Adult hemophagocytic lymphohistiocytosis causing multi organ dysfunction in a patient with multiple autoimmune disorders: when the immune system runs amok.
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ABSTRACT:
SUBMITTER: Fleischmann R
PROVIDER: S-EPMC4736532 | biostudies-other | 2016 Feb
REPOSITORIES: biostudies-other
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Project description:Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative.
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Project description:BackgroundCoagulation disorders are common in patients with hemophagocytic lymphohistiocytosis (HLH), associated with an increased risk of bleeding and death. We aim to investigate coagulation disorders and their outcome implications in critically ill patients with HLH.MethodsWe prospectively evaluated 47 critically ill patients with HLH (median age of 54 years [42-67]) between April 2015 and December 2018. Coagulation assessments were performed at day 1. Abnormal standard coagulation was defined as prothrombin time (PT) <50% and/or fibrinogen <2g/L. HLH aetiology was mostly ascribed to haematological malignancies (74% of patients).ResultsCoagulation disorders and severe bleeding events were frequent, occurring in 30 (64%) and 11 (23%) patients respectively. At day 1, median fibrinogen level was 2∙65g/L [1.61-5.66]. Fibrinolytic activity was high as suggested by increased median levels of D-dimers, fibrin monomers, PAI-1 (plasminogen activator inhibitor) and tPA (tissue plasminogen activator). Forty-one (91%) patients had a decreased ADAMTS13 activity (A Disintegrin-like And Metalloproteinase with ThromboSpondin type 1 repeats, member 13). By multivariable analysis, the occurrence of a severe bleeding (OR 3.215 [1.194-8.653], p = 0∙021) and SOFA score (Sepsis-Related Organ Failure Assessment) at day 1 (OR 1.305 per point [1.146-1.485], p<0∙001) were independently associated with hospital mortality. No early biological marker was associated with severe bleeding.ConclusionsHyperfibrinolysis may be the primary mechanism responsible for hypofibrinogenemia and may also participate in ADAMTS13 degradation. Targeting the plasmin system appears as a promising approach in severe HLH-related coagulation disorders.
| S-EPMC8330932 | biostudies-literature
Project description:IntroductionHemophagocytic lymphohistiocytosis (HLH) is a clinicopathologic syndrome produced by dysregulated activation of the immune system. Acute kidney injury (AKI) and proteinuria have been infrequently described in the setting of HLH, and investigations of underlying histopathologic changes in the kidney are limited.MethodsTo characterize kidney pathology in HLH, a retrospective review of 30 patients' clinical and laboratory data, and kidney tissue was performed (18 from autopsy, and 12 biopsied patients).ResultsHLH was associated with infection (83%), autoimmune disease (37%), and malignancy (20%), including 30% with concurrent autoimmune disease and infection. Nephrological presentations included subnephrotic range proteinuria (63%), AKI (63%), hematuria (33%), chronic kidney disease (CKD, 20%), nephrotic range proteinuria (13%), and nephrotic syndrome (7%); and 40% of patients required hemodialysis (HD). Among the 12 patients who underwent kidney biopsy, 6 subsequently showed improved kidney function and the remainder had progressive CKD with most progressing to end-stage kidney disease. Autopsy patients had a median terminal admission of 1 month, and 33% of the biopsied patients died (ranging from 0.3-5 months post-biopsy). Variable pathologies were identified, including acute tubular injury (ATI, 43%), lupus nephritis (LN, 23%), collapsing glomerulopathy (17%), thrombotic microangiopathy (TMA, 17%), and cortical necrosis (10%). Most autopsied patients had significant kidney pathology other than ATI that likely contributed to kidney function decline. A majority of patients with HLH exhibited kidney dysfunction that likely contributed to the poor prognosis.ConclusionKidney dysfunction in HLH should not be assumed to be solely attributable to ATI, and in certain scenarios a kidney biopsy may be warranted.
| S-EPMC10851018 | biostudies-literature
Project description:Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic hyperinflammation. It may occur as a genetic or sporadic condition, often triggered by an infection. The multifaceted pathogenesis results in a wide range of non-specific signs and symptoms, hampering early recognition. Despite a great improvement in terms of survival in the last decades, a considerable proportion of patients with HLH still die from progressive disease. Thus, prompt diagnosis and treatment are crucial for survival. Faced with the complexity and the heterogeneity of syndrome, expert consultation is recommended to correctly interpret clinical, functional and genetic findings and address therapeutic decisions. Cytofluorimetric and genetic analysis should be performed in reference laboratories. Genetic analysis is mandatory to confirm familial hemophagocytic lymphohistiocytosis (FHL) and Next Generation Sequencing is increasingly adopted to extend the spectrum of genetic predisposition to HLH, though its results should be critically discussed with specialists. In this review, we critically revise the reported laboratory tools for the diagnosis of HLH, in order to outline a comprehensive and widely available workup that allows to reduce the time between the clinical suspicion of HLH and its final diagnosis.
| S-EPMC10324660 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multiorgan failure, and other manifestations. The syndrome has a high mortality rate. More and more, it is recognized that while HLH can be appropriately used as a broad summary diagnosis, many pediatric patients actually suffer from an expanding spectrum of genetic diseases that can be complicated by the syndrome of HLH. Classic genetic diseases in which HLH is a typical and common manifestation include pathogenic changes in familial HLH genes (PRF1, UNC13D, STXBP2, and STX11), several granule/pigment abnormality genes (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4, CDC42, and the Epstein-Barr virus susceptibility diseases. There are many other genetic diseases in which HLH is an infrequent complication of the disorder as opposed to a prominent manifestation of the disease caused directly by the genetic defect, including other primary immune deficiencies and inborn errors of metabolism. HLH can also occur in patients with underlying rheumatologic or autoinflammatory disorders and is usually designated macrophage activation syndrome in those settings. Additionally, HLH can develop in patients during infections or malignancies without a known (or as-yet-identified) genetic predisposition. This article will attempt to summarize current concepts in the pediatric HLH field as well as offer a practical diagnostic and treatment overview.
