 COMPLICATED WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A CASE REPORT

Practice patterns and outcomes of hemophagocytic lymphohistiocytosis in adults: a 2-decade provincial retrospective review.

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 32months, median OS was 18.8months. 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.

Neonatal Onset of Hemophagocytic Lymphohistiocytosis Due to Prenatal Varicella-Zoster Infection in a Neonate with Griscelli Syndrome Type 2.

Type 2 Griscelli syndrome (Type2 GS) is a primary inborn error of the immune system, classified in the immune dysregulation group.1,2 There are three different types of the disease, with different genetic causes responsible for the autosomal recessive inheritance pattern. Although hypopigmentation is common in all variants, neurological involvement or immunodeficiency with varying severity is seen in different types. Molecular motor protein myosin 5 an (MYo5A) [Type1GS], guanosine Triphosphate (GTP) binding protein (RAB27A) [Type2GS], and mutation in human melanophilin (MLPH) [Type 3GS] which is limited to hypopigmentation are reported as the known genetic defects in GS.3 Severe, ineffective, and uncontrolled inflammatory reactions are referred to as the pathogenesis of Hemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening condition that can be defined as either primary or secondary. Secondary causes happen in the context of autoimmunity, malignancy, spontaneous, or infections.4 Prenatal infections play an important role in causing long-term complications in the fetus. Some of them include toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other organisms including syphilis, parvovirus, and Varicella zoster, known as TORCH syndrome (5).TORCH has been well described for a long time but there are limited reports of developing HLH in the context of prenatal infections. We described a type 2GS syndrome with neonatal-onset HLH triggered by a prenatal infection.

Hemophagocytic lymphohistiocytosis secondary to epstein-barr virus reactivation in a patient with COVID-19

Hemophagocytic Lymphohistiocytosis (HLH) in coronavirus disease 2019 (COVID-19) is a recognized complication of severe illness. However, this phenomenon has been reported most often in the setting of acute infection. Here we present a case of a patient with a history of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection that subsequently developed HLH weeks after treatment of COVID-19 and discharges from the hospital. Upon re-admission, work-up demonstrated the patient was experiencing Epstein-Barr virus (EBV) reactivation. As EBV infection is a known etiological trigger of HLH, this case provides an alternative mechanism for HLH seen in patients with a history of COVID-19 infection who present after the resolution of acute symptomatology.

Hemophagocytic Lymphohistiocytosis and Severe Hypoxemia in a Preterm Infant.

Hemophagocytic Lymphohistiocytosis and Severe Hypoxemia in a Preterm Infant.

Laboratory Examination in Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH) is derived from the word hemophagocytosis, in which macrophagesinfiltrate tissue extensively, and unspecifically phagocyte blood and bone marrow cells. The deviant activation of cytotoxicCD8+ T-cells causing the release of inflammatory cytokines is the core pathogenesis of HLH. Hemophagocyticlymphohistiocytosis is a regulatory disorder of the immune system, with clinical signs and symptoms of extremeinflammation and cytopenia, hepatitis, and severe and life-threatening central nervous system dysfunction. The name of theHLH disorder was recently proposed to be "Hyperinflammatory Lymphohistiocytosis" (also known as HLH). Enforcement ofHLH diagnosis by the Histiocyte Society based on HLH 2004 updated diagnostic criteria consists of five of the following eightdiagnostic criteria: fever, splenomegaly, cytopenia (two or more of three lineages in peripheral blood), hypertriglyceridemiaor hypofibrinogenemia, hyperferritinemia, hemophagocytes in the bone marrow/lien/lymph, the low or non-existentactivity of Natural Killer (NK) cells, increased sCD25. H-score, MH-score, and systemic Juvenile Idiopathic Arthritis(sJIA)/Macrophage Activated Syndrome (MAS) classification criteria are also used to enforce HLH diagnoses.Hemophagocytic lymphohistiocytosis is challenging to recognize and has a high mortality rate, especially in adults, rangingfrom 42 to 88%. Therefore, immediate diagnosis and therapy are essential. The introduction of HLH triggers is criticalbecause treatment is based on the underlying trigger. Cytokine storms due to Coronavirus Disease 19 (COVID-19) infectionhave significant similarities to the clinical and laboratory findings of HLH. Secondary HLH (sHLH) is suspected in severeCOVID-19 patients, so early diagnosis is potentially made based on the H-score.

HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE 1-ASSOCIATED ADULT T-CELL LEUKEMIA/LYMPHOMA AND PROGRESSION TO HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A CASE REPORT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus to be discovered [1]. Its infection can lead to adult T-cell leukemia/lymphoma (ATLL). Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with a mortality of 95% caused by overstimulation of the immune system [2,3,4]. This case report presents a male with HTLV-1—associated ATLL who developed HLH. CASE PRESENTATION: A 75 year-old Haitian male with a 22 pack-year smoking history presented to our hospital after a pre-syncopal episode with a 10 day history of pleuritic chest pain. Labs were significant for leukocytosis of 26.2 *10^9/L with lymphocyte predominance. Chest x-ray showed bilateral pleural effusions. Cytometry of the pleural fluid showed an aberrant population of CD4(+) T lymphocytes consistent with post-thymic T-cell lymphoma and atypical T lymphocytes, positive for CD45RO, CD25, and TCRab and negative for CD26 and CD56, consistent with ATLL. Bronchoscopy with endobronchial ultrasound-guided fine needle aspiration of lymph node stations 4R, 7, and 11L revealed aberrant T-cells. TCR gene rearrangement and HTLV-1 western blot confirmed ATLL due to HTLV-1. He was started on CHOP and brentuximab, but was readmitted weeks later with encephalopathy and acute hypoxic respiratory failure. CMV viremia was confirmed via serum PCR and ganciclovir was initiated. Labs were significant for elevated ferritin 9,464 ng/mL, triglycerides 162 mg/dL, D-dimer 549 ng/mL, low fibrinogen 150 mg/dL, and worsening cytopenia with hematocrit 27.1% and platelets 58*10^9/L. Bone marrow biopsy demonstrated histiocytes with engulfed erythroid cells, confirming HLH. The patient was treated with dexamethasone, but was too unstable for etoposide and died 12 days after readmission. DISCUSSION: Lymphoma is the third most common cause of malignant pleural effusion (MPE) and patients have an overall survival of 3-12 months after diagnosis [5]. Diagnostic tests for ATLL are usually done with serum and rarely from MPE, as was done in this case [6]. Signs of HTLV-1—associated ATLL include marked leukocytosis with atypical lymphocytes, rash, and lymphadenopathy [1]. Our patient did not have a rash, but had other signs and symptoms consistent with the presentation of HTLV-1—associated ATLL. HLH likely occurred from progression of HTLV-1—associated ATLL, but CMV viremia or chemotherapy could have contributed. The diagnosis of HLH is difficult because symptoms are nonspecific, requiring a high index of suspicion [7]. The optimal treatment for HLH is still unknown and a multidisciplinary approach is essential. CONCLUSIONS: This case demonstrates HLTV-1—associated ATLL that initially presented as MPE, and was a subsequent trigger for HLH. REFERENCE #1: Rodriguez-Zuniga MJM, Corte-Franco F, Qujiano-Gomero E. Adult T-Cell Leukemia/Lymphoma. Review of the Literature. Actas Dermosifiliogr. 2018;109(5):399-407 REFERENCE #2: Atteritano M, David A, Bagnato G, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1414-1424 REFERENCE #3: Bindra BS, Garcia de de Jesus K, Cisneros O, Jorge VM, Kaur H. Hemophagocytic Lymphohistiocytosis: Management and Special Consideration in Human Immunodeficiency Virus Positive Patients with Immune Reconstitution Syndrome. Cureus. 2019;11(8):e5402 DISCLOSURES: No relevant relationships by Michael Bender, source=Web Response No relevant relationships by Liane Emerson, source=Web Response No relevant relationships by Chaim Rube, source=Web Response

Haemophagocytic syndrome and COVID-19.

Primary and secondary haemophagocytic lymphohistiocytosis (HLH) are hyperferritinaemic hyperinflammatory syndromes with a common terminal pathway triggered by different etiopathogenetic factors. HLH is characterised by a decreased capacity of interferon gamma production with an activated NK phenotype profile similar to other hyperinflammatory syndromes. Viruses are closely linked to the development of HLH as infectious triggers, and the break of tolerance to self-antigens is considered a critical mechanism involved in the development of immune-mediated conditions triggered by viral infections. Emerging studies in patients with COVID-19 are suggesting a key role of monocytes/macrophages in the pathogenesis of this viral infection, and there is a significant overlap between several features reported in severe COVID-19 and the features included in the HLH-2004 diagnostic criteria. Therefore, SARS-Cov-2, as other respiratory viruses, may also be considered a potential etiological trigger of HLH. The frequency of HLH in adult patients with severe COVID-19 is lower than 5%, although this figure could be underestimated considering that most reported cases lacked information about some specific criteria (mainly the histopathological criteria and the measurement of NK cell function and sCD25 levels). Because HLH is a multi-organ syndrome, the diagnostic approach in a patient with severe COVID-19 in whom HLH is suspected must be carried out in a syndromic and holistic way, and not in the light of isolated clinical or laboratory features. In COVID-19 patients presenting with persistent high fever, progressive pancytopenia, and hepatosplenic involvement, together with the characteristic triad of laboratory abnormalities (hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia), the suspicion of HLH is high, and the diagnostic workup must be completed with specific immunological and histopathological studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10067-020-05569-4.

