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SUPPLEMENT ARTICLE Epidemiology of Infections after Solid-Organ Transplantation David R. Snydman Departments of Medicine and Pathology, New England Medical Center, and Tufts University School of Medicine, Boston Infections are a major determinant of the outcome of solid-organ transplantation. Their incidence varies because of a number of factors. The type of organ transplanted, the degree of immunosuppression, the need for additional antirejection therapy, and the occurrence of technical or surgical complications all affect the incidence of infection after transplantation. There are 3 general time frames to consider. In the first month, bacterial and candidal infections predominate. From the second through the sixth months, infections “classically” associated with transplantation become manifest. Beyond the sixth month, the clinical course is largely determined by the presence or absence of chronic rejection. The incidence of infection following solid-organ transplantation varies because of a number of factors. The type of organ transplanted, the degree of immunosuppression, the need for additional antirejection therapy, and the occurrence of technical or surgical complications all affect the incidence of infection after transplantation [1]. The anatomical region of the transplant dictates to a great extent the type of infection that may occur. Furthermore, investigators have demonstrated that viral infections, such as cytomegalovirus (CMV) and hepatitis C (HCV), influence the likelihood of opportunistic infections occurring, whether bacterial or fungal [2–4]. These infections presumably contribute to the net state of immunosuppression and weaken host defenses [5]. In addition, antirejection therapy also contributes to the increase in infectious complications [6]. The other major factor in the development of infection is exposure to a donor pathogen when a recipient is at risk for primary infection (i.e., absence of preexisting immunity). The most common manifestation of these risk strata is primary CMV infection and disease, in Reprints or correspondence: Dr. David R. Snydman, New England Medical Center, Box 238/750 Washington St., Boston, MA 02111 ([email protected]). Clinical Infectious Diseases 2001; 33(Suppl 1):S5–8 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3301S1-0002$03.00 which this subset has the highest risk of disease and complications, regardless of the type of organ transplanted [7]. The incidence of infection following solidorgan transplantation, stratified by type of pathogen and organ type, is listed in table 1. The timing of infection after organ transplantation is also influenced by a number of factors, including surgical complications, the level of immunosuppression, and environmental and epidemiologic factors that may affect exposure to certain pathogens. There are 3 general time frames to consider, namely, the first month (i.e., the early perioperative period), the second through the sixth month, and the late posttransplant period (beyond the sixth month) [8]. Most infections during the first month after transplantation are related to surgical complications (figure 1). They include bacterial and candidal wound infections, pneumonia, urinary tract infection, intravascular catheter sepsis, infections of biliary, chest, and other drainage catheters, and Clostridium difficile. These infections are similar to those occurring in general surgical patients. In the first month after transplantation, renal and pancreas transplant recipients are at risk for perigraft hematomas, lymphoceles, and urinary leaks [9]. Liver transplant recipients are at risk for portal vein thrombosis, hepatic vein occlusion, hepatic artery thrombosis, and biliary stricture formation and leaks [10]. Heart transplant reOrgan Transplant Infection Epidemiology • CID 2001:33 (Suppl 1) • S5 Table 1. Incidence of infectious diseases in solid-organ transplant recipients. Incidence of infection in patients receiving Type of infection Lung/ heart-lung Pancreas/ kidney-pancreas 21–30 35–66 35 9–35 53–75 50 1–42 10–18 6 Liver Kidney Heart Bacterial 33–68 47 Cytomegalovirus 22–29 8–32 Herpes simplex virus 3–14 53 Varicella-zoster virus 5–10 4–12 1–12 8–15 9 Candida species 1–26 2 1–5 10–16 32 Mycelial fungi 2–4 1–2 3–6 3–19 3 Pneumocystis carinii 4–11 5–10 1–8 15 NOTE. The data given here represent the range of values found in the literature and in the studies cited by Patel and Paya [1]. cipients are at risk for mediastinitis and infection at the aortic suture line, with resultant mycotic aneurysm, and lung transplant recipients are at risk for disruption of the bronchial anastomosis [11, 12]. The most common viral infection during the first month after transplantation is reactivated herpes simplex virus (HSV) infection in individuals seropositive for this virus before transplantation or the very rare occurrence of primary HSV infection in a seronegative recipient exposed to an HSV-seropositive donor organ. The prophylactic use of acyclovir during this period has, however, significantly reduced the incidence of this infection [13]. The period from the second to the sixth month after transplantation is the time during which infections “classically” associated with transplantation become manifest [14–18]. Opportunistic pathogens such as CMV, Pneumocystis carinii, Aspergillus species, Nocardia species, Toxoplasma gondii, and Listeria monocytogenes typically occur in this time frame (figures 2–4). In addition, during the 1–6-month interval after transplantation, reactivation of infection because of organisms present in the recipient before transplantation may occur. For example, the introduction of high-dose immunosuppression Figure 1. Timing of infections in relation to transplantation, conventional infections. C. difficile, Clostridium difficile; ICU, intensive