Infections inTransplant Recipients¶
Chapter 148 | Harrison's 22e · Part 5 – Infectious Diseases: Bacterial · Chapter 148
Key Clinical Points¶
- Transplant recipients (SOT/VCA) require lifelong immunosuppression, leading to persistent risk from both common and opportunistic pathogens.
- HCT patients face a high-risk window of transient immunosuppression and neutropenia, with infection risks categorized by time post-transplant.
- Allo-HCT carries a 35-50% incidence of GVHD, requiring specific prophylaxis (e.g., Tacrolimus/sirolimus + mycophenolate mofetil).
- Infections in immunocompromised hosts often present atypically or with multiple concurrent pathogens.
- Radiologic findings are frequently non-specific (e.g., Nocardia, TB, Aspergillosis), necessitating high clinical suspicion and multi-modal diagnostics.
- Management relies on a combination of prophylaxis, empirical therapy for neutropenic fever, targeted treatment, and source control.
1. DEFINITION & OVERVIEW¶
Transplant recipients include solid organ transplant (SOT), vascular composite allograft (VCA), and hematopoietic stem cell transplant (HCT) patients.
• SOT/VCA: Require lifelong immunosuppression to prevent graft rejection, leading to persistent risk from common and opportunistic pathogens. • HCT: Includes two primary types: ◦ Auto-HCT: Uses recipient-derived stem cells; primarily for multiple myeloma (80%), lymphoma, and select nonmalignant conditions (e.g., systemic sclerosis). ◦ Allo-HCT: Uses donor stem cells; used for acute leukemia, myelodysplastic/myeloproliferative disorders, aplastic anemia, hemoglobinopathies, and primary immunodeficiencies. • Immunosuppression Dynamics: Lifelong for SOT/VCA; typically temporary (months) for allo-HCT to manage GVHD risk.
2. EPIDEMIOLOGY & RISK FACTORS¶
• HCT Volume: Approximately 20,000 HCTs occur annually in the US (12,000 auto-HCT; 8,000 allo-HCT). • GVHD Risk: Allo-HCT recipients have a 35-50% incidence of GVHD. • Infection Timing (Table 148-1): ◦ Very Early (<1 month): Aerobic bacteria (Gram-positive and Gram-negative), HSV, and Candida. ◦ Early (<100 days): Candida, Aspergillus, CMV, EBV, Toxoplasma, community-acquired respiratory viruses, Pneumocystis, molds, and adenovirus. ◦ Late (>100 days): Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis), Nocardia, and other community-acquired respiratory viruses.
2.1 Site-Specific Risk Factors¶
• Genitourinary Tract: BK virus (common <100 days); HHV-6 and Toxoplasma (>100 days). ◦ Risk factors for UTI: Duration of indwelling catheters, female sex, and recurrence prior to transplant. ◦ BK Risk: High viremia (>10,000 copies/mL), older age, and male recipients. • Pulmonary: Risk factors include pretransplant colonization with resistant organisms, requirement for endotracheal intubation, and CLAD (a risk factor for and result of infection). • Cardiac: Toxoplasma (pretransplant serology D+/R–); Trypanosoma cruzi (seropositive donor exclusion); Ureaplama/Mycoplasma (risk of encephalopathy if ammonia >200 μmol/L).
3. CLINICAL FEATURES & PATHOGENS¶
Infections in immunocompromised hosts often present with atypical symptoms, delayed onset, or multiple concurrent pathogens.
• Bacterial Pathogens: Staphylococcus aureus (including MRSA), Pseudomonas aeruginosa, and encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis). • Fungal Pathogens: Candida spp., Aspergillus fumigatus, and other molds. • Viral Pathogens: Cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK polyomavirus, HSV, VZV, and respiratory viruses (RSV, influenza, SARS-CoV-2). • Opportunistic/Other: Nocardia, Toxoplasma gondii, Trypanosoma cruzi.
3.1 Diagnostic Challenges¶
• Atypical Presentation: E.g., CMV pneumonia may present with fever and hypoxia without classic pulmonary infiltrates. • Non-specific Imaging: Radiologic findings (e.g., consolidation, nodular opacities) are often non-specific (Figure 148-1). • Multi-pathogen Infection: Common due to profound immunosuppression.
4. DIAGNOSTIC APPROACH¶
- Clinical Assessment: Evaluate for atypical symptoms and evidence of multiple concurrent pathogens.
- Laboratory Testing: ◦ Microbiology: Blood cultures, tissue/fluid cultures (especially for intra-abdominal or graft sites). ◦ Virology: PCR for viral pathogens (CMV, EBV, BK). ◦ Mycology: Galactomannan assay for Aspergillus.
- Imaging: ◦ Chest X-ray/CT: Primary tool for pulmonary infections. ◦ Abdominal Ultrasound: For identifying abscesses or complications of biliary leaks.
