Hemophagocytic Lymphohistiocytosis (HLH) is a severe, life-threatening syndrome marked by hyperinflammation caused by an uncontrolled, overactive immune response. This involves the excessive activation and proliferation of immune cells, specifically T-lymphocytes and macrophages, which attack the body’s own tissues and organs. Secondary HLH (sHLH), also known as acquired HLH, develops in response to an external trigger in individuals without a known genetic predisposition. If left unrecognized, the resulting “cytokine storm” can rapidly lead to multi-organ failure.
How Secondary HLH Differs from Primary HLH
HLH is broadly categorized into primary and secondary forms, based on the presence or absence of inherited genetic defects. Primary HLH is an inherited condition, typically resulting from gene mutations that impair the immune system’s ability to properly kill target cells (cytotoxicity). This form often presents early in life, during infancy or early childhood.
Secondary HLH is an acquired disorder that usually presents in older children, adolescents, or adults. It arises when a severe illness triggers an immune response that the body cannot properly shut off, leading to unchecked immune cell activation. In primary HLH, the underlying pathology is a defect in the cytotoxic machinery of Natural Killer (NK) cells and cytotoxic T-cells. In secondary HLH, the immune cells are structurally sound but become overstimulated, causing them to release inflammatory signaling molecules.
Identifying the Underlying Triggers
Secondary HLH is typically triggered by one of three major categories of underlying conditions that push the immune system into overdrive. Identifying the specific trigger is important because successful treatment of the underlying cause is necessary for long-term resolution of the HLH episode.
Infection-Associated HLH (IA-HLH)
The most common triggers are infections. Viruses, particularly Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV), are frequent culprits, but bacterial, fungal, and parasitic infections can also initiate the syndrome. The body’s response to these pathogens becomes dysregulated, causing hyperinflammation.
Malignancy-Associated HLH (M-HLH)
M-HLH occurs when certain cancers, most often hematological malignancies, drive the overactive immune state. Lymphomas, especially T-cell and B-cell lymphomas, are the most common cancer types associated with M-HLH. In some cases, HLH is the first obvious manifestation of the underlying, undiagnosed cancer.
Macrophage Activation Syndrome (MAS)
The third major trigger category is rheumatologic or autoimmune disease, often referred to as Macrophage Activation Syndrome (MAS). This is sHLH occurring in the context of an autoimmune disorder, such as systemic juvenile idiopathic arthritis (sJIA) or systemic lupus erythematosus (SLE). In MAS, the chronic inflammation of the autoimmune disease suddenly spirals into a life-threatening hyperinflammatory state.
Clinical Manifestations and Physical Findings
The clinical presentation of secondary HLH is often non-specific, which can make early diagnosis challenging as it mimics severe sepsis or other systemic inflammatory conditions. The most common finding is a high and unremitting fever that does not respond to standard antibiotics.
Physical examination frequently reveals hepatosplenomegaly (enlargement of the liver and spleen), resulting from the infiltration of activated immune cells into these organs. Patients often appear acutely ill, and a rash or skin lesions may also be present.
The uncontrolled immune activity causes the destruction of blood cells, leading to cytopenias (low blood cell counts) affecting at least two blood cell lines, such as red blood cells, white blood cells, or platelets. In severe cases, inflammation can extend to the central nervous system, resulting in neurological symptoms like headaches, confusion, or seizures.
Confirmation Through Diagnostic Criteria
The diagnosis of secondary HLH relies on a combination of clinical suspicion, physical findings, and specific laboratory abnormalities. Physicians typically use the HLH-2004 diagnostic guidelines, which require a patient to meet five out of eight defined criteria, including fever and splenomegaly, along with specific laboratory markers.
Required lab findings include cytopenias affecting at least two lineages in the peripheral blood and evidence of dysregulated fat metabolism, such as hypertriglyceridemia or hypofibrinogenemia. A hallmark finding is an elevated serum ferritin level, often exceeding \(500 \mu \text{g/L}\).
Other criteria involve low or absent Natural Killer (NK) cell activity and elevated levels of soluble CD25 (sIL-2R), a marker reflecting the proliferation and activation of T-lymphocytes. The definitive pathological finding is hemophagocytosis, where activated macrophages are seen engulfing other blood cells in tissues like the bone marrow or lymph nodes, though this is not always present.
The H-score is a predictive model sometimes used to calculate a patient’s probability of having sHLH, incorporating clinical, laboratory, and etiological factors. In younger patients, genetic testing is necessary to rule out an underlying familial, or primary, form of the disease.
Therapeutic Approaches
Treatment for secondary HLH is aggressive and involves a dual strategy: immediate suppression of the hyperinflammatory state and treatment of the underlying trigger. The goal is to rapidly quell the cytokine storm to prevent irreversible organ damage.
Immediate management often involves intensive immunosuppression, frequently based on adapted protocols similar to those developed for pediatric HLH. These regimens include high-dose corticosteroids, such as dexamethasone, combined with a chemotherapy agent like etoposide (VP-16), and sometimes cyclosporine. Etoposide works to eliminate the hyperactivated T-cells and macrophages driving the inflammation.
The source of the immune activation must be addressed for long-term resolution. This means treating the underlying infection with appropriate antivirals, antifungals, or antibiotics, or initiating chemotherapy for an associated malignancy. If the trigger is an autoimmune disorder, intensive rheumatologic medications, such as specific cytokine blockers like anakinra, may be used to modulate the immune response. Patients with sHLH are typically managed in an intensive care setting due to the high risk of rapid multi-organ failure.