tacrolimus and Virus-Diseases

Introduced in 1995, mycophenolate mofetil (MMF) would become the most powerful antiproliferative agent in the field of organ transplantation, thereby supplanting azathioprine, the first antiproliferative agent introduced in the early 1960s. Its association with tacrolimus greatly improved kidney transplant (KT) prognosis by significantly reducing the incidence of posttransplant acute rejection. MMF is also reputed to be a safe medication, but the frequency of the gastrointestinal complications associated with it, even minor ones, has induced the marketing of a second molecule called enteric-coated mycophenolate sodium. This late form of mycophenolate was supposed to be better tolerated thanks to its pharmacokinetic properties but the studies did not show significant differences between the two molecules. Otherwise, the combination of MMF with tacrolimus has significantly increased the risk of infections, particularly viral, and of neoplasia. To reduce this risk and avoid any situation of under or overexposure while remaining effective, only a strict and long-term monitoring of MMF allows the maintenance of already established therapeutic targets within the predefined ranges. In KT, individualizing the prescription and targets of MMF according to immunologic risk, global immunosuppression, and posttransplant period, as for other immunosuppressants, is open to discussion and may be beneficial.

Topics: Adult; Drug Interactions; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Virus Diseases

Interleukin 33 (IL-33), a member of the IL-1 family, is constitutively expressed in epithelial and in endothelial cells at barrier sites, acting as a danger signal and adjuvanting the immune response following tissue damage and infection. Originally implicated in allergy, IL-33 is also known to be involved in innate and adaptive immune responses by enhancing natural killer, Th1, and CD4 and CD8 T-cell functions. The nature of the antiviral immune response orchestrated by IL-33 depends on the site of infection, the duration of the disease and the cytokine milieu. In this review, we focus on the distinctive contribution of IL-33 as an anti-infective and proinflammatory cytokine in response to cell death and viral infections. The dynamic role of IL-33 in the acute and chronic phases of infection with HIV, hepatitis B and C viruses, and with CMV is highlighted. This review will also discuss the potential immunotherapeutic and adjuvant roles of IL-33.. English language, indexed publications in PubMed were searched using combinations of following key words: "interleukin-33", "IL-33", "suppression of tumorigenicity 2", ST2", "sST2", "HIV", "HBV", "HCV", "CMV", "HPV", "immunotherapy" and "vaccine". Except for seminal studies, only articles published between 2010 and 2016 were included.

Topics: Animals; Antiviral Agents; Coinfection; Humans; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Signal Transduction; T-Lymphocyte Subsets; Tacrolimus; Virus Diseases

Pediatric heart transplantation is a surgical therapy for dilated cardiomyopathy and for complex congenital heart defects with low pulmonary artery resistance. However, it is still discussed as controversial because of uncertain long-term results. We report our experience with pediatric heart transplantation in a heterogeneous population.. Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 +/- 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.. Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 +/- 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.. Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.

Topics: Adolescent; Antiviral Agents; Bacterial Infections; Cardiomyopathy, Dilated; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Female; Follow-Up Studies; Ganciclovir; Germany; Graft Rejection; Heart Defects, Congenital; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Life Tables; Lymphoma, Non-Hodgkin; Male; Mycophenolic Acid; Pneumonia, Pneumocystis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Vascular Resistance; Virus Diseases

Topics: Animals; Anti-Infective Agents; Antiviral Agents; B-Lymphocytes; Bacterial Infections; Cyclosporine; HIV; Humans; Immunosuppressive Agents; Parasitic Diseases; Polyenes; Sirolimus; T-Lymphocytes; Tacrolimus; Virus Diseases

Topics: Bacterial Infections; Blood Pressure; Cadaver; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Kidney Transplantation; Male; Mycoses; Patient Selection; Postoperative Complications; Prednisolone; Tacrolimus; Time Factors; Tissue Donors; Virus Diseases

