Showing papers by "Mario Fernández-Ruiz published in 2022"

Cytomegalovirus in the transplant setting: Where are we now and what happens next? A report from the International CMV Symposium 2021

Abstract: The CMV Symposium in September 2021 was an international conference dedicated to cytomegalovirus (CMV) infection after solid organ or hematopoietic stem cell transplantation. This review provides an overview of the presentations given by the expert faculty, supplemented with educational clinical cases. Topics discussed include CMV epidemiology and diagnosis, the burden of CMV infection and disease, CMV‐specific immunity and management of CMV in transplant settings. Major advances in the prevention and treatment of CMV in the past decade and increased understanding of CMV immunity have led to improved patient outcomes. In the future, management algorithms may be individualized based on the transplant recipient's immune profile, which will mark the start of a new era for patients with CMV.

Risk of infection in patients with hematological malignancies receiving CAR T-cell therapy: systematic review and meta-analysis

Abstract: ABSTRACT Background Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment option for relapsed or refractory B-cell malignancies and multiple myeloma. Underlying and treatment-related variables may contribute to the development of infectious complications. Research design and methods We conducted a systematic review and meta-analysis on the incidence of overall and severe (grade ≥3) infection in patients with hematological malignancies receiving CAR T-cells. Secondary outcomes included the specific rates of bacterial, viral and invasive fungal infection (IFI), and infection-related mortality. PubMed, Embase and Web of Science databases were searched from inception to 27 May 2022. Sensitivity analysis were performed according to the type of malignancy and study design (randomized clinical trials [RCTs] or observational studies). Results Forty-five studies (34 RCTs) comprising 3,591 patients were included. The pooled incidence rates of overall and severe infection were 33.8% (I2 = 96.31%) and 16.2% (I2 = 74.41%). The respiratory tract was the most common site of infection. Most events were bacterial or viral, whereas the occurrence of IFI was rare. The pooled attributable mortality was 1.8% (I2 = 43.44%). Conclusions Infection is a frequent adverse event in patients receiving CAR T-cell therapy. Further research should address specific risk factors in this population.

Age-dependent association of clonal hematopoiesis with COVID-19 mortality in patients over 60 years

Abstract: Abstract Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four studies have attempted to associate CHIP with COVID-19 severity without conclusive findings. In the present work, we explore the association between CHIP and COVID-19 mortality. Genomic DNA extracted from peripheral blood of COVID-19 patients ( n = 241 deceased, n = 239 survivors) was sequenced with the Myeloid Solutions™ panel of SOPHiA Genetics. The association between clonality and age and clonality and mortality was studied using logistic regression models adjusted for sex, ethnicity, and comorbidities. The association with mortality was performed with patients stratified into four groups of age according to the quartiles of the distribution: 60–74 years, 75–84 years, 85–91 years, and 92–101 years. Clonality was found in 38% of the cohort. The presence of CHIP variants, but not the number, significantly increased with age in the entire cohort of COVID-19 patients, as well as in the group of survivors ( p < 0.001). When patients were stratified by age and the analysis adjusted, CHIP classified as pathogenic/likely pathogenic was significantly more represented in deceased patients compared with survivors in the group of 75–84 years (34.6% vs 13.7%, p = 0.020). We confirmed the well-established linear relationship between age and clonality in the cohort of COVID-19 patients and found a significant association between pathogenic/likely pathogenic CHIP and mortality in patients from 75 to 84 years that needs to be further validated.

Derivation of a score to predict infection due to multi-drug resistant Pseudomonas aeruginosa: A tool for guiding empirical antibiotic treatment.

