Heterogeneity of macrophage activation syndrome and treatment progression.

Macrophage activation syndrome (MAS) is a rare complication of autoimmune inflammatory rheumatic diseases (AIIRD) characterized by a progressive and life-threatening condition with features including cytokine storm and hemophagocytosis. Predisposing factors are typically associated with microbial infections, genetic factors (distinct from typical genetically related hemophagocytic lymphohistiocytosis (HLH)), and inappropriate immune system overactivation. Clinical features include unremitting fever, generalized rash, hepatosplenomegaly, lymphadenopathy, anemia, worsening liver function, and neurological involvement. MAS can occur in various AIIRDs, including but not limited to systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), systemic lupus erythematosus (SLE), Kawasaki disease (KD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), etc. Although progress has been made in understanding the pathogenesis and treatment of MAS, it is important to recognize the differences between different diseases and the various treatment options available. This article summarizes the cell types and cytokines involved in MAS-related diseases, the heterogeneity, and treatment options, while also comparing it to genetically related HLH.

Hemophagocytic lymphohistiocytosis in Egyptian children: diagnosis, treatment challenges, and outcome.

BACKGROUND: Hemophagocyticlymphohistiocytosis (HLH) is a spectrum of immune activation which could be genetically determined, or secondary to an underlying illness. Our aim was to present the clinico-genetic aspects of HLH among Egyptian children and to evaluate the patterns of reactivation and outcome with illustrations of overlap manifestations. RESEARCH DESIGNAND METHODS: We retrospectively collected the data of 55 patients with HLH, registered at Ain Shams University Children's Hospital,Cairo, Egypt. RESULTS: Median age at diagnosis was 19 months (range 2-180), 33 patients (60%) fulfilled the diagnostic HLH criteria at presentation. Fourteen (25.45%) patients had secondary HLH, 15 (27.27%) patients had genetically documented familial HLH (11 had variants in UNC13D gene and one in PRF1 gene), 3 had Griscelli and Chediak-Higashi syndromes. Sixteen patients (29.1%) had reactivations, 8 (50%) of them had molecularly confirmed HLH. We report the death of 40 patients, the median duration from the diagnosis to death of 5 months mostly due to disease activity. CONCLUSIONS: This study confirms that the nonspecific signs and symptoms of HLH are challenging. Genetic testing, though expensive and sophisticated, is integral for the diagnosis. The difficulty in finding non-related donors for stem cell transplantation and the early reactivations are the causes of the inferior outcome.

[L-DEP regimen salvage therapy for refractory primary hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus infection in 4 children].

Objective: To analyze the efficacy and safety of the L-DEP regimen (asparaginase, liposome doxorubicin, etoposide and methylprednisolone) as a salvage therapy for the refractory primary hemophagocytic lymphohistocytosis triggered by Epstein-Barr virus infection (EBV-pHLH) in children. Methods: In this retrospective case study, clinical and laboratory data before and after L-DEP regimen of 4 children diagnosed with EBV-pHLH in Beijing Children's hospital between January 2016 and June 2022 were collected, and the efficacy and safety of L-DEP regimen for the treatment of EBV-pHLH were analyzed. Results: Among 4 patients, there were 3 females and 1 male with the age ranged from 0.8 to 7.0 years. Two of them showed compound heterozygous mutations of PRF1, one with a heterozygous mutation of UNC13D, one homozygous mutation of ITK. Before the L-DEP therapy, all of them had anemia and a soaring level of soluble CD25, 3 patients had neutropenia and thrombopenia, 3 patients had a high level of ferritin, 3 patients had hypofibrinogenemia and 1 patient had hypertriglyceridemia. After receiving 1 or 2 cycles of L-DEP treatment, three achieved remission, including complete remission (1 case) and partial remission (2 cases), and the other one had no remission. The levels of blood cell counts, soluble CD25, triglyceride, fibrinogen and albumin were recovered gradually in 3 patients who got remission. All four patients underwent hematopoietic stem cell transplantation (HSCT) after L-DEP regimen, and three survived. All patients had no severe chemotherapy related complications. The main side effects were bone marrow suppression, infection and pancreatitis, which recovered after appropriate treatments, apart from one who died from severe infection after urgent HSCT. Conclusion: L-DEP regimen could be served as an effective and safe salvage treatment for refractory pediatric EBV-pHLH, and also provide an opportunity for patients to receive HSCT.

