Epidemiology of invasive fungal infections in lung transplant recipients on long‐term azole antifungal prophylaxis

Lung transplant recipients (LTR) at our institution receive prolonged and mostly lifelong azole antifungal (AF) prophylaxis. The impact of this prophylactic strategy on the epidemiology and outcome of invasive fungal infections (IFI) is unknown. This was a single‐center, retrospective cohort study. We reviewed the medical records of all adult LTR from January 2002 to December 2011. Overall, 16.5% (15 of 91) of patients who underwent lung transplantation during this time period developed IFI. Nineteen IFI episodes were identified (eight proven, 11 probable), 89% (17 of 19) of which developed during AF prophylaxis. LTR with idiopathic pulmonary fibrosis were more likely to develop IFI (HR: 4.29; 95% CI: 1.15–15.91; p = 0.03). A higher hazard of mortality was observed among those who developed IFI, although this was not statistically significant (hazard ratio [HR]: 1.71; 95% confidence interval [CI] [0.58–4.05]; p = 0.27). Aspergillus fumigatus was the most common cause of IFI (45%), with pulmonary parenchyma being the most common site of infection. None of our patients developed disseminated invasive aspergillosis, cryptococcal or endemic fungal infections. IFI continue to occur in LTR, and the eradication of IFI appears to be challenging even with prolonged prophylaxis. Azole resistance is uncommon despite prolonged AF exposure.     

The impact of hepatitis C virus infection on liver disease in renal transplant recipients

Abstract To assess the prevalence of hepatitis C virus (HCV) infection in renal transplant recipients and its impact on posttransplant liver disease, the sera from 176 recipients who had been followed for 1–20 years (mean 8.3 years) were tested for HCV-pecific antibody using enzyme immunoassay. HCV-pecific antibody was detected in 53 patients (30.1%) including 2 patients also positive for hepatitis B surface antigen (HBsAg). Among 167 HBsAg-negative patients, the presence of HCV-pecific antibody was associated with an increased incidence of chemically significant hepatitis (70.6% vs. 9.5% in anti-HCV-negative patients, P<0.01). Hepatitis was more likely to be chronic in anti-HCV-positive patients than in anti-HCV-negative patients (P<0.05) Serious liver disease developed in 4 of 51 anti-HCV-positive, HBsAg-negative patients: liver failure causing death in 3 and hepatoma in 1. Liver biopsy specimens from anti-HCV-positive patients showed more aggressive histological lesions compared with those from anti-HCV-negative patients. We conclude that HCV infection is quite prevalent in our renal transplant recipients and plays a major role in posttransplant chronic liver disease.     

Efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients with invasive fungal infections

Background: Fungal infections following solid-organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients.
Methods: Three open-label, second-line treatment studies evaluated ABLC as a treatment for severe, life-threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre-existing renal disease.
Results: The 79 solid-organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n=39); candidiasis (n=20); zygomycosis (n=8); cryptococcosis and histoplasmosis (n=3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis , Dactylaria gallopava , and an unspecified fungal infection (n=1 each). The median duration of ABLC therapy was 28 d (1–178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty-six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n=37) or improved (n=27) serum creatinine at the end of treatment.
Conclusions: ABLC is safe and effective treatment for fungal infections in solid-organ transplant recipients. Its renal-sparing properties are particularly suited for this high-risk population for renal failure.     

Biopsy‐proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal

Biopsy‐proven acute cellular rejection (ACR) is the primary efficacy endpoint in most randomized trials evaluating immunosuppression in liver transplantation. However, ACR is not a major cause of graft loss, and a certain grade of immune activation may be even beneficial for long‐term graft acceptance. Validated criteria to select candidates for liver biopsy are lacking, and routine clinical practice relies on liver tests, which are inaccurate markers of ACR. Indeed, both the agreement among clinicians to select candidates for liver biopsy and the correlation between the clinical suspicion of ACR and histological findings are poor. In randomized trials evaluating immunosuppression protocols, this concern grows exponentially due to the open‐label and multicenter nature of most studies. Therefore, biopsy‐proven ACR is a suboptimal efficacy endpoint given its limited impact on prognosis and the heterogeneous diagnosis, which may increase the risk of bias. Chronic rejection and/or graft loss would be more appropriate endpoints, but would certainly require larger studies with prolonged surveillances. An objective method to select candidates for liver biopsy is therefore urgently needed, and only severe episodes of histological ACR should be considered as potentially harmful. Emerging surrogate markers of ACR and antibody‐mediated rejection require further investigation to determine their clinical role.     

