Infections in Patients with Cancer¶

Chapter 79 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 79

Key Clinical Points¶

Neutropenic fever (NF) is defined as a single oral temperature ≥38.3°C or ≥38.0°C sustained over 1 h with an absolute neutrophil count (ANC) <500 cells/µL.
Empiric monotherapy for NF must include coverage for Pseudomonas aeruginosa (e.g., ceftazidime, cefepime, meropenem, piperacillin-tazobactam).
Vancomycin is not routinely added to initial empiric regimens unless MRSA risk factors are present.
Empiric antifungal therapy is recommended after 5 days of persistent fever in neutropenic patients or earlier if risk factors for invasive fungal disease (IFD) are present.
B-cell depletion increases the risk of infections from encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis) and respiratory viral infections.
T-cell immunodeficiency leads to a broad range of infections including Listeria, Salmonella, Nocardia, TB/NTM, and opportunistic pathogens like Pneumocystis jirovecii.
Adoptive cellular therapy requires specific prophylaxis against PJP (TMP-SMX), HSV/VZV (acyclovir), and molds (posaconazole).
Patients with functional asplenia require vaccination and antibiotic prophylaxis to prevent overwhelming sepsis from encapsulated bacteria.
HIV-positive cancer patients require antiretroviral therapy to achieve an undetectable viral load to reduce infection risks.
De-escalation of empiric antibiotics is safe if the patient is clinically stable and specific criteria are met.

1. DEFINITION & OVERVIEW¶

Infection is a critical complication of cancer and its treatment, contributing significantly to hospitalization and mortality. Management requires a multidisciplinary approach involving infection specialists, oncologists, and other relevant clinicians.

Key Prevention Strategies: • Standard infection control protocols. • Reduction of pathogen exposure. • Vaccination of patients and caregivers. • Targeted antimicrobial prophylaxis.

Diagnostic challenges arise when infections like neutropenic fever or lung lesions lack definitive diagnosis. Overlapping manifestations (e.g., pneumonia vs. drug-related pneumonitis) require aggressive evaluation, including biopsies where feasible.

1.1 General Concepts¶

Treatment plans for infections in immunocompromised patients are tailored based on:

• Evidence of infection clearance. • Presence of persistent infection foci (e.g., abscesses). • Specific pathogen identification. • Patient immune status.

Longer courses of treatment are required in severely immunocompromised patients. Individualized management must align with the patient's specific goals of care.

2. EPIDEMIOLOGY¶

Infection is a major complication of cancer therapy, primarily driven by chemotherapy-induced neutropenia. Advancements in cancer therapeutics have expanded treatment options but increased infection risks by compromising physical barriers (e.g., central venous catheters) and host immune responses.

3. ETIOLOGY & PATHOPHYISIOLOGY¶

Cancer therapy compromises physical barriers (mucosal lining, surgical wounds) and immune responses. Mucosal surfaces normally provide protection via secretions like IgA and lactoferrin.

Intrinsic Cancer Risk Factors: • Solid tumors: Risk of obstruction-related infections (e.g., postobstructive pneumonia, cholangitis, or UTI). • GI tumors: Risk of sepsis from enteric flora (e.g., S. gallolyticus, C. septicum) due to colonic perforation. • Hematologic malignancies: Risks include pancytopenia (AML, MDS), immunoglobulin deficiency (CLL, MM), and T-cell impairments (HTLV1-associated diseases).

Therapy-Related Risk Factors: • Neutropenia (ANC <500/µL): Increases risk of bacterial and fungal infections. • Prolonged, profound neutropenia (ANC <100/µL for ≥10 days): Increased risk of invasive aspergillosis, other molds, Candidemia, and HSV reactivation. • T-cell immunodeficiency: Risk of Listeria, Salmonella, Nocardia, TB/NTM, Pneumocystis jirovecii, and various viral reactivations (CMV, EBV, HHV-6, HHV-8). • B-cell depletion: Increased risk of encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis), respiratory viruses, and reactivation of HSV, VZV, and HBV; also risk of PML (JC virus). • Mucosal injury: Risk of local/GI flora infections (dental, enterocolitis, perianal) and bacteremia (coliforms, oral streptococci, enterococci, anaerobes). • Systemic corticosteroids: Broad suppression of innate/adaptive immunity. High-dose use (≥20 mg/day for ≥28 days) increases risk of opportunistic pathogens like Pneumocystis jirovecii.

