What is Pel‑Ebstein fever and how is it associated with Hodgkin lymphoma, including its diagnosis and management?

Pel-Ebstein Fever: Definition and Clinical Significance

Pel-Ebstein fever is a rare, cyclical fever pattern classically associated with Hodgkin lymphoma, characterized by 1-2 weeks of high fever (>38°C) alternating with afebrile periods of similar duration, during which lymph nodes enlarge during febrile episodes and shrink as fever subsides. 1

Clinical Characteristics

Fever Pattern

• The fever cycles consist of regular intervals of high-grade fever lasting 1-2 weeks, separated by completely afebrile periods of equal duration 1
• Lymph nodes demonstrably enlarge during fever peaks and reduce in size as fever subsides, a phenomenon documented by lymphography 1
• This cyclical pattern can produce regularly spaced Beau's lines on nails (the "ladder nail" sign), which serves as a physical examination clue pointing toward relapsing fever and underlying lymphoma 2

Association with Hodgkin Lymphoma

• While classically described as characteristic of Hodgkin lymphoma, Pel-Ebstein fever is actually very rare in clinical practice 3
• When present, it represents one of the B symptoms (fever >38°C) that significantly impacts staging and prognosis 4
• The fever pattern has been documented even in unusual presentations, such as isolated bone marrow relapse of Hodgkin lymphoma 3

Diagnostic Approach

Initial Evaluation

• When Pel-Ebstein fever is suspected, excisional lymph node biopsy is mandatory for definitive diagnosis of Hodgkin lymphoma; fine-needle aspiration is insufficient 5, 6
• Look specifically for regularly spaced Beau's lines on nail examination during physical assessment, as these provide an important diagnostic clue in fever of unknown origin 2
• Document the cyclical nature of fever carefully—prolonged fever lasting months to over a year may be the presenting symptom 7

Critical Diagnostic Pitfall

• In patients with B symptoms including fever, always rule out opportunistic infections before attributing symptoms solely to lymphoma, particularly in immunocompromised patients 8, 4
• The NCCN emphasizes that B symptoms in HIV-positive patients should always prompt investigation for opportunistic infection, as 90% of Hodgkin lymphoma cases in this population are EBV-associated 8

Confirmatory Testing

• Reed-Sternberg cells (CD15+/CD30+/CD20-) must be identified on excisional biopsy for classical Hodgkin lymphoma diagnosis 5, 6
• Bone marrow biopsy is necessary when isolated marrow involvement is suspected, as Pel-Ebstein fever can occur with bone marrow as the sole site of disease 3
• PET/CT staging is essential to evaluate disease extent 6

Management Implications

Treatment Response

• Fever typically resolves within 5 days of initiating appropriate chemotherapy, providing rapid symptomatic relief 7
• ABVD chemotherapy is the standard regimen, with modifications based on stage and risk factors 8, 5
• The presence of fever as a B symptom classifies even early-stage disease (Stage I-II) as "early unfavorable," requiring more intensive therapy than Stage A disease 4

Prognostic Significance

• B symptoms including Pel-Ebstein fever are unfavorable prognostic factors that influence treatment intensity 4
• Despite this, Hodgkin lymphoma remains curable in at least 80% of patients with modern treatment 5

Special Populations

• In HIV-positive patients with Hodgkin lymphoma and fever, growth factors may be required despite concerns about bleomycin toxicity, especially when CD4+ count is low 8
• Prophylactic antibiotics for gram-negative bacteria and PJP should be considered when CD4+ count is <200 cells/μL 8