We analyzed the relation between FK506 trough levels (ELISA: patients 1-41, IMx: patients 42-70) and rejection and/or viral infection episodes, retrospectively, in the first 70 consecutive cases of living related liver transplantation. Twenty patients (28.6%) had rejection episodes. Of the 13 patients who had evidence of rejection during the first 3 months, 6 patients without infection and 7 patients with viral infection showed low concentrations of FK506 (< 5 ng/ml). Twelve patients were treated and improved with high dose steroid administration and an increase in the FK506 dosage. One patient died of refractory rejection. Nine patients had evidence of rejection after the first 3 months. In 3 patients, weaning from FK506 initiated the rejection episodes. Five patients repeated rejection and 4 patients required a third immunosuppressant (azathioprine). Viral infection included CMV (11 cases), EBV (13 cases), HZV (3 cases), and HSV (1 case). Excess immunosuppression might have been the cause, but no clear correlation was found. We propose that the optimal dosage of FK506 obtained by monitoring the trough levels using the IMx method should maintain a 10-20 ng/ml level during the first month, and a 5-10 ng/ml level at the second and third months.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Female; Graft Rejection; Humans; Infant; Liver Transplantation; Male; Postoperative Complications; Retrospective Studies; Tacrolimus; Virus Diseases

Topics: Adult; Bacterial Infections; Cyclosporine; Female; Follow-Up Studies; Humans; Liver Transplantation; Male; Mycoses; Postoperative Complications; Tacrolimus; Virus Diseases

Topics: Bacterial Infections; Child; Humans; Liver Transplantation; Mycoses; Retrospective Studies; Tacrolimus; Virus Diseases

The current standard pharmacokinetic monitoring of immunosuppressive therapy does not consider inter- and intra-individual differences in the biological response to multidrug immunosuppressive therapy. The authors evaluated the blood levels of the immunosuppressive drugs IL-2 and IFN-γ in circulating lymphocytes as surrogate indicators of the development of viral infections after living kidney transplantation. This single-center prospective study included 20 kidney transplant recipients who underwent living-donor transplantation at the Mie University Hospital. All the study participants received tacrolimus, mycophenolic acid, methylprednisolone, and basiliximab. The area under the concentration curves (AUCs) of blood tacrolimus and serum mycophenolic acid were measured 1 day prior to transplantation and on post-transplantation days (PTD) for up to 5 months. IL-2 and IFN-γ levels in circulating lymphocytes were measured simultaneously. One recipient experienced an acute graft rejection. Although the AUC of tacrolimus at PTD 7 was significantly higher in the virus-infected group than that in the non-infected group, the AUC of mycophenolic acid did not differ significantly between the 2 groups. The expression levels of IFN-γ+ NK, IFN-γ+ CD4+ T, and CD8+ T cells in the infected group also tended to be higher than those in the noninfected group. During the study period, there was a clear difference in the expression of IFN-γ+ CD8+ T cells, which increased significantly during or after infection. Circulating IFN-γ+ CD8+ T cell counts may serve as promising biomarkers for predicting opportunistic viral infections early after kidney transplantation.

Topics: Humans; Immunosuppressive Agents; Interleukin-2; Kidney Transplantation; Lymphocyte Activation; Mycophenolic Acid; Pilot Projects; Prospective Studies; Tacrolimus; Virus Diseases

Immunosuppression is a known risk for post-transplant infections. Little data exist on the risk contributions of specific agents for various infections.. A triply robust propensity score-adjusted analysis was performed in a renal transplant cohort between February 2006 and January 2014. The study was performed to identify the incidence and the risk factors for developing a post-transplant infection. After initial bivariate analysis, a triply robust propensity score-adjusted multivariate logistic regression was performed.. The mean age of the 717 renal transplant recipients was 50.0 ± 13.3 years, with the majority being male (61.6%) and 349 (48.7%) experiencing at least 1 post-transplant infection. Neither race, graft type, nor insurance status was associated with an increased incidence or risk of infection. In a fully adjusted regression model, the immunosuppressants mycophenolic acid mofetil (OR 0.38, 95% CI 0.21-0.71; P < .001) and alemtuzumab (OR 0.40, 95% CI 0.19-0.85; P = .020) were protective.. Alemtuzumab and mycophenolic acid mofetil as immunosuppressant agents in a multiagent protocol appear to decrease the incidence of infection. Cytomegalovirus antigenemia was the greatest risk for infection and mycophenolic acid mofetil possessed the greatest protective effect on viral infections.