Current and emerging pharmacotherapies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis-like syndrome due to CAR T cell therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of multiple hematologic malignancies. Engineered cellular therapies now offer similar hope to transform the management of solid tumors and autoimmune diseases. However, toxicities can be serious and often require hospitalization. AREAS COVERED: We review the two chief toxicities of CAR T therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and the rarer immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. We discuss treatment paradigms and promising future pharmacologic strategies. Literature and therapies reviewed were identified by PubMed search, cited references therein, and review of registered trials. EXPERT OPINION: Management of CRS and ICANS has improved, aided by consensus definitions and guidelines that facilitate recognition and timely intervention. Further data will define optimal timing of tocilizumab and corticosteroids, current foundations of management. Pathophysiologic understanding has inspired off-label use of IL-1 receptor antagonism, IFNγ and IL-6 neutralizing antibodies, and janus kinase inhibitors, with data emerging from ongoing clinical trials. Further strategies to reduce toxicities include novel pharmacologic targets and safety features engineered into CAR T cells themselves. As these potentially curative therapies are used earlier in oncologic therapy and even in non-oncologic indications, effective accessible strategies to manage toxicities are critical.

Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

Hemophagocytic lymphohistiocytosis after solid organ transplantation: A challenge for clinicians.

Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a high mortality rate and a wide range of symptoms. Solid organ transplantation, which provides patients with a unique immunosuppressive state, is a less common predisposing factor for HLH. HLH after solid organ transplantation (HLH-SOT) is very rare and fatal. It is hard to diagnose and treat and extremely understudied. The use of immunosuppressants makes the situation of HLH-SOT more complex. This review summarizes the existing literature on HLH after solid organ transplantation and describes its triggers and symptoms, focusing on its diagnosis and treatment. We performed a literature search of case reports, case series, letters to the editor, and clinical quizzes describing patients with HLH after solid organ transplantation (HLH-SOT). We provide recommendations on the diagnosis protocol and treatment strategy based on the existing evidence.

Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL is caused by inactivating mutations in proteins that regulate cellular immunity. Here, we used an adeno-associated virus-based CRISPR-Cas9 system with an inhibitor of nonhomologous end joining to repair such mutations in potentially long-lived T cells ex vivo. Repaired CD8 memory T cells efficiently cured lethal hyperinflammation in a mouse model of Epstein-Barr virus-triggered FHL2, a subtype caused by perforin-1 (Prf1) deficiency. Furthermore, repair of PRF1 and Munc13-4 (UNC13D)-whose deficiency causes the FHL subtype FHL3-in mutant memory T cells from two critically ill patients with FHL restored T cell cytotoxicity. These results provide a starting point for the treatment of genetic T cell immune dysregulation syndromes with repaired autologous T cells.

X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India.