Abstract: Multidrug-resistant Pseudomonas aeruginosa (MDR-PSA) constitutes an emerging health problem. A predictive score of MDR-PSA infection would allow an early adaptation of empirical antibiotic therapy. We performed a single-centre case-control (1:2) retrospective study including 100 patients with MDR-PSA and 200 with a non–MDR-PSA infection. Cases and controls were matched by site of infection, clinical characteristics and immunosuppression. A point risk score for prediction of MDR-PSA infection was derived from a logistic regression model. Secondary outcomes (clinical improvement, complications and discharge) were also compared. Cases with MDR-PSA infection were younger than controls (67.5 vs. 73.0 y; P = 0.031) and have more frequent cirrhosis (9% vs. 2%; P = 0.005). Independent risk factors for MDR-PSA infection were prior antibiotic treatment (80% vs. 50.5%; P < 0.001), prior colonisation with MDR bacteria (41% vs. 13.5%; P < 0.001), hospital-acquired infection (63% vs. 47%; P = 0.009) and septic shock at diagnosis (33% vs. 14%; P < 0.001). Adequate therapy was less frequent in MDR-PSA infections (31% vs. 66.5% for empirical therapy; P < 0.001). The risk score included: previous MDR-PSA isolation (11 points), prior antibiotic use (3 points), hospital-acquired infection (2 points) and septic shock at diagnosis (2 points). It showed an area under the curve of 0.755 (95% CI: 0.70–0.81) and allowed to classify individual risk into various categories: 0–2 points (<20%), 3–5 points (25%–45%), 7–11 points (55%–60%), 13–16 points (75%–87%) and a maximum of 18 points (93%). Infections due to MDR-PSA have a poorer prognosis than those produced by non-MDR-PSA. Our score could guide empirical therapy for MDR-PSA when P. aeruginosa is isolated.

Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients

Abstract: Introduction There is robust evidence indicating that the SARS-CoV-2-specific humoral response is associated with protection against severe disease. However, relatively little data exist regarding how the humoral immune response at the time of hospital admission correlates with disease severity in unimmunized patients. Our goal was toidentify variables of the humoral response that could potentially serve as prognostic markers for COVID-19 progressionin unvaccinated SARS-CoV-2 patients. Methods A prospective cross-sectional study was carried out in a cohort of 160 unimmunized, adult COVID-19 patients from the Hospital Universitario 12Octubre. Participants were classified into four clinical groups based on disease severity: non-survivors with respiratory failure (RF), RF survivors, patients requiring oxygen therapy and those not receiving oxygen therapy. Serum samples were taken on admission and IgM, IgG, IgG subclass antibody titers were determined by ELISA, and neutralizing antibody titersusing a surrogate neutralization assay. The differences in the antibody titers between groups and the association between the clinical and analytical characteristics of the patients and the antibody titers were analyzed. Results Patients that developed RF and survived had IgM titers that were 2-fold higher than non-survivors (p = 0.001), higher levels of total IgG than those who developed RF and succumbed to infection (p< 0.001), and than patients who required oxygen therapy (p< 0.05), and had 5-fold higher IgG1 titers than RF non-survivors (p< 0.001) and those who needed oxygen therapy (p< 0.001), and 2-fold higher than patients that did not require oxygen therapy during admission (p< 0.05). In contrast, RF non-survivorshad the lowest neutralizing antibodylevels, which were significantly lower compared those with RF that survived (p = 0.03). A positive correlation was found between IgM, total IgG, IgG1 and IgG3 titers and neutralizing antibody titers in the total cohort (p ≤ 0.0036). Conclusions We demonstrate that patients with RF that survived infection had significantly higher IgM, IgG, IgG1 and neutralizing titers compared to patients with RF that succumb to infection, suggesting that using humoral response variables could be used as a prognostic marker for guiding the clinical management of unimmunized patients admitted to the hospital for SARS-CoV-2 infection.

Influence of single-nucleotide polymorphisms in TLR3 (rs3775291) and TLR9 (rs352139) on the risk of CMV infection in kidney transplant recipients

Abstract: 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.

Corrigendum: Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients

Abstract: [This corrects the article DOI: 10.3389/fimmu.2022.878812.].