Topics: Adult; Alemtuzumab; Case-Control Studies; Community-Acquired Infections; Cross Infection; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Propensity Score; Retrospective Studies; Risk Factors; Tacrolimus; Virus Diseases

AR is lower in pKTx recipients on Tac vs CsA. Data comparing infection outcomes for children treated with these agents are limited. We retrospectively studied infection outcomes in 96 pKTx recipients on a RDP. PS, DCGS, AR, and infection-free survival were assessed using Kaplan-Meier/log-rank tests and proportional hazards models. There were no differences in 1-year PS, DCGS, or AR between Tac and CsA recipients. After adjusting for AR, the hazard of CMV viremia was 4.0 times higher (95%CI: 1.04, 15.5; P = .044) and that of BK viremia was 3.8 times higher (95%CI: 1.5, 10.2; P = .007) in Tac recipients. The incidence of EBV viremia was similar between the groups (P = .56). PostTx lymphoproliferative disease was only observed in Tac recipients (3%). There was no difference in the incidence of pneumonia, urinary tract, or Clostridium difficile infections between Tac and CsA recipients. Among KTx recipients on RDP, the hazards of CMV and BK viremia within 1 year post-KTx were significantly higher in Tac recipients compared to CsA. Regular assessment for infections and lower Tac trough levels may be warranted in Tac recipients.

Topics: Adolescent; Bacterial Infections; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Male; Postoperative Complications; Prednisone; Proportional Hazards Models; Retrospective Studies; Tacrolimus; Treatment Outcome; Virus Diseases

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited response to currently available therapies. Alveolar type II (ATII) cells act as progenitor cells in the adult lung, contributing to alveolar repair during pulmonary injury. However, in IPF, ATII cells die and are replaced by fibroblasts and myofibroblasts. In previous preclinical studies, we demonstrated that ATII-cell intratracheal transplantation was able to reduce pulmonary fibrosis. The main objective of this study was to investigate the safety and tolerability of ATII-cell intratracheal transplantation in patients with IPF.. We enrolled 16 patients with moderate and progressive IPF who underwent ATII-cell intratracheal transplantation through fiberoptic bronchoscopy. We evaluated the safety and tolerability of ATII-cell transplantation by assessing the emergent adverse side effects that appeared within 12 months. Moreover, pulmonary function, respiratory symptoms, and disease extent during 12 months of follow-up were evaluated.. No significant adverse events were associated with the ATII-cell intratracheal transplantation. After 12 months of follow-up, there was no deterioration in pulmonary function, respiratory symptoms, or disease extent.. Our results support the hypothesis that ATII-cell intratracheal transplantation is safe and well tolerated in patients with IPF. This study opens the door to designing a clinical trial to elucidate the potential beneficial effects of ATII-cell therapy in IPF.

Topics: Adrenal Cortex Hormones; Aged; Alveolar Epithelial Cells; Anti-Infective Agents; Bacterial Infections; Bronchoscopy; Cell Transplantation; Disease Progression; Female; Forced Expiratory Volume; Ganciclovir; Graft Rejection; Humans; Idiopathic Pulmonary Fibrosis; Immunosuppressive Agents; Leucovorin; Male; Middle Aged; Mycophenolic Acid; Mycoses; Nystatin; Pulmonary Diffusing Capacity; Tacrolimus; Trachea; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Valganciclovir; Virus Diseases; Vital Capacity; Walk Test

Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty-four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX-R/EX-D (n = 21), EX-R/NEX-D (n = 8), NEX-R/EX-D (n = 8) and NEX-R/NEX-D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX-R/EX-D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX-R/EX-D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under- and over-immunosuppression.

Topics: Bacterial Infections; Child, Preschool; China; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Male; Pharmacogenetics; Postoperative Complications; Regression Analysis; Risk Factors; Tacrolimus; Treatment Outcome; Virus Diseases

The aim of this retrospective study was to determine the risk of viral infection in tacrolimus-treated kidney transplant patients.. We analyzed kidney transplant recipients from 2002 to 2012, reporting all episodes of viral infection. All patients received induction with basiliximab followed by a standard regimen with tacrolimus, steroids, and antimetabolites. Genotypes of cytochrome P450 (CYP) 3A5 were determined with the use of the polymerase chain reaction method.. Fifty-one patients (17 women, 34 men; mean age, 41.6 ± 65.7 years) underwent kidney transplantation with tacrolimus-based immunosuppressive therapy. Thirty patients were diagnosed with 34 viral infections, including herpes simplex, adenovirus, mumps, varicella, and cytomegalovirus (CMV). CMV was the most common viral infection. In multivariate analysis, the CYP3A5 1 allele (P = .049) and negative serology for CMV (P = .018) were factors independently associated with the incidence of viral infection. After excluding CMV infection in CMV-seropositive donor/CMV-seronegative (D+R-) recipients in the analysis, the presence of the CYP3A5 1 allele was found to be an independent risk factor for viral infection. Recipients with the CYP3A5 3/3 genotype (nonexpressors) showed significantly higher dose-adjusted tacrolimus trough concentrations than patients with the CYP3A5 1 allele (expressors; respectively, 104.6 ± 65.6 vs 52.6 ± 62.3 ng/mL per mg/kg/d).. The CYP3A5 1 allele is associated with viral infection, possibly as a result of higher peak concentrations of tacrolimus. Further analyses, such as area under the concentration-time curve (AUC) for tacrolimus and polymorphisms of drug metabolism enzymes such as CYP3A4 are required to evaluate the influence of CYP3A5 on viral infection in kidney transplantation.