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

A Nationwide Retrospective Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Adult Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder characterized by systemic hyperinflammation. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative treatment for primary and relapsed/refractory HLH, the optimal strategy has not been established. We retrospectively analyzed 56 adult patients (≥18 years) with primary and secondary HLH (mainly consisting of Epstein-Barr virus-associated HLH) who underwent allo-HSCT using the registry database of the Japanese Society for Transplantation and Cellular Therapy, including 26 patients who underwent cord blood transplantation (CBT). One-fourth of patients received myeloablative conditioning (MAC), mainly consisting of total body irradiation-based regimens. The 3-year overall survival (OS) was 40.6%, while the 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 19.8% and 39.6%, respectively. In univariable analysis, age at allo-HSCT (the 3-year OS: 27.5% for ≥ 25 years old vs 58.0% for < 25 years old, P = .025), conditioning intensity (7.1% for MAC vs 51.8% for reduced-intensity conditioning (RIC), P = .002), and donor source (26.0% for CBT vs 52.9% for bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), P = .030) were associated with significantly inferior OS. In multivariable analysis, older age at allo-HSCT (≥ 25 years old) (Hazard ratio [HR], 2.37; 95% CI, 1.01 to 5.58; P = .048), MAC (HR, 2.45; 95% CI, 1.09 to 5.53; P = .031), and CBT (HR, 2.21; 95% CI, 1.04 to 4.71; P = .040) were independently associated with worse OS. In addition, only conditioning intensity predicted higher NRM (the 3-year NRM: 78.6% for MAC vs 26.6% for RIC), while no factors were associated with the relapse rate. This study includes the largest number of adult HLH patients undergoing CBT. Although the use of CBT is acceptable, BMT/PBSCT are more favorable strategies in allo-HSCT in adult HLH. Regarding conditioning intensity, RIC regimens are more beneficial in this setting.

Sequential haplo-identical conditioning transplant regimen for pediatric patients with relapsed or refractory hemophagocytic lymphohistiocytosis.

Allogeneic hematopoietic stem cell transplantation (HSCT) currently stands as the sole remedy for individuals afflicted with hemophagocytic lymphohistiocytosis (HLH). In this study, we retrospectively evaluated how pediatric patients with relapsed or refractory (R/R) HLH responded to our institution's cocktail conditioning regimen. The disease was diagnosed according to criteria applicable to patients with familial/genetic, relapsing, or severe/persistent HLH. All donors were HLA haplo-identical family donors. In our cohort, sixty-five patients (P-HLH), including 28 with familial/genetic HLH, 36 with secondary HLH, and 1 with an unknown cause, underwent haplo-identical family donor HSCT. The conditioning regimen consisted of intravenous administration of etoposide (VP-16), busulfan, fludarabine, rabbit anti-human thymocyte globulin (r-ATG), and cyclophosphamide (Cy). Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GvHD) prevention. We observed that the median time for neutrophil recovery was 11 days (range, 8-24), and for platelet counts to exceed 20 × 109/L, it was 14 days (range, 7-130). There were 5 patients (7.7%) who experienced grades III to IV acute GvHD, and 6 patients (9.2%) developed extensive chronic GvHD. The estimated 3- and 5-year overall survival rates were 78.1% (95% CI, 65.8-84.6%) and 74.9% (95% CI, 61.2-84.4%), respectively. The estimated 3- and 5-year event-free survival rates were 73.5% (95% CI, 60.8-82.6%) and 70.3% (95% CI, 56.4-80.5%), respectively. Our findings demonstrate that our innovative conditioning regimen is both effective and safe, offering valuable insights for healthcare professionals evaluating the merits of existing therapies.

Relapsed/Refractory Peripheral T-Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis With UNC13D and CD27 Germline Mutations.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory disease characterized by familial and acquired forms. Here, we present the case of a 26-year-old male patient with relapsed/refractory peripheral T-cell lymphoma and concurrent HLH. Whole-exon sequencing revealed germline mutations associated with HLH, including those in critical genes such as CD27 and UNC13D and other germline heterozygous variants (NOTCH2, NOTCH3, IL2RA, TYK2, AGL, CFD, and F13A1). CD107a analyses consistently demonstrated impaired degranulation of cytotoxic T-lymphocytes and natural killer (NK) cells. Examination of the patient's family pedigree revealed that his father and mother harbored UNC13D and CD27 mutations, respectively; his brother carried the same CD27 heterozygous mutation. However, none of them manifested the disease. Despite the missense mutation of CD27 (c.779C>T; p.Pro260Leu) lacking previous documentation in databases, comprehensive analysis suggested non-pathogenic mutations in the CD27 variant, indicating minimal impact on T- and NK-cell functions. These results ultimately supported the option of hematopoietic stem cell transplantation (HSCT) as a successful curative therapeutic approach. As of this report, the patient has remained free of lymphoma and quiescent HLH 15.2 months post-HSCT. This study underscores the efficacy of genetic tests in identifying significant mutations and confirming their etiologies, providing an early basis for treatment decisions and the selection of suitable transplant donors.

