Complications of Cryptosporidium infection after pediatric liver transplantation: Diarrhea, rejection, and biliary disease.

BACKGROUND: Cryptosporidium enteritis can be devastating in the immunocompromised host. In pediatric liver transplant recipients, infection may be complicated by prolonged carriage of the parasite, rejection, and biliary tree damage and fibrosis. Herein, we report on six patients and their long-term outcomes following cryptosporidiosis. METHODS: We reviewed all cases of cryptosporidiosis in a pediatric liver transplant population over a 17-year period at a single center. Six patients with infection were identified, and their outcomes were analyzed. RESULTS: Infection was associated with significant diarrhea and dehydration in all cases, and led to hospitalization in one-half of patients. Four of the six patients developed biopsy-proven rejection following infection, with three of those patients developing rejection that was recalcitrant to intravenous steroid treatment. Additionally, three patients developed biliary tree abnormalities with similarity to sclerosing cholangitis. In one patient, those biliary changes led to repeated need for biliary drain placement and advancing fibrotic liver allograft changes. CONCLUSIONS: Cryptosporidiosis in pediatric liver transplant recipients may lead to significant complications, including recalcitrant episodes of rejection and detrimental biliary tree changes. We advocate for increased awareness of this cause of diarrheal disease and the allograft injuries that may accompany infection.

Sequential measurement of Trypanosoma cruzi parasitic load in endomyocardial biopsies for early detection and follow-up of Chagas disease reactivation after heart transplantation.

BACKGROUND: Reactivation of Chagas disease after heart transplantation is characterized by proliferation and dissemination of Trypanosoma cruzi parasites to several organs. Reactivation affecting the allograft can simulate acute cellular rejection, from which it should be distinguished through the analysis of endomyocardial biopsies (EMB). METHODS: We evaluated retrospectively 100 EMB collected in the first year of follow-up from 13 heart-transplanted, chagasic patients who presented reactivation and were successfully treated. Additionally, 37 EMB from 8 patients who did not present reactivation constituted the control group. We reviewed histopathology and performed a real-time PCR-based assay in order to evaluate the T cruzi parasitic load of each EMB. RESULTS: The parasitic load of the EMB at the time of reactivation ranged from 22.80 to 190 000/106 cells (median: 1555). In 6 patients, none of the EMB obtained prior to reactivation amplified T cruzi DNA. On the other hand, 10 EMB from 7 patients, obtained 9-105 days before reactivation (median: 26 days), showed parasitic load ranging from 8.25 to 625/106 cells (median: 167.55). In all patients, the parasitic load increased at the time of reactivation, usually sharply. After initiation of treatment, all patients showed negative PCR or a dramatic reduction of the parasitic load in the following EMB. None of the EMB from the control group amplified T cruzi DNA. CONCLUSIONS: Sequential measurement of T cruzi parasitic load in EMB is useful for monitoring Chagas disease reactivation after heart transplantation. Its increase suggests imminent reactivation and its decrease after treatment indicates favorable evolution for cure of the episode of reactivation.

An unusual cause of graft loss in pediatric liver transplant recipient-Fasciola hepatica.

Fascioliasis is caused by the trematode liver fluke Fasciola hepatica. Humans are accidental hosts getting infected after ingesting contaminated plants or water. 90 million people in 75 nations are at risk of infection with F hepatica. Immunosuppressed patients are higher risk of acquiring infection and may present with atypical manifestations. Patients can present with hepatic involvement, biliary features or a combination of both. Confirmation of the diagnosis is by demonstration of live parasites or eggs in bile or feces, serology (immunoelectrophoresis, indirect immunofluorescence, indirect hemagglutination), ELISA, typical imaging findings or a combination of any of the above. The drug of choice for treatment is triclabendazole. Fascioliasis should always be considered as a possibility in post-LT patients with findings of hepatobiliary disorder from endemic areas. Unfamiliarity with this infection in non-endemic areas often eludes prompt diagnosis thereby increasing the morbidity. We report the first case of fascioliasis in a pediatric liver transplant recipient leading to graft loss and mortality.

Effect of everolimus initiation and early calcineurin inhibitor withdrawal on myocardial FOXP3+ regulatory T cells in heart transplantation.

BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We hypothesized treatment with everolimus reduced the risk of CAV by modulating myocardial FoxP3 levels. METHODS: 15 patients from the Schedule trial comparing everolimus, MMF, steroid and early CNI (Everolimus, n=8) withdrawal to conventional CNI based immunosuppression (Controls, n=7) after de novo HTx were included and FoxP3+ cells were quantified in 56 endomyocardial biopsies, and compared in the two patient groups. CAV was evaluated invasively using coronary intravascular ultrasound (IVUS). RESULTS: Baseline FoxP3 biopsy levels were similar in the two groups. The Everolimus group showed a significant increase in Foxp3 densities from baseline to time of one-year follow-up (median (IQR)=4.8×10(-7)(20.4) Tregs/µm(2), P=0.046) while Controls showed no significant change (median (IQR)=3.1×10(-7)(6.5) Tregs/µm(2), P=0.116). At 1-month follow-up FoxP3 densities correlated with the observed change in TAV from baseline to time of 1-year follow-up (r=0.641, P=0.034). FoxP3 densities at 1-week predicted acute cellular rejection (ACR) levels at 1month (P=0.026). No other correlations with ACR were found. CONCLUSION: Everolimus treatment combined with early CNI elimination is associated with increased densities of Tregs 12-months post-HTx compared to patients receiving CNI based regimen. Furthermore, the density of myocardial FoxP3+ cells early after transplantation appears to predict at least one measure of CAV burden after one year.

[Toxoplasmic cyst and heart transplant: a case report of serological reactivation in an acute graft rejection context]. / Kyste toxoplasmique et transplant cardiaque : cas d'une réactivation sérologique dans un contexte de rejet de greffe.

We describe the case of a serological reactivation in a Toxoplasma-seropositive subject, following a cardiac transplantation transmitting cysts contained in the myocardial tissue. In a context of acute graft rejection, primary chemoprophylaxis enables to avoid onset of opportunistic toxoplasmosis, emerging with immunodepletion performed by high-dose steroids. Then, we draw up a brief review of the bibliographical literature about pathophysiological mechanisms of toxoplasmic reactivation in heart transplants.

Intravenous dexamethasone vs methylprednisolone pulse therapy in the treatment of acute endothelial graft rejection.

PURPOSE: To study the outcome of therapy for acute endothelial graft rejection with an intravenous (i.v.) pulse of dexamethasone vs methylprednisolone, in addition to topical corticosteroids. METHODS: Records of 98 eyes of 99 patients treated for endothelial graft rejection with a single i.v. pulse of dexamethasone or methylprednisolone in addition to topical steroids, between January 1999 and June 2004, were retrospectively reviewed. Baseline characteristics such as surgery-rejection interval, time taken to consult after onset of symptoms, history of failed grafts, extent of stromal vascularization, best-corrected visual acuity (BCVA) and corneal thickness at the time of presentation were noted. Main outcome measures following treatment for rejection included improvement in BCVA, change in corneal thickness, and reversal of graft rejection. RESULTS: Fifty-one patients were treated with i.v. methylprednisolone and 47 with i.v. dexamethasone, in addition to topical steroids. Both groups were found to be comparable with respect to baseline parameters, that is, time taken to present, history of failed grafts, extent of stromal vascularization, BCVA, and graft thickness. Graft rejection could be successfully reversed in 72.3% cases in the dexamethasone group and 49% in the methylprednisolone group (P=0.018). A significant improvement in visual acuity was recorded following treatment in both groups, with a better outcome in the dexamethasone group (P=0.012). Post-treatment pachymetry values were lower than pretreatment values in both groups, with significantly lower final pachymetry in the dexamethasone group (P=0.017). No adverse effects were observed. CONCLUSION: I.v. pulse therapy with dexamethasone may be used as an effective alternative to methylprednisolone in reversing acute endothelial graft rejection.

Use of alemtuzumab (Campath-1H) as induction therapy in pediatric kidney transplantation.

Alemtuzumab (Campath-1H) is a monoclonal antibody directed against CD52-positive B and T lymphocytes. Initial results of its use as an induction agent in adult renal transplantation have been encouraging. We report a case series of four low-risk pediatric renal transplantation patients who received 20 to 40 mg of alemtuzumab as induction followed by a steroid-free regimen consisting of a calcineurin inhibitor and mycophenolate mofetil. No infusion-related reactions occurred. Patients were aged 9 to 14 years with a mean creatinine of 1.2 mg/dL (range = 0.5-2.3 mg/dL) at a mean follow-up of 10 months (range = 4-16 months). One patient experienced biopsy-proven acute cellular rejections at 4 and 12 months posttransplantation, which were steroid sensitive. Lymphopenia post-alemtuzumab induction started to improve at 3 months posttransplantation. Two patients who received 40 mg of alemtuzumab experienced repeated infections that responded to 7-day courses of antibiotics. There was no cytomegalovirus disease detected. From these preliminary results, alemtuzumab seems to show a promising role to achieve adequate graft function with a steroid-free regimen among low-risk pediatric patients.

Fatal disseminated toxoplasmosis in a cardiac transplantation with seropositive match for Toxoplasma: should prophylaxis be extended?

