tacrolimus and Influenza--Human

An influenza neuraminidase inhibitor drug, oseltamivir (Os) may be prescribed to renal transplant patients to prevent and treat influenza A and B illness. A pharmacokinetic (PK) interaction between Os and immunosuppressive drugs might adversely affect the efficacy and/or toxicity of the latter agents. This study was conducted to determine whether adverse symptoms and acute drug interactions occur during their coadministration.. A randomized, crossover study design was utilized to study the effect of a 75-mg dose of Os on the steady-state PK of cyclosporine A (CyA), mycophenolate mofetil, or tacrolimus (Tac) in a convenience sample of 19 adults with a renal allograft by measurement of total plasma or blood drug concentrations (C(p)) over one 12-hour dose interval. Os PK parameters were determined from its concentrations and those of its metabolite, Os carboxylate, in plasma and urine over 48 hours.. Of 19 volunteers, 12 were men, with age (mean ± SD) 46 ± 11 years, weight 83 ± 19 kg, and calculated Cl(creatinine) 64 ± 27 mL/min. Adverse effects were minor and transient. Os did not affect the steady-state C(max), T(max), or area under the concentration versus time curve (AUC) over a 12-hour dose interval of CyA, mycophenolic acid, or Tac or the C(trough) of CyA or mycophenolate but increased the mean C(trough) of Tac by 13%.. The increase in Tac mean C(trough) during coadministration with Os is not likely clinically important. Os and Os carboxylate PK were similar to those in subjects with native kidneys and similar renal function who have been described in the literature.. These data from a single Os dose study suggest that coadministration is not expected to cause adverse symptoms nor alter the steady-state PK of CyA, mycophenolate mofetil, or Tac in stable adult renal transplant patients with mild renal insufficiency. The data enable a multiple-dose study that reflects clinical practice during influenza exposure and assesses the possibility that chronic exposure to Os might result in a different outcome.

Topics: Adult; Aged; Antiviral Agents; Biotransformation; Cohort Studies; Cross-Over Studies; Cyclosporine; Drug Interactions; Enzyme Inhibitors; Female; Half-Life; Humans; Immunosuppressive Agents; Influenza, Human; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neuraminidase; Oseltamivir; Tacrolimus; Young Adult

Antibody response to the inactivated influenza vaccine is not well described in kidney transplant recipients administered newer, but commonly used, immunosuppression medications. We hypothesized that kidney transplant recipient participants administered tacrolimus-based regimens would have decreased antibody response compared with healthy controls.. Prospective cohort study of 53 kidney transplant recipients and 106 healthy control participants during the 2006-2007 influenza season. All participants received standard inactivated influenza vaccine.. Kidney transplant recipients administered tacrolimus-based regimens at a single academic medical center and healthy controls.. Presence of kidney transplant.. Proportion of participants achieving seroresponse (4-fold increase in antibody titer) and seroprotection (antibody titer > or = 1:32) 1 month after vaccination.. Antibody titers before and 1 month after vaccination by means of hemagglutinin inhibition assays for influenza types A/H1N1, A/H3N2, and B.. A smaller proportion of the transplantation group compared with the healthy control group developed the primary outcomes of seroresponse or seroprotection for all 3 influenza types at 1 month after vaccination. The response to influenza type A/H3N2 was statistically different; the transplantation group had 69% decreased odds of developing seroresponse (95% confidence interval, 0.16 to 0.62; P = 0.001) and 78% decreased odds of developing seroprotection (95% confidence interval, 0.09 to 0.53; P = 0.001) compared with healthy controls. When participants less than 6 months from the time of transplantation were considered, this group had a significantly decreased response to the vaccine compared with healthy controls.. Decreased sample size, potential for confounders, outcome measure used is the standard but does not give information about vaccine efficacy.. Kidney transplant recipients, especially within 6 months of transplantation, had diminished antibody response to the 2006-2007 inactivated influenza vaccine.