Genetic and clinical characteristics of primary hemophagocytic lymphohistiocytosis in children.

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21 years (0.17-12.92 years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10-30 days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.

BACKGROUND: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. OBJECTIVE: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. METHODS: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. RESULTS: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003). CONCLUSIONS: HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Gene editing of hematopoietic stem cells restores T-cell response in familial hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for approximately 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene that result in impaired degranulation of cytotoxic vesicles and hence compromised T-cell- and natural killer-cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show high mortality. OBJECTIVE: We sought to develop and evaluate a curative genome editing strategy in the preclinical FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site in Unc13d intron 26 and develop clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV). METHODS: We employed clustered regularly interspaced short palindromic repeats (CRISPR)-Cas technology to delete the disease-causing mutation in HSCs and transplanted Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Safety studies included extensive genotyping and chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing (CAST-Seq)-based off-target analyses. Cure from HLH predisposition was assessed by LCMV infection. RESULTS: Hematopoietic cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T-cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wild-type cells were comparable. While LCMV challenge resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH. CONCLUSIONS: Our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T-cell response in the absence of genotoxicity-associated clonal outgrowth.

Characterization of Human Engraftment and Hemophagocytic Lymphohistiocytosis in NSG-SGM3 Neonate Mice Engrafted with Purified CD34+ Hematopoietic Stem Cells.

Immunodeficient mice bearing human immune systems, or "humanized" chimeric mice, are widely used in basic research, along with the preclinical stages of drug development. Nonobese diabetic-severe combined immunodeficiency (NOD-SCID) IL2Rγnull (NSG) mice expressing human stem cell factor, granulocyte-macrophage colony stimulating factor, and interleukin-3 (NSG-SGM3) support robust development of human myeloid cells and T cells but have reduced longevity due to the development of fatal hemophagocytic lymphohistiocytosis (HLH). Here, we describe an optimized protocol for development of human immune chimerism in NSG-SGM3 mice. We demonstrate that efficient human CD45+ reconstitution can be achieved and HLH delayed by engraftment of neonatal NSG-SGM3 with low numbers of human umbilical cord-derived CD34+ hematopoietic stem cells in the absence of preconditioning irradiation.

[Hemophagocytic lymphohistiocytosis: A retrospective analysis of 66 patients]. / Lymphohistiocytose hémophagocytaire : analyse rétrospective de 66 patients.

CONTEXT: Hemophagocytic lymphohistiocytosis is a rare syndrome with a poor prognosis, characterized by an uncontrolled dysregulation of the immune system. The rarity of this disease makes it difficult to obtain large cohorts. In this study, we analyzed the data of 66 patients: the objective was to describe the epidemiological, clinical, biological and therapeutic characteristics and to compare our results with those already published. METHODS: We conducted a retrospective study at the University Hospital of Montpellier from 2015 to 2021. Patients were included when the diagnosis of HLH was mentioned on the hospitalization report and when the HSCORE was higher than 50% (169). Prognostic analyses were performed by comparing the patients who died from HMH to those who didn't. RESULTS: The mean age the 66 patients included was 49.2 years, 62% were men. The percentage of deaths was 45.9%. Lymphoma was the main etiology, followed by infections, then autoimmune/autoinflammatory diseases. Fever, splenomegaly, hepatomegaly and organ failure were the main clinical manifestations. Pancytopenia was present in 62% of cases. Ferritin, triglycerides, LDH and AST were highly increased. Advanced age, associated lymphoma, and the severity of cytopenias were linked to a poor prognosis. DISCUSSION: The study of the clinico-biological, epidemiological and survival data of the patients in our cohort allowed us to confirm previously published data but also to discuss some of them.