Topics: Adult; Aged; Cytochrome P-450 CYP3A; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymorphism, Genetic; Tacrolimus; Virus Diseases

Limited data exist for the use of alemtuzumab (AL) induction in liver transplantation (LT) recipients. We compared the outcomes of hepatitis C virus-negative LT recipients who received AL induction followed by tacrolimus and mycophenolate mofetil without steroids to cohort who received no AL induction, tacrolimus, and a steroid taper. Fifty-five AL-induced recipients were compared to 85 non-AL-induced recipients with similar characteristics. Two-year patient survival (80% versus 88.2%, P = 0.0665) and graft survival (76.4% versus 82.4%, P = 0.1792) were not significantly different between the AL and non-AL groups, respectively. Other outcomes, including acute rejection (20% versus 30.3%), renal dysfunction (creatinine levels: 1.3 ± 0.3 versus 1.4 ± 0.6 mg/dL), and immunosuppressant monotherapy (29.1% versus 44.3%), were not significantly different between the AL and non-AL groups, respectively (P > 0.05). The number of rejection episodes (12 versus 42, P = 0.02) and the number of patients with new-onset hypertension (3 versus 15, P = 0.03) were lower in the AL group, although the incidence of all posttransplant infections was higher with AL (63.6% versus 44.3%, P = 0.03), primarily because of an increase in viral infections. In conclusion, a steroid-free AL induction regimen was associated with less hypertension and rejection but with more infectious complications; thus, the overall benefit of AL induction in LT recipients is called into question.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Chi-Square Distribution; Chicago; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Assessment; Risk Factors; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Virus Diseases

The aim of this preliminary, observational study was to evaluate the value of ImmuKnow (IK), a new tool to measure the net state of immunefunction among renal transplant recipients, in correlation with clinical and laboratory data among unselected renal transplant recipients. Forty-nine recipients of mean age of 51 years were enrolled and followed for 1 year after transplantation. All subjects received the same immunosuppressive strategy with basiliximab induction and tacrolimus, mycophenolate mofetil and steroid maintenance therapy. Samples for IK were collected before transplantation as well as at 7, 14, 21 and 42 days and after 3, 6, and 12 months. There were 54 samples with IK <225 ng/mL, 201 samples with normal IK values, and 135 samples with >525 ng/mL. We divided recipients into 3 groups with respect to their basal IK values: Group 1 (Gr1; IK <225 ng/mL); Group 2 (Gr2; normal values of IK between 226 and 524 ng/mL); and Group 3 (Gr3; IK >525 ng/mL). At 1 year, we observed a significant difference among IK values at the start and the end of the study: Gr1 vs Gr2, P<.0001; Gr2 vs Gr3, P<.06 and Gr 1 vs Gr 3, P<.01). We observed reduced IK values to predict an increased risk of infection, particularly with cytomegalovirus (CMV) replication while higher IK value did not correlate with an increased risk of acute rejection episodes. Reduction of serum creatine levels occurred within 1 year in all groups (P<.005), but there was a significant difference between Gr 2 versus Grs 1 and 3 (P<.0001 and P<.0005, respectively). There findings suggested that more stable IK values were associated with clinical quiescence and laboratory stability. In conclusion, our preliminary analysis showed a beneficial capacity of this assay to represent the global depression of the immune system. We noted that reduced IK values, as a sign of excessive immunosuppressive therapy, were associated with an increased risk of infection. We did not confirm the predictive value of higher IK values for an increased risk of an acute rejection episode.

