Hematopoietic Stem Cell Transplantation (Hsct)

• Pathogenesis: The myeloablative processes involved in HSCT result in the complete absence of innate and adaptive immune cells. This transient state of complete immunologic incompetence and the reconstitution that follows make the host extremely susceptible to infections.
• Etiology: Most infections occur in a predictable time frame after HSCT (Table 82-2 Common Sources of Infection after Hematopoietic Stem Cell Transplantation ).
  • - Bacterial infections:Neutropenia-related infectious complications are most common during the first month. Some centers give prophylactic antibiotics (e.g., quinolones) that may decrease the risk of gram-negative bacteremia but increase the risk of Clostridium difficile colitis.
    • Skin and bowel flora (e.g., S. aureus, coagulase-negative staphylococci, E. coli) are responsible for most infections in the first few days following HSCT, after which nosocomial pathogens and filamentous bacteria (e.g., vancomycin-resistant enterococci, Acinetobacter, antibiotic-resistant gram-negative bacteria, and Nocardia species) become more common.
    • In the late post-transplantation period (>6 months after reconstitution), bacteremia due to encapsulated organisms is most common, particularly among pts who are asplenic or hypogammaglobulinemic.
  • - Fungal infections: Fungal infections are increasingly common beyond the first week after HSCT, particularly among pts who receive broad-spectrum antibiotics. Infections with Candida species are most common, although resistant fungi (e.g., Aspergillus, Fusarium) are becoming more common because of the increased use of prophylactic fluconazole.
    • Prolonged treatment with glucocorticoids or other immunosuppressive agents increases the risk of infection with Candida or Aspergillus and of reactivation of endemic fungi even after resolution of neutropenia.
    • Maintenance prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX; 160/800 mg/d starting after engraftment and continuing for at least 1 year) is recommended to prevent Pneumocystis jirovecii pneumonia.
  • - Parasitic infections: Prophylaxis with TMP-SMX is also protective against disease caused by Toxoplasma as well as against late infections caused by certain bacteria, including Nocardia, Listeria monocytogenes, S. pneumoniae, and H. influenzae.
    • Given increasing international travel, parasitic diseases (e.g., caused by Strongyloides, Leishmania, Giardia, Cryptosporidium) that are typically restricted to particular environments may be more likely to be reactivated in pts after HSCT.
  • - Viral infections: Prophylactic acyclovir or valacyclovir for HSV-seropositive pts reduces rates of mucositis and prevents pneumonia and other HSV manifestations.
    • Zoster generally occurs several months after HSCT and usually is managed readily with acyclovir.
    • Human herpesvirus type 6 delays monocyte and platelet engraftment and may be linked to encephalitis or pneumonitis; the efficacy of antiviral treatment has not been well studied.
    • CMV disease (e.g., interstitial pneumonia, bone marrow suppression, colitis, and graft failure) usually occurs 30-90 days after HSCT. Severe disease is more common among allogeneic transplant recipients and is often associated with graft-versus-host disease, with pneumonia as the foremost cause of death. Preemptive therapy (initiation of antiviral therapy only after CMV is detected in blood) has supplanted prophylactic therapy (treatment of all transplant recipients when either the recipient or the donor is seropositive) because of the toxic side effects associated with ganciclovir.
    • EBV lymphoproliferative disease as well as infections caused by respiratory viruses (e.g., respiratory syncytial virus, parainfluenza virus, metapneumovirus, influenza virus, adenovirus) can occur. BK virus (a polyomavirus) has been found in the urine of pts after HSCT and may be associated with hemorrhagic cystitis.

Solid Organ Transplantation (Sot)

• Pathogenesis: After SOT, pts do not go through a stage of neutropenia like that seen after HSCT; thus the infections in these two groups of pts differ. However, solid organ transplant recipients are immunosuppressed for longer periods with agents that chronically impair T-cell immunity. Moreover, the persistent HLA mismatch between recipient immune cells (e.g., effector T cells) and the donor organ (allograft) places the organ at permanently increased risk of infection.
• Etiology: As in HSCT, the infection risk in SOT depends on the interval since transplantation.
  • Early infections (1 month): Infections are most commonly caused by extracellular organisms, which originate in surgical wound or anastomotic sites.
  • - Middle-period infections (1-6 months): The consequences of suppressing cell-mediated immunity become apparent, and infections result from acquisition-or reactivation-of viruses, mycobacteria, endemic fungi, and parasites.
    • CMV can cause severe systemic disease or infection of transplanted organs; the latter increases the risk of organ rejection, prompting increased immunosuppression that, in turn, increases CMV replication.
    • Diagnosis, treatment, and prophylaxis of CMV infection are the keys to interrupting this cycle.
  • - Late infections (>6 months): Infections in this period are similar to those in pts with chronically impaired T-cell immunity (e.g., Listeria, Nocardia, Rhodococcus, mycobacteria, various fungi, other intracellular organisms).
    • EBV lymphoproliferative disease occurs most commonly in pts who receive a heart or lung transplant (as well as the most intense immunosuppressive regimens); in these cases, immunosuppression should be decreased or discontinued, if possible, and consideration should be given to treatment with anti-B cell antibodies.
    • Prophylaxis against Pneumocystis pneumonia for at least 1 year is generally recommended for all solid organ transplant recipients.
    • The incidence of tuberculosis within the first 12 months after SOT is greater than that after HSCT and reflects the prevalence of tuberculosis in the local population.
• Specific issues: While the information given earlier is generally valid for all organ transplants, there are some organ-specific considerations.
  • - Kidney transplantation: TMP-SMX prophylaxis for the first 4-6 months decreases the incidence of early and middle-period infections, particularly UTIs related to anatomic alterations resulting from surgery. CMV is the predominant pathogen in the middle period; disease is evident in 50% of renal transplant pts presenting with fever 1-4 months after transplantation, prompting many centers to use valganciclovir prophylaxis for high-risk pts. BK viruria and viremia, often diagnosed as a late-onset disease, are associated with ureteral strictures, nephropathy, and vasculopathy and require a reduction of immunosuppression to lower rates of graft loss.
  • - Heart transplantation: Mediastinitis, generally caused by typical skin flora and rarely caused by Mycoplasma hominis, is an early complication of heart transplantation. The overall incidence of toxoplasmosis (a middle-period infection) is so high in the setting of heart transplantation that serologic screening and some prophylaxis (e.g., with TMP-SMX) are always warranted.
  • - Lung transplantation: Pts receiving a lung transplant are predisposed to pneumonia and mediastinitis in the early period. The high incidence of CMV disease (75-100% if either the donor or the recipient is seropositive) indicates the importance of antiviral prophylaxis; late disease may occur once prophylaxis is discontinued, although the pt is generally better able to handle it because of reduced immunosuppression.
  • - Liver transplantation: Bacterial abscesses and peritonitis are common early complications and often result from biliary leaks. Pts receiving a liver transplant have a high incidence of fungal infections correlated with preoperative glucocorticoid use, long-term antimicrobial use, and a high degree of immunosuppression. Recurrent (reactivated) hepatitis B and C infections are problematic. Administration of hepatitis B immunoglobulin and prophylaxis with antiviral agents active against hepatitis B virus has been successful in preventing reinfection with hepatitis B virus. Reinfection with hepatitis C virus occurs in all untreated pts, but direct-acting antivirals are now effective in both treating hepatitis C infections before transplantation and preventing reinfection of the graft after transplantation.