Hemophagocytic lymphohistiocytosis: A disorder of T cell activation, immune regulation, and distinctive immunopathology.

Hemophagocytic lymphohistiocytosis (HLH) is a disorder that has been recognized since the middle of the last century. In recent decades, increasing understanding of the genetic roots and pathophysiology of HLH has led to improved diagnosis and treatment of this once universally fatal disorder. HLH is best conceptualized as a maladaptive state of excessive T cell activation driving life-threatening myeloid cell activation, largely via interferon-gamma (IFN-γ). In familial forms of HLH (F-HLH), inherited defects of lymphocyte cytotoxic biology underlie excessive T cell activation, demonstrating the importance of the perforin/granzyme pathway as a negative feedback loop limiting acute T cell activation in response to environmental factors. HLH occurring in other contexts and without apparent inherited genetic predisposition remains poorly understood, though it may share some downstream aspects of pathophysiology including excessive IFN-γ action and activation of innate immune effectors. Iatrogenic forms of HLH occurring after immune-activating therapies for cancer are providing new insights into the potential toxicities of inadequately controlled T cell activation. Diagnosing HLH increasingly relies on context-specific measures of T cell activation, IFN-γ activity, and inflammation. Treatment of HLH largely relies on cytotoxic chemotherapy, though targeted therapies against T cells, IFN-γ, and other cytokines are increasingly utilized.

Inflamed-HLH, MAS, or something else?

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive and maladaptive inflammation. Primary HLH is most frequently encountered in young children, and, without timely recognition and therapy, can lead to multiorgan failure and death. It is most often diagnosed using the HLH-2004 criteria and by identifying pathological mutations. However, the HLH-2004 criteria are not specific for HLH, and patients can easily fulfill these diagnostic criteria in other proinflammatory states in which HLH-therapy would not be indicated, including hematologic malignancies, infections, and rheumatologic disease. Therefore, great care must be taken to ensure that the specific disease associated with features of HLH is accurately recognized, as consequences of improper treatment can be catastrophic. We propose a diagnostic pathway for patients for whom HLH is on the differential (visual abstract). Importantly, in situations in which the initial diagnostic workup is equivocal or unrevealing, reevaluation for occult malignancy, infection, or rheumatologic disease would be prudent, as occult presentations may be missed on primary evaluation. Temporizing medications can be used in critically ill patients while awaiting secondary evaluation. By using this framework, clinicians will be able to more reliably discern primary HLH from other pro-inflammatory states and thus provide timely, appropriate disease-specific therapy.

Inpatient recognition and management of HLH.

Hemophagocytic lymphohistiocytosis (HLH) is one of the life-threatening emergencies that a hematologist may be called upon to diagnose and manage. It is a hyperinflammatory process that develops in patients with genetic abnormalities, hematologic malignancies, chronic inflammatory states, or infections. The main clinical challenges are recognizing HLH, determining whether the immune response is aberrant or appropriate, and deciding upon therapy. Patients may present with fever, central nervous system symptoms, cytopenias, or elevated liver enzymes. Recognizing HLH is challenging because its features overlap with numerous systemic disorders, thus requiring a high level of suspicion and timely investigations to confirm the diagnosis and detect the underlying trigger. Once HLH is diagnosed, careful consideration of immunosuppressive therapy's potential benefit versus harm is necessary. Such therapy can sometimes be tailored to the underlying trigger. In the acute setting, the competing pressures of completing a thorough diagnostic process (including evaluation for the presence of lymphoma and infection) and the need for expedited treatment must be balanced. During the management of an HLH patient, continuous vigilance for the presence of as-yet unrecognized disease triggers, monitoring response, and identifying emerging complications is critical. This review will discuss the recognition and management of HLH in the inpatient setting.