In cardiac transplant, toxoplasmosis in the immunocompromised recipient can result either from the transmission of the parasite from a seropositive donor (D+) to a seronegative recipient (R-) with the transplanted organ (more common) or from the reactivation of a pre-transplant latent infection (D-/R+ or D+/R+). In the immunocompromised patient, toxoplasmosis is a life-threatening disease. We report a case of disseminated toxoplasmosis following heart transplantation in a Toxoplasma seropositive recipient before transplantation (R+) (IgG 1:160, IgM negative) who received an organ from a Toxoplasma seropositive donor (D+) (IgG 1:640, IgM negative). No anti-Toxoplasma prophylactic treatment was administered. A number of complications arose in the postoperative period, as well as Enterobacter cloacae and Cytomegalovirus (CMV) (reactivation) infections, but neither serological nor histological toxoplasma recrudescence was evidenced. The patient died on post transplant day 41. Post-autopsy histological examinations revealed an unexpected diffuse toxoplasmosis (lungs, brain, heart).

Is toxoplasmosis prophylaxis necessary in cardiac transplantation? Long-term follow-up at two transplant centers.

Cardiac transplant recipients are often given prophylactic treatments to prevent opportunistic infections such as Pneumocystis carinii. Toxoplasmosis prophylaxis is commonly prescribed for transplant recipients who have not been exposed to this disease but receive a heart from an exposed donor. We reviewed the collective 28-year experience at two urban transplant programs with 596 patients, and found no cases of toxoplasmosis, but all patients received trimethoprim-sulfamethoxazole to prevent Pneumocystis pneumonia. We conclude that specific anti-toxoplasmosis prophylaxis is unnecessary in heart transplant recipients.

T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection.

Alloreactive T lymphocytes can be primed through direct presentation of donor MHC:peptide complexes on graft cells and through indirect presentation of donor-derived determinants expressed by recipient APCs. The large numbers of determinants on an allograft and the high frequency of the alloreactive repertoire has further led to speculation that exposure to environmental Ags may prime T cells that cross-react with alloantigens. We sought to develop a model in which to test this hypothesis. We found that CD4(+) T cells obtained from C57BL/6 (B6) mice that clinically resolved Leishmania major infection exhibited statistically significant cross-reactivity toward P/J (H-2(p)) Ags compared with the response to other haplotypes. B6 animals that were previously infected with L. major specifically rejected P/J skin grafts with second set kinetics compared with naive animals. Although donor-specific transfusion combined with costimulatory blockade (anti-CD40 ligand Ab) induced prolonged graft survival in naive animals, the same treatment was ineffective in mice previously infected with L. major. The studies demonstrate that cross-reactive priming of alloreactive T cells can occur and provide direct evidence that such T cells can have a significant impact on the outcome of an allograft. The results have important implications for human transplant recipients whose immune repertoires may contain cross-reactively primed allospecific T cells.

Frequency of infections and their relation to episodes of acute rejection among heart allograft recipients.

OBJECTIVES: Infections and episodes of acute rejections are major factors affecting allograft survival during the first year after transplantation. The frequency of infections, and the relation of injections to rejection episodes were studied among heart allograft recipients with the follow-up time one year. METHODS: The study population consisted of 58 patients receiving a heart allograft through 1985 to 1990. Low-dose triple-drug therapy was used for immunosuppression, and rejections were treated either with methylprednisolone, antithymocyte globulin, or the combination of methylprednisolone and antithymocyte globulin. The patients received 2 g of vancomycin i.v. 2 days postoperatively, and no further antibacterial prophylaxis was used. The diagnosis of infection was based on clinical symptoms and on microbiological or serological demonstration of an infection. When the correlations between severe infections and rejections were examined, only infections occurring within 1 month from the onset of the rejection were included. Chi-square test was used for statistical analysis. RESULTS: Seventy-nine infections were registered (1.6 +/- 1.4 episodes/patients); 74% of the patients underwent at least one infection episode. Most infections, 61% (49), occurred during the first three posttransplant months, cytomegalovirus and bacterial agents accounting for the most important aetiology. No difference in the overall infection frequency existed between the patients with or without rejections. Twenty seven infection episodes were recorded in 18/50 patients with rejections (p = NS), 11 of them in relation to rejection in 5/18 patients. The frequency of infections after antirejection therapy either with antithymocyte globulin or the combination of methylprednisolone and antithymocyte globulin (7/11) was higher than with methylprednisolone alone (4/20) (p < 0.05). Infections were the primary cause of death in 50%. The rest of deaths were caused by acute rejections. CONCLUSION: There was a typical pattern of infections occurring mainly during the first three months after transplantation, and a significant tendency towards severe infections after intense antirejection therapy with antithymocyte globulin.