Hemophagocytic syndromes — An update

doi:10.1016/j.blre.2014.03.002

Blood Reviews

Volume 28, Issue 4, July 2014, Pages 135-142

https://doi.org/10.1016/j.blre.2014.03.002 Get rights and content

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome and not an independent disease. HLH represents the extreme end of a severe uncontrolled hyperinflammatory reaction that can occur in many underlying conditions. Genetic forms of HLHs are due to defects in transport, processing and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes, and are not restricted to manifestation in childhood. Acquired forms of HLH are encountered in infections, autoinflammatory and autoimmune diseases, malignancies, acquired immune deficiency. Functional tests allow for differentiation between genetic and acquired HLH. Treatment aims at suppressing hypercytokinemia and eliminating activated and infected cells. It includes immunomodulatory and immunosuppressive agents, cytostatics, T-cell and cytokine antibodies. In genetic HLH cure can only be achieved with hematopoietic stem cell transplantation. Reduced-intensity conditioning regimens have considerably improved survival.

Introduction

Hemophagocytic syndromes, also called hemophagocytic lymphohistiocytosis (HLH) have experienced a steadily growing attention over the past 10 years. More than 1500 publications on this topic have appeared since 2004. Hemophagocytic syndromes are found in all age groups. Genetic forms, formerly thought to be restricted to children, are now reported with increasing frequency also in adults. Underlying conditions, predisposing to HLH, encompass malignancies, autoinflammatory and autoimmune diseases, metabolic diseases and acquired immune deficiencies such as AIDS, iatrogenic immune suppression and organ or stem cell transplantation. This paper is an update of the review on hemophagocytic syndromes which appeared in this journal in 2007 [1].

Section snippets

What is HLH?

HLH is a clinical syndrome, caused by severe hypercytokinemia due to a highly stimulated but ineffective immune response. HLH is not a disease by its own; it has to be viewed as the consequence of an inherited or acquired inability of the immune system to cope with a trigger which in most cases is an infectious agent.

Clinical symptoms and laboratory findings

Cardinal symptoms of HLH are prolonged fever, hepatosplenomegaly and pancytopenia. Characteristic laboratory values include increased ferritin, triglycerides, transaminases, bilirubin, lactate dehydrogenase, soluble interleukin-2 receptor α-chain, and decreased fibrinogen (Table 1). Symptoms of HLH reflect immune activation and hypercytokinemia [1]: fever is caused by interleukins and tumor necrosis factor (TNF). Cytokines suppress lipoprotein lipase [2] and hematopoiesis. Activated macrophages

Classification of HLH

HLH may have genetic causes (Table 2) or may be acquired under a variety of conditions in the presumed absence of a predisposing genetic condition. In infants and very young children, HLH is predominantly but not exclusively due to immune defects with mutations in genes responsible for cytotoxic function of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Genetic diseases can manifest with HLH throughout life, but beyond toddler age the leading causes of HLH are infections,

Pathogenesis

Whereas many publications have contributed to our knowledge of the pathogenesis of genetic HLH, the processes leading to acquired HLH still remain a matter for speculation.

Diagnosis

An extensive review dedicated only to the diagnostic work-up in HLH has been recently published [23]. Eventually, the following questions must be answered:

•
Are clinical and laboratory parameters compatible with the acute syndrome HLH?
•
Is there an underlying triggering condition?
•
Is there a hereditary predisposition?

HLH-directed treatment

Before the identification of effective treatment, the full picture of HLH was invariably fatal. In the 1980s, epipodophyllin toxin derivatives including etoposide with glucocorticosteroids were successfully used to induce remission in HLH patients. A decade later the first international study was established (HLH-1994) for both hereditary and acquired HLH with etoposide and dexamethasone, followed by a maintenance therapy (cyclosporin A and pulses of etoposide and dexamethasone) for patients

Conclusions

Several aspects of HLH have led to growing fascination of both clinical and laboratory researchers during the past decades: the mesmerizing ambiguity of too much and too little immune system at the same time; the multitude of conditions in which an identical inflammatory picture can be found; the complexity of genetic disorders that not only affect immunity but also overlap with other systems; and not least, the confirmation that cooperative international work in clinical and basic research has

Acknowledgements

The authors would like to thank Stephan Ehl for the critical discussion of the manuscript; Ingo Müller and Udo zur Stadt for the constant scientific input; Sandra Standke, Manuela Adao and Anke Clodius for their steady support in the documentation and lab work.

