The impact of invasive fungal diseases on survival after lung transplantation.

BACKGROUND: Recipients of lung transplants are at high risk of infectious complications. We investigated the epidemiology of infections after lung transplantation and determined their impact on survival. METHODS: We retrospectively reviewed the medical records of patients who underwent lung transplantation at Mayo Clinic (Rochester) during 1990-2005. Survival analyses were performed using Kaplan-Meier estimation and Cox proportional hazard modeling. RESULTS: Sixty-nine lung transplants were performed during the 16-yr study period. The mean (+/-SD) patient age was 50.5 +/- 9.7 yr; 45% were male. During the mean (+/-SD) follow-up period of 1188 (+/-1288) d, the cumulative percentage of patients with infections were: bacteria (52%), cytomegalovirus (CMV) (49%), other viruses (32%), fungi (19%), mycobacteria (7%), and Pneumocystis jiroveci (1%). The median survival time after lung transplantation was 5.02 yr. Kaplan-Meier estimation of one-, three-, and five-yr survival was 80%, 61%, and 50%, respectively. Overall, 37 (54%) patients died due to graft rejection and failure (35%), invasive fungal diseases (16%), post-transplant lymphoproliferative disorder and other malignancies (14%), cardiovascular diseases (5%), CMV disease (3%), bacterial infection (3%), or other causes (24%). Survival analysis using Kaplan-Meier estimation showed that invasive fungal disease (Aspergillus sp., n = 9, Candida sp., n = 2, Alternaria sp., n = 1, Rhizopus sp., n = 1, and/or Mucor sp., n = 1) was significantly associated with mortality (p = 0.0104). After adjusting for age and graft rejection, invasive fungal disease remains a significant predictor of mortality (p = 0.0262). CONCLUSION: Invasive fungal disease is significantly associated with all-cause mortality after lung transplantation. An aggressive antifungal preventive strategy may lead to improved survival after lung transplantation.

A prospective longitudinal analysis of cytomegalovirus (CMV)-specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection.

Cytomegalovirus (CMV)-specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV-specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine-flow cytometry, we enumerated interferon-gamma producing CMV-specific CD4+ and CD8+ T cells at serial time points among CMV-mismatched (D+/R-) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (+ or - SD) time of 151 (+ or - 33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue-invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R-) status (HR: 13, 95% CI: 1.6-106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1-27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change-over-time in CMV-specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE-1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV-specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV-specific T cell assays will need to be assessed in a larger cohort of CMV D+/R- kidney recipients who remain at high-risk of delayed-onset CMV disease.

Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation.

BACKGROUND: During the contemporary era of antiviral prophylaxis, the impact of delayed-onset primary cytomegalovirus (CMV) disease on the outcome of kidney transplantation is not known. We evaluated the incidence, clinical features, risk factors, and outcomes of CMV disease among high-risk kidney transplant recipients. METHODS: The medical records of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors were reviewed. Cox proportional hazards regression was used to identify factors associated with CMV disease and to assess its impact on allograft loss and mortality. RESULTS: None of the 176 CMV-seronegative recipients of kidney transplants from CMV-seropositive donors developed breakthrough CMV disease during a median of 92 days (interquartile range, 90-92 days) of oral ganciclovir or valganciclovir prophylaxis. Thereafter, 51 patients (29%) developed CMV disease at a median of 61 days (interquartile range, 40-143 days) after stopping antiviral prophylaxis. Early-onset bacterial and fungal infection (hazard ratio, 3.61; 95% confidence interval, 1.78-7.33; p < .001) and a Charlson comorbidity index > or =3 (hazard ratio, 2.21; 95% confidence interval, 1.15-4.22; p = .011) were associated with a higher risk of delayed-onset primary CMV disease, and postrejection antiviral prophylaxis (hazard ratio, 0.29; 95% confidence interval, 0.09-0.94; P = .039) was associated with a lower risk of such CMV disease. A time-dependent Cox regression analysis revealed a statistically significant association between tissue-invasive CMV disease and allograft loss or mortality (hazard ratio, 2.85; 95% confidence interval, 1.22-6.67; P = .016). CONCLUSION: This study of a large cohort of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors illustrates the ongoing challenge of delayed-onset primary CMV disease and its impact on transplantation outcomes despite antiviral prophylaxis. Better strategies for CMV disease prevention after kidney transplantation are warranted.

Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes.

BACKGROUND: Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir-resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug-resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis. METHODS: The medical records of all CMV D+/R- kidney, pancreas, liver, and heart recipients were screened for CMV disease, and the clinical course and outcomes of patients with drug-resistant CMV were reviewed. RESULTS: During a four-yr-study period, a total of 225 CMV D+/R- transplant patients received valganciclovir prophylaxis for a median of 92 d. Sixty-five (29%) of the 225 patients developed delayed-onset primary CMV disease, including nine (14%) suspected to have drug-resistant virus. Four (6.2%) had confirmed UL97 or UL54 mutations. All except one patient manifested gastrointestinal tissue-invasive disease. Together with reduction in immunosuppression, intravenous foscarnet with or without CMV hyperimmunoglobulin was the most common treatment. Drug-associated nephrotoxicity was commonly observed and resulted in allograft loss in two patients. During the mean follow-up of 2.2 yr, allograft loss and mortality occurred in two of four patients with proven and in three of five patients with clinically suspected drug-resistant CMV. CONCLUSIONS: Cytomegalovirus disease because of clinically suspected or genotypically confirmed drug-resistant CMV is not uncommon in CMV D+/R- solid organ transplant patients who received valganciclovir prophylaxis. Because of its significant morbidity and mortality, an optimized strategy of CMV prevention is warranted to reduce the negative impact of drug-resistant CMV on the successful outcome of organ transplantation.

Delayed-onset primary cytomegalovirus disease after liver transplantation.

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor-positive/recipient-negative (D+/R-) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R- liver transplant recipients who received antiviral prophylaxis. Sixty-seven CMV D+/R- liver transplant recipients (mean age+/-standard deviation: 49.5+/-11.4 years; 75% male) received oral ganciclovir [n=9 (13%)] or valganciclovir [n=58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91-100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed-onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P=0.01) and younger age at transplant (P=0.03) were associated with an increased risk, whereas diabetes mellitus (P<0.001) was significantly associated with a lower risk of delayed-onset primary CMV disease. Allograft loss or mortality occurred in 8 (12%) patients during the median follow-up period of 3.31 (range: 0.8-5.9) years. No significant association was observed between CMV disease and patient and allograft survival. In conclusion, CMV disease remains a common complication in CMV D+/R- liver transplant patients during the contemporary era of antiviral prophylaxis. Female patients and younger patients are at increased risk of delayed-onset primary CMV disease.