Dynamics of Human Anelloviruses in Plasma and Clinical Outcomes Following Kidney Transplantation

Abstract: Background. Torque teno virus, the major member of the genus Alphatorquevirus, is an emerging biomarker of the net state of immunosuppression after kidney transplantation. Genetic diversity constitutes a main feature of the Anelloviridae family, although its posttransplant dynamics and clinical correlates are largely unknown. Methods. The relative abundance of Alphatorquevirus, Betatorquevirus, and Gammatorquevirus genera was investigated by high-throughput sequencing in plasma specimens obtained at various points during the first posttransplant year (n = 91 recipients). Total loads of all members of the Anelloviridae family were also quantified by an “in-house” polymerase chain reaction assay targeting conserved DNA sequences (n = 195 recipients). In addition to viral kinetics, clinical study outcomes included serious infection, immunosuppression-related adverse event (opportunistic infection and cancer)‚ and acute rejection. Results. Alphatorquevirus DNA was detected in all patients at every point, with an increase from pretransplantation to month 1. A variable proportion of recipients had detectable Betatorquevirus and Gammatorquevirus at lower frequencies. At least 1 change in the predominant genus (mainly as early transition to Alphatorquevirus predominance) was shown in 35.6% of evaluable patients. Total anelloviruses DNA levels increased from baseline to month 1, to peak by month 3 and decrease thereafter, and were higher in patients treated with T-cell depleting agents. There was a significant albeit weak-to-moderate correlation between total anelloviruses and TTV DNA levels. No associations were found between the predominant Anelloviridae genus or total anelloviruses DNA levels and clinical outcomes. Conclusions. Our study provides novel insight into the evolution of the anellome after kidney transplantation.

Genetic polymorphisms in TLR3, IL10 and CD209 influence the risk of BK polyomavirus infection after kidney transplantation

Abstract: 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.

Is there a real risk of bacterial infection in patients receiving targeted and biological therapies?

Abstract: Over the past decades, the advent of targeted and biological therapies has revolutionized the management of cancer and autoimmune, hematological and inflammatory conditions. Although a large amount of information is now available on the risk of opportunistic infections associated with some of these agents, the evidence regarding the susceptibility to bacterial infections is more limited. Biological agents have been shown to entail a variable risk of bacterial infections in pivotal randomized clinical trials and post-marketing studies. Recommendations on risk minimization strategies and therapeutic interventions are therefore scarce and often based on expert opinion, with only a few clear statements for some particular agents (i.e. meningococcal vaccination for patients receiving eculizumab). In the present review the available information regarding the incidence of and risk factors for bacterial infection associated with the use of different groups of biological agents is summarized according to their mechanisms of action, and recommendations based on this evidence are provided. Additional information coming from clinical research and real-world studies is required to address unmet questions in this emerging field. La introducción de terapias dirigidas y biológicas ha revolucionado a lo largo de las últimas décadas el tratamiento del cáncer y de las enfermedades autoinmunes, hematológicas e inflamatorias. Si bien existe abundante información acerca del exceso de riesgo de infección oportunista vinculado a algunos de estos agentes, la evidencia disponible sobre el riesgo de infección bacteriana específicamente es más limitada. En el marco de los ensayos clínicos pivotales y de estudios poscomercialización se ha demostrado un riesgo variable de infección bacteriana asociada al uso de terapias biológicas. Por ese motivo las recomendaciones para su minimización y abordaje terapéutico son escasas, y a menudo basadas en la opinión de expertos, con tan solo algunos escenarios de alto riesgo claramente establecidos para ciertos agentes (como la recomendación de vacunación anti-meningocócica en pacientes tratados con eculizumab). En la presente revisión se actualiza la información disponible respecto a la incidencia de infección bacteriana relacionada con las diferentes familias terapéuticas según su mecanismo de acción y sus factores de riesgo, aportándose igualmente algunas recomendaciones basadas en esta evidencia. Se requieren más estudios de investigación clínica en vida real para aclarar las preguntas sin resolver en este novedoso campo.