Topics: Adenosine Triphosphate; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Biomarkers; CD4-Positive T-Lymphocytes; Drug Monitoring; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunity, Cellular; Immunosuppressive Agents; Italy; Kidney Transplantation; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Pilot Projects; Predictive Value of Tests; Recombinant Fusion Proteins; Risk Assessment; Risk Factors; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Virus Diseases

Immunosuppressive regimens for lung transplantation frequently fail to prevent rejection and are toxic. Alemtuzumab was used as induction to investigate whether oral immunosuppression could be reduced. From November 2006 to March 2008, 20 consecutive lung transplant patients received alemtuzumab induction, with reduced maintenance immunosuppression; tacrolimus (target level 10 ng/ml), mycophenolate mofetil (MMF) 250 mg bid and prednisone 7.5 mg. Twenty control cases transplanted before 2006 were treated with standard immunosuppression; tacrolimus (target level 10 ng/ml), MMF 750 mg bid and prednisone 15 mg qd. End-points included patient and graft survival, acute rejection (AR) and infection rate. There were no significant differences in six-month and 12-month survival (alemtuzumab 90% vs. controls 95%, P=0.52 and 76% vs. 95%, respectively, P=0.19). AR events were similar (alemtuzumab 2/16 vs. controls 5/20, P=0.43) - as were - bacteria positive bronchoalveolar lavage (BAL) cultures (alemtuzumab 4.9+/-7.3 per patient per year vs. controls 2.7+/-3.3, P=0.26) and viral or fungal infections (alemtuzumab 0.4+/-1.4 per patient per year vs. controls 0.1+/-0.3, P=0.87; alemtuzumab 3.9+/-6.6 vs. controls 2.3+/-1.9, P=0.57, respectively). Alemtuzumab induction and reduced immunosuppression appears to offer comparable early survival, rejection and infection rates to high-dose standard immunosuppression.

Topics: Administration, Oral; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Bronchitis; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Length of Stay; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Prednisone; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Tacrolimus; Time Factors; Treatment Outcome; Virus Diseases

Haemophagocytic syndrome (HPS) is known as a relatively rare complication in autoimmune diseases. Here we analysed the clinical features of HPS in patients with systemic autoimmune diseases.. One thousand and fourteen patients with systemic autoimmune diseases admitted to Hokkaido University Hospital from 1997 to 2007 were recruited [350 SLE, 136 RA, 98 polymyositis/dermatomyositis (PM/DM), 88 SSc, 91 vasculitis syndrome, 37 primary SS, 26 adult onset Still's disease (AOSD) and 188 other diseases]. Clinical features and treatment outcomes were retrospectively analysed.. Thirty cases (3.0%) fulfilled HPS criteria (progressive cytopenia in two or more lineages and haemophagocytosis in reticuloendothelial systems). Underlying diseases were SLE (18), RA (2), PM/DM (2), SSc (2), vasculitis (1), SS (2) and AOSD (3). Nineteen patients were diagnosed as having autoimmune-associated HPS, eight infection-associated, one drug-induced and one developed HPS after haematopoietic stem cell transplantation. For the treatment of HPS, high-dose corticosteroid monotherapy was given in 26 cases, being effective in 12 (46%). Ten out of 15 patients with corticosteroid-resistant autoimmune-associated HPS were treated with CsA, cyclophosphamide or tacrolimus, leading to the remission in 80%. The overall mortality rate was 20%. Multivariate analysis showed that the presence of infections and CRP level >50 mg/l on HPS related with poor prognosis.. The prevalence of HPS among in-hospital patients with systemic autoimmunity is not ignorable. Administration of immunosuppressants was effective in cases with autoimmune-associated HPS, whereas prognosis was poor in infection-associated HPS.

Topics: Adult; Aged; Autoimmune Diseases; Bacterial Infections; Cyclophosphamide; Cyclosporine; Glucocorticoids; Humans; Immunosuppressive Agents; Lymphohistiocytosis, Hemophagocytic; Middle Aged; Prognosis; Retrospective Studies; Tacrolimus; Virus Diseases; Young Adult