Selective treatment of early acute rejection after liver transplantation: Effects on liver,infection rate,and outcome

To evaluate the results of selective treatment of biopsy-proven mild acute rejection episodes, we retrospectively studied 1-week liver biopsies of 103 patients with a primary liver graft in relation to liver function tests. The overall incidence of rejection was 35 %. In four patients the biopsy showed histological features consistent with rejection; in 27 patients it showed mild acute rejection (grade 1), and in 5 patients it showed moderate acute rejection (grade 2). Study group 1 consisted of 19 untreated patients with grade 1 rejection and group 2 of 8 treated patients with grade 1 rejection. At 30 and 90 days, no differences in liver function tests were found. The infection rate, histology after 1 year, and survival in the two groups did not differ. It may, therefore, be concluded that withholding treatment in histologically proven mild acute rejection is possible in selected patients based on histological, biochemical, and clinical criteria. This may reflect the functional diversity of morphologically similar lymphocytic infiltrates observed in graft biopsies showing features of mild acute rejection.Liver Transplant Group     

Selective treatment of early acute rejection after liver transplantation: effects on liver, infection rate, and outcome

Abstract To evaluate the results of selective treatment of biopsy-proven mild acute rejection episodes, we retrospectively studied 1-week liver biopsies of 103 patients with a primary liver graft in relation to liver function tests. The overall incidence of rejection was 35 %. In four patients the biopsy showed histological features consistent with rejection; in 27 patients it showed mild acute rejection (grade 1), and in 5 patients it showed moderate acute rejection (grade 2). Study group 1 consisted of 19 untreated patients with grade 1 rejection and group 2 of 8 treated patients with grade 1 rejection. At 30 and 90 days, no differences in liver function tests were found. The infection rate, histology after 1 year, and survival in the two groups did not differ. It may, therefore, be concluded that withholding treatment in histologically proven mild acute rejection is possible in selected patients based on histological, biochemical, and clinical criteria. This may reflect the functional diversity of morphologically similar lymphocytic infiltrates observed in graft biopsies showing features of mild acute rejection.     

Characteristics of Epstein–Barr viraemia in adult liver transplant patients: A retrospective cohort study

Therapeutic immunosuppression following solid organ transplantation increases the risk of Epstein–Barr (EBV) viraemia, which is implicated in post‐transplant lymphoproliferative disease (PTLD). We retrospectively analysed the incidence of EBV viraemia and clinical outcomes in 98 liver transplant recipients. Patients underwent EBV DNA monitoring by whole‐blood PCR: EBV levels were correlated with clinical parameters and outcomes for a median of 249 days. 67% patients developed EBV viraemia (EBV DNA ≥100 copies/ml) and 30% had sustained viraemia. There was a trend towards higher hazard ratios for viraemia with exposure to aciclovir (HR 1.57, P = 0.12) or in recipients of a poorly HLA‐matched graft (HR 1.62, P = 0.10). These associations became significant in the subgroup with >90 days surveillance; HR 2.54 (P = 0.0015) for aciclovir and HR 1.99 (P = 0.03) for poorly matched grafts. The converse was true with ganciclovir (HR 0.56 P = 0.13). Viraemia was more prolonged in men (median duration 7 days vs 1; P = 0.01) and in those with lower UKELD scores (11 days vs 1 day; P = 0.001) but shortened with ganciclovir exposure (P = 0.06). Younger patients were more likely to have high peak viral loads (P = 0.07). No clinical signs or symptoms or adverse outcomes were associated with EBV reactivation.     