Risk Factors and Outcomes for Multidrug Resistant Pseudomonas aeruginosa Infection in Immunocompromised Patients

Abstract: Background: Pseudomonas aeruginosa (PSA) infection often occurs in immunocompromised patients, which also face an increased risk of multidrug-resistant (MDR) bacteria. A deeper knowledge of the risk factors for MDR-PSA infection in this patient population may help to choose appropriate empirical antibiotic therapy. Methods: a single-center case-control (1:2) retrospective study that included 48 patients with underlying immunosuppression developing MDR-PSA infection (cases) and 96 patients also immunocompromised that were infected with non-MDR-PSA (controls) was conducted. Both groups were matched by site of infection, clinical features and type of immunosuppression. Risk factors for MDR-PSA were assessed by logistic regression. Clinical outcomes were also compared between both groups. Results: immunosuppression was due to solid cancer in 63 (43.8%) patients, solid organ transplantation in 39 (27.1%), hematological disease in 35 (24.3%) and other causes in 7 (4.9%). Independent risk factors for MDR-PSA infection were diabetes mellitus (odds ratio [OR]: 4.74; 95% confidence interval [CI]: 1.63–13.79; p = 0.004), antibiotic therapy in the previous 3 months (OR: 5.32; 95% CI: 1.93–14.73; p = 0.001), previous MDR-PSA colonization (OR: 42.1; 95% CI: 4.49–394.8; p = 0.001) and septic shock (OR: 3.73; 95% CI: 1.36–10.21; p = 0.010). MDR-PSA cases were less likely to receive adequate empirical therapy (14 [29.2%] vs. 69 [71.9%]; p < 0.001). 30-day clinical improvement was less common in MDR-PSA cases (25 [52.1%] vs. 76 [79.2%]; p = 0.001). Conclusions: diabetes mellitus, previous MDR-PSA colonization, prior receipt of antibiotics and septic shock acted as risk factors for developing MDR-PSA infections in immunocompromised patients, who have a poorer outcome than those infected with non-MDR-PSA strains.

Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study

Abstract: Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients.

Isavuconazole for the Treatment of Invasive Mold Disease in Solid Organ Transplant Recipients: A Multicenter Study on Efficacy and Safety in Real-life Clinical Practice

Abstract: Background. Isavuconazole has theoretical advantages over other mold-active triazoles for the treatment of invasive aspergillosis and mucormycosis after solid organ transplantation (SOT). The available clinical experience, nevertheless, is scarce. Methods. We performed a retrospective study including all adult SOT recipients with proven or probable invasive mold disease (IMD) that received isavuconazole for ≥24 h as first-line or salvage therapy at 10 Spanish centers between September 2017 and November 2021. The primary efficacy outcome was clinical response (complete or partial resolution of attributable symptoms and findings) by weeks 6 and 12. Safety outcomes included the rates of treatment-emergent adverse events and premature isavuconazole discontinuation. Results. We included 81 SOT recipients that received isavuconazole for a median of 58.0 days because of invasive aspergillosis (n = 71) or mucormycosis (n = 10). Isavuconazole was used as first-line (72.8%) or salvage therapy due because of previous treatment-emergent toxicity (11.1%) or refractory IMD (7.4%). Combination therapy was common (37.0%), mainly with an echinocandin or liposomal amphotericin B. Clinical response by weeks 6 and 12 was achieved in 53.1% and 54.3% of patients, respectively, and was more likely when isavuconazole was administered as first-line single-agent therapy. At least 1 treatment-emergent adverse event occurred in 17.3% of patients, and 6.2% required premature discontinuation. Daily tacrolimus dose was reduced in two-thirds of patients by a median of 50.0%, although tacrolimus levels remained stable throughout the first month of therapy. Conclusions. Isavuconazole is a safe therapeutic option for IMD in SOT recipients, with efficacy comparable to other patient groups.

Recurrence of immune complex and complement-mediated membranoproliferative glomerulonephritis in kidney transplantation.

