Monitoring for cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) may be useful for individualizing valganciclovir (VGCV) prophylaxis after kidney transplantation (KT). We performed a ...commercial ELISA‐based interferon (IFN)‐γ release assay (QTF‐CMV) from posttransplant months 2‐5 (362 points) in 120 CMV‐seropositive KT recipients that received antithymocyte globulin as induction therapy and VGCV prophylaxis (median of 92 days). Forty‐seven patients (39.3%) had CMV infection after discontinuation of prophylaxis. The QTF‐CMV assay was reactive, nonreactive, and indeterminate in 264 (72.9%), 90 (24.9%), and 8 points (2.2%). The QTF‐CMV assay at prophylaxis discontinuation exhibited suboptimal accuracy for predicting protective CMV‐CMI (sensitivity: 77.4%; specificity: 34.3%; positive predictive value PPV: 64.1%; negative predictive value NPV: 50.0%), with no differences in 1‐year CMV infection rates between patients with negative (nonreactive or indeterminate) or reactive results (45.8% vs 36.1%; P = .244). Specificity and PPV to predict protective CMV‐CMI improved by elevating the IFN‐γ cutoff value to 1.13 IU/mL (65.7% and 71.4%) and 7.0 IU/mL (85.7% and 76.2%), although NPVs decreased. The QTF‐CMV assay as per manufacturer's interpretative criteria performed poorly to predict protection from CMV infection following discontinuation of VGCV prophylaxis among ATG‐treated CMV‐seropositive KT recipients. This performance is slightly improved by modifying the IFN‐γ positivity threshold.
This study of CMV‐seropositive kidney transplant recipients who received induction therapy with antithymocyte globulin demonstrates that monitoring of cell‐mediated immunity with a commercial ELISA‐based interferon‐γ release assay performed poorly to predict protection from CMV infection following discontinuation of valganciclovir prophylaxis. See Kumar and Humar’s editorial on page 1961.
The best method for monitoring cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) among high‐risk kidney transplant (KT) recipients remains uncertain. We assessed CMV‐CMI by ...intracellular cytokine staining (ICS) by flow cytometry and a commercial interferon (IFN)‐γ release assay (QuantiFERON®‐CMV QTF‐CMV) at posttransplant months 3, 4, and 5 in 53 CMV‐seropositive KT recipients that had received induction therapy with antithymocyte globulin (ATG) and a 3‐month course of valganciclovir prophylaxis. The discriminative capacity (areas under receiver operating characteristics curve auROCs) and diagnostic accuracy to predict immune protection against CMV infection from the discontinuation of prophylaxis to month 12 were compared between both methods. There was significant although moderate correlations between CMV‐specific IFN‐γ‐producing CD8+ T‐cell counts enumerated by ICS and IFN‐γ levels by QTF‐CMV at months 3 (rho: 0.493; p = 0.005) and 4 (rho: 0.440; p = 0.077). The auROCs for CMV‐specific CD4+ and CD8+ T‐cells by ICS were nonsignificantly higher than that of QTF‐CMV (0.696 and 0.733 vs. 0.678; p = 0.900 and 0.692, respectively). The optimal cut‐off of ≥0.395 CMV‐specific CD8+ T‐cells yielded a sensitivity of 86.4%, specificity of 54.6%, positive predictive value of 79.2% and negative predictive value of 66.7% to predict protection. The corresponding estimates for QTF‐CMV (IFN‐γ levels ≥0.2 IU/mL) were 78.9%, 37.5%, 75.0%, and 42.9%, respectively. The enumeration of CMV‐specific IFN‐γ‐producing CD8+ T‐cells at the time of cessation of prophylaxis performed slightly better than the QTF‐CMV assay to predict immune protection in seropositive KT recipients previously treated with ATG.
Abstract
Regardless of vaccination status, progression to severe coronavirus disease 2019 (COVID‐19) is still a relevant cause of morbidity among immunocompromised patients. Despite the proven ...efficacy of nirmatrelvir/ritonavir (NMV/r), concerns remain regarding the potential for drug‐to‐drug interactions (DDIs) and the safety in this at‐risk population. We aimed to evaluate the clinical outcomes of immunocompromised patients treated with NMV/r, as well as the occurrence of DDIs and treatment‐emergent adverse events (TEAEs). This retrospective observational study included all the patients with some form of immunosuppression and laboratory‐confirmed COVID‐19 that received NMV/r at our center from April to August 2022. The main outcome was worsening of the clinical status (increase of ≥1 point from baseline in a validated clinical progression scale) by Days +7 and +28 after the initiation of therapy. Safety outcomes included the rates of any TEAE and potentially severe DDIs. We included 110 patients. Main causes of immunosuppression were hematological malignancy (58.2%) (mainly multiple myeloma 22.7% and non‐Hodgkin lymphoma 13.6%), active chemotherapy (30.0%) and hematopoietic stem cell transplantation (14.5%). Clinical worsening by Days +7 and +28 was observed in four (3.6%) and five patients (4.5%), respectively. Only one patient had a positive SARS‐CoV‐2 polymerase chain reaction test at Day +28. At least one potentially severe DDI was observed in 56.4% of the patients. The rate of attributable TEAEs was 10.9%, although only two patients (1.8%) required premature discontinuation of NMV/r. Early initiation of NMV/r therapy should be considered in immunocompromised patients with COVID‐19, with particular attention to interacting medications.