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection. In this study, 5600 12-h trough MPA samples from 121 renal transplant recipients immunosuppressed with mycophenolate mofetil (MMF) and tacrolimus in a steroid sparing protocol (steroids for 7 days only) were sequentially analyzed. Higher MPA levels were associated with lower hemoglobin concentrations and anemia (hemoglobin <10 g/dL). Similarly, higher MPA levels were associated with lower total white cell counts and an increased incidence of leucopenia (total white cell count <4.0 x 10(9)/L). Hypoalbuminemia and renal impairment were also associated with hemotoxicity. MMF-associated diarrhea and viral infection were associated with higher MPA levels. Conversely, biopsy-proven acute rejection within the first month post-transplantation was associated with lower MPA levels. Anti-CD25 antibody induction was also associated with reduced rejection rates. No association was seen between MPA levels and platelet count, thrombocytopenia or bacterial infection. An MPA level of 1.60 mg/L early post-transplantation best discriminated patients with and without rejection, and an MPA level of 2.75 mg/L best discriminated patients with and without toxicity later post-transplantation.

Topics: Adult; Bacterial Infections; Bone Marrow; Diarrhea; Dose-Response Relationship, Drug; Drug Monitoring; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Count; Leukopenia; Male; Middle Aged; Monitoring, Physiologic; Mycophenolic Acid; Platelet Count; Tacrolimus; Thrombocytopenia; Virus Diseases

To assess the long-term efficacy of intestinal transplantation under tacrolimus-based immunosuppression and the therapeutic benefit of newly developed adjunct immunosuppressants and management strategies.. With the advent of tacrolimus in 1990, transplantation of the intestine began to emerge as therapy for intestinal failure. However, a high risk of rejection, with the consequent need for acute and chronic high-dose immunosuppression, has inhibited its widespread application.. During an 11-year period, divided into two segments by a 1-year moratorium in 1994, 155 patients received 165 intestinal allografts under immunosuppression based on tacrolimus and prednisone: 65 intestine alone, 75 liver and intestine, and 25 multivisceral. For the transplantations since the moratorium (n = 99), an adjunct immunosuppressant (cyclophosphamide or daclizumab) was used for 74 transplantations, adjunct donor bone marrow was given in 39, and the intestine of 11 allografts was irradiated with a single dose of 750 cGy.. The actuarial survival rate for the total population was 75% at 1 year, 54% at 5 years, and 42% at 10 years. Recipients of liver plus intestine had the best long-term prognosis and the lowest risk of graft loss from rejection (P =.001). Since 1994, survival rates have improved. Techniques for early detection of Epstein-Barr and cytomegaloviral infections, bone marrow augmentation, the adjunct use of the interleukin-2 antagonist daclizumab, and most recently allograft irradiation may have contributed to the better results.. The survival rates after intestinal transplantation have cumulatively improved during the past decade. With the management strategies currently under evaluation, intestinal transplant procedures have the potential to become the standard of care for patients with end-stage intestinal failure.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Cyclophosphamide; Daclizumab; Graft Survival; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppression Therapy; Intestines; Liver Transplantation; Monitoring, Immunologic; Prednisone; Prognosis; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Virus Diseases

As experience with tacrolimus (FK506, Prograf) accumulates and reduced rejection rates are increasingly demonstrated, some transplant centers are adopting tacrolimus-based primary immunosuppressive regimens for their patients undergoing pancreas/kidney transplantation. The guidelines provided in this article based on the experience of four major US transplant centers, cover issues related to dosing, blood levels, concomitant use of mycophenolate mofetil (MMF), antifungal and antiviral prophylaxis, and drug interactions. For post-transplant immunosuppression some centers initiate oral tacrolimus administration on postoperative day 1, 2, or 3, while others wait until day 6 or 7, when renal or gastrointestinal function has resumed. Most centers endeavor to achieve higher target trough levels (approximately 10-20 ng/mL, but not higher) in the first 3 months post-transplant, reducing levels thereafter. Several centers are now using MMF instead of azathioprine as an adjunct to tacrolimus. Conversion from cyclosporine to tacrolimus during maintenance therapy is often considered in the event of rejection or when adverse events do not respond to dosage reduction.