Abstract: INTRODUCTION Membranoproliferative glomerulonephritis (MPGN) represents a histologic pattern of glomerular injury which may be due to several etiologies. Few studies have comprehensively analyzed the recurrence of MPGN according to the current classification system. METHODS We collected a multicenter, retrospective cohort of 220 kidney graft recipients with biopsy-proven native kidney disease due to MPGN between 1981-2021 in 11 hospitals. Demographic, clinical and histologic parameters of prognostic interest were collected. The main outcomes were time to kidney failure, time to recurrence of MPGN, and disease remission after recurrence. RESULTS The study group included 34 complement-mediated and 186 immune complex-mediated MPGN. Eighty-one patients (37%) reached kidney failure in a median follow-up of 79 months. The main predictors of this event were the development of rejection episodes, and disease recurrence. Fifty-four patients (25%) had a disease recurrence in a median of 16 months after kidney transplantation. The incidence of recurrence was higher in patients with dysproteinemia (67%) and complement-mediated MPGN(62%). In the multivariable model, complement-mediated MPGN emerged as a predictor of recurrence. Thirty-three patients reached kidney failure after recurrence. The main determinants of no remission were: early time to recurrence (<15 months), eGFR < 30 ml/min/1.73m2 and serum albumin < 3.5 g/dl at the time of recurrence. CONCLUSIONS One-fourth of patients with native kidney disease due to MPGN developed clinical recurrence in the allograft, especially in cases with complement-mediated disease or in those associated with dysproteinemia. The kidney outcomes of disease recurrence with currently available therapies are heterogeneous and thus, more effective and individualized therapies are needed.

Reduction of Instrumentation-Related Spine Surgical Site Infections After Optimization of Surgical Techniques. A Single Center Retrospective Analysis.

Abstract: STUDY DESIGN Retrospective cohort study. OBJECTIVE Although surgical risk factors for developing spine surgical site infections (S-SSI) have been identified, the impact of such knowledge in its prevention has not been demonstrated. METHODS We evaluated in 500 patients undergoing spine surgery between 2011 and 2019 at Hospital 12 de Octubre the changes in S-SSI rates over time. Surgical variables independently related to S-SSI were analyzed by univariate and multivariate analysis using binary logistic regression models. A case-control sub-analysis (1:4), matched by the surgical variables identified in the overall cohort was also performed. RESULTS Twenty cases of S-SSI were identified (4%), with a significant decrease in the incidence rate across consecutive time periods (6.6% [2011-2014] vs .86% [2015-2019]; P-value <.0001)). Multivariate analysis identified arthrodesis involving sacral levels (odds ratio [OR]: 2.57; 95% confidence interval [95%CI]: 1.02-6.47; P-value = .044) and instrumentation over 4-8 vertebrae (OR: 2.82; 95%CI: 1.1-7.1; P-value = .027) as independent risk factors for S-SSI. The reduction in the incidence of S-SSI concurred temporally with a reduction in instrumentations involving 4-8 vertebrae (55% vs 21.8%; P-value <.0001) and sacral vertebrae (46.9% vs 24.6%; P-value <.0001) across both periods. The case-control analysis matched by these surgical variables failed to identify other factors independently related to the occurrence of S-SSI. CONCLUSIONS Spinal fusion of more than 4 levels and the inclusion of sacral levels were independently related to the risk of S-SSI. Optimization of surgical techniques by reducing these two types of instrumentation could significantly reduce S-SSI rates.

Impact of polymorphisms in genes orchestrating innate immune responses on replication kinetics of Torque teno virus after kidney transplantation

