What are the common causes of fever in immunocompromised patients with a history of hematological malignancies after undergoing bone marrow aspiration (BMA) biopsy?

Common Causes of Fever After Bone Marrow Aspiration Biopsy in Immunocompromised Patients with Hematological Malignancies

In immunocompromised patients with hematological malignancies who develop fever after bone marrow aspiration biopsy, bacterial infection—particularly gram-negative organisms (Pseudomonas aeruginosa, E. coli, Klebsiella)—is the most common and life-threatening cause, requiring empirical broad-spectrum antibiotics within 2 hours regardless of whether the fever is procedure-related or disease-related. 1

Primary Infectious Causes (Most Common)

Bacterial Infections

• Gram-negative bacteria are the predominant cause of fever in neutropenic patients with hematological malignancies, with Pseudomonas aeruginosa, Klebsiella, and E. coli being the most frequent pathogens that can rapidly progress to life-threatening sepsis 1
• Gram-positive organisms account for a significant proportion of infections, including coagulase-negative staphylococci, Staphylococcus aureus (including MRSA), and viridans group streptococci 2, 1
• Resistant organisms are increasingly encountered, with VRE and carbapenem-resistant gram-negatives accounting for 20-50% of isolates in some centers 1
• The infection risk increases dramatically when neutrophil counts fall below 500/mcL, with 10-20% of patients developing bloodstream infections when counts are below 100/mcL 2

Fungal Infections

• Candida species cause superficial mucosal infections that can progress to bloodstream infections when chemotherapy-induced mucositis disrupts mucosal barriers 1
• Aspergillus and other molds typically cause life-threatening sinus and lung infections after more than 2 weeks of neutropenia 1
• Pneumocystis jirovecii should be suspected when lung infiltrates develop with elevated LDH, particularly in patients not receiving prophylaxis 1

Viral Infections

• Herpes simplex virus (HSV) and cytomegalovirus (CMV) are frequently encountered, especially in bone marrow transplant recipients 1
• Respiratory viruses can cause significant morbidity in immunocompromised hosts 1

Disease-Related Non-Infectious Causes

Underlying Malignancy

• Bone marrow infiltration by the hematological malignancy itself causes both fever and cytopenias, particularly in advanced or refractory disease 2
• Patients with refractory hematologic malignancies experience marrow failure from the underlying disease and from multiple lines of prior cytotoxic therapy 2
• In chronic lymphocytic leukemia (CLL), nearly 90% of heavily pretreated patients (median 3 prior regimens) experience serious infectious complications requiring hospitalization 2

Drug-Induced Fever

• Chemotherapy agents are the most common cause of bone marrow suppression leading to fever and leukopenia 2
• Drug-induced fever occurs with a mean lag time of 21 days after drug initiation, and fever may take 1-7 days to resolve after stopping the offending agent 3
• Rash and eosinophilia are uncommon in drug-induced fever, making this diagnosis challenging 3

Procedure-Related Complications (Rare)

While the bone marrow aspiration/biopsy procedure itself can theoretically cause complications, pain, bleeding, and infection are rare complications when performed at the posterior iliac crest 4. However, in the context of immunocompromised patients with hematological malignancies:

• The increased frequency of obtaining bone marrow biopsies in these patients (for fever and cytopenia workup) may lead to increased ascertainment of underlying infections rather than procedure-related infections 2
• Direct procedure-related infection is uncommon but must be considered if fever develops immediately post-procedure with local signs 4

Critical Management Algorithm

Immediate Action (Within 2 Hours)

Empirical broad-spectrum antibiotics must be initiated within 2 hours of fever presentation, as outcomes are substantially better with prompt treatment and delay significantly worsens outcomes 1, 3. This applies regardless of whether the fever is suspected to be procedure-related or disease-related.

• Use anti-pseudomonal β-lactams (ceftazidime, piperacillin-tazobactam) or carbapenems (meropenem, imipenem) as first-line therapy 1
• Obtain blood cultures, chest radiograph, and urine cultures concurrently with or after antibiotic initiation—never delay antibiotics to obtain these studies 3
• Add vancomycin only if specific indications exist: hemodynamic instability, suspected catheter-related infection, or known MRSA colonization 3

Risk Stratification

High-risk patients include those with: 1

• Absolute neutrophil count <100/mcL
• Prolonged neutropenia (>7 days expected)
• Acute leukemia
• Status post high-dose chemotherapy

Escalation Strategy

• If fever persists beyond 4-7 days despite antibiotics, initiate empirical antifungal therapy with voriconazole or liposomal amphotericin B 1
• Perform chest CT and bronchoscopy with BAL if lung infiltrates develop or fever persists beyond 7 days 1
• Use galactomannan testing (threshold ≥0.5 in blood, ≥1.0 in BAL) to support Aspergillus diagnosis 1
• Quantitative PCR for Pneumocystis >1450 copies/mL from BAL should trigger treatment with high-dose trimethoprim-sulfamethoxazole 1

Critical Pitfalls to Avoid

• Never delay antibiotics in neutropenic patients to pursue a diagnosis of neoplastic fever or drug-induced fever—infection must be excluded first with empiric treatment 3
• Avoid rectal examinations and rectal temperatures during neutropenia due to risk of introducing infection through bacterial translocation 3
• Do not assume fever is procedure-related or neoplastic without extensive negative workup for infection, including atypical organisms, fungi, and catheter-related infections 3
• The majority of febrile neutropenic patients have no identifiable infection source and negative cultures, yet still require urgent empirical antibiotics 1
• Procalcitonin elevations (>0.5 ng/mL) can help discriminate bacterial infection from other causes, as chronic inflammatory states and malignancy do not typically elevate procalcitonin 3