Rafael San Juan

Tuberculosis after Solid-Organ Transplant: Incidence, Risk Factors, and Clinical Characteristics in the RESITRA (Spanish Network of Infection in Transplantation) Cohort

BACKGROUND It is necessary to clarify the incidence of and risk factors for tuberculosis (TB) among solid-organ transplant (SOT) recipients as well as changes in the chronology, clinical presentation, and prognosis of the disease. METHODS A total of 4388 SOT recipients were monitored prospectively at 16 transplant centers included in the Spanish Network for Research in Infectious Diseases (REIPI). TB episodes were studied, and the incidence rate was calculated. Certain variables were analyzed, by Cox regression analysis, as potential risk factors for TB. RESULTS Among the 4388 SOT recipients, 21 cases of TB were reported (0.48%). The median duration of follow-up was 360 days (range, 0-720 days). The global incidence of TB was 512 cases per 10(5) patients per year (95% confidence interval [CI], 317-783), which was higher than that in the general population in Spain (18.9 cases per 10(5) inhabitants per year; relative risk [RR], 26.6). The highest incidence (2072 cases per 10(5) patients per year; 95% CI, 565-5306) was observed among lung transplant recipients (RR, 73.3). Of the TB cases, 95% occurred within the first year after transplant, and 76% were pulmonary forms. Crude mortality was 19.0%, and attributable mortality was 9.5%. Multivariate analysis identified recipient age (RR, 1.05; 95% CI, 1.0-1.1) and receipt of a lung transplant (RR, 5.6; 95%, 1.9-16.9) as independent risk factors. CONCLUSIONS TB incidence is increased among SOT recipients. The risk factors identified were age and receipt of a lung transplant. TB-attributable mortality (9.5%) is still high.

Impact of Current Transplantation Management on the Development of Cytomegalovirus Disease after Renal Transplantation

BACKGROUND Current advances in transplantation practices may influence the development of cytomegalovirus (CMV) disease after renal transplantation. METHODS From September 2003 through February 2005, 1470 renal transplant recipients (55 of whom were kidney-pancreas transplant recipients) were prospectively studied in the 16 transplant centers affiliated with the Spanish Network of Infection in Transplantation, with use of an ad hoc-designed online database. Univariate and multivariate analyses with logistic regression were performed to detect risk factors for CMV disease. RESULTS A total of 105 episodes of CMV disease (37 with visceral involvement) developed in 99 (6.7%) of 1470 patients. Attributable mortality appeared in 1 (1.0%) of 105 cases. Multivariate analysis showed that, apart from CMV serological mismatch, presence of rejection episodes, and the use of antilymphocitic drugs, a simultaneous pancreas transplantation (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5-9), use of cyclosporine (OR, 1.7; 95% CI, 1.18-2.9), a donor >60 years of age (OR, 2.3; 95% CI, 1.5-3.7), and chronic graft malfunction (OR, 1.8; 95% CI, 1.14-2.9) were independently associated with CMV disease, whereas use of sirolimus had a protective effect (OR, 0.27; 95% CI, 0.1-0.78). CONCLUSIONS Additional risk factors related to current transplantation practices influence the epidemiology of CMV after renal transplantation and should be taken into account in the design of prophylactic strategies in this population of kidney or kidney-pancreas recipients.

Prophylaxis With Caspofungin for Invasive Fungal Infections in High-Risk Liver Transplant Recipients

Objective. The aim of this prospective, multicenter, noncomparative, open-label trial was to evaluate the prophylactic use of caspofungin in adult liver transplant recipients at high risk of developing invasive fungal infections (IFI). Methods. Patients received caspofungin for at least 21 days. A successful treatment outcome was defined as the absence of breakthrough IFI during the first 100 days after the onset of caspofungin. Results. According to study design, 71 patients were included. In the modified intention-to-treat analysis, successful treatment outcome was obtained in 88.7%. Two patients developed IFI: a Mucor and a Candida albicans surgical wound infections, respectively. Six more patients discontinued caspofungin because of drug-related altered liver function. No clinical side effects were related to caspofungin. Altered analytical data compatible with grade IV toxicity, irrespective of caspofungin attribution, were observed in 27.7% of patients at the end of caspofungin prophylaxis and in 15.4% of patients in safety visit (14 days after ending caspofungin administration) (P=0.13). Eight patients died, six during caspofungin administration and two during follow-up period, but none were attributed to IFI or caspofungin toxicity. Conclusion. These results show that caspofungin could be considered an efficacious and well-tolerated drug as antifungal prophylaxis in high-risk liver transplant recipients.