Abstract: Background: Torque teno virus (TTV) DNAemia has been proposed as a surrogate marker of immunosuppression after kidney transplantation (KT), under the assumption that the control of viral replication is mainly exerted by T-cell-mediated immunity. However, Tthe impact on post-transplant TTV kinetics of single genetic polymorphisms (SNPs) in genes orchestrating innate responses remains unknown. We aimed to characterize the potential association between 14 of these SNPs and TTV DNA levels in a single-center cohort of KT recipients. Methods: Plasma TTV DNAemia was quantified by real-time PCR in 221 KT recipients before transplantation (baseline) and regularly through the first 12 post-transplant months. We performed genotyping of the following SNPs: CTLA4 (rs5742909, rs231775), TLR3 (rs3775291), TLR9 (rs5743836, rs352139), CD209 (rs735240, rs4804803), IFNL3 (rs12979860, rs8099917), TNF (rs1800629), IL10 (rs1878672, rs1800872), IL12B (rs3212227) and IL17A (rs2275913). Results: The presence of the minor G allele of CD209 (rs4804803) in the homozygous state was associated with undetectable TTV DNAemia at the pre-transplant assessment (adjusted odds ratio: 36.96; 95% confidence interval: 4.72–289.67; p-value = 0.001). After applying correction for multiple comparisons, no significant differences across SNP genotypes were observed for any of the variables of post-transplant TTV DNAemia analyzed (mean and peak values, areas under the curve during discrete periods, or absolute increments from baseline to day 15 and months 1, 3, 6 and 12 after transplantation). Conclusion: The minor G allele of CD209 (rs4804803) seems to exert a recessive protective effect against TTV infection in non-immunocompromised patients. However, no associations were observed between the SNPs analyzed and post-transplant kinetics of TTV DNAemia. These negative results would suggest that post-transplant TTV replication is mainly influenced by immunosuppressive therapy rather than by underlying genetic predisposition, reinforcing its clinical application as a biomarker of adaptive immunity.

Role of cytomegalovirus infection after kidney transplantation on the subsequent risk of atherosclerotic and thrombotic events

Abstract: Whether cytomegalovirus (CMV) infection increases the risk of cardiovascular complications after kidney transplantation (KT) through different indirect effects remains controversial. We analyzed the incidence of post-transplant atherosclerotic (PAEs) and thrombotic events (PTEs) in 465 KT recipients according to the previous exposure to any level or high-level (≥1,000 IU/mL) CMV viremia (either asymptomatic or clinical disease) by means of landmark analysis beyond days 30, 180 and 360 after transplantation. Proportional hazards models were constructed with death and graft loss as competing risks. After a median of 722 days, the cumulative incidences of PAE and PTE were 6.0% each. Most PAEs (53.6%) occurred beyond post-transplant day 360, whereas most PTEs (60.7%) were diagnosed between days 30–180.The incidence of PAE beyond day 180 was higher among patients with previous CMV viremia compared to those without (two-year rates: 4.7% versus 0.4%; P -value = 0.035). This difference was more pronounced in recipients developing high-level viremia (6.3% versus 0.7%, respectively; P -value = 0.013). After multivariate adjustment for age, pre-transplant cardiovascular risk, antiplatelet and statin therapy and graft function, however, associations were not maintained either for any-level (hazard ratio [HR]: 1.84; 95% confidence interval [CI]: 0.48–7.05) or high-level CMV viremia (HR: 2.84; 95% CI: 0.78–10.36). No significant differences were found in the remaining landmark analyses (days 30 or 360) or for the outcome of PTE either. Our study does not support that CMV infection independently contributes to the risk of PAE or PTE after KT. • CMV immunomodulatory effects may increase the risk of cardiovascular complications after kidney transplantation. • We assessed cumulative and recent CMV exposure by means of landmark analysis beyond days 30, 180 and 360 after transplantation. • Proportional hazards models were constructed with death and graft loss as competing risks. • CMV exposure after adjustment was not associated with an increased risk of subsequent post-transplant atherosclerotic or thrombotic events at any of the post-transplant periods.

Long-Term Follow-Up of Patients Diagnosed with COVID-19-Associated Pulmonary Aspergillosis (CAPA)

Abstract: COVID-19-associated pulmonary aspergillosis (CAPA) have been documented during the COVID-19 pandemic. The vast majority of these patients do not meet the classic EORTC/MSGERC criteria for invasive pulmonary aspergillosis. The question arises as to whether there may have been an over-diagnosis of this disease. Here we review our experience and analyze the evolution of 27 patients who were diagnosed with CAPA during hospital admission. Surviving patients were followed-up for a mean time of 15 months (SD 3.78) by a group of experts and clinical records of diseased patients were reviewed. After expert evaluation and follow-up, 10 patients were finally assumed as CAPA according to expert opinion. These cases represent 40% of the initially CAPA assumed cases. Our data suggest the need to reconsider actual diagnosis criteria for CAPA what could drive to better identification of these patients.