Relationship between renal resistance index and renal function in liver transplant recipients after cessation of calcineurin inhibitor

Abstract:  End stage renal disease is a major complication after orthotopic liver transplantation (OLT). Vasoconstriction of renal arterial vessels because of calcineurin inhibitor (CNI) treatment plays a pivotal role in the development of renal insufficiency following OLT. Renal resistance can be measured non-invasively by determining the resistance index (RI) of segmental arteries by color-coded duplex ultrasonography, a measure with predictive value for future renal failure. Sixteen OLT patients on long-term CNI therapy were recruited prospectively and randomly assigned either to receive the m-TOR inhibitor sirolimus (SRL) or to continue on CNI treatment, and were followed for one yr. Serum creatinine (crea) declined after conversion to SRL, whereas it tended to increase in patients remaining on CNI (meanΔ crea SRL: −27, −18, −18, −15 μmol/L; meanΔ crea CNI: 4, 5, 8, 11 μmol/L at 1, 3, 6, 12 months, p = 0.02). RI improved after switching to SRL and was lower on SRL than on CNI (meanΔRI SRL: −0.04, −0.04, −0.03, −0.03; meanΔRI CNI: −0.006, 0.004, −0.007, −0.01 after 1, 3, 6, 12 months, p = 0.016). Individual changes of RI correlated significantly with individual changes of crea ( r  = 0.54, p < 0.001). Conversion from CNI to SRL can ameliorate renal function accompanied by a reduction of intrarenal RI after OLT.     

肝移植受者围手术期应用替加环素预防感染的效果及低纤维蛋白原血症发生情况

目的  探讨肝移植受者围手术期使用替加环素预防感染的效果及低纤维蛋白原血症发生情况。方法  回顾性分析40例使用替加环素进行预防感染的肝移植受者的临床资料,分析受者感染事件和供者来源感染事件发生情况;分析替加环素治疗时、结束时及治疗结束后（7±2）d受者临床指标变化情况;总结低纤维蛋白原血症的发生及治疗情况。结果  40例肝移植受者中,2例受者发生感染,分别为黑曲霉和巨细胞病毒感染,均不属于替加环素抗菌谱所覆盖的范围,调整抗感染方案后感染情况控制良好。9例供肝相关培养阳性,但均未发展为供者来源性感染事件。40例受者均于术后2周左右肝功能恢复良好出院,其中6例于术后2~4 d出现低纤维蛋白原血症伴凝血功能障碍,而转氨酶、胆红素、感染相关指标术后逐步下降,白蛋白水平稳定,予以补充人纤维蛋白原及凝血酶原复合物,凝血功能好转,但纤维蛋白原水平持续下降。停用替加环素后,纤维蛋白原水平逐渐恢复至正常,考虑可能为替加环素相关药物不良反应。结论  肝移植受者围手术期使用包含替加环素在内的预防感染方案可以降低敏感细菌导致的感染发生率,但药物使用期间需密切关注低纤维蛋白原血症的发生。     

Study of intercurrent infection pattern in hepatitis C seropositive renal transplant recipients,relationship with T-cell function

Background: We assessed the effect of hepatitis C seropositivity on the percentage of various T-cells in living donor renal transplant recipients (LDRTRs) and their association with intercurrent infections post renal transplantation (post-Tx).

Methods: One hundred and thirty-three matching LDRTRs [A (seronegative) (68 patients) and B (seropositive) (65 patients) by ELISA] were studied prospectively 10 days, 6 months and 12 months post-Tx for intercurrent infections, acute rejection and T-cell% by flow cytometry.

Results: CD4⁺, CD8⁺, CD4/CD8 were significantly higher 10 days post-Tx in Group B compared to Group A, p < 0.001. A significant increase in CD8% was seen 6-month post-Tx among Group B compared to Group A. No difference was detected between groups in (CD4⁺, CD8⁺, CD4/CD8, CD3–CD16/65⁺%), rate and severity of intercurrent infection, rate of acute rejection, 12 months post-Tx. A significantly higher rate of severe infections particularly urinary tract infections (UTI) was noted in Group B compared to Group A the first 3 months post-Tx particularly in those who received the combination of antithymocyte globulin (ATG) or basiliximab, tacrolimus, steroids, mycophenolate mofetil (MMF). CD4⁺% correlated negatively with intercurrent infections in Group B 6 months post-Tx.