Abstract
Previous studies have suggested that exposure to statins confers a protective effect in bloodstream infection (BSI) due to the anti‐inflammatory and immunomodulatory properties attributed to ...these lipid‐lowering drugs. Scarce evidence is available for the solid organ transplant population. Therefore, we compared the time to clinical cure (primary outcome) and the time to fever resolution, new requirement of intensive care unit admission or renal replacement therapy, and 30‐day all‐cause mortality (secondary outcomes) between kidney transplant (KT) recipients with post‐transplant BSI that were receiving or not statin therapy for at least the previous 30 days. We included 80 KT recipients that developed 109 BSI episodes (43 39.4% and 66 60.6% episodes within the statin and non‐statin groups, respectively). The median interval since the initial prescription to BSI was 512 days (interquartile range IQR: 172–1388). Most episodes were of urinary source and due to Enterobacterales. There were no differences in the median time to clinical cure in the statin and non‐statin groups (3.4 IQR: 3–6.8 versus 4 IQR: 2–6 days;
p
‐value = .112). The lack of effect was confirmed by multiple linear regression analysis adjusted for confounding factors (standardized
β
coefficient = 0.040;
p
‐value = .709). No significant differences were observed for any of the secondary outcomes either. Vital signs and laboratory values at BSI onset and after 72–96 h were similar in both groups. In conclusion, previous statin therapy had no apparent protective effect on the outcome of post‐transplant BSI among KT recipients.
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Background
The natural history of candidemia in kidney transplant recipients (KTR) remains poorly understood. This study aimed to evaluate mortality, prognostic factors and overall graft loss after ...candidemia in KTRs.
Methods
This is a retrospective multicentre study enrolling all KTRs ≥15 years old with candidemia diagnosed at hospitals in Brazil, Spain and Italy from 2010 to 2020. Primary endpoints were mortality rates at 14 and 30 days. Secondary endpoints were prognostic factors of 14‐day mortality and overall graft loss.
Results
We enrolled 93 KTRs of which 75 were from Brazil. The mean time interval from transplantation to the onset of candidemia was 45.2 ± 61.5 months. 42% of all patients were on haemodialysis, 31.3% had an episode of sepsis and 39% underwent surgery within 30 days before fungemia. European patients were more likely to receive echinocandin (32 vs. 72%, p < .001). 22.7% of Brazilian patients did not receive any antifungal before death. All‐cause mortality at 14 days was higher in Brazil (41.3 vs. 11.1%, p = .016). Candida colonisation (OR 6.91 95% CI: 1.08–44.3, p = .042) and hypotension (OR 4.87 95% CI: 1.62–14.66, p = .005) were associated with 14‐day mortality. Echinocandin treatment had a protective effect (OR 0.19 95% CI: 0.05–0.73, p = .015). Graft loss at 90 days occurred in 48% of patients (70.7 in Brazil vs. 22.2% in Europe, p < .01).
Conclusions
Candidemia in KTR is usually documented late after engraftment in patients requiring HD, surgical procedures and dysbiosis secondary to antibiotic use. Mortality was higher in Brazil. Echinocandin therapy was associated with improved survival.
Abstract
Genetic determinants of BK polyomavirus infection after kidney transplantation remain poorly investigated. We assessed the potential impact of 13 different single nucleotide polymorphisms ...within genes mainly involved in innate immune responses on the risk of BKPyV viremia in 204 KT recipients. After a median follow-up of 1121.5 days, the cumulative incidence of any-level BKPyV viremia was 24.5% (50/204). There was a significant association between the minor T allele of
TLR3
(rs3775291) SNP and the development of BKPyV viremia (adjusted hazard ratio aHR: 2.16; 95% confidence interval CI: 1.08–4.30;
P
value = 0.029), whereas the minor G allele of
CD209
(rs4804803) SNP exerted a protective role (aHR: 0.54; 95% CI: 0.29–1.00;
P
value = 0.050). A higher incidence of BKPyV viremia was also observed for the minor G allele of
IL10
(rs1800872) SNP, although the absence of BKPyV events among homozygotes for the reference allele prevented multivariable analysis. The BKPyV viremia-free survival rate decreased with the increasing number of unfavorable genotypes (100% no unfavorable genotypes, 85.4% 1 genotype, 70.9% 2 genotypes, 52.5% 3 genotypes;
P
value = 0.008). In conclusion, SNPs in
TLR3
,
CD209
and
IL10
genes play a role in modulating the susceptibility to any-level BKPyV viremia among KT recipients.
