Chronic viral hepatitis enhances the risk of infection but not acute rejection in renal transplant recipients

To assess the impact of chronic viral hepatitis on host immune response, we analyzed the incidence of acute rejection and the frequency of infections in 86 patients infected with hepatitis B and C viruses and had developed clinical evidence of chronic liver disease and 1283 control patients who were transplanted at our center during the same period, but had no evidence of chronic viral hepatitis. To compare the mean number of rejections and the mean number of infections between the two groups, we used multivariate linear regression analysis, which allowed us to adjust simultaneously for the effects of 10 other risk variables with potential impact on graft rejection and posttransplant infection. During a mean follow up of 5.3+/-5.2 years, 62% of hepatitis patients and 54% of control patients had experienced an acute rejection (P=NS). The mean rejections/patient in the hepatitis group was 1.3+/-0.14 versus 1.03+/-0.03 in control (P=NS). In the linear regression analysis, the number of acute rejections in the hepatitis group was 0.16 higher than in control (P=NS). With reference to infection, 84% of hepatitis patients experienced an infectious complication in the posttransplant period, compared with 75% in the control (P=0.05). The mean number of infections/patient was 5.7+/-0.73 in the hepatitis group compared with 3.9+/-0.14 in the control group (P=0.002). The linear regression model had shown that the hepatitis group had a relative increase of 1.18 infections/pt, compared with control. Of the different sites of infection, the hepatitis group had a significant increase in bloodstream (0.48+/-0.08 vs. 0.25+/-0.02) P=0.003; pulmonary (0.60+/-0.09 vs. 0.38+/-0.03) P=0.03; and CNS infections (0.08+/-0.03 vs. 0.02+/-0.004) P=0.05 compared with control. Among the different microorganisms causing infection, the hepatitis patients had a significant increase in gram negative bacterial infections compared with the control group (74% vs. 61%) P=0.04. Our data suggest that chronic viral hepatitis is associated with a significant increase in overall infections, and that of potentially fatal infections involving CNS, lungs and bloodstream. Since there is no significant increase in the rate of graft rejection, one could consider a cautious reduction in the doses of maintenance immunosuppressive agents in renal transplant patients with chronic viral hepatitis. The reduced immunosuppression may in turn lower the death rate from sepsis and progressive hepatic failure.     

Pulmonary aspergillosis in cystic fibrosis lung transplant recipients

STUDY OBJECTIVE: To define the prevalence of colonization and infection of the lower respiratory tract (LRT) with Aspergillus in lung transplant recipients with and without cystic fibrosis (CF). DESIGN: Retrospective review. SETTING: Large university lung transplant center. MATERIALS AND METHODS: The postoperative course of 31 CF and 53 non-CF double lung or double lobar transplant recipients receiving allografts from April 1991 to February 1996 was reviewed. All recipients were subjected to surveillance bronchoscopy and biopsy at predetermined intervals and when clinically indicated. BAL fluid (BALF) and biopsy material were examined by appropriate fungal culture and staining techniques. Infection was defined by the finding of tissue-invasive disease on biopsy specimens. RESULTS: Seven of the 31 CF recipients (22%) had Aspergillus isolated from cultures of sputum prior to transplantation. Following transplantation, 15 CF recipients (48%) had Aspergillus isolated from either sputum or BALF, including 4 of the 7 recipients identified with the fungus prior to transplantation. By contrast, 21 of the 53 non-CF recipients (40%) had Aspergillus isolated from the LRT following transplantation, none having had the fungus isolated prior to transplantation. The prevalence of Aspergillus did not differ between these groups (p = 0.51). Infections with Aspergillus occurred in 4 of the CF recipients (27%) and did not differ from the 3 infections (14%) identified in the non-CF recipients (p = 0.36). However, three of the four infections in the CF recipients involved the healing bronchial anastomosis and occurred prior to postoperative day 60. All three of these recipients had Aspergillus preoperatively. Postoperative infection was more common in the CF recipients having Aspergillus preoperatively than in those CF recipients without preoperative Aspergillus (p = 0.02). CONCLUSIONS: Isolation of Aspergillus from the LRT following double lung transplantation is common and generally not associated with tissue-invasive disease. Those CF recipients with Aspergillus isolated in cultures of sputum preoperatively are at risk for postoperative infections with this agent. The healing bronchial anastomosis is particularly vulnerable.     

Where do young adult renal transplant recipients fit in?

Young adult renal transplant recipients often have unique concerns and interests. To give them an opportunity to share these concerns with peers, a support group was established at Boston Children's Hospital. Despite a less than enthusiastic beginning, this group is now well attended, meets four times a year, and has continued for over 4 years. The group has become a comfortable setting where the participants discuss their unique perspectives on schooling, family, and relationships.     

