Carlos Lumbreras

Clinical Presentation And Outcome Of Tuberculosis In Kidney, Liver, And Heart Transplant Recipients In Spain1

BACKGROUND Tuberculosis is unusual in transplant recipients. The incidence, clinical manifestations, and optimal treatment of this disease in this population has not been adequately defined. The present study was undertaken to assess the incidence, clinical features, and response to therapy of Mycobacterium tuberculosis infection in solid-organ transplant recipients. METHODS We evaluated retrospectively the incidence, clinical characteristics, diagnostic procedures, antituberculous treatment, clinical course, and factors influencing mortality in 51 solid-organ transplant recipients who developed tuberculosis after transplantation. We also reviewed the world literature on tuberculosis in solid-organ transplantation. RESULTS The overall incidence of tuberculosis was 0.8%. The localization was pulmonary in 63% of the cases, disseminated in 25%, and extrapulmonary in 12%. Tuberculosis developed from 15 days to 13 years after surgery (mean, 23 months). In one third of the cases, diagnosis was not suspected initially, and in three cases, diagnosis was made at necropsy. Fever was the most frequent symptom, followed by constitutional symptoms, cough, respiratory insufficiency, and pleuritic pain. Fifteen patients (33%) developed hepatotoxicity during treatment; hepatotoxicity was severe in seven cases. Hepatotoxicity was higher in patients receiving four or more antituberculous drugs (50%) than in patients receiving three drugs (21%; P=0.03). Serum levels of cyclosporine decreased in the 26 patients under the simultaneous use of rifampin. Nine of them (35%) developed acute rejection, and five (56%) died, in comparison with 3 of 17 patients (18%) who did not develop rejection after the use of cyclosporine and rifampin (P=0.03). Although microbiological response was favorable in 94% of the 35 patients who completed 6 or more months of treatment, 16 other patients (31%) died before diagnosis or in the course of treatment. None of the patients treated for more than 9 months died as a consequence of tuberculosis, whereas the mortality rate was 33% among those treated for 6 to 9 months (P=0.03). Use of antilymphocyte antibodies or high doses of steroids for acute rejection before tuberculosis was associated with a higher mortality rate. CONCLUSIONS M tuberculosis causes serious and potentially life-threatening disease in solid-organ transplant recipients. Treatment with at least three drugs during 9 months or more, avoiding the use of rifampin, appears to be appropriate.

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.

Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation

Treatment of recurrent hepatitis C in liver transplant is controversial. The aim of our study was to evaluate the clinical and histological efficacy of pegylated interferon alpha 2b (PEG‐IFN) and ribavirin therapy of recurrent hepatitis C after liver transplantation (LT). We prospectively included 47 liver transplant patients with: 1) a positive test for hepatitis C virus (HCV)‐ribonucleic acid (RNA) in serum; 2) alanine aminotransferase (ALT) >45 UI/mL; and 3) a liver biopsy showing chronic hepatitis without rejection in the previous 2 months. Patients received PEG‐IFN (1.5 μg/kg/week) and ribavirin (800‐1,000 mg/day) for 12 months. Follow‐up was based on biochemical (ALT), virological (RNA‐HCV), and histological (liver biopsy) examinations. Follow‐up lasted a minimum of 6 months after the end of antiviral therapy. Sustained virological response (SVR) was achieved in 23% of the patients. A total of 33 (70%) patients had normalized ALT levels at the end of therapy. Inflammatory portal and lobular score declined significantly in patients with SVR (P < 0.05) but not in nonresponder patients. Fibrosis did not change significantly in either group. SVR was significantly associated with low γ‐glutamyltransferase GGT (P = 0.04) and HCV‐RNA levels (P = 0.03), a virological response at 12 weeks (P = 0.002) and patients compliance (P = 0.04). Ten (21%) patients were withdrawn prematurely due to adverse effects. In conclusion, Therapy with PEG‐IFN and ribavirin achieved SVR and a significant histological improvement in 23% of liver transplant recipients with chronic hepatitis C. Toxicity is an important drawback of this therapy. Liver Transpl 12:1805‐1812, 2006.

Clinical Significance of Donor-Unrecognized Bacteremia in the Outcome of Solid-Organ Transplant Recipients

We evaluated the clinical significance of unrecognized bacteremia in the organ donor (i.e., blood culture results that were reported to be positive after transplantation) on the outcome of transplant recipients. Twenty-nine of 569 liver and heart donors (5%) had bacteremia at the time of organ procurement, but there were no documented instances of transmission of the isolated bacteria from the donor to the recipient. Unrecognized bacteremia in the donor does not have a negative clinical impact on the outcome of organ transplant recipients.