Topics: Administration, Oral; Antifungal Agents; Antiviral Agents; Drug Interactions; Drug Therapy, Combination; Fluconazole; Graft Rejection; Guidelines as Topic; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Mycoses; Pancreas Transplantation; Tacrolimus; United States; Virus Diseases

Experience with lung transplantation in infants and young children is limited. Small size, vulnerability to infection, and limited modalities for rehabilitation and surveillance of the transplanted lung make this group particularly challenging.. We reviewed the course of all children up to the age of 25 months who underwent lung transplantation at two centers between July 1990 and February 1995.. Lung transplantation was performed in 17 patients under the age of 25 months, with concurrent cardiac repair in 14. Prior thoracic surgery had been performed in 12; six patients had mechanical ventilation, and three were supported with extracorporeal membrane oxygenation while waiting for lungs. The mean waiting time was 37 days (range 1 to 197 days). Hospital survival was 12 of 17 (71%); there was one late death. Early deaths were due to hemorrhage (two patients), cytomegalovirus and lymphoproliferative disease (one patients), and viral pneumonitis (two patients). The one late death was due to overwhelming gastroenteritis of unknown origin. One additional patient had graft failure caused by viral pneumonitis and underwent successful retransplantation. Bronchial stenosis occurred at 3 of 33 anastomoses. At a mean follow-up of 22 months, surviving patients were well, without supplemental oxygen, and, although small in stature, had normal linear growth.. Lung transplantation is a reasonable therapy for very young patients with limited life expectancy and no other therapeutic alternative, with outcomes comparable with those achieved in older patients. Early recognition of lung transplant candidates and advances in the prevention, diagnosis, and treatment of viral illness may improve survival in these patients.

Topics: Actuarial Analysis; Azathioprine; Cause of Death; Cyclosporine; Graft Rejection; Heart Defects, Congenital; Humans; Immunosuppressive Agents; Infant; Lung Diseases; Lung Transplantation; Prednisone; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome; Virus Diseases

Topics: Bacterial Infections; Diabetes Mellitus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Pancreas Transplantation; Tacrolimus; Virus Diseases

Under FK506-based immunosuppression, 16 cadaveric small bowel transplantations were performed in 15 recipients with (n = 5) or without (n = 11) the large bowel. Twelve (80%) patients are alive after 1.5 to 19 months, 11 bearing their grafts, of which 4 include colon. The actuarial one-year patient and graft survivals are 87.5% and 65.9%, respectively. Five grafts were lost to acute (n = 4) or chronic (n = 1) rejection, and 3 of these patients subsequently died after 376, 440, and 776 days total survival. Six recipients developed severe CMV infection that was strongly associated with seronegative status preoperatively and receipt of grafts from CMV positive donors; 3 died, and the other 3 required prolonged hospitalization. Currently, 9 patients are free from TPN 1-18 months postoperatively, 2 require partial TPN, and one has returned to TPN after graft removal. The results show the feasibility of small bowel transplantation but emphasize the difficulty of managing these recipients not only early but long after their operation.

Topics: Adult; Bacterial Infections; Child; Child, Preschool; Colon; Female; Graft Rejection; Humans; Infant; Intestine, Small; Male; Middle Aged; Mycoses; Organ Transplantation; Postoperative Care; Tacrolimus; Virus Diseases

Topics: Adult; Bacterial Infections; Female; Follow-Up Studies; Graft Rejection; Humans; Intestine, Small; Male; Middle Aged; Mycoses; Postoperative Complications; Prednisone; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors; Virus Diseases

This prospective study characterizes the incidence, etiology, timing, risk factors, and outcome of the infectious complications after 88 consecutive liver transplantations in 79 patients receiving tacrolimus (FK506) as primary immunosuppression with a median follow-up of 880 days. Infections occurred in 59% (47/79) of the patients, and 39% had major infections. Of the major infections, 55% were bacterial, 22% were viral, and 22% were fungal. Bacteremia accounted for 30% of major bacterial infections. Sixty percent of bacteremias occurring within the first 3 months were catheter related, while 75% of those occurring more than 3 months after transplant were of a biliary source. Patients with recurrent hepatitis C virus hepatitis and patients requiring dialysis after transplant had a significantly higher rate of infections as compared with other patients. Overall mortality was 18%, and 29% of all deaths were associated with infection. Only invasive aspergillosis was associated with infectious mortality. Our data suggest that the potent immunosuppressive agent FK506 is not associated with a higher incidence of infectious complications as compared with previous studies using CsA.

Topics: Adult; Aged; Bacterial Infections; Female; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Infections; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Prospective Studies; Risk Factors; Survival Rate; Tacrolimus; Treatment Outcome; Virus Diseases

Topics: Adult; Anti-Bacterial Agents; Bacterial Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Mycoses; Opportunistic Infections; Risk Factors; Tacrolimus; Virus Diseases