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1.
Comparative Study of Intravenous Immunoglobulin and Leflunomide Combination Therapy With Intravenous Immunoglobulin Single Therapy in Kidney Transplant Patients With BK Virus Infection: Single-Center Clinical Trial
Rasaei, N., Malekmakan, L., Gholamabbas, G., Abdizadeh, P.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2023;21(10):814-819
Abstract
OBJECTIVES Nephropathy due to BK virus infection is a major cause of graft dysfunction and loss. No specific treatment has been developed for the BK virus. Here, we compared the combination of intravenous immunoglobulin and leflunomide versus intravenous immunoglobulin to treat BK virus nephropathy after renal transplant. MATERIALS AND METHODS This study was a randomized controlled clinical trial. Sixteen kidney transplant patients with BK virus infection were randomly divided into 2 groups; 1 group received intravenous immunoglobulin, and another group received leflunomide and intravenous immunoglobulin. P < .05 was considered statistically significant. RESULTS Results of a polymerase chain reaction test for BK virus after 2 months of treatment were negative in 3 patients in the intravenous immunoglobulin group and in 7 patients in the intravenous immunoglobulin + leflunomide group. The amount of BK virus decreased significantly in each group, and a significant difference was observed between the 2 groups after 3 months (P = .014). The average level of creatinine in the intravenous immunoglobulin group at 1, 2, and 3 months after treatment was 1.7 ± 0.23, 1.8 ± 0.5, and 1.5 ± 0.3, respectively, and in the intravenous immunoglobulin + leflunomide group was 2.1 ± 0.75, 1.76 ± 0.37, and 1.4 ± 0.18, respectively (P > .05). CONCLUSIONS Although BK viral load decreased significantly in both groups, there was a significant difference between patients who received intravenous immunoglobulin versus those who received the combination of intravenous immunoglobulin + leflunomide after 3 months. The addition of leflunomide to the intravenous immunoglobulin treatment seems to have a better effect in reducing BK viral load. However, further studies with a larger sample and longer duration are needed.
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2.
Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis
Zhong, C., Chen, J., Yan, Z., Xia, R., Zeng, W., Deng, W., Xu, J., Wang, Y., Miao, Y.
Transplant immunology. 2023;:101953
Abstract
BACKGROUND The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. METHODS We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. RESULTS A total of 33 published studies involving 950 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I(2) = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I(2) = 83%), 71% (95% CI: 0.63-0.78; I(2) = 0), 87% (95% CI: 0.82-0.93; I(2) = 45%), and 80% (95% CI: 0.59-1.00; I(2) = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. CONCLUSIONS Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.
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3.
Preliminary Results of a Randomized Clinical Trial of Intravenous Immunoglobulin in Solid Organ Recipients with Severe Infection and Secondary Antibody Deficiency
Carbone J, Montanchez J, Cifrian J, Laporta R, Ussetti P, Zatarain E, Sousa I, Munoz P, Ezzahouri I, Salcedo M, et al
J Heart Lung Transplant. 2020;39(4s):S45-s46
Abstract
PURPOSE Infection is a cause of death in solid organ transplantation. Secondary antibody deficiency is a risk factor of severe infection in solid organ transplantation. In a multicenter randomized clinical trial we evaluated the efficacy and safety of an intravenous immunoglobulin (IVIG) protocol to decrease the rate of re-infection in solid organ recipients with severe infections and secondary antibody deficiency. METHODS Adult patients (20 Heart, 12 Lung, 5 Kidney, 3 Liver Recipients) with post transplant severe infections and secondary antibody deficiency (IgG levels < 600 mg/dL at the time of the infectious complication) were included. IVIG protocol: Two doses of 15 grams followed by other 3 doses of 20 grams of a 5% IVIG product. 40 patients were randomized to receive IVIG in combination with conventional antimicrobial therapy (n=20) or conventional antimicrobial therapy alone (n=20). At the time of this preliminary report 36 patients that completed the protocol were analysed (17 IVIG+antimicrobial therapy, 19 antimicrobial therapy alone). Distinct specific antibodies were tested at the time of inclusion in the clinical trial and at the time of final visit (visit 7 at 30-45 days after last IVIG dose or similar time in no-IVIG patients) in a subgroup of patients to assess the kinetics of humoral immunity reconstitution. RESULTS The primary outcome measure (rate of re-infection) was significantly lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (35.3 vs 68.4%, chi-square test, p=0.047). Time to reach normal IgG (IgG > 750 mg/dL) was shorter in IVIG group (55+/-44 vs 93+/-42 days, p=0.06). Significantly higher levels of specific anti-cytomegalovirus, anti-clostridium difficile toxins A and B was demonstrated at visit 7 in patients who received IVIG as compared with patients that were treated with antimicrobial therapy alone. CONCLUSION In a randomized clinical trial we have preliminarily demonstrated that IVIG is associated with reconstitution of distinct specific antibodies and with a lower rate of re-infection in solid organ transplantation with severe infection and secondary antibody deficiency.
