Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease in which hyperactivation of the immune takes place, resulting in genetic mutation and causing infection. It also triggers neoplastic (cancerous) growth and inflammation. The main causative agent for this disease is the release of inflammatory cytokines. Other causative agents for HLH are infections, auto-immune disorders, and malignancy. The symptoms of HLH are:
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High persistent fever.
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Enlargement in the size of the spleen (hepatosplenomegaly).
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Low count of blood.
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Elevated levels of enzymes.
Prompt diagnosis and treatment are required as this disease remains under-recognized. The mortality rate of patients with HLH is high. This article provides a comprehensive overview of HLH syndromes, incorporating updates on pathogenesis, classification, diagnosis, and therapy.
What Is Hemophagocytic Lymphohistiocytosis?
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease. HLH is treated with chemotherapy. It can also be treated with a glucocorticoid or cyclosporin A. It is important to address the underlying trigger for other forms of HLH. HLH is characterized by the uncontrolled activation of cytotoxic lymphocytes and macrophages, leading to cytokine-mediated tissue damage and dysfunction in multiple organs. Untreated HLH is fatal; therefore, early recognition and prompt treatment are crucial for patient survival. Clinical manifestations include rapid deterioration, fever, hepato-splenomegaly, coagulopathy, hepatic injury, blood cytopenia, hyperferritinemia, and reduced or absent NK cytolytic activity. While well-established diagnostic criteria exist for F-HLH, effective criteria for secondary HLH are currently under development based on epidemiological and mechanistic studies.
What Are the Causes of Hemophagocytic Lymphohistiocytosis?
Key soluble mediators in HLH immunopathology include interferon-gamma (IFN-g), interleukin (IL)-1b, and IL-18. When HLH occurs within rheumatological diseases like systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (ASD), or systemic lupus erythematosus (SLE), it is commonly referred to as macrophage activation syndrome (MAS). Recent findings indicate that heterozygous or low-penetrance mutations in F-HLH-associated genes play a role in the pathogenesis of some secondary HLH and MAS cases.
What Are the Types of Hemophagocytic Lymphohistiocytosis?
Traditionally, HLH has been categorized into primary or familial (F-HLH) and secondary or sporadic or reactive forms.
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Familial HLH (F-HLH) - F-HLH is an inheritable condition caused by highly penetrant genetic mutations affecting cytolytic functions, lymphocyte survival, or inflammasome activation.
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Secondary HLH - Secondary HLH is primarily triggered by acquired factors like chronic inflammation, infection, or malignancy. Secondary HLH was first described in 1979 by Risdall et al., who proposed that viral infections in immunocompromised hosts are induced by dysregulation of the immune system.
This classification system fails to inform the treatment and prognosis of HLH. Therefore, the North American Consortium for Histiocytosis introduced a new classification system based on diagnostic criteria.
The following are the classifications of HLH based on clinically recognizable categories:
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Familial HLH.
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M-HLH - HLH associated with malignancy is called M-HLH.
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Rh-HLH - HLH associated with rheumatic conditions is called Rh-HLH. It is also called MAS.
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Rx-HLH - HLH occurring after certain immune-activating therapies or with drug hypersensitivity is called Rx-HLH.
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IC-HLH - HLH occurs with immune compromise, either primary or acquired, which is called IC-HLH.
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HLH-NOS - HLH, which is not associated with other specific conditions, is called HLH-NOS.
What Are the Symptoms of Hemophagocytic Lymphohistiocytosis?
HLH is a clinical syndrome consisting of several disease entities. Traditionally, patients have fever, hepatosplenomegaly, and cytopenias. These symptoms are often accompanied by laboratory findings such as hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, liver dysfunction, transaminitis, elevated bilirubin, low or absent NK cell activity, and elevated cytokines, particularly soluble interleukin-2 receptor (sIL-2r). Furthermore, neurologic involvement may manifest as asymptomatic radiographic abnormalities, excessive protein or pleocytosis in the CSF, or clinical signs such as seizures, encephalopathy, etc. Furthermore, hemophagocytosis is not always present at diagnosis and may be absent in more than half of individuals with symptomatic HLH, even if it can occasionally be seen histopathologically in the spleen, lymph nodes, bone marrow, liver, or cerebrospinal fluid. Given that the understanding of Nikiforov et al. contrasted the clinical presentation of pediatric and adult-onset HLH because the information about the diagnosis and clinical presentation comes from earlier pediatric literature. While the frequency of splenomegaly and fever were similar in adults, the frequency of hepatomegaly varied (18 to 67 percent) in adults compared to 95 percent in children. The laboratory results showed differences in the frequencies of hypofibrinogenemia, renal failure, and hypoalbuminemia but similarities in the frequencies of cytopenias, hypertriglyceridemia, ferritin, sIL-2r, liver dysfunction, and hemophagocytosis. Evaluation of CSF pleocytosis and low/absent NK cell activity was not possible due to low reporting.
What Is the Treatment of Hemophagocytic Lymphohistiocytosis?
Treatment for F-HLH involves cytotoxic and immunosuppressive agents as a bridge to life-saving hematopoietic stem cell transplantation (HSCT). MAS is treated with high-dose intravenous corticosteroids (CS) and targeted IL-1 blockade. In other forms of secondary HLH, identifying and addressing disease triggers such as infection, drugs, or malignancy is a critical aspect of therapy. Despite significant progress in the last two decades, mortality in HLH, particularly in adult forms, remains unacceptably high. Therefore, there is an urgent need for improved classification systems, more accurate diagnostic tools, and more effective and less toxic therapies. These advancements will stem from an enhanced understanding of the cellular and molecular foundations of HLH.
The five main tenets of current HLH therapy are as follows:
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Reducing hyperinflammation with Cyclosporin A, corticosteroids, and/or cytokine-targeting medications.
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Eliminating activated immune cells with Etoposide, corticosteroids, and/or antithymocyte globulin (ATG).
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Treating infectious agents with targeted antimicrobials.
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Replacing the immune system with HCT in primary, refractory, or recurrent HLH.
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Providing supportive care through prophylactic antimicrobials and transfusions.
Conclusion
The prompt and sensitive diagnostic tool should be used in the diagnosis of hemophagocytic lymphohistiocytosis due to the high mortality rate in HLH. The prognosis of the disease is poor despite the use of new therapeutic agents. Enhanced comprehension of the cellular and molecular mechanisms of HLH will lead to the development of safer and more efficient therapies. It is essential to coordinate future initiatives aimed at creating evidence-based, customized therapies to enhance outcomes for this often overlooked and diverse entity.