- Tissue Biopsy: Indicated when clinical suspicion is high for fungal or CMV infections.
4.1 Special Considerations¶
• Latent TB: Requires pre-transplant screening; risk of reactivation in SOT recipients. • Drug Resistance: High prevalence of carbapenemase-producing Enterobacteriaceae.
5. MANAGEMENT & PROPHYLAXIS¶
- Prophylaxis (Table 148-3): ◦ Candida: Fluconazole (for patients with mucosal integrity disruption). ◦ Aspergillus/Molds: Posaconazole. ◦ HBV: Entecavir (for those at risk of infection). ◦ HSV/VZV: Acyclovir or valacyclovir. ◦ CMV: Letermovir (preferred in HCT) or valganciclovir. ◦ Pneumocystis jirovecii: Trimethoprim-sulfamethoxazole (TMP-SMX). Second line: Dapsone, pentamidine, or atovaquone. ◦ Toxoplasma gondii: TMP-SMX or atovaquone. ◦ Strongyloides stercoralis: Ivermectin. ◦ LTBI: Isoniazid or rifampin (if active TB is ruled out).
- Empirical Therapy: ◦ Neutropenic Fever: Piperacillin-tazobam + vancomycin.
- Targeted Therapy: ◦ Aspergillus: Voriconazole.
- Source Control: ◦ Surgical/Interventional Radiology: Essential for bacterial/fungal infections of the graft, anastomosis, or intra-abdominal sites (e.g., biliary leaks).
- GVH Prevention: ◦ Allo-HCT: Tacrolimus/sirolimus + mycophenolate mofetil.
6. KEY CLINICAL PEARLS¶
• SOT vs. HCT: SOT requires lifelong immunosuppression; HCT involves a high-risk window of transient immunosuppression and neutropenia. • Timing Matters: In HCT, the risk profile shifts from bacterial/viral (<1 month) to fungal/viral (<100 days) to community-acquired pathogens (>100 days). • Source Control: Critical for any localized infection (e.g., intra-abdominal or graft site) involving bacteria or fungi. • Prophylaxis Standards: Standardized regimens exist for Pneumocystis (TMP-SMX), HSV/VZV (Acyclovir/Valacyclovir), and CMV (Valganciclovir/Letermovir). • Clinical Vigilance: Atypical presentations and non-specific imaging (Figure 148-1) require high clinical suspicion for opportunistic infections.
Reference Tables¶
TABLE 148-1 Common Sources of Infection After Hematopoietic Stem Cell Transplantation¶
Harrison's 22e, p.1155
| INFECTION SITE | PERIOD AFTER TRANSPLANTATION | ||
|---|---|---|---|
| VERY EARLY (<1 MONTH) | EARLY (BEFORE 100 DAYS) | LATE (>100 DAYS) | |
| Disseminated | Aerobic bacteria (gram-negative, gram-positive) |
Candida, Aspergillus, CMV, EBV, Toxoplasma |
Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) |
| HSV, Candida | HSV, VZV | ||
| Lungs | Aerobic bacteria (gram-negative, gram-positive), Aspergillus, other molds |
CMV, community-acquired respiratory viruses, Pneumocystis, Toxoplasma, molds, adenovirus |
Community-acquired respiratory viruses, Pneumocystis, Nocardia, S. pneumoniae, H. influenzae NTM (cGVHD) |
| Clostridioides difficile | CMV, adenovirus, norovirus | ||
| Genitourinary tract | BK virus | BK virus, adenovirus | |
| HHV-6, Toxoplasma | |||
| Bone marrow | CMV, Toxoplasma | CMV |
TABLE 148-2 Common Infections After Solid Organ Transplantation by Site of Infection and Transplant Type¶
Harrison's 22e, p.1159
| INFECTED SITE | TYPE OF INFECTION | RISK FACTOR | MANAGEMENT |
|---|---|---|---|
| Transplanted organ | Bacterial and fungal infections of the graft, anastomotic site, and surgical wound |
Prior colonization of the donor with MDR organisms |
Institute targeted antimicrobial treatment as soon as prior colonization is known (peritransplant or immediately posttransplant). Source control (surgical or interventional radiology) and continued directed antimicrobials. Optimal duration after source control is unknown. Usual correlates of adequate treatment are clinical, laboratory, and radiologic resolution. |
| Bacterial, yeast infections are most common; NTM (rare, mostly thoracic transplants) |
Pain, erythema, discharge, or dehiscence of wounds, typically within the first 30 days posttransplant |
||
| Intra-abdominal infections in liver transplant recipients |
Bacterial and yeast infections | Secondary to biliary anastomoses leaks, or Roux-en-Y hepaticojejunostomy or other anastomoses that increase the risk of intestinal reflux into the biliary system; hepatic necrosis, from hepatic vascular thrombosis |
Obtain blood cultures. Deep tissue or fluid cultures obtained intraoperatively or by IR. Source control. Antimicrobials adjusted based on microbiologic results (polymicrobial infections are the norm). Optimal duration of antimicrobials is unknown. Usual correlates of adequate treatment are clinical, laboratory, and radiologic resolution. |