3.1 Risk Factors Summary (Table 79-1)¶

• Neutropenia (ANC <500/µL): Gram-negative and gram-positive bacteria; common in chemotherapy and hematologic malignancies. • Prolonged, profound neutropenia (<100/µL for ≥10 days): Candidemia, invasive aspergillosis, and HSV reactivation. • T-cell immunodeficiency: Listeria monocytogenes, Salmonella species, Nocardia species, TB/NTM, Pneumocystis jirovecii, and various viral reactivations (CMV, EBV, HHV-6, HHV-8). • B-cell immunodeficiency: Encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis), respiratory viruses, HBV reactivation, and PML. • Splenectomy/Functional Asplenia: Encapsulated bacteria (life-threatening sepsis), Malaria, and Babesiosis. • Mucosal Injury: Localized infections by oral/GI flora (dental, enterocolitis, perianal) and bacteremia (coliforms, streptococci, enterococci, anaerobes).

4. CLINICAL FEATURES¶

Fever is the primary indicator of infection in neutropenic patients. Localizing signs may be absent due to lack of inflammatory response, necessitating early empiric treatment.

Key Clinical Observations: • Neutropenic Fever (NF): Infectious in origin but microbiologically confirmed in only ≈40% of cases. • Diagnostic Tools: Plasma cell-free DNA PCR identifies bacterial etiologies more frequently than standard cultures.

Specific Conditions Management: • Diarrhea: May occur 48–72 h post-chemotherapy. Requires hydration/electrolyte repletion and high-dose loperamide (4 mg initial, 2 mg every 2 h up to 16 mg/day). Octreotide or opiates for refractory cases. • Mucositis: Manage with topical anesthetics and barrier preparations for mild cases. • Alopecia: Caused by anthracyclines/alkylating agents; requires psychological support and cosmetic resources. • Gonadal Dysfunction & Pregnancy: Avoid first-trimester treatment if pregnancy continues. Alkylating agents cause azoospermia/amenorrhea; sperm banking/egg preservation considered. Hormone replacement is contraindicated in hormonally responsive tumors.

5. DIFFERENTIAL DIAGNOSIS¶

Distinguish infection from drug toxicity (e.g., pneumonia vs. drug-related pneumonitis) and cancer-associated fever.

Diagnostic Challenges: • Overlapping features require aggressive evaluation, including biopsies where possible. • In hematologic malignancies with severe thrombocytopenia, invasive diagnostics may be unsafe, necessitating early empirical therapy.

6. INVESTIGATIONS & DIAGNOSIS¶

Neutropenic Fever Definition: • Single oral temperature ≥38.3°C or ≥38.0°C sustained over 1 h with an absolute neutrophil count (ANC) <500/µL.

Diagnostic Algorithm for Neutropenic Fever: 1. History/Physical Exam: Assess for infection portals (catheter sites, mouth, perianal area). 2. Blood Cultures: Obtain from central and peripheral sites; repeat if a gram-positive isolate is detected. 3. Empiric Monotherapy: Initiate with Pseudomonas coverage (e.g., ceftazidime, cefepime, meropenem, piperacillin-tazobactam). 4. Timing: Administer antibiotics within 1 h of fever onset. 5. Follow-Up: Continue the same antibiotic unless new clinical or microbiologic data emerge. 6. Modification: Adjust regimen only if new features (e.g., hypotension) or new microbiology results are available.

7. MANAGEMENT & TREATMENT¶

Initial Management of Neutropenic Fever: • Obtain blood cultures from central/peripheral sites. • Initiate empiric monotherapy with Pseudomonas coverage (ceftazidime, cefepime, meropenem, or piperacillin-tazobactam). • Administer antibiotics within 1 h of fever onset. • Maintain current antibiotic unless new clinical/microbiologic data emerge.
Antifungal Management: • Empiric antifungal therapy is recommended after 5 days of persistent fever or earlier if risk factors for invasive fungal disease (IFD) are present.
Supportive Care: • Diarrhea: Hydration/electrolyte repletion; high-dose loperamide (4 mg initial, 2 mg every 2 h up to 16 mg/day); octreotide for refractory cases. • Mucositis: Topical anesthetics and barrier preparations. • Alopecia: Psychological support and cosmetic resources.

