Sequential treatment of cytomegalovirus infection or disease with a short course of intravenous ganciclovir followed by oral valganciclovir: efficacy, safety, and pharmacokinetics.

Oral (p.o.) or intravenous (IV) ganciclovir (GCV) has been the first-line agent for prevention and treatment of cytomegalovirus (CMV) infection and disease in solid organ transplantation (SOT). The introduction of p.o. valganciclovir, with higher bioavailability than p.o. GCV, has proven to be a suitable approach toward outpatient p.o. therapy for CMV infection/disease. The present single-arm, exploratory pilot trial performed with 21 patients investigates the efficacy and safety of a short therapeutic course (21 days) based on an initial IV treatment with GCV (5 mg/kg twice daily, for 5 days) followed by p.o. valganciclovir (900 mg twice daily, for 16 days) for CMV infection/disease in SOT patients. In all cases, doses were adjusted for renal function. Moreover, the study allowed comparison of exposure to GCV after p.o. valganciclovir with respect to IV GCV in the same patients. Response to treatment was monitored until day 180. Viral load eradication was achieved in 66.7% of patients, on day 21. Although not statistically significant, a trend was seen toward increased persistence of viral load on day 21 for patients with donor positive/recipient negative CMV serostatus or receiving either anti-rejection therapy or polyclonal anti-thymocyte globulin. CMV clinical infection recurred in 14.3% of patients, with higher recurrence rates in patients with risk factors for persistence of viremia. Exposures to GCV after using IV GCV or p.o. valganciclovir showed comparable values (P=0.054). This short course, combining initial IV GCV and subsequent p.o. valganciclovir, may provide effective exposure and therapeutic response in the treatment of CMV infection in SOT patients with adequate drug exposure and with the additional potential benefit of shortening the length of hospital stay, which may result in cost reduction and improved patient comfort.

Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study.

BACKGROUND: To facilitate the design of strategies for prevention of invasive aspergillosis in solid-organ transplant recipients, this study investigates whether the development of early-onset and late-onset aspergillosis are related to different risk factors, thereby distinguishing 2 risk populations for this serious complication. METHODS: A retrospective case-control study was performed, including 156 cases of proven or probable invasive aspergillosis in patients recruited from 11 Spanish centers since the start of the centers' transplantation programs. RESULTS: Among all patients, 57% had early-onset IA (i.e., occurred during the first 3 months after transplantation). Risk factor analysis in this group identified as significantly associated risk factors a more complicated postoperative period, repeated bacterial infections or cytomegalovirus disease, and renal failure or the need for dialysis. Among patients with late-onset infections (i.e., occurred > 3 months after transplantation), who comprised 43% of cases, the patients at risk were older, were in an overimmunosuppressed state because of chronic transplant rejection or allograft dysfunction, and had posttransplantation renal failure. CONCLUSIONS: Risk factors in patients with early-onset cases and patients with late-onset cases of posttransplantation invasive aspergillosis are not the same, a fact that could have implications for the preventive approaches used for this infection.

Incidence and molecular typing of Mycobacterium kansasii in a defined geographical area in Catalonia, Spain.

A retrospective population-based study was conducted between January 1990 and December 1998 to investigate the incidence of Mycobacterium kansasji disease and the heterogeneity of the isolates in a well-defined geographical area in Catalonia, Spain. A total of 136 patients were identified. Overall incidence and incidence in AIDS patients was 1.5 (95% CI 1.2-1.8) and 1089.6 (95% CI 689-1330) cases/100,000 persons per year respectively, which is comparable to that reported from most of other geographical areas. Surprisingly, although 7 subtypes of M. kansasii have been consistently reported, in the present study 91 of the 93 isolates (97.8%) tested for genotype were subtype I, regardless of HIV status of the patients. In conclusion, the high rate of infection observed in the AIDS population contributes significantly to the burden of the M. kansasii disease in our area. M. kansasii disease in our geographical area was almost exclusively caused by subtype I regardless of HIV status.