Value of serial quantification of fungal DNA by a real-time PCR-based technique for early diagnosis of invasive aspergillosis in patients with febrile neutropenia.

ABSTRACT A study was designed to assess the reliability of the serial detection of Aspergillus sp. DNA to diagnose invasive aspergillosis (IA) in patients with febrile neutropenia. Two blood and two serum samples were taken weekly from 83 patients. A total of 2,244 samples were analyzed by real-time quantitative PCR. Twelve (14.4%) patients were diagnosed with IA. Taking two consecutive positive results as the diagnostic criterion, PCR detected 11 cases, with 4 false positives, giving sensitivity, specificity, positive, and negative predictive values of 91.6%, 94.4%, 73.3%, and 98.5%, respectively. On analyzing in conjunction with high-resolution chest tomography (HRCT) and galactomannan (GM) testing, the combination of serial PCR and GM detected 100% of aspergillosis cases, with a positive predictive value of 75.1%. This diagnostic strategy presented, according to CART analysis, a receiver-operator curve with an area under the curve of 0.97 (95% confidence interval, 0.895 to 1.032; P < 0.01), with a relative risk of IA 6.92 times higher than the control population and with predictive success of 95.2%. As regards early diagnosis, the serial detection of Aspergillus DNA took on average 21 days less than HRCT and 68 days less than GM. The serial detection of Aspergillus DNA using real-time quantitative PCR has great diagnostic applicability, which increases when combined with GM quantification.

GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available.

Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients

We sought to examine the impact of asymptomatic bacteriuria on renal transplant outcome by retrospectively analyzing 189 renal transplant recipients for whom systematic screening uncovered 298 episodes of asymptomatic bacteriuria in 96 recipients. These patients were treated and all were followed for 36 months. Significant risk factors included female gender, glomerulonephritis as the disease that led to transplantation, and double renal transplant. There were no differences in serum creatinine, creatinine clearance, or proteinuria between patients with and without bacteriuria. The incidence of pyelonephritis in these patients was 7.6 episodes per 100 patient-years compared with 1.07 in those without asymptomatic bacteriuria. Between two to five and more than five bacteriuria episodes were significant independent factors associated with pyelonephritis whereas more than five episodes was a significant independent factor associated with rejection. Thus, we found no differences in renal function prognosis between patients who do not develop asymptomatic bacteriuria and those uncovered by systematic screening and who received treatment following kidney transplantation. Despite this treatment, the incidence of pyelonephritis was much higher in the group of patients with detected asymptomatic bacteriuria.

Clinical Implications of Respiratory Virus Infections in Solid Organ Transplant Recipients: A Prospective Study

Background. There is limited information about clinical consequences of respiratory virus infections (RVI) in solid organ transplant recipients. No prospective epidemiological study has been published previously. Methods. We selected a cohort of 152 transplant recipients (cardiac, hepatic and renal transplant recipients). Median time from transplantation was 17 months (range 1–50). They were prospectively followed-up for RVI during 7 months (October to April). Clinical and microbiological evaluation (cell culture, shell vial and polymerase chain reaction technique) of each RVI episode was made. Results. We detected 81 RVI (0.91 episodes/patient/year). Complications were detected in 15/81 episodes (18.5%): acute bronchitis (10 cases), pneumonia (three cases; 3.7% of RVI episodes) and bacterial sinusitis (2 cases). In 4 of 81 episodes (5%), patients needed hospitalization. A respiratory virus was isolated in 17 of 68 nasopharyngeal samples (six respiratory syncytial virus, six influenza, four picornavirus, one adenovirus). Fever presented an 83% positive predictive value for the diagnosis of influenza virus infection among those with a positive microbiological isolation. There were no episodes of acute rejection coincidentally with RVI. Only 54% of the subjects had been previously vaccinated against influenza. Conclusions. Incidence of RVI among solid organ transplant recipients is similar to general population but complications are higher. A relationship between RVI and rejection was not detected. The rate of influenza vaccination was lower than expected. The presence of fever in a transplant recipient with RVI strongly suggests influenza infection.

