Risk Of Infection-related Mortality Research Articles

#1116 Hyperuricemia worsens bacterial sepsis by suppressing neutrophil functions in CKD

Abstract Background and Aims Patients with kidney disease, especially those on dialysis, are more susceptible to infections such as peritonitis, sepsis, pneumonia, and are at a higher risk for infection-related mortality. Pathogenic mechanisms underlying the secondary immunodeficiency in kidney disease include gut dysbiosis and barrier dysfunction, persistent inflammation, immune paralysis due to increased levels of immunoregulatory metabolites (e.g. uric acid) and proteins (e.g. FGF23) [1]. Currently, it is unknown whether CKD-related hyperuricemia may contribute to the immune paralysis in this context. We hypothesized that hyperuricemia (HU) may aggravate the innate immune response to infection in CKD in mice. Method Mono- and polybacterial sepsis was induced by LPS injection or cecal ligation and puncture in Alb-creERT2;Glut9lox/lox mice with HU and/or CKD, and in Glut9lox/lox (healthy) control mice. After 24 hours, systemic inflammation was evaluated by measuring serum cytokine levels, immune cell activation and recruitment, and neutrophil extracellular trap release. Tissue injury in liver, heart, and kidney was assessed by performing RT-qPCR and immunohistochemistry. In addition, kidney function was determined by measuring the glomerular filtration rate (GFR). Additionally, mice were treated with urate-lowering therapy to reduce serum uric acid levels and the immune response and functional outcomes after sepsis is quantified. Results We found that both mono- and polybacterial sepsis caused systemic inflammation as indicated by an increased number of blood neutrophils (see Figure), neutrophil activation and pro-inflammatory cytokine levels as compared to the PBS-treated or sham-operated control groups in Glut9lox/lox healthy mice, respectively. Mice with sepsis also displayed a slightly worsened kidney function. Interestingly, HU significantly increased neutrophil numbers but decreased their activation status and the ability of neutrophils to form neutrophil extracellular traps in Alb-creERT2;Glut9lox/lox mice with sepsis as compared to the control groups, which was further aggravated in mice with CKD-related HU (CKD+HU). This impaired inflammatory response was partially reversible by lowering serum uric acid with febuxostat. Conclusion Our results identify hyperuricemia related or unrelated to kidney disease as immune regulator in bacterial infection by suppressing neutrophil functions in mice. Specifically targeting uric acid may help to overcome the secondary immunodeficiency related to kidney disease during infection but enhances sterile inflammation [2].

A comparison of urgent-start of hemodialysis vs urgent initiation of peritoneal dialysis: a meta-analysis study.

To investigate the effects of urgent-start HD(USHD) and urgent-start PD(USPD) on dialysis patients and provide references for relevant clinical practice. A literature search was conducted in Chinese and English databases (PubMed, Web of Science, Cochrane Library, CNKI, Wanfang, VIP) and the cutoff date for which was July 30, 2023. Studies comparing USHD and USPD were included and I2 statistics and Q tests were used to determine heterogeneity among them. Risk ratios (RR) with 95% confidence intervals (CI) were computed for count data. Nine studies met the inclusion criteria. The all-cause mortality rate was 0.173 (0.070, 0.277) for USPD versus 0.214 (0.142, 0.286) for USHD, indicating that USPD had a protective effect against all-cause mortality compared to USHD (RR = 0.76, 95% CI 0.63-0.91). Patients receiving USPD had lower risks of infection-related mortality (RR = 0.19; 95% CI 0.05-0.76), bacteremia (RR = 0.38; 95% CI 0.18-0.80), and composite complications (RR = 0.54; 95% CI 0.41-0.71). However, no significant differences were found between USHD and USPD for cardiovascular mortality (RR = 0.68; 95% CI 0.28-1.68) or cancer mortality (RR = 0.44; 95% CI 0.15-1.29). Compared to USHD, USPD has better protective effects against all-cause mortality, infection-related mortality, bacteremia, and composite complications. However, more high-quality research is still needed to further investigate the impacts of the two dialysis modalities on patients.