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.

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.

Successful treatment of mucor infection after liver or pancreas-kidney transplantation.

BACKGROUND Mucormycosis is a rare and opportunistic infection usually associated with hematologic diseases, diabetes mellitus, renal failure, solid tumors, and organ transplantation. METHODS We present five cases of mucor infection after transplantation (three after a series of 750 orthotopic liver transplantation and two after a series of 13 simultaneous pancreas-kidney transplantation in patients with type 1 diabetes) subjected to medical and surgical treatment and analyze the factors related to the development of this infection. RESULTS The clinical forms were two cutaneous (laparotomy wound or prior surgical drain site), two rhino-maxillary, and one pulmonary. As risk factors for mucormycosis all patients had pre- or posttransplantation diabetes, and showed at least one episode of acute rejection that required aggressive immunosuppression (2-7 g of methylprednisolone; also three patients were treated with antithymocyte globulin [ATG] monoclonal antibody [orthoclone and/or OKT3]). We also found renal failure, acidosis, malnutrition, and Candida and cytomegalovirus infections as factors related to mucor infection. Diagnosis of fungal infection was confirmed by exudate or fluid culture in three cases and by biopsy in two. All patients were treated with liposomal amphotericin B (from 3.5 to 5.6 g of total dose) and resection until the surgical margins were free of infection. All patients survived after this severe infection. CONCLUSIONS With an early diagnosis of mucormycosis by clinical findings, culture, or tissue biopsy, and aggressive treatment consisting of administration of liposomal amphotericin B and surgical resection of all infected tissue, excellent results are achieved.

A review of critical periods for opportunistic infection in the new transplantation era.

Background. The risk of opportunistic infection (OI) is considered to be maximum during the first six months after solid organ transplantation. The aim of this study was to know the incidence and risk factors for OI in the late period (>6 months) compared with the early period (<6 months) after solid organ transplantation. Methods. We used the online database of the Spanish Network of Infection in Transplantation (RESITRA), which prospectively analyzed 2,702 solid organ transplantation recipients from August 2003 to February 2005. Univariate and multivariate analyses were performed to calculate the risk factors associated with the development of late OI. Results. A total of 131 patients (6%) developed 176 infectious episodes in the late period. Although the incidence of infection and cytomegalovirus disease (0.4 per 1000 transplant days and 0.05 per 1000 transplant days, respectively) was lower than in the early period (3.5 per 1000 transplant days and 0.8 per 1000 transplant days; P<0.0001), the incidence of other OIs was similar in both periods (0.05 per 1000 transplant days versus 0.03 per 1000 transplant-days, P=0.5). Patients with the higher risk for developing late OI were those receiving early cytomegalovirus prophylaxis, patients who developed two or more episodes of acute rejection during the early period, patients with recurrent bacterial infection during the early period, patients with renal failure requiring dialysis, and patients with chronic graft malfunction. Conclusions. Our data suggest that in some high-risk patients, the critical period of risk for OI must be expanded beyond the first six months after transplant.

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.

Encrusted pyelitis and cystitis by Corynebacterium urealyticum (CDC group D2) : a new and threatening complication following renal transplant

We evaluated the pathogenic role of Corynebacterium urealyticum in the development of encrusted pyelitis (EP) and encrusted cystitis (EC), and their clinical consequences in renal transplant recipients. During a 4-year period, we studied seven renal transplant recipients with EP and two with EC. The records of 320 other renal transplant patients studied during the same period were used as a control group. C urealyticum (> or = 10(5) CFU/ml) was isolated from 4 patients with EP (urine 3, blood 1) and from 1 patient with EC (urine). Alkaline urines with struvite crystals, microscopic hematuria, and sterile conventional urine cultures were present in all our cases. All the patients with EP developed obstructive uropathy with deterioration of the renal function and pyelonephritis (4 patients) or renal abscesses (3 patients). Chronic urinary discomfort and macroscopic hematuria were present in the 2 patients with EC. Long-term vesical and ureteral catheterization were considered the most important risk factors for the development of EC and EP, respectively. Vancomycin was successfully used in 5 cases, but all the patients required a derivative procedure or a surgical resection of the incrustations to improve. We conclude that EP and EC should be investigated in renal transplant patients who develop pyelonephritis, obstructive uropathy, or chronic urinary symptoms. EP and EC could lead to the loss of their grafts. C urealyticum appears to have a pathogenic role in these entities.