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Cited by (347)

Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation
2024, Blood
Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival
2024, Blood
We evaluated malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) in Sweden regarding population-based incidence, clinical features, and survival. From 1997 to 2018, we identified 307 adults (≥18 years old) and 9 children (209 males, 107 females; P < .001) with both an HLH-related diagnosis and malignant disease, corresponding to 0.19 per 100 000 adults annually (0.15/100 000 for the entire population), increasing from 0.026 (1997-2007) to 0.34 (2008-2018) (P < .001). In the latest 7-year period (2012-2018), the annual incidence was 0.45 per 100 000 adults (n = 246). This incidence varied between the 6 health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100 000 adults annually (P < .001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies, with the highest proportion (2.5%) in young males. Among the 316 patients, the 1-month probability of survival, likely representing the HLH episode, increased significantly from 52% (95% confidence interval [CI], 40-63) (1997-2007) to 71% (95% CI, 65-76) (2008-2018), whereas 2-year survival remained poor (25%; 95% CI, 20-30). Altogether, 52% were lymphomas, 29% leukemias, 8% other hematological malignancies, and 11% solid tumors. Males were more affected than females by mal-HLH, also taking the over-representation of males with hematological malignancies into account (P = .0012). Validation by medical-file reviews revealed 13% over-reporting of HLH. We conclude that the annual mal-HLH incidence has increased 10-fold and was at least 0.71 per 100 000 adults from 2012 to 2018, that is, 0.62 per 100 000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.
Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants
2024, Journal of Allergy and Clinical Immunology
The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear.
We sought to assess a potential link between HLHa outcomes and HLH-related gene variants.
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.
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).
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
2024, Journal of Allergy and Clinical Immunology
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.
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).
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.
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.
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.
Predictive model for early death risk in pediatric hemophagocytic lymphohistiocytosis patients based on machine learning
2023, Heliyon
Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening disease in children, with a high early mortality rate. This study aimed to construct machine learning model to predict the risk of early death using clinical indicators at the time of HLH diagnosis.
This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data was collected from pediatric HLH patients diagnosed by the HLH-2004 protocol between January 2006 and December 2022. Six machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction.
The study included 587 pediatric HLH patients, and the early mortality rate was 28.45 %. The logistic and XGBoost model with the best performance after feature screening were selected to predict early death of HLH patients. The logistic model had an AUC of 0.915 and an accuracy of 0.863, while the XGBoost model had an AUC of 0.889 and an accuracy of 0.829. The risk factors most associated with early death were the absence of immunochemotherapy, decreased TC levels, increased BUN and total bilirubin, and prolonged TT. We developed an online calculator tool for predicting the probability of early death in children with HLH.
We developed the first web-based early mortality prediction tool for pediatric HLH to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200061315).
MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity
2023, Blood Advances
Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype.

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REVIEWHemophagocytic syndromes — An update

Abstract

Introduction

Section snippets

What is HLH?

Clinical symptoms and laboratory findings

Classification of HLH

Pathogenesis

Diagnosis

HLH-directed treatment

Conclusions

Acknowledgements

J Autoimmun

Blood

Blood

Blood

Blood

Clin Immunol

Lancet

Injury

Blood

Blood

J Pediatr

Cell

Blood

Blood

Blood

Blood

J Pediatr

Blood

Blood

J Immunol Methods

Blood

Blood

Blood

Biol Blood Marrow Transplant

Familial and acquired hemophagocytic lymphohistiocytosis

Eur J Pediatr

Lipoprotein alterations and plasma lipoprotein lipase reduction in familial hemophagocytic lymphohistiocytosis

Acta Paediatr Scand

The macrophage and fibrinolysis

Semin Thromb Hemost

GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis

Pediatr Blood Cancer

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

Haematologica

MUNC13-4 protein regulates the oxidative response and is essential for phagosomal maturation and bacterial killing in neutrophils

J Biol Chem

Nationwide survey of hemophagocytic lymphohistiocytosis in Japan

Int J Hematol

Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virus-associated hemophagocytic syndrome

J Clin Invest

Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin

Pediatr Blood Cancer

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood

Korean J Pathol

Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis

Eur J Haematol

Haemophagocytic syndrome in rheumatic patients A systematic review

Eur Rev Med Pharmacol Sci

Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice

J Clin Invest

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Genes Immun

Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis

Br J Haematol

Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation

Swiss Med Wkly

Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis

Aids

Hemophagocytic syndrome in renal transplant recipients: report of 17 cases and review of literature

Transplantation

Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation

Bone Marrow Transplant

Hemophagocytic syndrome in a 4-month-old infant with biotinidase deficiency

Pediatr Blood Cancer

Cobalamin C disease presenting with hemophagocytic lymphohistiocytosis

Pediatr Hematol Oncol

Secondary hemophagocytosis in 3 patients with organic acidemia involving propionate metabolism

Pediatr Hematol Oncol

REVIEW
Hemophagocytic syndromes — An update