Topics: Adult; Antibodies, Viral; Chronic Disease; Cohort Studies; Female; Humans; Immunity; Immunosuppressive Agents; Influenza Vaccines; Influenza, Human; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Orthomyxoviridae; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Glycine decarboxylase (GLDC) was prioritized as a candidate susceptibility gene to severe influenza in humans. The higher expression of GLDC derived from genetic variations may confer a higher risk to H7N9 and severe H1N1 infection. We sought to characterize GLDC as functional susceptibility gene that GLDC may intrinsically regulate antiviral response, thereby impacting viral replication and disease outcome. We demonstrated that GLDC inhibitor AOAA and siRNA depletion boosted IFNβ- and IFN-stimulated genes (ISGs) in combination with PolyI:C stimulation. GLDC inhibition and depletion significantly amplified antiviral response of type I IFNs and ISGs upon viral infection and suppressed the replication of H1N1 and H7N9 viruses. Consistently, GLDC overexpression significantly promoted viral replication due to the attenuated antiviral responses. Moreover, GLDC inhibition in H1N1-infected BALB/c mice recapitulated the amplified antiviral response and suppressed viral growth. AOAA provided potent protection to the infected mice from lethal infection, comparable to a standard antiviral against influenza viruses. Collectively, GLDC regulates cellular antiviral response and orchestrates viral growth. GLDC is a functional susceptibility gene to severe influenza in humans.

Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Genetic Predisposition to Disease; Glycine Dehydrogenase (Decarboxylating); Humans; Immunity, Innate; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza, Human; Mice, Inbred BALB C; Orthomyxoviridae Infections; Tacrolimus; Treatment Outcome; Virus Replication

Annual vaccination is routinely used in organ transplant recipients for immunization against seasonal influenza. However, detailed analysis of the kinetics of vaccine-induced immune responses in this population is lacking. In this study, we investigated the kinetics of vaccine strains-specific antibody responses to trivalent influenza vaccine in a group of renal transplant recipients and a control group. First, we found that the geometric mean hemagglutination inhibition titer against all 3 vaccine strains in the transplant cohort was significantly low when compared to control subjects. Next, whereas the control group sera showed significantly higher HA-specific IgG and isotype IgG1 antibodies at all four time points, a similar increase in the transplant group was delayed until day 28. Interestingly, within the transplant group, subjects receiving belatacept/MMF/prednisone-based regimen had significantly lower levels of total IgG and HA-specific IgG when compared to tacrolimus/MMF/prednisone-based regimen. Even though IgG-ASC response in both cohorts peaked at day 7 post-vaccination, the frequency of IgG-ASC was significantly low in the transplant group. Taken together, our studies show delayed kinetics and lower levels of influenza vaccine-specific antibody responses in renal transplant recipients and, more importantly, indicate the need to probe and improve current vaccination strategies in renal transplant recipients.

Topics: Adult; Antibodies, Viral; Antibody Formation; Cohort Studies; Female; Graft Rejection; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunosuppression Therapy; Influenza A virus; Influenza Vaccines; Influenza, Human; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Transplant Recipients; Vaccination

Among infectious diseases, influenza is the most common cause of infection in Japan and worldwide. We aimed to evaluate the effect of influenza vaccination in kidney transplantation (KTx) recipients.. We retrospectively evaluated the records of 98 participants who underwent KTx at our institution between March 2009 and May 2016. All patients received tacrolimus or cyclosporine, mycophenolate mofetil, and methylprednisolone for maintenance immunosuppression after KTx. In accordance with the criteria of our institution, everolimus was administered for the maintenance of immunosuppression after KTx. We compared the rate of influenza infection during the 2016-2017 season (8 months, from October 2016-May 2017) between KTx patients treated with 1 or 2 doses of influenza vaccine (treatment group, n = 71) and KTx patients who did not receive a vaccine (nontreatment group, n = 27).. Among patient characteristics, only the prevalence of diabetes mellitus differed significantly between the groups (treatment group: 9.9%, 7 of 71 patients; nontreatment group: 29.6%, 8 of 21 patients; P = .02). Influenza infection occurred at similar rates in the 2 groups (treatment group, 5.63% 4 of 71 patients; nontreatment group: 3.70%, 1 of 27 patients; P = .70).. Among KTx patients managed in our institution, treatment with 1 or 2 doses of influenza vaccine did not reduce the rate of influenza infection in the 2016-2017 season, suggesting that influenza vaccination may currently be ineffective in KTx patients.