| S-EPMC8212354 | biostudies-literature
Project description:BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH. HLH patients usually fulfill multiple but not all eight diagnostic criteria. Different combinations of the fulfilled criteria may naturally cluster into previously undescribed subsets or phenotypes that may have different pathophysiology and demonstrate different risks for a poor outcome. The objectives of this study were to identify HLH subgroups according to the fulfillment of diagnostic criteria and evaluate the risk of multiple organ dysfunction syndrome (MODS) and 30-day mortality for subgroups. We retrospectively collect medical records of patients with discharge diagnosis of HLH between June 2015 and October 2018 from a tertiary children's hospital in China. Latent class analysis was used to identify class defining variables from HLH diagnostic items, and subgroups were defined according to different combinations of the class defining variables.ResultsTriglyceride and fibrinogen were identified as the class defining variables. When evaluated in combinations, patients with hypertriglyceridemia and normal fibrinogen levels during hospitalization had the lowest risks for MODS (27.8%, OR = 1) and 30-day mortality (18.8%, OR = 1), and patients with normal triglyceride and hypofibrinogenemia had the highest risks for MODS (86.2%, OR = 16.24, P = 0.0002) and 30-day mortality (57.1%, OR = 5.78, P = 0.0187). The fulfillment status of hypertriglyceridemia and hypofibrinogenemia within 72 h of hospital admission was also associated with the risk of adverse outcomes.ConclusionsThe fulfillment status of hypertriglyceridemia and hypofibrinogenemia were associated with the risks of MODS and 30-day mortality among pediatric HLH patients. Further studies are needed to validate this association and investigate its clinical utility in the severity evaluation for HLH.
| S-EPMC8996201 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.
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Project description:The human immune system depends on the activity of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells in order to fight off a viral infection. Understanding the molecular mechanisms during this process and the role of individual proteins was greatly improved by the study of familial hemophagocytic lymphohistiocytosis (FHL). Since 1999, genetic sequencing is the gold standard to classify patients into different subgroups of FHL. The diagnosis, once based on a clinical constellation of abnormalities, is now strongly supported by the results of a functional flow-cytometry screening, which directs the genetic study. A few additional congenital immune deficiencies can also cause a resembling or even identical clinical picture to FHL. As in many other rare human disorders, the collection and analysis of a relatively large number of cases in registries is crucial to draw a complete picture of the disease. The conduction of prospective therapeutic trials allows investigators to increase the awareness of the disease and to speed up the diagnostic process, but also provides important functional and genetic confirmations. Children with confirmed diagnosis may undergo hematopoietic stem cell transplantation, which is the only cure known to date. Moreover, detailed characterization of these rare patients helped to understand the function of individual proteins within the exocytic machinery of CTL, NK, and NKT cells. Moreover, identification of these genotypes also provides valuable information on variant phenotypes, other than FHL, associated with biallelic and monoallelic mutations in the FHL-related genes. In this review, we describe how detailed characterization of patients with genetic hemophagocytic lymphohistiocytosis has resulted in improvement in knowledge regarding contribution of individual proteins to the functional machinery of cytotoxic T- and NK-cells. The review also details how identification of these genotypes has provided valuable information on variant phenotypes.
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Project description:BackgroundA20 haploinsufficiency (HA20) is a newly introduced autosomal dominant autoinflammatory disorder, also known as Behcet's-like disease. Some of the most common symptoms of the disease are recurrent oral, genital, and/or gastrointestinal (GI) ulcers, episodic fever, musculoskeletal symptoms, cutaneous lesions, and recurrent infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of multi-organ failure due to excessive immune activation. HLH has been reported in a few HA20 patients. Herein, we report two children with the primary presentation of HLH, with a mutation in TNFAIP3, in favor of HA20.Case presentationsOur first patient was a 4-month-old boy who presented with fever, irritability, pallor, and hepatosplenomegaly. Pancytopenia, elevated ferritin, and decreased fibrinogen levels were found in laboratory evaluation. He was diagnosed with HLH and was treated with methylprednisolone and cyclosporine. Two years later, whole exome sequencing (WES) indicated a mutation in TNFAIP3 at NM_001270507: exon3: c.C386T, p.T129M, consistent with A20 haploinsufficiency. Etanercept, a TNF inhibitor, was prescribed, but the parents were reluctant to initiate the therapy. The patient passed away with the clinical picture of cerebral hemorrhage. The second patient was a 3-month-old boy who presented with a fever and hepatosplenomegaly. Laboratory evaluation found pancytopenia, hyperferritinemia, hypoalbuminemia, hypertriglyceridemia, and hypofibrinogenemia. With the establishment of the HLH diagnosis, he was treated with etoposide, dexamethasone, and cyclosporine, and recovered. WES results revealed a heterozygous de novo variant of TNFAIP3 (c. T824C in exon 6, 6q23.3) that leads to a proline to leucine amino acid change (p. L275P). He was treated with etanercept and has been symptom-free afterward.ConclusionsThis report is a hypothesis for developing of the HLH phenotype in the presence of TNFAIP3 mutation. Our results provide a new perspective on the role of TNFAIP3 mutation in HLH phenotypes, but more extensive studies are required to confirm these preliminary results.
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Project description: Not available
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