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4.
Intravenous immunoglobulin to prevent myasthenic crisis after thymectomy and other procedures can be omitted in patients with well-controlled myasthenia gravis
Gamez J, Salvado M, Carmona F, de Nadal M, Romero L, Ruiz D, Jauregui A, Martinez O, Perez J, Sune P, et al
Therapeutic advances in neurological disorders. 2019;12:1756286419864497
Abstract
Background: Myasthenic crisis (MC) is a potentially life-threatening complication of myasthenia gravis. Its precipitating factors include surgical procedures, particularly thymectomy. The role of preoperative intravenous immunoglobulin (IVIg) in preventing MC in patients scheduled for thymectomy and other surgery with general anaesthesia is unknown. Our objective was to test the hypothesis that preoperative IVIg is effective in preventing myasthenic crisis in patients with myasthenia gravis scheduled for surgery under general anaesthesia, including thymectomy. Methods: A prospective, randomized, double-blind, single-centre study was conducted over a 4-year period. The treatment group received IVIg, 0.4 g/kg/day preoperatively for 5 consecutive days, and the placebo group received saline solution under the same conditions. The two groups were age-matched, with similar functional status, and Myasthenia Gravis Foundation of America class. All patients had well-controlled myasthenia gravis with minimal manifestations before surgery. The primary outcome measured was MC. Intubation times, time in the recovery room, number of postoperative complications, and days of hospitalization were the secondary outcomes measured. Results: A total of 47 patients were randomized, 25 to the IVIg group and 22 to placebo. There were 19 men and 28 women, with a mean age of 58.6 years, mean body mass index of 27.8 kg/m(2), and mean acetylcholine receptor antibodies of 12.9 nmol/l. The mean forced vital capacity was 84.4%. The mean quantitative myasthenia gravis sum score was 6.3. Ten patients (five in each arm) had a history of MC. Thymectomy was performed in 16 patients. Only one patient in the placebo group presented with MC requiring non-invasive ventilation (but no reintubation) for 6 days. Neither differences between groups in the univariate analysis nor risk factors for MC in the multivariate analysis were found. Conclusions: Preoperative IVIg to prevent MC does not appear to be justified in well-controlled myasthenia gravis patients. This study provides class I evidence that preparation with IVIg to prevent MC is not necessary in well-controlled myasthenia gravis patients scheduled for surgery with general anaesthesia.
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5.
Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: a systematic review and meta-analysis. Part II: Non-kidney transplant
Bourassa-Blanchette S, Patel V, Knoll GA, Hutton B, Fergusson N, Bennett A, Tay J, Cameron DW, Cowan J
Clinical transplantation. 2019;:e13625
Abstract
Immunoglobulin (IG) is commonly used to desensitize and treat antibody-mediated rejection in solid organ transplant (SOT) recipients. The impact of IG on other outcomes such as infection, all-cause mortality, graft rejection, and graft loss is not clear. We conducted a similar systematic review and meta-analysis to our previously reported Part I excluding kidney transplant. A comprehensive literature review found 16 studies involving the following organ types: heart (6), lung (4), liver (4) and multiple organs (2). Meta-analysis could only be performed on mortality outcome in heart and lung studies due to inadequate data on other outcomes. There was a significant reduction in mortality (OR 0.34 [0.17-0.69]; 4 studies, n=455) in heart transplant with hypogammaglobulinemia receiving IVIG versus no IVIG. Mortality in lung transplant recipients with hypogammaglobulinemia receiving IVIG was comparable to those of no hypogammaglobulinemia (OR 1.05 [0.49, 2.26]; 2 studies, n=887). In summary, IVIG targeted prophylaxis may decrease mortality in heart transplant recipients as compared to those with hypogammaglobulinemia not receiving IVIG, or improve mortality to the equivalent level with those without hypogammaglobulinemia in lung transplant recipients, but there is a lack of data to support physicians in making decisions around using immunoglobulins in all SOT recipients for infection prophylaxis. This article is protected by copyright. All rights reserved.