Adverse Effects and Non-Relapse Mortality of BCMA-Directed Immunotherapies : An FDA Adverse Event Reporting System (FAERS) Database Study

Background: The FDA-approved BCMA-directed immunotherapies, which consist of chimeric antigen receptor T (CAR T) cell therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), alongside the bispecific antibody teclistamab, have improved outcomes for patients with relapsed/refractory multiple myeloma (MM). Despite their effectiveness, these treatments have distinct toxicity profiles, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, and the risk of infections, all contributing to non-relapse mortality. In this study, we analyzed these adverse events using data from the FDA Adverse Event Reporting System (FAERS) database. Method: We conducted a comprehensive search of the FAERS database from 2019 to 2023 to identify adverse effect reports of interest, associated with ide-cel, cilta-cel, and teclistamab. To ensure data accuracy, we excluded duplicate reports and cases where multiple BCMA-directed agents were associated with a single incident. Reporting odds ratio (ROR) was calculated by dividing the odds of a certain event occurring with the agent by the odds of the same event occurring with all other BCMA agents in the same database. Furthermore, to assess NRM, we excluded reports of progressive or refractory MM from the analysis of fatal cases. Results: A total of 1314 individual cases, with 3377 reported adverse reactions, were identified. Among them, 353 cases were associated with cilta-cel, 496 with ide-cel, and 465 with teclistamab. The most frequently reported adverse events included CRS at 12.8%, followed by fatigue (3.9%), pyrexia (3.2%), ICANS (3.0%), and non-ICANS neurotoxicity (1.9%). Ide-cel showed the highest ROR for CRS (1.64, 95% CI 1.33-2.02), whereas the ROR for ICANS was lowest with teclistamab (0.55, 95% CI 0.32-0.93). Ide-cel showed the highest ROR for non-ICANS neurotoxicity (2.45, 95% CI: 1.86-3.23). Bell's palsy was exclusively associated with cilta-cel, with 11 reported cases, while Parkinsonism was reported in 6 cases with cilta-cel, 2 cases with ide-cel, and none with teclistamab.Teclistamab had a notably higher proportion of infection-related events, accounting for 23.7% of all reported cases, as compared to 13.7% for cilta-cel and 2.9% for ide-cel. The ROR for infection was highest with teclistamab at 5.21 (95% CI: 4.14 - 6.56). Out of the total reported deaths (n=225 cases), NRM was observed in 189 patients, accounting for 84% of all mortality cases. In the analysis of NRM , ide-cel was associated with 42 reported deaths, with CRS (n=17; 40%), ICANS (n=8; 19%), sepsis (n=7; 17%), and hemophagocytic lymphohistiocytosis (HLH) (n=6; 14%) being the most common reported adverse events in this group. For cilta-cel, 59 deaths were reported, with CRS (n=17; 29%), ICANS (n=13; 22%), and HLH (n=9; 15%) as the most common adverse events in patients who suffered NRM. In the case of teclistamab, among the 88 NRM cases, the most frequent adverse events reported were COVID-19 (11.4%), pneumonia (11.4%), sepsis (9.1%), and septic shock (9.1%). Teclistamab exhibited the highest OR for NRM at 1.73 compared to 1.28 with cilta-cel and 0.42 with ide-cel. The findings will be presented with updated data. Conclusion: Our analysis of the FAERS dataset demonstrates a prominent risk of CRS and ICANS with CAR-T therapy, as well as a high risk of infection related mortality with teclistamab. Non-ICANS neurotoxicity was more pronounced with ide-cel compared to cilta-cel, potentially influenced by the longer follow-up period and wider uptake of ide-cel as it was the first FDA-approved CAR T therapy. We also note a higher NRM with both cilta-cel and teclistamab compared to ide-cel. While the exact attributes of NRM cannot be accessed in the database, complications of CAR T therapy and infections were the most common events noted in the group with NRM. Our analysis is limited by the nature of the FAERS database, where reporting is not mandatory, and selection bias cannot be eliminated. Since these agents share a similar indication for MM, clinicians will need to carefully consider their distinct toxicity profiles when choosing and sequencing treatments.