| Recurrent cholangitis (bacteria and yeast) |
Biliary strictures: anastomotic (acute) or nonanastomotic (chronic allograft rejection) |
||
| Urinary tract infections in kidney transplant |
Recurrent cystitis and pyelonephritis (bacteria, in particular Enterobacteriaceae); Mycobacterium tuberculosis and yeasts are less frequent causes of UTI but should be suspected when there is pyuria and/or hematuria and negative cultures |
Duration of indwelling urinary tract catheters, female recipients, as well as recurrent UTI prior to the transplant |
Prompt catheter and ureteral stent removal. Targeted antimicrobials. If recurrent UTI, evaluate for anatomic abnormalities (ureteral reflux, ureterovesical junction stenosis, neurogenic bladder, bladder diverticulum). |
| BK, rarely JC virus | Heightened immunosuppression, male recipient, older age, and a high BK viremia (>10,000 copies/mL) |
||
| Pneumonia and tracheobronchitis in lung transplant |
Bacterial infections: severe or recalcitrant community-acquired viral pathogens (RSV, influenza, SARS-CoV-2); invasive mold infections; fungal tracheobronchial infection; NTM pulmonary disease |
Pretransplant colonization with resistant organisms, requiring endotracheal intubation prior to the transplant, and mucociliary dysfunction, are significant risk factors for bacterial infections; CLAD is a risk factor for and a result of recurrent viral, bacterial, fungal, and mycobacterial infections |
Early antimicrobial therapy if possible. For viral respiratory pathogens, prevention with seasonal annual vaccination is recommended, with monoclonal antibodies when available. In patients with CLAD, respiratory rehabilitation and pulmonary toileting. |
| Bacterial or Candida mediastinitis, with or without sternal osteomyelitis; less common Nocardia spp., NTM, or molds |
Diabetes mellitus, surgical reoperation, and acute rejection |
||
| Myocarditis, pericarditis, and cardiomyopathy in heart transplant |
Toxoplasma gondii infection | Toxoplasma pretransplant serology D+/R– |
Diagnosis is established by the identification of tachyzoites in the endomyocardial biopsy or PCR in tissue and/or pericardial fluid. Preemptive monitoring via blood PCR and TMP-SMX prophylaxis reduce incidence of disease. |
| Trypanosoma cruzi | Pretransplant recipient seropositivity (hearts from seropositive donors are not used) |
Clinical manifestations are fever, myocarditis, and painful skin lesions. Preemptive monitoring via blood PCR to detect early reactivation is indicated in all previously known seropositive recipients. Antitrypanosomal treatment (benznidazole or nifurtimox) for all patients with reactivation and tissue- invasive disease. |
|
| Ureaplasma spp. systemic infection (less commonly Mycoplasma spp.) that results in encephalopathy due to high ammonia levels >200 μmol/L |
Donor lung colonization |
TABLE 148-3 Prophylactic Regimens Commonly Used to Decrease Risk of Infection in Transplant Recipients¶
Harrison's 22e, p.1164
| RISK FACTOR | ORGANISM | PROPHYLACTIC DRUG | EXAMINATION(S)a |
|---|---|---|---|
| Neutropenia, mucositis | Candida | Fluconazole | Candida is part of the normal GI flora; everyone with disruption of the mucosal integrity is at risk |
| Aspergillus and other molds | Posaconazole | ||
| Travel to or residence in an area with known risk of endemic fungal infection |
Histoplasma, Blastomyces, Coccidioides, Talaromyces marneffei |
Triazoles considered in context of clinical and laboratory assessment |
Chest imaging, antigen testing, serology |
| HBV | Entecavir | ||
| Chronic hepatitis C | HCV | Prophylaxis not used; treat to achieve persistent virological response |
HCV serology, HCV RNA |
| HSV, VZV, significantly lower efficacy for CMV, EBV |
Acyclovir or valacyclovir | ||
| CMV | Letermovir (more experience in HCT) or valganciclovir (active against HSV and VZV) |
||
| Exposure (unknown reservoir) or colonization |
Pneumocystis jirovecii | Trimethoprim-sulfamethoxazole (TMP-SMX) Second line: dapsone, pentamidine, atovaquone |
|
| Toxoplasma gondii Strongyloides stercoralis |
TMP-SMX or atovaquone for toxoplasma Ivermectin for Strongyloides |
||
| LTBI | Mycobacterium tuberculosis | Isoniazid or rifampin in patients with recent seroconversion, positive chest imaging, or recent known exposure and no previous treatment, once active TB is ruled out |
TST and/or IGRA; if indeterminate, clinical assessment of exposure and risk |