Risk stratification for cytomegalovirus (CMV) infection after kidney transplantation (KT) remains to be determined. Since endosomal toll-like receptors (TLRs) are involved in viral sensing, we ...investigated the impact of common single-nucleotide polymorphisms (SNPs) located within
TLR3
and
TLR9
genes on the occurrence of overall and high-level (≥1,000 IU/ml) CMV infection in a cohort of 197 KT recipients. Homozygous carriers of the minor allele of
TLR3
(rs3775291) had higher infection-free survival compared with reference allele carriers (60.0% for TT versus 42.3% for CC/CT genotypes;
P
-value = 0.050). Decreased infection-free survival was observed with the minor allele of
TLR9
(rs352139) (38.2% for TC/CC versus 59.3% for TT genotypes;
P
-value = 0.004). After multivariable adjustment, the recessive protective effect of the
TLR3
(rs3775291) TT genotype was confirmed (adjusted hazard ratio aHR: 0.327; 95% CI: 0.167–0.642;
P
-value = 0.001), as was the dominant risk-conferring effect of
TLR9
(rs352139) TC/CC genotypes (aHR: 1.865; 95% CI: 1.170–2.972;
P
-value = 0.009). Carriers of the
TLR9
(rs352139) TC/CC genotypes showed lower CMV-specific interferon-γ-producing CD4+ T-cell counts measured by intracellular cytokine staining compared with the TT genotype (median of 0.2 versus 0.7 cells/μl;
P
-value = 0.003). In conclusion,
TLR3/TLR9
genotyping may inform CMV infection risk after KT.
Background
Immunomodulatory effects attributable to cytomegalovirus (CMV) would predispose to BK polyomavirus (BKPyV) infection after kidney transplantation (KT), although available evidence is ...conflicting. It has been suggested that (val)ganciclovir therapy may increase the risk of BKPyV viremia and BKPyV‐associated nephropathy (BKPyVAN) as a result of drug‐induced T‐cell impairment.
Methods
We investigated whether CMV replication and/or (val)ganciclovir exposure (either as prophylaxis or treatment) were associated with the development of BKPyV viremia or BKPyVAN in a prospective cohort of 399 KT recipients. CMV infection (any level or high‐level viremia and area under the curve of DNAemia) and (val)ganciclovir exposure (any duration of therapy and cumulative days of treatment) during the first post‐transplant year were explored through separate landmark survival analyses.
Results
Cumulative incidence of BKPyV viremia and BKPyVAN after a median follow‐up of 551 days was 23.1% and 2.5%, respectively. One‐year rates of CMV infection and (val)ganciclovir therapy were 47.4% and 54.1%, respectively. No differences were observed in BKPyV viremia‐ or BKPyVAN‐free survival according to previous CMV infection or (val)ganciclovir exposure in any of the landmark analyses. Adjusted Cox models confirmed this lack of association.
Conclusion
Our findings do not confirm the existence of a relevant impact of CMV infection or (val)ganciclovir therapy on the risk of post‐transplant BKPyV events.
Background
Invasive fungal infection, particularly intraabdominal candidiasis, exerts a negative impact on the outcome of pancreas transplant recipients (PTRs). Optimal antifungal prophylaxis in this ...context remains unclear.
Methods
We performed a single‐centre retrospective study to compare the incidence of invasive candidiasis during the first 6 post‐transplant months in a cohort of 218 PTRs over two periods in which different agents for antifungal prophylaxis were used: fluconazole (Fluco‐Px) from March 1995 to June 2012, and micafungin followed by fluconazole (Mica‐Px) from July 2012 to December 2018.
Results
A total of 152 and 66 PTRs received Fluco‐Px and Mica‐Px. Mean age was 39.7 ± 7.8 years, 56.4% (123/218) were males, and 85.3% (186/218) underwent simultaneous pancreas–kidney transplantation. Invasive candidiasis occurred in 21.7% (33/152) of PTRs under Fluco‐Px compared to 24.2% (16/66) of those under Mica‐Px (p‐value = .681). Median time from transplantation to infection was 8 days (interquartile range IQR: 6–16) under Fluco‐Px versus 6.5 (IQR: 3.3–15.8) under Mica‐Px (p‐value = .623). Non‐albicans Candida species comprised 27.5% (11/40) and 25.0% (4/16) of episodes under Fluco‐Px and Mica‐Px respectively (p‐value = .849). Surgical site infection was the most common form in both groups (82.5% 33/40 and 87.5% 14/16; p‐value = .954). Multivariable analysis identified cold ischaemia time of the pancreas and kidney grafts, surgical reintervention and insulin requirement after transplantation as risks factor for invasive candidiasis.
Conclusion
This retrospective study did not reveal a significant benefit from the initial use of micafungin‐based antifungal prophylaxis over fluconazole among PTRs in terms of invasive candidiasis.