8. SPECIAL POPULATIONS¶

• HIV-positive Patients: Require antiretroviral therapy to achieve an undetectable viral load to reduce infection risks.

• Adoptive Cellular Therapy: Requires specific prophylaxis: ◦ PJP: Trimethoprim-sulfamethoxazole (TMP-SMX). ◦ HSV/VZV: Acyclovir. ◦ Molds: Posaconazole.

• Functional Asplenia: Patients require vaccination and antibiotic prophylaxis to prevent overwhelming sepsis from encapsulated bacteria.

• Gonadal Dysfunction & Pregnancy: ◦ Avoid first-trimester treatment if pregnancy continues. ◦ Alkylating agents cause azoospermia/amenorrhea; sperm banking/egg preservation considered. ◦ Hormone replacement contraindicated in hormonally responsive tumors.

9. KEY PEARLS & HIGH-YIELD POINTS¶

• Empiric Antibiotics: Vancomycin is not routinely added to initial empiric regimens unless MRSA risk factors are present. • Antifungal Timing: Empiric antifungal therapy is recommended after 5 days of persistent fever or earlier if high risk for IFD exists. • De-escalation: Safe if the patient is clinically stable and specific criteria are met. • Diagnostic Tools: Plasma cell-free DNA PCR identifies bacterial etiologies more frequently than standard cultures in NF. • Risk Thresholds: ◦ Neutropenia (ANC <500/µL) → Gram-negative and gram-positive bacteria. ◦ Prolonged/Profound Neutropenia (ANC <100/µL for ≥10 days) → Candidemia, invasive aspergillosis, and HSV. ◦ High-dose steroids (≥20 mg/day for ≥28 days) → Pneumocystis jirovecii.

Reference Tables¶

TABLE 79-1 Immune Defects and Associated Infections in Cancer Patients¶

Harrison's 22e, p.578

HOST DEFENSE DEFECT	PREDOMINANT PATHOGENS	PATIENTS WITH CANCER AT GREATEST RISK
Neutropenia (ANC <500/µL)	Gram-negative and gram-positive bacteria	Cytotoxic chemotherapy, underlying hematologic malignancy (e.g., myelodysplasia, acute leukemia)
	Increased risk of bacterial infections Candidemia Invasive aspergillosis and other molds HSV reactivation Respiratory viral infections
T cell immunodeficiency	Common bacterial infections Intracellular bacteria (e.g., Listeria monocytogenes, Salmonella species) Nocardia species Tuberculosis and NTM Respiratory viral infections Reactivation of herpes viruses (HSV, VZV); with severe impairment: CMV, EBV-associated lymphoproliferative disease; HHV-6-associated marrow suppression or encephalopathy, and HHV-8-associated malignancies) Mucosal candidiasis Pneumocystis jirovecii Dimorphic fungal infections (e.g., histoplasmosis, coccidioidomycosis) Cryptococcus neoformans Invasive aspergillosis and other molds Toxoplasmosis Strongyloides hyperinfection	Underlying hematologic malignancy including primary T cell malignancies AIDS-associated malignancies Corticosteroids, TNF-α blockade Janus kinase inhibitors Purine analogues Alemtuzumab GVHD Lymphodepletion for adoptive cellular therapy
	Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) Respiratory viral infections Reactivation of HSV and VZV Reactivation of HBV PML (reactivation of JC virus)
Splenectomy and functional asplenia	Encapsulated bacteria (can result in life-threating sepsis) Malaria, babesiosis	Functional asplenia in chronic GVHD
	Localized infections by oral and GI flora (e.g., dental infections, neutropenic enterocolitis, perianal infection) Bacteremia (coliforms, oral streptococci, enterococci, anaerobes; can be polymicrobial)
Systemic corticosteroids	Broad suppressive effect on innate and adaptive immunity related to dose and duration of treatment Increased risk of common bacterial and viral infections Prolonged high-dose corticosteroids (e.g., prednisone equivalent to ≥20 mg/day for ≥28 days) increases risk of multiple opportunistic pathogens associated with impaired T cell immunity (e.g., Pneumocystis jirovecii)	Corticosteroids are common components of antineoplastic regimens for hematologic cancers (e.g., for acute lymphoblastic leukemia, lymphomas, and multiple myeloma) and are administered concurrently with other immunosuppressive therapies Other common indications for corticosteroids are to reduce inflammation from central nervous system tumors and as therapy for immune-related toxicities