Conclusion: HCV⁺?patients are more prone to intercurrent infections the first 3 months post-Tx. Infection rate correlates positively with pre-transplant HCV seropositivity and immunosuppressive regimen.     

Incidence of acute cellular rejection following granulocyte colony‐stimulating factor administration in lung transplantation: A retrospective case‐cohort analysis

Granulocyte colony‐stimulating factor (GCSF) is an option to treat leukopenia in lung transplant recipients. Conflicting evidence exists regarding its effects on acute cellular rejection (ACR). A retrospective, case‐cohort study was conducted to assess whether the use of GCSF in lung transplant recipients is associated with an increased incidence of ACR. Patients had to have received at least one dose of GCSF but were excluded if they received GCSF within 30 days prior to transplant or received a lymphocyte‐depleting agent within 14 days of GCSF administration. Thirty‐five patients who received GCSF within 3 months of transplant met inclusion criteria and 105 patients were identified as controls based on a 1:3 allocation scheme. Incidence of ACR was 57.1% in the GCSF group versus 50.5% in the control group (relative risk (RR)=1.13; 95% CI, 0.80 to 1.59; P=.48). At 3 months post‐transplant, 74.3% of the GCSF group had a dose reduction or discontinuation of their antiproliferative agent versus 17.1% of the control group (RR=4.33; 95% CI, 2.73 to 6.89; P<.0001). Rejection severity and incidence of infections was similar among groups. These findings show that GCSF administration within 3 months following lung transplantation was not associated with a higher incidence or severity of ACR.     

A study of the pharmacokinetic profile of low-dose hepatitis B immune globulin in long-term liver transplant recipients for chronic hepatitis B infection.

Post-transplant protocols for hepatitis B (HBV) prophylaxis using high-dose intravenous hepatitis B immune globulin (10,000 IU) with or without lamivudine are commonly reported. Our centre has previously reported a low-dose intramuscular (i.m.) protocol and lamivudine with excellent results. There have been, however, no pharmacokinetic studies of i.m. hepatitis B immune globulin (HBIG) in this setting. The objective of this study was to determine the pharmacokinetic profile of i.m. HBIG in long-term post-liver-transplant recipients to determine a rational dosing protocol. Six stable liver transplant recipients receiving monthly i.m. HBIG injections for greater than one year were enrolled in this study. All patients had no detectable HBV DNA levels. HBIG titers (anti-HBs) were measured predose, then three times weekly for four weeks and then twice weekly until the serum HBIG titers were 100 IU/L or less. The pharmacokinetic parameters were calculated using noncompartment methods. The mean time to maximum concentration was 10.5 d (range 4-20 d) and the mean half-life was 20 d (range 13.5-23.5 d). Based on these pharmacokinetic parameters in stable long-term post-transplant patients, a rational dosing protocol was developed that allows for more appropriate utility of HBIG and improved patient convenience.     

Effect of interleukin‐2 receptor antibody therapy on acute rejection risk and severity,long‐term renal function,infection and malignancy‐related mortality in renal transplant recipients

In renal transplantation, the use of interleukin‐2 receptor antibody (IL‐2Ra) has been associated with reduced rejection rates, but the effect of this agent on rejection severity and type, long‐term graft function and risk of infection and malignancy‐related mortality remains unclear. Using Australia and New Zealand Dialysis and Transplant Registry, all live‐ and deceased‐donor renal transplant recipients in Australia between 2000 and 2006 were included. Of the 3344 renal transplant recipients, 1874 (56.0%) received no induction and 1470 (44.0%) had received IL‐2Ra. Compared with no induction, IL‐2Ra was associated with reduced rejection risk (relative risk 0.70, 95% CI 0.60, 0.81) and higher estimated glomerular filtration rate at 5 years (difference in means 3.51, 95% CI 0.83, 6.19). Severity and type of rejection were similar in both the groups. The adjusted rate of death attributed to malignancy for no induction and IL‐2Ra per 1000 patient‐years was 1.48 and 1.63, respectively, whereas death attributed to infection was 2.42 and 2.16 respectively. This registry analysis demonstrates that IL‐2Ra induction in kidney transplantation is associated with substantial clinical benefits of reduced risk of acute rejection and improved long‐term graft function without an increase in adverse events.     

