Hemophagocytic Lymphohistiocytosis Diagnosis and Clinical Presentation

Diagnostic Criteria

• The diagnosis of Hemophagocytic Lymphohistiocytosis (HLH) should be made using the HLH-2004 criteria, which requires either a molecular diagnosis consistent with HLH or fulfillment of 5 out of 8 specific clinical and laboratory parameters, as recommended by the American Society of Hematology 1, 2
• The 8 parameters for HLH diagnosis include fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent NK cell activity, ferritin ≥500 μg/L, and soluble CD25 ≥2400 U/mL, according to the European Hematology Association 1, 2

Clinical Presentation

• Prolonged high fever is one of the most consistent features of HLH, often >39.4°C, as noted by the American College of Physicians 1, 2
• Hepatosplenomegaly is present in the majority of cases, according to the American Society of Hematology 1, 2
• Cytopenias affecting two or more cell lines, including anemia, thrombocytopenia, and neutropenia, are common in HLH patients, as reported by the European Hematology Association 1, 2

Diagnostic Workup

• A systematic approach to diagnosis should include laboratory evaluation, bone marrow examination, imaging studies, CNS evaluation, and trigger identification, as recommended by the American Society of Hematology 1, 2, 3, 4
• Laboratory tests should include complete blood count, ferritin, triglycerides, fibrinogen, soluble CD25, liver enzymes, and coagulation studies, according to the European Hematology Association 1, 2, 3, 4

Age-Related Considerations

• The likelihood of malignancy-associated HLH increases with age, with 68% of cases in adults over 60 years triggered by lymphoma, compared to 38% in ages 30-59, 10% in ages 15-29, and 0% under age 14, as noted by the International Society of Geriatric Oncology 4

Diagnostic Pitfalls

• HLH can present identically to sepsis or multiple organ dysfunction syndrome, making differentiation challenging in critically ill patients, and a high index of suspicion is essential, as reported by the Society of Critical Care Medicine 3, 4

Hemophagocytic Lymphohistiocytosis Diagnosis and Symptoms

Documented Cutaneous Manifestations of HLH

• The American Society of Clinical Oncology lists skin rash as a presenting symptom of CAR T-cell therapy-related HLH, referring to visible eruptions rather than itching 5, 6

Core Presenting Symptoms of HLH

• The American Society of Clinical Oncology recommends considering diagnostic tests for HLH in patients with hepatosplenomegaly (enlarged liver and spleen) 5, 6
• The American Society of Clinical Oncology suggests that hyperferritinemia (elevated ferritin levels) is a key feature of HLH 5, 6
• Swollen lymph nodes are a common systemic symptom of HLH, according to the American Society of Clinical Oncology 5, 6
• Jaundice is a systemic symptom of HLH, as indicated by the American Society of Clinical Oncology 5, 6
• Respiratory problems, such as coughing and trouble breathing, are additional systemic symptoms of HLH, as noted by the American Society of Clinical Oncology 5, 6
• Gastrointestinal symptoms, including stomach ache, vomiting, and diarrhea, are common in HLH patients, according to the American Society of Clinical Oncology 5, 6
• Neurological problems, such as headaches, trouble walking, vision disturbances, and weakness, are also associated with HLH, as indicated by the American Society of Clinical Oncology 5, 6

Diagnosis and Management of Hemophagocytic Lymphohistiocytosis (HLH)

Diagnostic Approach

• The European Hematology Association recommends assessing whether the combination, extent, and progression of clinical and laboratory abnormalities are unusual, unexpected, and otherwise unexplained, and not to delay empirical treatment while waiting for all diagnostic criteria to be met if clinical suspicion is high 7, 8, 9
• Hemophagocytosis itself is neither sensitive nor specific, and may be absent on initial bone marrow examination, so do not rule out HLH based solely on absence of hemophagocytosis 7, 8, 9

Essential Diagnostic Workup

• Obtain ferritin levels, as rapidly rising levels indicate active disease 9
• Perform coagulation studies, including PT, PTT, and D-dimer, to assess disease activity 8
• Bone marrow aspiration and biopsy should be performed to screen for hemophagocytosis, evaluate for underlying malignancy, and differentiate treatment toxicity from active HLH 7, 8, 9

Trigger Identification

• In any patient with HLH, malignancy should be considered as a possible underlying disease, with the likelihood increasing dramatically with age 7, 8, 9
• Mandatory malignancy screening should include peripheral blood and bone marrow screening for blasts, chest X-ray, CT or ultrasound of abdomen and enlarged lymph nodes, and biopsy of suspicious lymph nodes or cutaneous lesions 7, 8, 9

Monitoring Disease Activity

• Platelets rapidly reflect HLH activity, and a drop in platelet count indicates disease flares 7, 8
• Monitor ferritin levels, as they increase rapidly in active HLH but normalize slowly 9
• Monitor temperature, spleen size, and liver function tests every 12-24 hours to assess treatment response 7

Age-Related Considerations

• In adults, nearly half of published HLH cases are triggered by neoplasm 7, 8
• In children and adolescents, malignant context has a reported prevalence of only 8% 7, 8