B-lymphocytes and co-stimulatory molecules in Mycobacterium tuberculosis infection.

SETTING: The immunological mechanisms that lead to the control of Mycobacterium tuberculosis infection are not well known. OBJECTIVE: To study the role of lymphocyte subsets and co-stimulatory molecules in M. tuberculosis infection. DESIGN: In 35 patients with pulmonary tuberculosis (PTB) and their contacts, 29 persons with tuberculin skin test conversion (TSTC) and 20 healthy individuals with negative tuberculin skin test (NTST), we studied T-lymphocyte subsets (CD3, CD4, CD8, alphabetaTCR and gammadeltaTCR), B-cells, monocytes and co-stimulatory molecules CD28 and CD86 in peripheral blood. The results were analysed at univariate and multivariate level through discriminant analysis. RESULTS: At univariate level, compared with TSTC and NTST, PTB patients presented a decrease in CD4+ T-cells (P = 0.002), and B-cells (P = 0.02 and 0.001, respectively). With regard to NTST subjects, PTB patients also showed a decrease in the percentage of CD86+ monocytes (P = 0.02) and an increase in the percentage of CD86+ B-lymphocytes (P = 0.02). At multivariate level, CD4+ T-lymphocytes showed statistical differences between PTB and TSTC subjects (P = 0.001). B-lymphocytes were discriminant between PTB and NTST (P < 0.001) and between TSTC and NTST individuals (P = 0.01). CONCLUSION: The number of total CD4+ T-cells is the best discriminant parameter for distinguishing between disease and infection, whereas the B-cell count is the best between healthy and infected individuals.

Hepatitis tóxica en gestantepor labetalol / Labetalol-induced toxic hepatitis in pregnancy

El labetalol, un antihipertensivo que actúa como bloqueador de los receptores alfa-beta adrenérgicos, se utiliza ampliamente para el tratamiento de la hipertensión durante la gestación así como en el tratamiento tensional de la preeclampsia y de la eclampsia. Además, es un fármaco con un buen perfil de seguridad y escasos efectos secundarios, entre los que por su frecuencia destaca el ortostatismo. La hepatotoxicidad, aunque poco frecuente, también se ha descrito en relación con la utilización de este fármaco. (AU)

[Analysis of 500 liver transplantations at Bellvitge Hospital, Spain]. / Análisis de 500 trasplantes hepáticos en el Hospital de Bellvitge.

BACKGROUND: We present the experience of the liver transplantation program at the Hospital of Bellvitge with 500 transplantations performed during 15 years, to describe changes in liver transplantation observed throughout the time and to analyze the long term results. PATIENTS AND METHOD: Five groups each one including 100 consecutive transplantations are studied. RESULTS: The main indications were hepatocellular carcinoma (23%), alcoholic cirrhosis (22.8%), and post-hepatitis C cirrhosis (18.8%). Sixty-five retransplantations were performed in 59 patients (13%), being the more frequent indications arterial thrombosis (13 patients) and primary nonfunction of graft (10 patients). In 10 patients a hepatorenal transplantation was performed. In group I, the most frequent donor cause of death was cranial traumatism (80%), while in group V it was the vascular pathology (52%). There were other significative differences between these groups of patients (I vs V): patients with stage 2 or 3 from UNOS status (45 vs 19%), blood use (29.6 [26] vs 4.6 [5.3] PRBC), ICU stay (13 [13] vs 7.4 [11] days), hospital stay (40 [52] vs 23.7 [17] days), rejection rate (46 vs 20%) and primary graft nonfunction (9 vs 3%). However, the infection rates (48 vs 54.5%) and biliary tract complications (26 vs 20%) have not shown statistically significant differences. Actuarial one and 5-year survival are 83 and 70% respectively. CONCLUSIONS: An important and progressive improvement of liver transplantation results has been observed. However, de novo tumours, hepatitis C virus recurrence and chronic rejection can limit long term results.