Infections and risk factors for infection-related mortality after pediatric allogeneic hematopoietic stem cell transplantation in Mexico: A single center retrospective study.

To identify the type of infections and risk factors for infection-related mortality (IRM) after allogeneic hematopoietic stem cell transplantation (HSCT). Retrospective cohort study of patients <16 years of age treated in 2010-2019 was conducted. Unadjusted hazard ratios (HR) and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CIs) were estimated using Cox regression. Cumulative incidence was calculated. Data for 99 pediatric patients were analyzed. The myeloablative conditioning was the most used regimen (78.8%) and the hematopoietic stem cell source was predominantly peripheral blood (80.8%). Primary graft failure occurred in 19.2% of patients. Frequency of acute graft-versus-host disease was 46.5%. Total of 136 infectious events was recorded, the most common of which were bacterial (76.4%) followed by viral infection (15.5%) and then fungal infection (8.1%). The best predictors for infection subtypes where the following: a) for bacterial infection (the age groups of 10.1-15 years: aHR = 3.33; 95% CI: 1.62-6.85 and. >15 years: aHR = 3.34; 95% CI: 1.18-9.45); b) for viral infection (graft versus host disease: aHR = 5.36; 95% CI: 1.62-17.68), however, for fungal infection statistically significant predictors were not identified. Related mortality was 30% (n = 12). Increased risk for infection-related mortality was observed in patients with unrelated donor and umbilical cord stem cells recipients (HR = 3.12; 95% CI: 1.00-9.85). Frequencies of infections and infection-related mortality appear to be similar to those reported. Unrelated donors and stem cells from umbilical cord recipients were associated with a high risk of mortality.

Risk of serious infection and infection mortality in patients with psoriasis: A nationwide cohort study using the Taiwan National Health Insurance claims database.

The risks of serious infections that lead to hospitalization and mortality in patients with psoriasis in Asia have not been comprehensively studied. We examined the incidence of serious infection and infection mortality in patients with psoriasis. This population-based retrospective cohort study used the Taiwan National Health Insurance claims database from 2000 to 2017. Adult patients with psoriasis were identified by a relevant International Classification of Diseases (ICD) code and matched to six comparators without psoriasis on age and sex. Psoriasis patients were categorized as having moderate-to-severe disease once exposed to systemic therapies, phototherapy or biologic therapies. The incidence of serious infection and infection mortality were identified by ICD codes from inpatient hospitalization and death registration. Cox proportional hazard models were used to compare the risk, and the results were adjusted for covariates and presented as adjusted hazard ratios (aHR) and 95% confidence interval (95% CI). Overall, 185,434 psoriasis patients and 1,112,581 comparators were included. A higher rate of serious infection (aHR: 1.21, 95% CI: 1.19-1.22) was found in patients with psoriasis compared to matched comparators without psoriasis, and the risk was enhanced when patients had moderate-to-severe psoriasis (aHR: 1.30, 95% CI: 1.27-1.34). Specifically, there was an increased risk of serious infection due to respiratory infections (aHR: 1.11, 95% CI: 1.09-1.13), skin/soft-tissue infections (aHR: 1.57, 95% CI: 1.52-1.62), sepsis (aHR: 1.23, 95% CI: 1.19-1.27), urinary tract infections (aHR: 1.11, 95% CI: 1.08-1.14), hepatitis B (aHR: 1.18, 95% CI: 1.06-1.30) and hepatitis C (aHR: 1.49, 95% CI: 1.32-1.69). Furthermore, psoriasis patients were associated with a higher risk of infection-related mortality (aHR: 1.15, 95% CI: 1.11-1.18) compared to matched comparators. Patients with psoriasis had a higher risk of serious infection and infection mortality, which was enhanced by moderate-to-severe psoriasis. Practitioners should be aware of the increased risk in patients with psoriasis, but it should not be a barrier to offering effective treatment.