Autologous Hematopoietic Stem Cell Transplantation for Patients with Lymphoma-Associated Hemophagocytic lymphohistiocytosis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS) is a kind of secondary HLH (sHLH). It suffers the worst outcome among sHLH. Allo-HSCT is often considered necessary. Autologous stem cell transplantation (auto-SCT) is widely used in the treatment of lymphoma, especially for high-risk NHL. There have been no clinical reports on the use of auto-SCT in LAHS in the past 20 years. Methods: We retrospectively evaluated 12 LAHS patients who received auto-SCT at our center from January 2013 to January 2020. Follow-up started at the date of LAHS diagnosis and ended at the date of death or last examination. Overall survival (OS) was calculated from the diagnosis of HLH to death of any cause. Results: The median period between diagnosis and auto-SCT is 6.7 months. All 12 patients achieved remission after transplantation. Follow-up to 1 January 2021, 8 patients remained disease-free, 4 patients relapsed and 2 of them died eventually. The median follow-up time is 20.9 months, and the median overall survival time has not been reached yet. The 3-year OS rates was 71%. Compared with LAHS patients who did not undergo transplantation during the same period (median OS time is 3.4 months), patients who underwent auto-SCT had a significantly better prognosis (P=0.001). Even if the lymphoma reaches CR after treatment, auto-SCT still provides a better prognosis compared to CR patients without transplantation (P=0.037). Compared with lymphoma patients without HLH who underwent auto-SCT during the same period, they had a similar prognosis (P=0.350). Conclusion: LAHS, as a common type in secondary HLH, may have a better prognosis after removing the trigger of HLH. In this study, the autologous transplantation in LAHS can significantly improve the prognosis, and provide LAHS a similar prognosis as high-risk lymphoma without HLH.

Epstein-Barr virus associated haemophagocytic lymphohistiocytosis treated with anakinra and rituximab: A case report

Abstract Background Haemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening syndrome characterised by hyperinflammation and macrophage activation. Viral infections such as Epstein-Barr virus (EBV) are a well-recognised trigger of HLH but the treatment of such cases is not well-defined. We present a case of primary EBV driven HLH that was successfully treated with the interleukin-1 inhibitor anakinra in addition to rituximab and high-dose steroids. Case A 22-year-old female with no past medical history developed a mononucleosis-like illness lasting five days characterised by fevers, sore throat and neck swelling. Two weeks following this she presented with fevers, night sweats, fatigue and right upper quadrant pain. She was diagnosed with HLH based on high fevers with hyperferritaemia, hypertriglyceridaemia, pancytopaenia, abnormal liver function tests and hepatosplenomegaly. Extensive investigation revealed an EBV viral load of 23,000,000 copies/ml with nil other obvious triggers. A diagnosis of primary-driven EBV HLH was made. She was treated with the interleukin-1 inhibitor anakinra, methylprednisolone and IVIG and a single dose of rituximab. Following the commencement of treatment, the patient made a dramatic improvement. Her EBV viral load reduced to 660 within nine days and her blood counts and liver function returned to normal. She was discharged from hospital on day sixteen. She continued the anakinra for 5 weeks at a weaning dose and completed a 12-week weaning dose of steroids. She has returned to her studies and has no lasting complications from her illness. Discussion This case highlights the potential of primary EBV infection to cause fulminant HLH. The prompt diagnosis and treatment of HLH using anakinra and rituximab in addition to conventional HLH treatment was safe, and associated with a dramatic clinical improvement. The use of anakinra has been documented in other cases of HLH but none, to our knowledge, of primary EBV-driven HLH with no underlying haematological or rheumatological condition.

Haemophagocytic lymphohistiocytosis in human immunodeficiency virus: a systematic review of literature.

