What are the symptoms of hemophagocytic (hemophagocytic lymphohistiocytosis) syndromes?

Clinical Manifestations of Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis presents with persistent high fever, hepatosplenomegaly, cytopenias affecting multiple cell lines, and markedly elevated ferritin levels, often progressing rapidly to multiorgan failure if untreated. 1

Cardinal Clinical Features

Constitutional Symptoms

• Fever is nearly universal and characterized by high, persistent, unremitting temperatures that do not respond adequately to antipyretics 1, 2
• Prolonged fever without clear infectious source should raise immediate suspicion for HLH 2, 3

Organomegaly

• Hepatosplenomegaly is a hallmark finding, though it may be absent in some secondary forms 1, 2
• Splenomegaly is one of the HLH-2004 diagnostic criteria and occurs frequently 4
• Lymphadenopathy may be present, particularly in malignancy-associated cases 5

Hematologic Abnormalities

• Cytopenias affecting two or more cell lines (anemia, thrombocytopenia, neutropenia) are characteristic 1, 2
• Hemoglobin <90 g/L, platelets <100 × 10⁹/L, and neutrophils <1.0 × 10⁹/L define the cytopenia criteria 4
• Persistent unexplained cytopenias should prompt evaluation for HLH 3

Neurologic Manifestations

• Neurologic involvement occurs in a substantial proportion of patients and includes headaches, vision disturbances, gait abnormalities, altered mental status, and seizures 1
• Cerebromeningeal symptoms with spinal fluid pleocytosis (mononuclear cells) and elevated protein may be present 4
• Grade 3-4 neurotoxicity requires lumbar puncture evaluation 1

Multiorgan Dysfunction

Hepatic Involvement

• Hepatitis with elevated transaminases and bilirubin is common 1
• Histological findings in liver biopsy may resemble chronic persistent hepatitis 4
• Jaundice may be present as the disease progresses 4

Coagulation Abnormalities

• Coagulopathy with hypofibrinogenemia (fibrinogen ≤1.5 g/L) is a diagnostic criterion 4, 1
• Disseminated intravascular coagulation (DIC) can develop in severe cases and is associated with mortality 3
• Elevated d-dimers are characteristic laboratory findings 4

Other Organ Systems

• Pulmonary edema and respiratory dysfunction may occur 1
• Renal dysfunction develops as part of multiorgan failure 1
• Skin rash and edema may be present 4

Laboratory Hallmarks

Hyperferritinemia

• Rapidly rising ferritin >5000 ng/mL is highly suggestive of HLH, with levels often reaching 7000-10,000 mg/L or rarely >100,000 mg/L 4, 1
• Ferritin ≥500 μg/L is the diagnostic threshold in HLH-2004 criteria, though values >10,000 mg/L are >90% sensitive and specific in children 4
• Hyperferritinemia should always prompt inclusion of HLH in the differential diagnosis 4

Lipid and Protein Abnormalities

• Hypertriglyceridemia (fasting triglycerides ≥3.0 mmol/L or ≥265 mg/dL) is a diagnostic criterion 4, 2
• Hypoproteinemia and hypoalbuminemia occur due to the hyperinflammatory state 4
• Elevated very low-density lipoprotein (VLDL) and low high-density lipoprotein (HDL) may be present 4

Inflammatory Markers

• Elevated soluble CD25 (soluble IL-2 receptor ≥2400 U/mL) is a diagnostic criterion with excellent diagnostic performance (area under the curve 0.90) 4, 1
• Elevated CRP, IL-6, INF-γ are often present 1
• Lactate dehydrogenase elevation is characteristic 4

Electrolyte Disturbances

• Hyponatremia occurs frequently 4

Hemophagocytosis

• Hemophagocytosis in bone marrow, spleen, or lymph nodes represents activated macrophages engulfing blood cells 4, 2
• Hemophagocytic activity may not be evident at initial presentation and serial marrow aspirates over time may be needed 4
• The absence of hemophagocytosis on initial bone marrow examination does not exclude HLH—only 4 of 7 patients in one series showed definite evidence on initial examination 3

Critical Clinical Pitfall

The early signs and symptoms are nonspecific and may masquerade as a normal infection, sepsis, or viral syndrome-like illness. 2, 3, 5 The key distinguishing feature is that patients with HLH cannot control the hyperinflammatory response, leading to progressive deterioration rather than improvement. 2 Maintain a high index of suspicion in patients with persistent fever, cytopenias, hepatosplenomegaly, and ferritin >5000 ng/mL, as delayed diagnosis significantly increases mortality. 1, 3