Clinical outcome of SARS-CoV-2 infections occurring in multiple myeloma patients after vaccination and prophylaxis with tixagevimab/cilgavimab.

Patients with multiple myeloma (MM) frequently reported immune impairment with an increased risk for infection-related mortality. We aimed to evaluate the immune response in MM patients vaccinated for SARS-CoV-2 during active treatment. We enrolled 158 patients affected by active MM or smoldering MM (SMM) and 40 healthy subjects. All subjects received 2 or 3 doses of the BNT162b2 (Pfizer/BioNTech) vaccine, and the anti-spike IgG values were evaluated after every dose. We applied the Propensity Score Matching (PSM) as a consequence of the limited sample size and its heterogeneity to adjust for differences in baseline clinical variables between MM patients who achieved or not a vaccine response after 2 or 3 doses. At 30 days from the second dose, the median antibodies level in MM was 25.2 AU/mL, lower than in SMM and in the control group. The same results were confirmed after the third dose, with lower median anti-spike IgG levels in MM, compared to SMM and control group. Following PSM, lack of response to SARS-CoV-2 complete vaccination plus boost was associated with age more than 70 years old and use of high-dose of steroids. We failed to identify an association between specific treatment types and reduced vaccine response. The use of prophylaxis with tixagevimab/cilgavimab for 40 non-responder patients after 3 doses of vaccine has proven to be an effective and safe approach in reducing the risk of serious illness in the event of a breakthrough SARS-CoV-2 infection, faced with a mild symptomatic course, and in providing protection instead of long-term humoral immune vaccine responses. Following PSM, only the high-risk cytogenetic abnormalities were associated with an increased risk of developing a breakthrough SARS-CoV-2 infection. Monitoring the immune response is fundamental in MM patients that remain highly vulnerable to SARS-CoV-2 despite the vaccine. The use of prophylaxis with tixagevimab/cilgavimab can guarantee better protection from the severe form of the disease.

Glycaemic status, insulin resistance, and risk of infection-related mortality: a cohort study.

The impact of non-diabetic hyperglycaemia and insulin resistance on infection-related mortality risk remains unknown. We investigated the association of glycaemic status and insulin resistance with infection-related mortality in individuals with and without diabetes. Cohort study based on Kangbuk Samsung Health Study and national death records. About 666 888 Korean adults who underwent fasting blood measurements including glucose, glycated haemoglobin (HbA1c), and insulin during health-screening examinations were followed for up to 15.8 years. Infection-related mortality, therefore we used Cox proportional hazards regression analyses to estimate hazard ratios (HRs) and 95% CIs for infection-related mortality. Vital status and infection-related mortality were ascertained through national death records. Variable categories were created based on established cut-offs for glucose and HbA1c levels and homeostatic model assessment of insulin resistance (HOMA-IR) quintiles. During a median follow-up of 8.3 years, 313 infectious disease deaths were dentified. The associations of glucose and HbA1c levels with infection-related mortality were J-shaped (P for quadratic trend<.05). The multivariable-adjusted HR (95% CIs) for infection-related mortality comparing glucose levels <5, 5.6-6.9, and ≥7.0 mmol/L to 5.0-5.5 mmol/L (the reference) were 2.31 (1.47-3.64), 1.65 (1.05-2.60), and 3.41 (1.66-7.00), respectively. Among individuals without diabetes, the multivariable-adjusted HR for infection-related mortality for insulin resistance (HOMA-IR ≥75th centile versus <75th centile) was 1.55 (1.04-2.32). Both low and high glycaemic levels and insulin resistance were independently associated with increased infection-related mortality risk, indicating a possible role of abnormal glucose metabolism in increased infection-related mortality.