A description of general health risks in adult liver transplant recipients

The focus of posttransplant care and clinical research has been on the management of rejection and short-term side effects associated with immunosuppressive therapy. Long-term side effects have only recently been recognized as potential health problems in liver transplant recipients. The aim of this pilot study was to determine the feasibility of using the Healthier People Version 4.0 Health Risk Appraisal as a tool for identifying existing and potential risk factors for premature disease and death among asymptomatic liver transplant recipients and to describe health risks in adult liver transplant recipients. The sample consisted of 50 adult first-time liver transplant recipients. It was found that this tool highlights health risks affecting life expectancy and pinpoints risks that an individual can control. It also provides practitioners with information necessary to design appropriate prevention and health promotion strategies to assure better health and quality of life for patients following liver transplantation.     

Clinical significance of CMV-specific T helper responses in lung transplant recipients

BACKGROUND: Cytomegalovirus (CMV) disease continues to be a major problem for lung transplant patients who generate an inefficient immune response to control this viral infection. Both T helper and cytotoxic T cells are thought to play an important role in prevention and control of CMV disease. We investigated the clinical significance of CMV-specific memory responses in lung transplant recipients. METHOD: Peripheral blood samples (140) were collected from 99 lung transplant recipients. Patients were grouped according to their pre-transplant CMV serological status as recipient/donor (R-/D+, 25 patients), 28 R+/D+ patients, 35 R+/D- patients and 11 R-/D- patients. Memory responses to CMV whole antigen, 5 CMV proteins, and tetanus toxoid (TT) were measured in a 6-day proliferative assay. Results were expressed as the stimulation index (SI = experimental cpm/background cpm), and were considered positive if the SI was >3 and the cpm values were over 1,000. RESULTS: The frequency of positive CMV memory responses was similar in three groups: 64% for R-/D+, 63% for R+/D+ and 56% for R+/D- except for R-/D- (21%). The memory response to TT was similar for all four groups (70% of samples were positive). The level of responsiveness to individual CMV proteins was much higher in R+/D+ group (65%) than the other two groups (35% for R+/D-, and 31% for R-/D+). We determined the temporal relationship between the presence of CMV-specific memory responses and the diagnosis of CMV disease. In the R-/D+ group, 16 of 17 patients who had CMV disease eventually developed CMV-specific memory. In those patients (n = 3) who failed to develop CMV-specific T helper response for a prolonged time, all had recurrent CMV disease. In the R+/D+ group, 4 of 8 patients with CMV disease exhibited CMV-specific memory responses. Three of 4 patients in whom we observed a persistent absence of CMV-specific memory had multiple episodes of CMV pneumonitis. In the R+/D- group, only one of 4 patients with CMV disease had suppressed CMV-specific memory response after first episode of CMV pneumonitis and had recurrent disease. CONCLUSION: In lung transplant recipients, the loss or persistent lack of CMV-specific memory following infection was associated with chronic CMV disease. These data suggest that monitoring T helper memory responses following primary CMV infection or after augmented immunosuppression for treatment of rejection may identify those patients at risk for morbidity associated with recurrent CMV disease.     

Impact of ganciclovir prophylaxis on heart-lung and lung transplant recipients

BACKGROUND: Cytomegalovirus infection threatens pulmonary allograft survival and function. This retrospective study details the experience of ganciclovir prophylaxis against cytomegalovirus infection and its sequelae. METHODS: Eight-nine lung and heart-lung transplant recipients with positive cytomegalovirus serology were analyzed. The 37 recipients who underwent transplantation before September 1989 received no prophylaxis. The 52 subsequent recipients received ganciclovir prophylaxis. RESULTS: Thirty-six non-prophylaxed versus 42 prophylaxed patients had cytomegalovirus events with cumulative incidences of 100% and 86% (p < < 0.01), and median onsets of 37 +/- 21 versus 85 +/- 35 days, respectively (p < < 0.01); 22 non-prophylaxed versus 27 prophylaxed patients had cytomegalovirus pneumonitis with cumulative incidences of 60% and 55% (p < < 0.01), and median onsets of 34 +/- 14 and 84 +/- 26 days, respectively (p < < 0.01). Respiratory failure caused by cytomegalovirus pneumonitis developed in nine of the non-prophylaxed versus two of the prophylaxed patients (p < < 0.01). The significant estimated survival benefit in patients who received prophylaxis (p = 0.04) was not apparent when reanalysis was performed after exclusion of patients with respiratory failure (p = 0.36). Ganciclovir prophylaxis produced a significant delay in the development of obliterative bronchiolitis with a median time to onset of 1072 +/- 280 days versus 432 +/- 189 days for the non-prophylaxis cohort (p < < 0.01). CONCLUSIONS: Ganciclovir prophylaxis (1) improves recipient survival by reducing the severity of disease and essentially eliminating respiratory failure caused by cytomegalovirus pneumonitis, (2) reduces the incidence and delays the onset of cytomegalovirus events and pneumonitis, and (3) delays the onset of obliterative bronchiolitis.     

