What is the protocol for bone marrow examination in a patient with Pyrexia of Unknown Origin (PUO)?

Protocol for Bone Marrow Examination in Pyrexia of Unknown Origin (PUO)

Bone marrow examination is not routinely indicated as a first-line investigation in all patients with PUO but should be performed selectively based on specific clinical indicators and after initial workup fails to identify the cause. 1, 2

Indications for Bone Marrow Examination in PUO

• Bone marrow examination should be considered when there are unexplained cytopenias (anemia, leukopenia, thrombocytopenia) in patients with PUO 1, 3
• It is particularly valuable in patients with involvement of reticuloendothelial organs (e.g., splenomegaly) 2, 3
• Bone marrow biopsy has higher diagnostic yield in immunocompromised patients, especially those with HIV infection 4
• Consider bone marrow examination in elderly patients with PUO as they have higher likelihood of hematological malignancies 2, 5
• When other investigations including advanced imaging (CT, PET/CT) fail to identify the cause of fever 6, 5

When to Skip Bone Marrow Examination

• In patients with suspected Hodgkin lymphoma, routine bone marrow biopsy may be omitted if PET scan is negative or shows homogeneous bone marrow uptake 7, 1
• The bone marrow may be assumed to be involved if the PET scan displays multifocal (≥3) skeletal lesions 7
• In typical cases of lymphomatoid papulosis (LYP) with absence of palpable enlarged lymph nodes, absence of hepatosplenomegaly, normal laboratory tests, and absence of B symptoms 7

Procedure Protocol

• Both bone marrow aspiration and trephine biopsy should be performed concurrently for optimal diagnostic yield 3
• Trephine biopsy offers significantly higher diagnostic yield (76%) compared to aspiration alone (16.5%) in PUO cases 3
• Bone marrow samples should be processed for:
  • Morphological examination 3
  • Cultures for bacteria, mycobacteria, and fungi 4, 3
  • Immunohistochemistry for suspected lymphoma or other malignancies 1
  • Special stains for infectious organisms 3

Diagnostic Yield and Common Findings

• Overall diagnostic yield of bone marrow examination in PUO ranges from 26-33% 4, 3
• Common diagnoses established through bone marrow examination in PUO include:
  • Granulomatous diseases (tuberculosis, sarcoidosis, fungal infections) - most commonly detected on trephine biopsy 3
  • Hematological malignancies (lymphoma, leukemia) 1, 3
  • Leishmaniasis 3
  • Aplastic anemia or pure red cell aplasia 3

Practical Considerations

• Granulomas are frequently found in trephine biopsies (70% of cases) but are rarely identified in aspiration smears (1.6%) 3
• Bone marrow examination should be performed before starting empiric antimicrobial therapy to avoid false negative results 8
• Consider the timing of bone marrow examination in relation to other diagnostic tests - ideally after non-invasive tests have been completed but before empiric therapy is initiated 6, 8

Common Pitfalls to Avoid

• Relying solely on bone marrow aspiration without trephine biopsy significantly reduces diagnostic yield 3
• Performing bone marrow examination too early in the diagnostic workup before completing basic investigations and imaging 6, 5
• Failure to send bone marrow samples for appropriate microbiological cultures and special stains 4, 3
• Starting empiric antimicrobial therapy before obtaining bone marrow samples 8