Diagnosis and management of hemophagocytic lymphohistiocytosis (HLH) in patients with human immunodeficiency virus (HIV) infection are scarcely described in the published literature. The aim of this systematic review was to delineate the triggers of HLH in patients with HIV and understand the role of steroids in the management. We conducted a comprehensive search of English medical literature via the Medline ⁄ PubMed database using different synonyms of "HIV" AND "HLH". The review was registered in PROSPERO (CRD42018099987). The titles and abstracts of the 185 articles between January 1986 and April 2018 were reviewed. The final analysis was done from 42 articles with 52 patients. HLH was associated with malignancy in 17 patients, while infection was found in 25 patients. No cause was identified in eight patients, out of which four had acute HIV infection. Death was reported in 21 patients. Presence of either malignancy (p = 0.051) or opportunistic infection (p = 0.69) was not associated with increased chances of death by univariate analysis. A total of 26 patients were treated with steroids, while etoposide was used in only four patients. Administration of steroids as a treatment of HLH was associated with more chances of death (p = 0.048). Malignancy and Opportunistic infections are important triggers for HLH in patients with HIV. Acute HIV by itself can act as a trigger for HLH. Evidence on the use of steroids as a treatment of HLH in patients with HIV is not convincing.

Hemophagocytic Lymphohistiocytosis Syndrome As Presenting Sign For Acute Monocytic Leukaemia- A Case Report.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare aggressive syndrome of excessive immune activation. Clinical manifestations of this syndrome mimic various other clinical conditions making the diagnosis harder to achieve. These manifestations are believed to be a result of cytokine storm which leads, eventually, to a multi-organ failure and eventually death. The latter two might be prevented if HLH was diagnosed early.&#x0D; HLH is classified into primary consist of monogenic disorders and secondary occurs as a complication in various settings such as infection, autoimmune disease, and malignancy.&#x0D; In hematologic malignancies, HLH is classically associated with specific entities, mainly, lymphoma or induced by treatment-related infections. Acute myeloid leukemia, on the other hand, is less common trigger with only few case reports.&#x0D; &#x0D; Case presentation: An 83-years-old, 5 years free of transitional cell man, presented with unstable atrial fibrillation was intubated and shortly after that he developed a multi-organ failure. Bicytopenia and a high level of ferritin aroused a clinical suspicion of HLH syndrome.&#x0D; Further evaluation revealed high levels of soluble interleukin 2 receptors and no activity of natural killers cells. A bone marrow was performed and it did not show phagocytosis, however, acute myeloid leukemia (AML) was diagnosed. AML was suggested to be associated with chemotherapy that our patient received 5 years earlier.&#x0D; &#x0D; Conclusion: Hemophagocytic lymphohistiocytosis can be present as a multi-organ failure requiring a high index of suspicion. Chemotherapy related-AML can be a trigger for HLH.

Double Negative Alpha Beta T Cells in Pediatrics Patients with Hemophagocytic Syndromes

Abstract Introduction Autoimmune lymphoproliferative syndrome (ALPS) and hemophagocytic lymphohistiocytosis (HLH) share clinical and laboratory features including lymphandenpathy, splenomegaly and pancytopenia. We sought to measure αβ double negative T cells (αβ DN T cells) among patients with established diagnosis of HLH and study its relation to disease activity and severity. Methods we conducted a follow-up controlled study, comprising 25 patients fulfilling diagnosis of HLH according to criteria set forward by the pediatric HLH study Group of the Histiocyte Society, in addition to 25 healthy matched controls. Patients were subjected to clinical evaluation and flow cytometric measurement of αβ DN T Cells percentages at presentation and 9 weeks after start of HLH induction treatment. Results In 17 (68%) patients, infection was the trigger of HLH while the trigger was malignancy in three (12%), and rheumatological disorders in two patients (8%). At enrollment, 15 patients (60%) has elvated αβ DN T cells (&amp;gt;2%), with median (IQR) counts of 1.71 (1.25-2.12) that were significantly higher that the control values (median (IQR): 0.7 (0.4-0.8) (p &amp;lt; 0.001). Initial αβ DN T cells counts of patients were also higher at enrollment as compared to results at the end of week 9 (median (IQR): 0.76 (0.45–1.17), p = 0.018). Survivors (n = 17 [68%] )and non-survivors (n = 8 [32%]) had comparable levels of αβ DN T cells at enrollment (p = 0.861).αβ DN T cells correlated positively with ALT (p = 0.019) and negatively with CD4/CD8 ratio (p = 0.023). Conclusion Elevated αβ DN T cell counts may not be specific for ALPS and their mild elevation might be related to the HLH process. Wider scale studies with longer periods of follow up are needed to validate the results and properly anticipate the correlation between both medical conditions.