Clinical evaluation of an in-house IS6110 polymerase chain reaction for diagnosis of tuberculosis.

The aim of this study was to clinically validate a heminested polymerase chain reaction (PCR) method, based on the IS6110 insertion segment of Mycobacterium tuberculosis complex, for the diagnosis of tuberculosis. Samples of pulmonary, extrapulmonary and blood origin were collected prospectively from 331 patients. All samples were processed to detect acid-fast bacilli by direct stain, culture and PCR. The gold standard comparison was a clinically based final case definition of tuberculosis corresponding to group 3 of the American Thoracic Society's classification system. The sensitivities of stain, culture and PCR were 41%, 65% and 59%, respectively. Overall specificity exceeded 97% for all techniques. The combination of PCR and direct stain achieved a sensitivity similar to that of culture alone. The PCR method detected 74 of 95 (78%) culture-positive results. In a hospital setting, PCR could be a useful, reliable tool for diagnosis of tuberculosis and may be introduced as a complementary routine diagnostic laboratory method.

Pyoderma gangrenosum with liver, spleen and bone involvement in a patient with chronic myelomonocytic leukaemia.

Pyoderma gangrenosum is a neutrophilic dermatosis of unknown aetiology. Visceral involvement by pyoderma gangrenosum is rare, the lung being the most frequent site of extracutaneous disease. We describe a 73-year-old man with pyoderma gangrenosum and chronic myelomonocytic leukaemia in whom aseptic hepatosplenic abscesses and bony lesions were associated.

Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA.

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.

[Endocarditis caused by group B streptococci in adults]. / Endocarditis por estreptococo del grupo B en adultos.

OBJECTIVE: To evaluate clinical characteristics, treatment and outcome of group B streptococcal endocarditis in nonpregnant adults. METHODS: We included all cases of Streptococcus agalactiae endocarditis diagnosed according to the Duke criteria between 1980 and 1994 in a 1000-bed university hospital, where a prospective surveillance of all cases of bacteremia is regularly performed. RESULTS: There were 9 episodes of S. agalactiae endocarditis, that account for the 10.5% of 85 bacteremia caused by this organism and 2.6% of 336 infectious endocarditis (in non-drug abusers) during the study period. They occurred in 6 males and 3 females with an average age of 60 years (44-86 years). Three patients had underlying disease and three had been previously diagnosed of having valvulopathy. There were no cases of prosthetic valve endocarditis. The valves most frequently involved were the aortic and mitral valves. Only one patient had large vessel embolization. All isolates were penicillin-susceptible (MIC < 0.12 microgram/ml). Most of the patients were treated with penicillin plus an aminoglycoside and 6 patients also underwent surgery combined with the medical therapy after an average of 40 days (13-60 days). The overall mortality was 11%. CONCLUSIONS: S. agalactiae is a rare cause of infectious endocarditis. Combination of surgery with the antibiotic therapy might decrease mortality rates of this infection.

pp65 antigenemia as a marker of future CMV disease and mortality in HIV-infected patients.

We retrospectively evaluated the role of pp65 antigenemia (AGM) as a marker of cytomegalovirus (CMV) disease and mortality in 241 HIV-infected patients with fever. Of 225 patients in whom CD4 count was available, 189 (84%) had counts below 100/microL and 209 (92.8%) below 200/microL, 149 patients had negative AGM (AGM-) and 92 had positive AGM (AGM+), AGM+ patients were at a more advanced stage of HIV disease, as evaluated by CD4 count (p < 0.001) and prior AIDS diagnosis (p < 0.001). Overall, 29 patients (12%) presented concomitant CMV disease (18 retinitis): 24 (26%) in the AGM+ group and 5 (3.3%) in the AGM- group (p < 0.001). AGM had a negative predictive value of 96.6% but a positive predictive value of 26% which increased to 65% if a cut-off of > 10 CMV-positive cells/10(5) leukocytes was considered. The cumulative rate of future CMV disease at 3 months was 0% in AGM patients, 3% in patients with AGM 1-10/10(5) and 36% in patients with AGM > 10/10(5). In a multivariate analysis, no antiretroviral therapy, AGM+ and CMV disease were independently associated with mortality. The role of AGM as a marker of present CMV disease is limited. However, quantitative AGM may select patients at a high risk of future CMV disease. In addition, AGM may be a marker of shorter survival in severely immunosuppressed HIV-infected patients.