Increased gelatinolytic activity in bronchoalveolar lavage fluid in stable lung transplant recipients

Proteolytic enzymes have been proposed to play a role in the pathogenesis of various inflammatory pulmonary diseases accompanied by parenchymal remodeling. To assess the role of inflammatory cells and proteolytic enzymes in the development of chronic allograft rejection after lung transplantation, bronchoalveolar lavage fluid (BALF) samples from clinically stable lung transplant (LT) recipients (i.e., without evidence of active infection or rejection), heart transplant (HT) recipients, and healthy volunteers (NL) were analyzed for total white blood cell (WBC) count and differential cell count, along with gelatinolytic/type IV collagenolytic activity. The LT group displayed a significantly increased total WBC count, neutrophil count, and percent neutrophils compared with the NL group, confirming the presence of inflammation. Furthermore, gelatin zymography revealed a significant increase in activity of the 72 and 92 kD gelatinases in the LT group compared with the NL group. A positive correlation existed between neutrophil counts and the increase in proteolytic activity. Immunosuppressive therapy did not account for the findings, since no significant difference in cell counts or proteolytic activity existed between the NL and HT control groups. These findings, together with those of others that relate chronic lung allograft dysfunction to an increase in BALF neutrophils and collagen matrix remodeling, collectively indicate that up-regulated proteolytic activity may have a role in chronic rejection after lung transplantation.     

Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity

In the posterior partially edentulous jaw, implants may be used to supplement existing natural dentition. Frequently, the maxillary sinuses and the mandibular nerve preclude the fabrication of freestanding implant-retained prostheses. However, if an implant and a natural abutment are combined, a fixed prosthesis can be fabricated, restoring the arch into the premolar area. The histories of three patients with attachments connecting implant-retained ceramotitanium crowns with crowns on natural abutments are described. A design for a rigid custom-made attachment for the Br?nemark system, using standard components with a machine-duplication, spark-erosion technique, is suggested.     

Toxoplasma gondii infection in marrow transplant recipients: a 20 year experience

Twelve of 3803 consecutive marrow allograft patients treated at this center over the past 20 years have had a post-transplant tissue diagnosis of toxoplasmosis: 10 at autopsy and 2 by brain biopsy. This infection was identified in none of 509 autologous marrow recipients. Occurrence of toxoplasmosis was 0.31 cases per 100 allogeneic transplants and 1.0 per 100 autopsies. An estimated 15% of allogeneic transplant recipients were seropositive for Toxoplasma gondii and 2% of seropositive patients developed toxoplasmosis. Pre-transplant serology was positive by both dye and agglutination tests in 11 infected patients tested. Sequential IgG, IgM, IgA, IgE antibody titers to T. gondii and the differential agglutination ratio were not helpful in diagnosing toxoplasmosis. Median day of clinical presentation was day 59 post-transplant (35-97 days) and of diagnosis, day 62 after transplant (37-143 days). Eleven patients had graft-versus-host disease (GVHD) of grades II-IV. All 12 patients died. Infection was diagnosed prior to death in only 16% of patients and contributed to death in at least 40%. Histopathology revealed tachyzoites of T. gondii most prevalent in brain (100%), heart (67%) and lungs (33%), and toxoplasma cysts alone in heart (33%) and lungs (22%). Toxoplasma infection was diagnosed in two patients receiving trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis suggesting this was insufficient prophylaxis for toxoplasmosis. Toxoplasmosis appeared to occur by reactivation within the first 6 months after marrow transplant. Infection developed in patients who were seropositive for T. gondii pre-transplant, had received allogeneic marrow and had severe GVHD.     

Metabolic myopathy as a cause of the exercise limitation in lung transplant recipients