Topics: Adult; Cyclosporine; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Influenza Vaccines; Influenza, Human; Japan; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus

Influenza may present a high morbidity and mortality in solid organ transplanted patients (SOTP). Annual influenza virus vaccine is recommended for SOTP. However, low levels of seroconversion in SOTP have been reported. The aim of this study was to evaluate the immunogenicity of 2009 pandemic influenza A (H1N1) - A(H1N1)pdm09--vaccine in kidney transplant patients and to analyze which features might affect seroconversion.. This study was conducted from March to August 2010 at the Renal Transplantation Unit of University of São Paulo, Brazil. A total of 85 renal transplant patients attending the outpatient unit received one 15-μg intramuscular dose of A(H1N1) pdm09 influenza vaccine (reassortant vaccine virus A/California/7/2009 [NYMC X-179A]). Blood samples were collected immediately before and 21 days after the vaccine was given. Antibody response was measured by the standard hemagglutination-inhibition (HI) assay. The primary immunogenicity endpoint for this study was seroconversion in previously seronegative patients (HI titers <1:40), and the secondary endpoint was the identification of features that could affect seroconversion in this population.. Five (5.9%) patients presented HI titers prevaccination ≥ 1:40 and were excluded from further analysis. Seroconversion in previously negative patients occurred in 27 (34%) of 80 patients. Prevaccination HI titers geometrical mean was 5.8 and postvaccination 19.6 (ratio 3.4). Significant seroconversion rate factors were female gender, non-Caucasian ethnicity, and post-transplant time before vaccination. No impact was seen on seroconversion for age, donor type, tacrolimus and cyclosporine blood levels, renal function, or blood lymphocyte counts. Mycophenolate (MPA) showed a lower rate of seroconversion when compared with azathioprine. Tacrolimus and cyclosporine had similar seroconversion rates. Sirolimus use was associated with the highest rate of seroconversion, although these patient numbers were low. Immunosuppresssion containing MPA was considerably less effective in seroconversion than drug combinations with no MPA. Patients receiving sirolimus had more chance of seroconversion. HI titers geometric means pre/post vaccine were as follows: MPA (n = 56): 5.8/12.8; tacrolimus (n = 50): 5.9/16.2; cyclosporine (n = 18): 5.4/24.2; azathioprine (n = 19): 6.2/51.6; and sirolimus (n = 6): 8/80. By univariate analysis, being female and non-White were variables associated with 3.3 times more chance of seroconversion than being male and White. In the multivariate analysis, the variables remaining in the model showed similar hazard ratios.. In this study, the monovalent A(H1N1)pdm09 influenza vaccine demonstrated low rates of seroconversion, particularly in patients on MPA, but with potentially higher response rates in patients on sirolimus.

Topics: Antibodies, Viral; Azathioprine; Brazil; Cyclosporine; Female; Humans; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Influenza, Human; Kidney Transplantation; Male; Mycophenolic Acid; Pandemics; Prospective Studies; Risk Factors; Sex Factors; Sirolimus; Tacrolimus; White People

Topics: Bone Marrow Transplantation; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lymphohistiocytosis, Hemophagocytic; Lymphoma, Mantle-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Pandemics; Tacrolimus

Topics: Adult; Antiviral Agents; Critical Care; Diagnosis, Differential; Disease Outbreaks; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza, Human; Intensive Care Units; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Opportunistic Infections; Oseltamivir; Postoperative Complications; Prednisone; Respiratory Insufficiency; Tacrolimus

The purpose of this study was to evaluate the humoral immune response to influenza vaccination in lung transplant recipients. Antibody levels to the three viral antigens included in the 1999-2000 trivalent influenza vaccine (A/Sydney/5/97-like (H3N2), A/Beijing262/95-like (H1N1), and B/Yamanashi/16/ 98) were measured before and 4 weeks postvaccination in 43 lung transplant recipients and 21 healthy adult controls. The ability to develop protective antibody levels, a serological response, and the magnitude of change in levels were assessed. The humoral immune response to influenza vaccination was significantly lower in the transplant group for all three viral antigens. To A/Sydney, 95% of the control group and 40% of the transplant group developed protective levels (p=0.0009); to A/Beijing, 71% of the control group and 30% of the transplant group developed protective levels (p=0.004); and to B/Yamanashi, 48% of the control group and 19% of the transplant group developed protective levels (p=0.02). Those receiving cyclosporine had lower antibody responses when compared to those receiving tacrolimus (r=-0.3056, p=0.0463). The humoral immune response to influenza vaccination in lung transplant recipients is poor. Lung transplant recipients receiving cyclosporine may have a lower antibody response than those receiving tacrolimus. Alternative prevention strategies may be needed.

Topics: Adult; Antibodies, Viral; Antibody Formation; Cohort Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Influenza Vaccines; Influenza, Human; Lung Transplantation; Male; Middle Aged; Reference Values; Tacrolimus; Vaccination