What are the causes and management of fever in an immunocompromised patient with leukopenia, possibly due to chemotherapy, HIV/AIDS, or other immunosuppressive conditions?

Causes of Fever with Leukopenia

Fever with leukopenia demands urgent evaluation and empirical broad-spectrum antibiotics within 2 hours, as bacterial infections can progress rapidly in immunocompromised patients, even when no source is identified. 1

Primary Infectious Causes

Bacterial Pathogens

• Gram-negative bacteria are the most common cause, particularly Pseudomonas aeruginosa, Klebsiella, and E. coli, which can cause life-threatening sepsis in neutropenic patients 1
• Gram-positive organisms now account for a significant proportion of infections, with coagulase-negative staphylococci, Staphylococcus aureus (including MRSA), and viridans group streptococci being prevalent 1
• Resistant organisms including VRE and carbapenem-resistant gram-negatives are increasingly encountered, accounting for up to 20-50% of isolates in some centers 1
• Pneumococcal infections with penicillin-resistant strains can cause severe disease 1

Fungal Infections

• Candida species cause superficial mucosal infections (thrush) and 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 >2 weeks of neutropenia 1
• Pneumocystis jirovecii should be suspected when lung infiltrates develop with elevated LDH, particularly in patients not on prophylaxis 1

Viral Pathogens

• 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

Non-Infectious Causes

Malignancy-Related

• Bone marrow infiltration by hematologic malignancies (acute leukemia, chronic lymphocytic leukemia, lymphoma) causes both fever and leukopenia 2
• Myelodysplastic syndromes impair normal blood cell production 2
• Aplastic anemia causes pancytopenia including leukopenia 2

Medication-Induced

• Chemotherapy agents are the most common cause of bone marrow suppression leading to leukopenia 2
• Azathioprine and 6-mercaptopurine cause bone marrow toxicity with leukopenia in approximately 3.2% of patients, with severe leukopenia occurring in 5.3-16% depending on the condition treated 2
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events 2
• Immunosuppressive medications used in autoimmune disorders and post-transplant settings 2

Drug-Drug Interactions

• Targeted therapies (midostaurin, venetoclax, gilteritinib) combined with CYP3A4 inhibitors (azole antifungals, macrolides) can exacerbate myelosuppression 1

Critical Management Principles

Immediate Actions

• Initiate empirical broad-spectrum antibiotics within 2 hours of fever presentation, as outcomes are substantially better with prompt treatment 1
• Use anti-pseudomonal β-lactams (ceftazidime, cefoperazone, piperacillin-tazobactam) or carbapenems (imipenem, meropenem) as first-line therapy 1
• Screen for SARS-CoV-2 in all febrile patients with hematologic malignancies whenever possible 1

Risk Stratification

• High-risk patients include those with absolute neutrophil count <100/mcL, prolonged neutropenia (>7 days expected), acute leukemia, or following high-dose chemotherapy 1, 2
• Infection risk increases dramatically when neutrophil counts fall below 500/mcL, with 10-20% risk at counts <100/mcL 2

Diagnostic Approach

• Blood cultures should be obtained before antibiotics, but treatment must not be delayed 1
• Examine peripheral blood smear to determine which white blood cell lines are affected and look for morphological abnormalities 2
• Consider bone marrow examination in patients with unexplained persistent leukopenia, especially older adults 2
• Chest CT and bronchoscopy with BAL should be performed if lung infiltrates develop or fever persists beyond 7 days 1

Antifungal Considerations

• Initiate empirical antifungal therapy (voriconazole or liposomal amphotericin B) after 4-7 days of persistent fever despite antibiotics, or earlier if lung infiltrates suggest fungal infection 1
• Galactomannan testing (threshold ≥0.5 in blood, ≥1.0 in BAL) supports Aspergillus diagnosis 1
• Quantitative PCR for Pneumocystis >1450 copies/mL from BAL should trigger treatment with high-dose trimethoprim-sulfamethoxazole 1

Duration of Therapy

• If neutrophils ≥0.5 × 10⁹/L and patient afebrile for 48 hours with negative cultures, antibiotics can be discontinued 1
• If neutrophils <0.5 × 10⁹/L but afebrile for 5-7 days without complications, antibiotics can be discontinued except in high-risk cases (acute leukemia, post-high-dose chemotherapy) where continuation until neutrophil recovery is often warranted 1

Common Pitfalls

• The majority of febrile neutropenic patients have no identifiable infection source and negative cultures, yet still require urgent empirical antibiotics 1
• Do not delay antibiotics for diagnostic procedures—outcomes depend on treatment within 2 hours 1
• Avoid rectal temperatures and examinations during neutropenia due to risk of introducing infection 1
• TPMT testing does not exclude risk of thiopurine-induced leukopenia, as only 27% of cases are explained by common TPMT variants 2
• Profound leukopenia can develop suddenly between blood tests in patients on thiopurines (approximately 3% of patients) 2
• Enterococci and Candida isolated from non-sterile sites (sputum, urine, swabs) do not represent causative pathogens for lung infiltrates 1
• Growth factors (G-CSF) should be avoided in patients with moderate-to-severe SARS-CoV-2 infection due to risk of exacerbating inflammatory pulmonary injury 1