Steroids do not enhance the risk of developing tuberculosis or other AIDS-related diseases in HIV-infected patients treated for Pneumocystis carinii pneumonia.

OBJECTIVE: To evaluate the risk of developing tuberculosis or other AIDS-related diseases (ARD) in HIV-infected patients treated with corticosteroids as adjunctive therapy for Pneumocystis carinii pneumonia (PCP). DESIGN: Retrospective study. SETTING: Infectious Disease Service of a 1000-bed university teaching hospital in Barcelona, Spain. PATIENTS: HIV-infected patients diagnosed with PCP from 1985 to 1992. Patients were classified into two groups: steroid (group A) and non-steroid (group B) adjunctive therapy. Baseline characteristics, antibiotherapy, dose and duration of steroidal treatment were analysed. Endpoints were either the development of tuberculosis or other ARD or death. RESULTS: From the 129 patients included in this study 72 were in group A and 57 in group B. No differences between groups were observed in baseline characteristics or mean follow-up period (15 versus 14 months, respectively). The mean total dose of steroids was 420 mg (range, 160-1260 mg) methylprednisolone or its equivalent in dexamethasone, with a mean treatment duration of 12 days (range, 4-33 days). No differences were found in the occurrence of tuberculosis or other endpoints in the first 6 months of follow-up. In addition, the cumulative rate of developing tuberculosis was 7% in group A and 12% in group B at 12 months of follow-up, and 13 versus 12% at 24 months (P = 0.622, Mantel-Cox): 4 versus 4% at 12 months and 27 versus 24% at 24 months (P = 0.873) for non-tuberculosis mycobacterial infection, and 40 versus 42% at 12 months, and 88 versus 66% at 24 months (P = 0.330) for non-mycobacterial ARD. The cumulative survival rate was 79 versus 71% and 46 versus 34% at 12 and 24 months, respectively (P = 0.526). CONCLUSIONS: Our data suggest that the use of corticosteroids during PCP in HIV-infected patients at the doses and for the duration used in our patients did not enhance the risk of developing or relapsing tuberculosis or other ARD.

Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV.

OBJECTIVE: To evaluate the efficacy and safety of two oral, intermittent drug regimens for the simultaneous primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with HIV infection. DESIGN: Nonblinded randomized study: Patients received either 1) trimethoprim-sulfamethoxazole (160 mg-800 mg orally twice a day on a thrice weekly regimen) or 2) 100 mg of dapsone plus 50 mg of pyrimethamine orally twice weekly. SETTING: University teaching hospital in Barcelona. PATIENTS: 230 patients infected with HIV who had CD4 cell counts of less than 200 x 10(6)/L and who had not previously had P. carinii pneumonia or toxoplasmosis. MEASUREMENTS: Clinical and biological evaluations; adverse reactions; and end points of P. carinii pneumonia, toxoplasmosis, and death. RESULTS: After a median follow-up of 430 days, 6 (6.3%) of 96 evaluable patients receiving dapsone-pyrimethamine and 0 of 104 evaluable patients receiving trimethoprim-sulfamethoxazole developed P. carinii pneumonia (P < 0.0001). The cumulative rates of P. carinii pneumonia at 12 and 24 months were 0% and 0% for patients receiving trimethoprim-sulfamethoxazole and 4% and 11% for patients receiving dapsone-pyrimethamine (Mantel-Cox, P = 0.014). However, only one episode of P. carinii pneumonia developed while patients were taking these drugs. No differences were observed for toxoplasmosis (one episode in the trimethoprim-sulfamethoxazole arm and two in the dapsone-pyrimethamine arm), with cumulative rates at 12 and 24 months of 0% and 4% for the trimethoprim-sulfamethoxazole arm and 2% and 7% for the dapsone-pyrimethamine arm (P = 0.65). Similar mortality rates were observed during follow-up (P = 0.85). Nineteen patients (9.5%) discontinued therapy with the drugs because of adverse effects: Ten were in the trimethoprim-sulfamethoxazole arm and 9 were in the dapsone-pyrimethamine arm (P = 0.95). CONCLUSIONS: Thrice-weekly trimethoprim-sulfamethoxazole is an effective and well-tolerated regimen for the simultaneous primary prophylaxis of P. carinii pneumonia and toxoplasmosis in patients infected with HIV. Twice-weekly dapsone-pyrimethamine appears to be a safe and effective alternative.