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6.
Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a multicenter, prospective, randomized, double blind clinical trial
Moreso F, Crespo M, Ruiz JC, Torres A, Gutierrez-Dalmau A, Osuna A, Perello M, Pascual J, Torres IB, Redondo-Pachon D, et al
American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017;18((4):):927-935
Abstract
There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2 ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions and DSA at one year. The planned sample size was 25 patients per group. During 2012-2015, twenty-five patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2+/-14.4 vs. -6.6+/-12.0 mL/min/1.73 m2, p-value=0.475), increase of proteinuria (+0.9+/-2.1 vs. +0.9+/-2.1 g/day, p-value=0.378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA. This article is protected by copyright. All rights reserved.
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7.
The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline
Shehata N, Palda VA, Meyer RM, Blydt-Hansen TD, Campbell P, Cardella C, Martin S, Nickerson P, Peltekian K, Ross H, et al
Transfusion Medicine Reviews. 2010;24((Suppl 1):):S7-S27.
Abstract
This guideline for the use of immunoglobulin (IG) for sensitized patients undergoing solid organ transplantation (SOT) is an initiative of the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products of Canada to (1) provide guidance for Canadian practitioners involved in the care of patients undergoing SOT and transfusion medicine specialists on the use of IG and (2) standardize care, limit adverse events, and optimize patient care. A systematic expert and bibliography literature search up to July 2008 was conducted, with 791 literature citations and 45 reports reviewed. To validate the recommendations, the guideline was sent to physicians involved in SOT in Canada and a patient representative. The recommendations identify (1) sensitized patients undergoing SOT that would have a better survival and decreased morbidity by receiving IG preoperatively, postoperatively, and for the treatment of organ rejection; (2) patients who may not have any benefit from receiving IG; and (3) potential adversities to IG.
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8.
Hepatitis B immunoglobulins and/or lamivudine for preventing hepatitis B recurrence after liver transplantation: a systematic review
Chen J, Yi L, Jia JD, Ma H, You H
Journal of Gastroenterology & Hepatology. 2010;25((5):):872-9.
Abstract
BACKGROUND Currently, hepatitis B immunoglobulins (HBIg) and/or lamivudine have become the main options for prevention of hepatitis B recurrence after liver transplantation. AIM: To assess the benefits of HBIg and/or lamivudine for prevention of hepatitis B recurrence after liver transplantation. METHODS We conducted a search of electronic databases and a manual search of bibliographical lists of relevant articles. All randomized clinical trials and non-randomized studies that meet the pre-specified criteria were included. However, results of non-randomized studies were reported under 'exploratory analyses' in the result section. The outcome measure was hepatitis B recurrence. RESULTS Two randomized and 44 non-randomized studies were included. Meta-analysis of two randomized studies shows one week HBIg combined with lamivudine regimen had equivalent effect compared with long-term high-dose HBIg regimen for preventing hepatitis B recurrence (RR 1.23; 95% CI 0.38-4.03; P = 0.73). For 44 non-randomized studies, only qualitative systematic review was performed. With long-term HBIg prophylaxis, hepatitis B recurrence rate ranged from 3.7% to 65%; with lamivudine prophylaxis, hepatitis B recurrence rate varied from 3.8% to 40.4%; Long-term high-dose HBIg plus lamivudine prophylaxis can reduce the risk of HBV recurrence to less than 10%. CONCLUSIONS Long-term HBIg prophylaxis or lamivudine prophylaxis can reduce the risk for hepatitis B virus recurrence. Long-term high-dose HBIg combined with lamivudine can further reduce HBV recurrence to less than 10%.
