What causes hlh in adults

Overview

Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening syndrome characterized by widespread inflammation and organ damage caused by an overactive immune system. Normally, the immune system effectively eliminates pathogens and abnormal cells. In HLH, this system goes into overdrive, leading to a cytokine storm – an excessive release of inflammatory signaling molecules. This storm activates immune cells, such as macrophages and cytotoxic T lymphocytes, which then engulf healthy blood cells (a process called hemophagocytosis) in the bone marrow, spleen, liver, and lymph nodes. This destruction of blood cells leads to cytopenias (low counts of red blood cells, white blood cells, and platelets), contributing to anemia, increased susceptibility to infections, and bleeding problems.

What Causes HLH in Adults?

Unlike primary HLH, which is caused by genetic defects in immune regulation and usually presents in infancy, HLH in adults is most often secondary HLH. This means it is triggered by an acquired condition rather than an inherited one. The adult immune system, while generally robust, can be overwhelmed by various insults, leading to the dysregulation seen in HLH. The causes can be broadly categorized as follows:

1. Infections

Infections are the most common precipitating factor for secondary HLH in adults. The immune system's attempt to fight off the pathogen can become uncontrolled, leading to the HLH cascade. Viral infections are particularly notorious:

• Viral Infections: Epstein-Barr virus (EBV) is a very common trigger, often leading to infectious mononucleosis which can then precipitate HLH. Other viruses implicated include cytomegalovirus (CMV), herpes simplex virus (HSV), parvovirus B19, and even HIV.
• Bacterial Infections: Severe bacterial infections like sepsis, tuberculosis, and staphylococcal infections can also trigger HLH.
• Fungal and Parasitic Infections: Less common, but still possible, are triggers like Pneumocystis jirovecii pneumonia (PCP) or disseminated fungal infections.

2. Malignancies (Cancers)

Cancer is another major cause of HLH in adults, with estimates suggesting it accounts for up to 50% of secondary HLH cases. The presence of cancer can directly trigger HLH through tumor-associated inflammation or indirectly by weakening the immune system, making it more susceptible to other triggers like infections.

• Hematologic Malignancies: Lymphomas (especially Hodgkin and non-Hodgkin lymphoma), leukemias (acute myeloid leukemia, acute lymphoblastic leukemia), and myelodysplastic syndromes are strongly associated with HLH. The malignant cells themselves can sometimes exhibit hemophagocytic activity or induce it in other immune cells.
• Solid Tumors: While less common than hematologic malignancies, HLH can also be triggered by solid tumors such as gastric cancer, breast cancer, or neuroblastoma.

3. Autoimmune Diseases (Autoinflammatory Conditions)

Adults with pre-existing autoimmune or autoinflammatory conditions are at an increased risk of developing HLH. The chronic inflammation associated with these diseases can predispose the immune system to dysregulation.

• Systemic Lupus Erythematosus (SLE): Lupus is a well-recognized trigger for HLH.
• Rheumatoid Arthritis (RA): Severe or treatment-resistant RA can sometimes be associated with HLH.
• Adult-Onset Still's Disease (AOSD): This inflammatory condition shares many features with HLH and can directly lead to or mimic it.
• Dermatomyositis/Polymyositis: Inflammatory muscle diseases can also be associated.

4. Other Causes

A variety of other factors can precipitate HLH in adults:

• Immunosuppression and Immunomodulation: Ironically, treatments aimed at suppressing the immune system (e.g., post-transplant immunosuppression) or certain immunomodulatory drugs can sometimes trigger HLH.
• Reactions to Medications: Certain drugs can cause HLH as a rare side effect.
• Pregnancy: HLH can occur during pregnancy, potentially related to hormonal changes or the immune system's adaptation.
• Trauma or Surgery: Significant physiological stress from major surgery or trauma can, in rare instances, trigger HLH.

Primary vs. Secondary HLH in Adults

While primary HLH (due to genetic mutations affecting immune cell function) is rare in adults, it does occur. These genetic defects impair the ability of T cells and NK cells to kill target cells, leading to persistent immune activation. However, the vast majority of adult HLH cases are secondary, meaning they are triggered by one of the acquired conditions listed above. Distinguishing between primary and secondary HLH is crucial for treatment, as primary HLH may require different long-term management strategies, including hematopoietic stem cell transplantation.

Diagnosis and Treatment

Diagnosing HLH in adults requires a high index of suspicion, especially in patients with known risk factors (infections, cancer, autoimmune disease). Diagnostic criteria often involve clinical symptoms (fever, enlarged spleen and liver, cytopenias) combined with laboratory findings (low ferritin, high triglycerides, low fibrinogen, evidence of hemophagocytosis in bone marrow biopsy). Treatment is typically aggressive and involves addressing the underlying trigger while also managing the immune overactivation, often with immunosuppressive therapy (like corticosteroids and cyclosporine) and chemotherapy. In severe or refractory cases, stem cell transplantation may be considered.