Diagnostic and therapeutic approach to pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitors

Abstract: The advent of immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and the programmed cell death (PD-1)/PD-1 ligand 1 (PD-L1) axis has transformed the treatment paradigm for multiple cancer types. ICIs are able to restore T-cell-mediated antitumor responses and do not entail an increased risk of infection per se. However, immunotherapy is associated to a unique form of toxicity due to the off-target effects on healthy tissues of the excessively enhanced immune response in form of immune-related adverse events (irAEs). Although ICI-induced pneumonitis ranks the fifth of all irAEs in terms of frequency of occurrence, it is associated with a relevant attributable mortality. This review summarizes the incidence, risk factors, clinical and radiological presentation, and therapeutic approach of ICI-induced pneumonitis. Particular focus is on the differential diagnosis of new or worsening pulmonary infiltrates in cancer patients receiving ICI therapy. Finally, the impact on the risk of opportunistic infection of ICIs and immunosuppressive therapy used to treat associated irAEs is reviewed. The diagnosis and management of suspected ICI-induced pneumonitis remains clinically challenging.

Correction to: Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies

Abstract: [This corrects the article DOI: 10.1093/ofid/ofab250.].

Tocilizumab therapy in SARS-CoV-2 pneumonia: A matched retrospective cohort analysis

Abstract: The effect of immunomodulatory therapy with tocilizumab for coronavirus disease 2019 (COVID-19) in real-life clinical practice remains controversial.Single-center retrospective matched cohort analysis including 47 consecutive patients treated with intravenous tocilizumab for severe COVID-19 pneumonia ("TCZ group"), matched by age, comorbidities, time from symptoms onset and baseline SpO2/FiO2 ratio with 47 patients receiving standard of care alone ("SoC group").There were no significant differences between the TCZ and SoC groups in the rate of clinical improvement (hospital discharge and/or a decrease of ≥2 points on a six-point ordinal scale) by day 7 (51.1% [24/47] versus 48.9% [23/47]; P-value = 1.000). No differences were observed at day 14 in terms of clinical improvement (72.3% versus 76.6%; P-value = 0.791), all-cause mortality (10.6% versus 12.8%; P-value = 1.000), and the composite of invasive mechanical ventilation and/or death (25.5% versus 23.4%; P-value = 1.000) either. Patients in the TCZ group had a more rapid normalization of C-reactive protein levels.No apparent benefit was observed in patients with severe COVID-19 treated with tocilizumab as compared to a matched retrospective cohort.El efecto del tratamiento inmunomodulador con tocilizumab en la COVID-19 sigue siendo controvertido.Estudio unicéntrico de cohortes retrospectivas pareadas que incluyó a 47 pacientes con COVID-19 grave tratados con tocilizumab intravenoso («grupo TCZ»), emparejados por edad, comorbilidades mayores, evolución de síntomas y cociente SpO2/FiO2 basal con 47 pacientes que recibieron tratamiento estándar únicamente («grupo SoC»).No observamos diferencias significativas entre los grupos de TCZ y SoC en la tasa de mejoría clínica (alta hospitalaria y/o descenso de ≥ 2 puntos en una escala ordinal de 6 puntos) al día 7 (51,1% [24/47] vs. 48,9% [23/47]; P = 1,000). Tampoco hubo diferencias al día 14 en las tasas de mejoría clínica (72,3% vs. 76,6%; P = 0,791), mortalidad (10,6% vs. 12,8%; P = 1,000) o en el compuesto de ventilación mecánica invasiva y/o muerte (25,5% vs. 23,4%; P = 1,000). Los pacientes en el grupo de TCZ presentaron una normalización más rápida de la proteína C reactiva.Respecto a una cohorte retrospectiva pareada, no detectamos un beneficio asociado al tratamiento con tocilizumab en pacientes con neumonía por COVID-19.

Fluconazole versus micafungin for initial antifungal prophylaxis against Candida in pancreas transplant recipients: A comparative study of two consecutive periods

Abstract: 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.