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9.
Prevention of recurrent hepatitis B virus infection after liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? Systematic review and meta-analysis
Katz LH, Paul M, Guy DG, Tur-Kaspa R
Transplant Infectious Disease. 2010;12((4):):292-308.
Abstract
OBJECTIVES To evaluate antiviral prophylaxis against hepatitis B virus (HBV) following liver transplantation. METHODS Systematic review and meta-analysis. Clinical trials and comparative cohort studies comparing the use of hepatitis B immunoglobulin (HBIg), antivirals, or both following liver transplantation for HBV infection were included. The primary outcome was reappearance of hepatitis B surface antigen (HBsAg). Other outcomes included all-cause and HBV-related mortality, HB-related active liver disease, and reappearance of HBV DNA after transplantation. Relative risks (RR) with 95% confidence intervals (CIs) are reported. RESULTS Twenty studies (22 comparisons) were included. Ten studies compared HBIg to combination treatment, 9 compared antivirals to combination treatment, and 3 compared lamivudine (LAM) to HBIg. Combination treatment reduced HBsAg reappearance (RR 0.28; 95% CI 0.12-0.66), and was superior to HBIg alone in all other outcome measures. Combination treatment was significantly better than antivirals in preventing reappearance of HBsAg (RR 0.31; 95% CI 0.22-0.44), even when low-dose HBIg was given. No significant difference was found between HBIg and LAM monotherapy for all measured outcomes. Major limitations with regard to comparability of the study groups in non-randomized trials were revealed. CONCLUSIONS Combination treatment with HBIg and LAM reduced HBV recurrence following liver transplantation, compared with HBIg or LAM alone, and reduced mortality compared with HBIg alone.
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10.
Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation
Katz LH, Tur-Kaspa R, DG Guy, Paul M
Cochrane Database of Systematic Reviews. 2010;((7):):CD006005.
Abstract
BACKGROUND Recurrence of hepatitis B virus (HBV) infection in the liver graft is a grave complication following liver transplantation for HBV cirrhosis. Hepatitis B immunoglobulin (HBIg) seems effective in increasing survival after liver transplantation. HBIg and anti-viral drugs are given alone or in combination for its prevention. OBJECTIVES To assess the benefits and harms of different regimens for preventing HBV reactivation following liver transplantation. SEARCH STRATEGY We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2010. We attempted to identify further trials by reviewing the reference lists and contacting the principal authors of identified trials. SELECTION CRITERIA Randomised clinical trials addressing benefits and harms of lamivudine or adefovir dipivoxil alone or in combination with hepatitis B immunoglobulins (HBIg) for preventing recurrent HBV infection in patients who are liver transplanted due to HBV infection with or without hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS Two authors independently assessed the trials for risk of bias and extracted data. We contacted study authors whenever information was lacking. We collected information on adverse events. The primary outcomes were all-cause mortality and reappearance of hepatitis B surface antigen in serum after liver transplantation. Relative risks were calculated from individual trials. MAIN RESULTS Four trials, recruiting 136 participants, were included. Two trials compared lamivudine alone versus HBIg alone. Randomisation was performed one week after transplantation in one of the trials and after six months after transplantation in another; from transplantation until randomisation, HBIg alone was given to all patients in the two trials. A third trial compared combination treatment with lamivudine and HBIg versus lamivudine alone after one month of combination treatment, and a fourth trial compared the combination of lamivudine and HBIg versus a combination of lamivudine and adefovir dipivoxil after at least 12-month of lamivudine and HBIg combination treatment. Statistically significant differences were not detected in any of the comparisons and outcomes. All trials were open-labelled, and none of the trials were adequately powered to show a difference in HBV recurrence. No meta-analyses were performed since the identified trials assessed different comparisons. AUTHORS' CONCLUSIONS This review could not derive clear evidence from randomised clinical trials for the treatment of patients with chronic HBV following liver transplantation for preventing recurrence of HBV infection. Large randomised clinical trials comparing long-term combination treatment to each of the monotherapy alone, including the newer antiviral drugs, are needed.