Direct‐acting antivirals are effective and safe in HCV/HIV‐coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study

Direct‐acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV‐coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV‐coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV‐monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV‐coinfected patients had a median (IQR) CD4 T‐cell count of 366 (256‐467) cells/µL. HIV‐RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV‐RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon‐free regimens with DAAs for post‐LT recurrence of HCV infection in HIV‐infected individuals were highly effective and well tolerated, with results comparable to those of HCV‐monoinfected patients.     

Association of TNF‐α, TGF‐β1, IL‐10, IL‐6, and IFN‐γ gene polymorphism with acute rejection and infection in lung transplant recipients

Infection and rejection are common complications faced by lung transplant recipients (LTRs) and have become major impediments to long‐term survival. Cytokines may play an important role in the development of these complications. In this study, we explored the correlation between TNF‐α (?308 A/G), TGF‐β1 (+869 T/C, +915 G/C), IL‐10 (?592 C/A, ?819 T/C, ?1082 G/A), IL‐6 (?174 G/C), and IFN‐γ (+874 T/A) gene polymorphisms and the incidence of acute rejection and infection. Transplant outcomes were reviewed in a retrospective cohort of 113 LTRs from a single center between December 2004 and November 2012. Cytokine polymorphisms were measured using sequence‐specific primer‐based PCR. HLA typing was performed for the donors and recipients. We found that the LTRs with the IL‐10 ?819 CC and ?592 CC genotypes had a significantly decreased risk of infection (p = 0.017, OR = 0.177, 95% CI = 0.04–0.85). However, we found no significant association between cytokine polymorphisms and acute rejection. Furthermore, the data revealed that the occurrence of acute rejection was strongly associated with infection episodes (χ² = 8.5256, p < 0.01). These results suggest that LTRs possessing the IL‐10 ?819 CC and ?592 CC genotype may be protected from the occurrence of infection. Our results demonstrated that infection is an important cause of acute rejection for LTRs.     

Cytomegalovirus (CMV) infection and risk of mortality in allogeneic hematopoietic stem cell transplantation (Allo‐HSCT): A systematic review,meta‐analysis,and meta‐regression analysis

Controversy surrounds the potential association between cytomegalovirus (CMV) infection and increased risk of mortality after allogeneic hematopoietic stem cell transplantation (Allo‐HSCT). A systematic literature search was conducted using the PubMed, EMBASE, and Web of Science databases, assessing the association between CMV infection, as documented by the pp65 antigenemia assay or by polymerase chain reaction (PCR) using blood specimens, and overall mortality (OM) and nonrelapse mortality (NRM) in the allo‐HSCT setting. Pooled effects were estimated using the generic inverse variance random effects model. Heterogeneity was evaluated by Cochrane's Q test and I² statistics. The source of heterogeneity was investigated by meta‐regression and subgroup analyses. Twenty‐six of 1367 studies fulfilled eligibility criteria. CMV infection identified by PCR monitoring was significantly associated with an increased risk of OM and NRM (hazard ratio 1.47, 95% confidence interval [1.20‐1.81], P ≤ .001; hazard ratio 1.68, 95% confidence interval [1.14‐2.49], P = .05, respectively). In this setting, the use of preemptive antiviral therapy (PET) resulted in a twofold increased risk of OM and NRM. The estimated effect sizes were associated with allo‐HSCT modalities. Although our analyses point to an association between CMV infection and an increased risk of OM and NRM in allo‐HSCT recipients, the high heterogeneity across studies prevented drawing of robust conclusions on this matter.