care unit; UTI, urinary tract infection; VRE, vancomycin-resistant enterococci. S6 • CID 2001:33 (Suppl 1) • Snydman may result in clinical illness because of reactivation of Mycobacterium tuberculosis, an occult focus of bacterial infection, viral hepatitis, Histoplasma capsulatum, or Coccidioides immitis. Chronic or latent infection of the donor that involves the allograft—such as HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), or fungal or mycobacterial infection—may be transmitted to the immunosuppressed recipient and become clinically apparent during the early and middle periods. Examination of the timing of viral infections following transplantation demonstrates 2 clusters, those that occur at the 2–3month period (although there is a wide range of timing in their occurrence) and those that typically occur much later (figure 2). Cytomegalovirus, HBV, HCV, and adenovirus frequently occur within 30–60 days after transplant [19–22]. Human herpesvirus type 6 is being increasingly recognized as reactivating within 6 weeks after transplant [23–25]. In contrast, some viral infections—such as varicella-zoster virus infection and polyomavirus infections—may occur much later [26, 27]. Epstein-Barr virus has a wide distribution in the latent period before clinical expression to posttransplant lymphoproliferative syndrome [28]. Conventional fungal infections, such as Candida, occur early in the postoperative period [29] (figure 3). Aspergillosis also Figure 2. Timing of infections in relation to transplantation, unconventional viral infections. CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; HHV-6, human herpesvirus type 6; VZV, varicella-zoster virus. Figure 3. Timing of infections in relation to transplantation, conventional and unconventional fungal infections. Figure 4. Timing of infections in relation to transplantation, unconventional bacterial and other organisms. TB, tuberculosis. tends to occur relatively early, frequently among those patients who either have intense exposure because of epidemiologic factors, such as construction, or among those who require intense immunosuppression and are doing poorly [30]. The epidemiology of infections with the pathogenic fungi—such as Cryptococcus, histoplasmosis, and coccidioidomycosis—varies somewhat from the aforementioned pattern (figure 3). These infections tend to occur later in the time course, require environmental exposure, and may well occur while such patients are outpatients and doing well [16, 17]. The unconventional bacterial infections mentioned previously, namely, Nocardia and Listeria, can occur at almost any time, although the most common occurrence is 2–6 months after transplantation. Parasitic infection with Toxoplasma, when it arises, does so several months after transplantation [31] (figure 4). From 6 months after transplantation onward, most transplant recipients do relatively well, suffering from the same infections seen in the general community. These include influenza virus infection, urinary tract infection, and pneumococcal pneumonia. The only opportunistic viral infection commonly seen during this period is reactivated varicella-zoster virus infection manifesting as herpes zoster. Rarely, CMV retinitis occurs. Two situations predispose patients to other infection in this late posttransplant period. First, patients who have had frequent episodes of acute rejection requiring augmented immunosuppressive therapy or those with chronic rejection who are maintained at a higher baseline level of immunosuppression remain at risk for the opportunistic agents more classically seen in the second to sixth months after transplantation (Cryptococcus neoformans, CMV, P. carinii, L. monocytogenes, and Nocardia species). Second, patients with chronic infections, such as HIV, HBV, and HCV infections, may suffer from comorbidity associated with these agents. In transplant recipients undergoing retransplantation, the aforementioned timetable may be altered, with infections characteristic of any given period occurring simultaneously and, in general, with an increased severity of infection. Retransplantation itself, with more complex surgery and previous immunosuppression, is a major factor in infection development. It should be noted that the epidemiology of infections after transplantation is changing dramatically because of improved surgical technique; the recognition that some forms of prophylaxis are highly effective in prevention of infections such as P. carinii, T. gondii, and CMV; improved types of immunosuppressive agents; and improved diagnostic capabilities [32–40]. For example, comparison of infections following liver transplantation in 3 eras and with improved measures for prophylaxis show improved survival and very few opportunistic infections (table 2) occurring in the most recent era [14, 32, 38]. Thus, the natural history of opportunistic disease is changing and should continue to improve through efforts to improve the prevention, diagnosis, and treatment of such infections. Table 2. Comparison of frequency (%) of infectious complications among 3 cohorts of orthotopic liver transplant recipients treated in the last 15 years, with comparisons of prophylaxis on cytomegalovirus (CMV) infection and disease and outcome, by era. Era 1984–1985 1987–1990 1993–1995 Infectious complication Observational (n p 101) Placebo (n p 72) CMVIG (n p 69) Placebo (n p 154) Gcv (n p 150) Invasive fungal disease 29 19.4 10.1 CMV disease 22 31 19 19.5 4.5 1.3 4.8 Mortality 26 25 17 10.4 6.7 NOTE. CMVIG, cytomegalovirus immunoglobulin for intravenous administration; Gcv, ganciclovir. Data from previously published studies [14, 32, 38]. Organ Transplant Infection Epidemiology • CID 2001:33 (Suppl 1) • S7 References 1. Patel R, Paya CV. Infections in solid organ transplantation recipients. 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