Characteristics of and risk factors for relapse of brucellosis in humans.

For 16 years we prospectively observed 530 adult patients with brucellosis to analyze the characteristics of and risk factors for relapse. Clinical and laboratory findings from 86 relapsed patients were milder during the relapse episode when compared with those for the same patients during the initial disease. Blood cultures were positive for Brucella melitensis in 65% of cases during relapse and in approximately 80% of cases during the initial disease. Risk factors that were identified as being independently associated with relapse (by logistic regression analysis) were "less-effective" antibiotic therapy (OR, 8.3; 95% CI, 4.6-15.1), positive blood cultures during initial disease (OR, 2.7; 95% CI, 1.2-6.2), < or = 10-day duration of the disease before treatment (OR, 1.9; 95% CI, 1.1-3.6), male sex (OR, 1.8; 95% CI, 1.02-3.8) and a platelet count of < or = 150 x 10(3)/mm3 (OR, 1.7; 95% CI, 1.1-2.8). These data show that relapse of brucellosis is sometimes difficult to diagnose and that it can be an insidious disease. In addition to inappropriate antibiotic therapy, other factors, such as those indicating a more aggressive disease and/or a deficient immunologic response, seem to play an important role in the relapse of brucellosis.

Utility of the gallium-67 citrate scan for the early diagnosis of tuberculosis in patients infected with the human immunodeficiency virus.

Diagnosis of tuberculosis in patients infected with the human immunodeficiency virus (HIV) is sometimes difficult because of atypical clinical and radiographic findings. The aim of this retrospective study was to determine the utility of a gallium-67 citrate scan (67Ga scan) of the chest for the early diagnosis of tuberculosis in patients infected with HIV. We selected 174 67Ga scans performed as a part of the clinical evaluation of 145 HIV-infected patients with normal pulmonary parenchyma (seen on chest radiographs) and fever of unknown origin. Scans were evaluated as to whether there was uptake in lymphoid regions (a positive 67Ga scan) or not (a negative scan). Tuberculosis was the most common condition associated with a positive 67Ga scan (48[72.7%] of 66 positive 67Ga scans). Nodal uptake had a 72.7% positive predictive value and a 92.6% negative predictive value for tuberculosis. In our experience, 67Ga scanning is a useful tool for the clinical evaluation of HIV-infected patients with unexplained fever. In areas with a high prevalence of tuberculous infection, a 67Ga scan of an HIV-infected patients that shows nodal uptake allows the clinician to initiate prompt empirical antituberculous therapy while waiting for culture results. Conversely, a 67Ga scan that does not show nodal uptake makes the diagnosis of tuberculosis unlikely.

Hypersensitivity hepatitis due to pyrazinamide.

Pyrazinamide hepatotoxicity is considered secondary to a direct and dose-related toxic effect. At currently used doses, pyrazinamide provides effective short-term treatment and is free from serious side effects. We report a case of pyrazinamide-induced hepatitis for which the rechallenge data strongly suggest a hypersensitivity mechanism.