BACKGROUND: Cardiopulmonary exercise (CPEx) studies of lung transplant (LTx) recipients have found low maximum oxygen consumptions because of an as yet unexplained mechanism. Although it is likely that a significant problem resides within the mitochondria, this study determines whether a defect in oxygen uptake or utilization is present. METHODS: Six LTx recipients and six age- and sex-matched, healthy control subjects were studied to assess the possibility of a mitochondrial myopathy in LTx recipients. We used standard CPEx testing in conjunction with near-infrared spectroscopy (NIRS), a noninvasive optical technique to assess peripheral oxygen uptake in exercising muscle. NIRS analyzes the absorption spectra of hemoglobin and myoglobin at 760 and 850 nm to determine the relative oxygen saturation of these compounds during exercise with respect to baseline values. Relative changes in oxygen saturation are determined from the application of Beers law to changes in absorbance to compute changes in optical density (deltaOD). The LTx recipients and control subjects performed maximal noninvasive CPEx studies with NIRS analysis of the vastus lateralis muscle. RESULTS: All subjects had a circulatory limitation to exercise. The LTx group had a significantly lower percent predicted maximum oxygen consumption than the control group (45.3%+/-14% vs 100.8%+/-15.6%, [mean +/- SD] P < .001) and earlier onset of the anaerobic threshold (30.3%+/-7.6% vs 60.3%+/-8.0% of predicted VO2max, P < .0001) The LTx recipients demonstrated a significantly smaller deltaOD at maximum exercise as determined by NIRS analysis (0.024+/-0.005 deltaOD vs 0.054+/-0.03 deltaOD, P < .05). CONCLUSIONS: LTx recipients have an impaired maximal exercise capacity because of a disorder of peripheral oxygen utilization. This may be caused by a cyclosporine-induced mitochondrial myopathy.     

Hypertension in thoracic transplant recipients

There are many mechanisms underlying the hypertension which occurs after thoracic transplantation. Previous disease, effects of cyclosporin, tacrolimus and steroid immunosuppression and cardiac denervation are major contributory factors. Abnormal sodium and water balance is an important common mediating factor. A new approach is clearly needed for classifying the severity of hypertension in these patients taking into account day-night variation and total blood pressure (BP) load. This would allow improved strategies for investigation and treatment. The evidence suggests that ambulatory BP measurements should be included in the assessment of initial severity of post-transplant hypertension as well as response to treatment. Further studies are needed to look at the effects of raised clinic and 24-h ambulatory BP and its treatment on longer term morbidity and mortality in thoracic transplant patients.     

Viral and immunologic aspects of Epstein-Barr virus infection in pediatric liver transplant recipients

Pediatric allograft recipients in particular are at increased risk for Epstein-Barr virus (EBV)-associated disorders. Early identification and diagnosis of EBV-associated disorders is critical, since disease progression can often be halted by reduction of immunosuppression. In this study we examined viral and immunologic parameters of EBV infection in the circulation of pediatric liver recipients to identify factors associated with disease. Peripheral blood DNA from pediatric liver recipients was analyzed by PCR for the EBV genes coding for the nuclear antigen 1 (EBNA-1) and the viral capsid antigen gp220. Sequences for these viral genes could be readily detected in the circulation of 36.5% of patients. Moreover, identification of the EBV genome was associated with symptomatic infection, suggesting that circulating EBV may be a useful marker of disease. Since EBV-infected B cells release the low-affinity IgE receptor (sCD23), we measured sCD23 in the circulation of pediatric liver recipients and found it to be elevated in patients with detectable virus or symptoms of infection. However, sCD23 was also elevated in cases where no EBV was detectable, suggesting that factors other than viral infection could stimulate release of sCD23. To further characterize the immune response to EBV infection, the peripheral levels of IL-4, IL-5, IL-10, and IFN-gamma were determined in pediatric liver recipients. Each of these cytokines was elevated in patients with symptoms or circulating virus compared with stable, age-matched liver recipients. IL-4, in particular, was significantly increased, indicating an important role for this cytokine in EBV infection. Together, these findings suggest that (1) monitoring circulating levels of EBV may be useful in patients at high risk and (2) cytokines that promote B cell growth and differentiation contribute to EBV-associated disorders.     

Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management

Tuberculosis is a serious opportunistic infection in transplant recipients. On the basis of the compilation of published reports in the literature, the incidence of Mycobacterium tuberculosis infection in organ transplant recipients worldwide ranged from 0.35% to 15%. Nonrenal transplantation (P = .004), rejection within 6 months before the onset of tuberculosis (P = .02) and type of primary immunosuppressive regimen (P = .007) were predictors of M. tuberculosis infection occurring within 12 months after transplantation. Thirty-three percent (155) of 476 transplant patients with tuberculosis had disseminated infection; receipt of OKT3 or anti-T cell antibodies (P = .005) was a significant predictor of disseminated tuberculosis. Overall, the mortality rate among 499 patients was 29%; disseminated infection (P = .0003), prior rejection (P = .006), and receipt of OKT3 or anti-T cell antibodies (P = .0013) were significant predictors of mortality in patients with tuberculosis. Clinically significant hepatotoxicity due to isoniazid occurred in 2.5%, 4.5%, and 41% of renal, heart and lung, and liver transplant recipients, respectively. The diagnosis and effective management of tuberculosis after transplantation warrant recognition of the unique epidemiological and clinical characteristics of tuberculosis in transplant recipients.