Bacillus Calmette-Guérin (BCG) Infection Following Intravesical BCG Administration as Adjunctive Therapy For Bladder Cancer: Incidence, Risk Factors, and Outcome in a Single-Institution Series and Review of the Literature

AbstractBacillus Calmette-Guérin (BCG) is the most effective intravesical immunotherapy for superficial bladder cancer. Although generally well tolerated, BCG-related infectious complications may occur following instillation. Much of the current knowledge about this complication comes from single case reports, with heterogeneous diagnostic and therapeutic approaches and no investigation on risk factors for its occurrence. We retrospectively analyzed 256 patients treated with intravesical BCG in our institution during a 6-year period, with a minimum follow-up of 6 months after the last instillation. We also conducted a comprehensive review and pooled analysis of additional cases reported in the literature since 1975. Eleven patients (4.3%) developed systemic BCG infection in our institution, with miliary tuberculosis as the most common form (6 cases). A 3-drug antituberculosis regimen was initiated in all but 1 patient, with a favorable outcome in 9/10 cases. There were no significant differences in the mean number of transurethral resections prior to the first instillation, the time interval between both procedures, the overall mean number of instillations, or the presence of underlying immunosuppression between patients with or without BCG infection. We included 282 patients in the pooled analysis (271 from the literature and 11 from our institution). Disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections were the most common presentations of disease. Specimens for microbiologic diagnosis were obtained in 87.2% of cases, and the diagnostic performances for acid-fast staining, conventional culture, and polymerase chain reaction (PCR)-based assays were 25.3%, 40.9%, and 41.8%, respectively. Most patients (82.5%) received antituberculosis therapy for a median of 6.0 (interquartile range: 4.0–9.0) months. Patients with disseminated infection more commonly received antituberculosis therapy and adjuvant corticosteroids, whereas those with reactive arthritis were frequently treated only with nonsteroidal antiinflammatory drugs (p < 0.001 for all comparisons). Attributable mortality was higher for patients aged ≥65 years (7.4% vs 2.1%; p  = 0.091) and those with disseminated infection (9.9% vs 3.0%; p = 0.040) and vascular involvement (16.7% vs 4.6%; p = 0.064). The scheduled BCG regimen was resumed in only 2 of 36 patients with available data (5.6%), with an uneventful outcome. In the absence of an apparent predictor of the development of disseminated BCG infection after intravesical therapy, and considering the protean variety of clinical manifestations, it is essential to keep a high index of suspicion to initiate adequate therapy promptly and to evaluate carefully the risk-benefit balance of resuming intravesical BCG immunotherapy.

Hepatitis C virus, an important risk factor for tuberculosis in immunocompromised: experience with kidney transplantation

Little is known about the role of hepatitis C virus (HCV) infection in the development of tuberculosis (TB) in patients with immunosuppression. We performed a retrospective case–control study (1:4) to investigate by univariate and multivariate logistic regression analysis the importance of HCV infection in the development of TB in a cohort of kidney transplant recipients (KTR). TB was diagnosed in 16 out of 2012 (0.8%) KTR between 1976 and 2004. The percentage of HCV‐positive patients was significantly higher in cases than in controls (56.3% vs. 18.8%; P = 0.02). By multivariate analysis, the only two independent risk factors associated with the development of TB were the presence of HCV infection (P = 0.003; OR = 6.5; 95% CI 1.9–23) and serum creatinine over 1.5 mg/dl (P = 0.03; OR = 4.8; 95% CI 1.1–21). HCV infection and chronic graft dysfunction are important risks factors for TB in KTR.

Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) is a major cause of long-term morbidity and mortality after heart transplantation (HTx), whose relationship with CMV infection is uncertain. This study evaluated the influence of CMV infection in the development of CAV. METHODS We enrolled 166 consecutive HTx recipients who underwent their first transplant from January 1995 to July 2002. All patients received 14 days of intravenous ganciclovir and were prospectively monitored for CMV infection during the first year after HTx. CAV was diagnosed by coronary angiography performed at 1, 5, and 10 years after HTx, following the new criteria of the International Society for Heart and Lung Transplantation. We collected all variables potentially related with the development of CAV. Risk factors were studied using a complementary log-log model. RESULTS After a median follow-up of 11 years (range, 1-17 years), 72 patients (43%) developed CAV (63.8% CAV(1), 15.2% CAV(2), 20.8% CAV(3)). Symptoms secondary to CAV were present in 32% of these patients, and 8% died because of it. In the regression multivariate analysis, independent variables associated with the development of CAV were donor age (hazard ratio [HR], 1.028; 95% confidence interval [CI], 1.002-1.053; p < 0.028), presence of cellular acute rejection ≥ 2R (HR, 1.764; 95% CI, 1.011-3.078; p < 0.0414), CMV infection (HR, 2.334; 95% CI, 1.043-5.225; p < 0.0354), and not having been treated with a calcium channel blocker (HR, 0.472; 95% CI, 0.275-0.811; p < 0.0055). CONCLUSIONS Standardized angiographic criteria show CMV infection is associated with the development of CAV.