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Invasive Fungal Infections in Transplant Recipients
Abstract & Commentary
By Ellen Jo Baron, PhD, D(ABMM), Professor Emerita, Stanford University School of Medicine Interim Director, Clinical Virology Laboratory, is Associate Editor for Infectious Disease Alert.
Dr. Baron reports no financial relationships relevant to this field of study.
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 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.
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 detection 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. In both studies, audits of non-surveyed incident cohorts showed that most infected patients (> 95%) had been detected and included.
Patients were followed for development of IFI, as defined by the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG).4 Although the consensus group has since refined the definitions to narrow the range of possible infections and broaden the criteria for probable infections,5 these two TRANSNET publications were based on the original criteria. "Proven" infections require unequivocal evidence of fungi in the tissues or the bloodstream, preferably based on culture results, but histopathological findings in association with tissue damage (seen on histology or by some form of imaging) are also acceptable proof. "Probable" infections are those with a combination of patient criteria (such as prolonged neutropenia, steroid use, graft-vs.-host disease, etc.), microbiological criteria (including factors such as a positive beta-galactomannan test result, isolation of a fungus from a non-tissue site, positive fungal antigen test result, or other evidence), and two minor, or one major, clinical criteria involving signs and symptoms such as radiological or other imaging study evidence, cough with hemoptysis, skin lesions, etc. The "possible" category, which included patients with one host factor and either microbiological or clinical criteria traditionally associated with invasive fungal disease, was not included for evaluation in these surveillance data, which adds to the strength of these publications. Readers are referred to the original documents for complete original and current definitions of IFI.4,5
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. Slightly more (56%) of these cases were proven than probable. 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.
At least two positive findings emerged among the results of this study. First, the incidence of Candida infections is lower than seen in previous surveys conducted approximately 20 years ago.6 The authors suggest that widespread use of azole prophylaxis may account for this decrease. Second, the overall incidence in this U.S. cohort is much less than the 19% of HSCT patients cared for in St. Petersburg who developed IFI over a similar time period.2 The populations differed in that more pediatric patients were included in the Russian survey; however, 61% of the infections occurred in adults. The one note of caution based on the results of the TRANSNET study is that the cumulative incidence curves demonstrated that invasive aspergillosis disease, particularly at sites performing more of the higher-risk allogeneic transplantations, has not decreased despite broad use of prophylactic antifungal therapies and, in fact, has shown a slight increase; whereas, invasive candidiasis has remained stable. Reasons are unclear, but the authors suggest shifts in choice of patients and immunotherapeutic regimens. Another factor that should not be discounted is the possible improved ability of microbiology laboratories to detect agents of invasive fungal disease. More sites are performing beta-galactomannan studies (specific to Aspergillus) or, even better, beta-glucan studies (positive for many yeasts and molds), to detect antigens of fungi in the bloodstream before clinical signs and symptoms are observed.7,8 Perhaps use of chromogenic media for yeast isolation and identification has also enhanced laboratory detection.9 A non-controversial conclusion is that better diagnostic tests are needed. 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.
The IFI among the solid-organ transplant recipients were assessed using the same EORTC-MSG criteria as summarized above over only the three-year period from 2002 to 2005. 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). Only 2.3% of patients developed zygomycosis. Invasive candidiasis had the highest 12-month cumulative incidence estimate (1.9%), followed by invasive aspergillosis (0.7%). 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.
As seen in the HSCT recipients, the incidence of invasive fungal disease increased slightly over the surveillance period in this cohort of patients, but in the solid-organ recipients, the increase was due to Candida infections (1.4% in 2002 to 2.3% in 2005), whereas Aspergillus incidence remained stable.
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.
Another conclusion supported by the slightly increasing incidence of IFI in these patients is that the ability of diagnostic studies to detect IFI in time for caregivers to react preemptively is still limited. Studies evaluating non-invasive, usually molecular-based, assays have been published; however, the results have been less than optimal. In one report, Hebart et al used the presence of any of numerous Candida and Aspergillus species fungal genetic elements in whole blood, as detected with a nucleic acid amplification assay, compared with clinical criteria alone to initiate treatment with liposomal amphotericin-B in allogeneic stem-cell transplant recipients.10 Although more patients received early treatment based on polymerase chain reaction (PCR) results and survival for the two groups was better among the PCR-based treated individuals during the first 30 days, the 90-day survival was identical and showed no benefit for patients for whom PCR diagnostic tests were performed. As have numerous studies in the last few years, these authors called for further studies on the benefits of using PCR in patients at risk for IFI.
Both of the TRANSNET studies summarized here concluded that the true incidence of IFI was likely to have been underestimated due to the imperfect capabilities of diagnostic assays at this time. To quote Kontoyiannis et al, "...the precise epidemiology of invasive mold infections will remain uncertain until validated, sensitive, and specific non–culture based diagnostic methods become available."