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Invasive infections: Be wary of delayed onset in transplants
Once infected, many patients will die within one year
By Ellen Jo Baron, PhD, D(ABMM), professor Emerita and interim director of the clinical virology laboratory at Stanford University School of Medicine in Palo Alto, CA.
Synopsis: The Transplant-Associated Infection Surveillance Network (TRANSNET) conducted a multicenter, prospective, observational study of invasive fungal infections involving U.S. sites performing hematopoietic stem cell (HSCT) transplant (22 sites) and solid organ transplant procedures (15 sites) during five years from 2001-2006. Aspergillus was the most common agent in stem-cell transplant recipients, and Candida was most common among solid-organ recipients. The predominant species of Candida was glabrata among stem-cell recipients and albicans in the solid-organ group. Surprisingly, although the overall incidence was low (< 4%), the incidence of invasive fungal infections in both transplant recipient populations increased slightly over the time period being surveyed.
Sources: Kontoyiannis DP, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091-1100; Pappas P, et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50:1101-1111.
Commentary: There are approximately 16,000 hematopoietic stem cell transplants (HSCT) and > 29,000 solid-organ transplants performed in the United States each year. Invasive fungal infections are among the most serious sequelae faced by these patients. Numerous studies have been published on cumulative experiences from individual centers, such as the recent 10-year Stanford experience with yeast infections in heart and lung transplant recipients,1 as well as an interesting study evaluating invasive fungal infections (IFI) in allogeneic HSCT recipients in St. Petersburg, Russia, carried out over approximately the same time frame as the U.S. study.2 But such single-site experiences should not be extrapolated, since results will vary based on types of procedures, institutional practices, and environmental exposures. In fact, the role of the external environment may be more important than appreciated. A study that measured the relative numbers of Aspergillus spores (using molecular methods) at various locations within a pediatric hospital, during a remodeling project featuring internal construction, showed that concentrations of spores in the environment outside the hospital and heavy foot traffic in the carpeted lobby were the factors most responsible for increased Aspergillus spore concentrations detected inside the hospital.3
The data presented in the two companion papers from the TRANSNET group represent the first multicenter, longitudinal study investigating all of the invasive fungal infections seen in a large population of transplant recipients over a geographically diverse area. The results of these investigations should be useful for developing criteria for risk stratification and to inform prospective policy development regarding prevention and therapy of IFI in transplant patients. The HSCT study involved 16,200 recipients from 22 institutions over the five-year study period. Only 9% were pediatric patients; the average age was 50, and patients were primarily white (82%) and male (59%). Most recipients received autologous cells (59%), with the rest receiving matched-related allogeneic (22%), allogeneic unrelated (16%), and mismatched related (3%). Among approximately 16,500 solid-organ recipients followed in the second study, there were 39% liver, 24% renal, 20% lung, 9% pancreas, 75 heart, and < 2% small bowel transplants, some involving simultaneous transplantation of more than one organ system. Patient characteristics were very similar to those of the HSCT recipients, with a low (< 5%) prevalence of pediatric patients. Among stem-cell transplant recipients, patients who received allogeneic grafts were more likely to develop IFI, with 78% of IFI occurring in that group. Equal numbers of those who had matched-related donors (38%) and unrelated donors (34%) became infected, but only 6% of patients receiving cells from mismatched-related donors became infected.. Invasive aspergillosis was the most common infection (43%), with A. fumigatus comprising 44% of the cases, although 26% were unidentified, and some of those certainly also could have been A. fumigatus. A total of 28% of patients developed invasive candidiasis, with the most common species being C. glabrata (33%), followed by C. albicans (20%). The median time to development of infection was 61 days for Candida and 99 days for Aspergillus. The Fusarium infections (3% of total) had a median time of 125 days and the zygomycete infections (8%) developed a median of 135 days post-transplantation.
Unfortunately, overall mortality among the HSCT cohort who developed IFI was still high. For patients with Fusarium infections, the one-year mortality was highest (93%), 75% for patients with aspergillosis, 72% for patients with zygomycosis, and 66% for patients developing candidiasis.
Solid-organ transplant recipients were also generally at low risk of developing an IFI during the surveillance period post-transplantation, with an overall one-year incidence < 4%. However, receipt of some organ systems placed patients at increased risk; for example, 8.6% of lung and heart-lung recipients (from 11 institutions) developed IFI, compared with only 1.3% for kidney transplants (15 sites). There appeared to be site-to-site variation in incidences of infections similar to those seen in the HSCT patient study. Among the 1,208 infections detected in 1,063 patients, 53% were Candida, with C. albicans being most common (46% of all candidiasis), followed by C. glabrata (25%). Invasive aspergillosis accounted for 19% of the diagnoses, with cryptococcosis next most prevalent (8% of infections). Median time to development of IFI was longer for the solid-organ recipients than was observed for HSCT patients, with 103 days observed for invasive candidiasis, 184 days for development of invasive aspergillosis, and 312 days for zygomycosis, with the other endemic fungal infections, such as histoplasmosis and coccidioidomycosis, appearing at a median of 343 days. An extended period of 575 days marked the median time until development of cryptococcosis.
A sad conclusion from this report is that once solid-organ transplant patients become infected, their prognosis is poor, although not as bad as that for HSCT patients. The one-year mortality after infection was 41% for patients with invasive aspergillosis, 39% for infections due to molds other than Aspergillus, 34% for invasive candidiasis, and 73% for cryptococcosis. Many of the observed infections occurred more than one year after transplantation, and 25% of IFI developed more than three years after the transplantation in this group. These results suggest that diagnostic studies, prevention strategies, and treatment interventions must take into consideration the long time frame required for monitoring these patients.