Interventional Antibiotic Treatment Replacing Antibiotic Prophylaxis during Allogeneic Hematopoietic Stem Cell Transplantation Is Safe and Feasible: A Single-Center Analysis

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of infection-related mortality during the pre-engraftment period. Systemic antibiotic prophylaxis (SAP) is widely used during the period of neutropenia but is associated with disruption of the intestinal microbiome, an increased risk of Clostridium difficile infection (CDI) and colonization with multi-drug resistant (MDR) bacteria. Aims: We retrospectively assessed the safety and efficacy of a change in our center policy from SAP to an exclusively interventional antibiotic treatment (IAT) in adult patients undergoing allogeneic HSCT. Outcome measures were overall survival (OS) and non-relapse mortality (NRM) at 3 years, antibiotic administration, incidence of blood-stream infections (BSI) and incidence and severity of acute and chronic graft-versus-host disease (GVHD). Methods: Cefotaxime was used as standard of care prophylaxis during neutropenia after HSCT prior to January 2018. After a 12 months transition time during which both strategies were employed in parallel, SAP was replaced by an IAT strategy with meropenem being administered immediately by nursing staff in case of neutropenic fever or any other signs of infection, and subsequently deescalated to piperacillin/tazobactam (pip/taz) when appropriate. We compared 67 consecutive patients undergoing HSCT in 2017, all of whom received antibiotic prophylaxis (SAP cohort) with all patients in 2019 comprising the IAT cohort (n=68). Use of antibiotics is reported as number of daily doses per 100 care days (DDD/100CD) until discharge after HSCT. Results: Patient characteristics are summarized in table 1. Median age was 56 years, 82% of patients were grafted with peripheral blood stem cells (PBSC) for acute leukemia (74%) from a matched unrelated or related donor (MUD, 61%; MRD 17%). Patient characteristics were well balanced between the SAP and IAT cohorts, except those patients transplanted in 2019 were more likely to have an HCT-CI ≥ 3 (56% vs 36%, p=0.025) and receive reduced-intensity conditioning (62% vs 40%, p=0.025). In the SAP and IAT cohort, neutropenic fever was observed in 46% and 62% of patients (p=0.085). However, the cumulative incidence (CI) of BSI by day +100 post-HSCT was significantly higher in the IAT vs SAP cohort (40% vs 13%, p<0.001), which did not result in more patients admitted to the intensive care unit (13% vs 6%, p=ns) and did not translate into a higher CI of NRM at 3 years (10% vs 9%, p=ns). With a median follow-up of 1052 days, 3-year OS was 70% and 69% for the SAP and IAT cohort, resp. (p=ns, figure 1). CI of acute GVHD grade II-IV or chronic GVHD of any grade at 3 years was 34% (p=ns) and 45% (p=ns), resp., resulting in identical survival free of acute GVHD grade III-IV, chronic GVHD requiring systemic immunosuppressive therapy and relapse-free survival (GRFS) of 36% (p=ns) in both groups. We observed a tendency to a higher CI of severe chronic GVHD in the SAP cohort (27% vs 13%, p=0.08). There was no significant difference between the two cohorts in terms of newly detected colonization with MDR bacteria during conditioning and after HSCT (VRE 17%; ESBL 5%; 3/4 MRGN 5%; MRSA 0%) and the incidence of CDI was likewise equal in both cohorts (13%, p=ns). Compared to SAP, IAT resulted in significantly fewer days of antibiotic therapy (24 vs 18, p<0.001) and accordingly less administration of cefotaxime (12.8 vs 3.8 DDD/100CD), teicoplanin (26.2 vs 6.3 DDD/100CD), vancomycin (11.5 vs 8.3 DDD/100CD) and meropenem (23.1 vs 16.7 DDD/100CD). Solely use of pip/taz increased (14.3 vs 23.6 DDD/100CD), while the amount of imipenem remained unchanged (7.6 versus 7.8 DDD/100CD). Thus, we observed a significant 40% reduction of the median antibiotic consumption (p=0.0312) in 2019. In the multivariate analysis, only age > 60 years and a high or very high disease risk index were identified as negative prognostic factor for OS. Conclusion/Summary: Our single center experience in conducting HSCT without antibiotic prophylaxis but with strict guidelines for prompt antibiotic intervention demonstrated no disadvantage in OS and NRM, despite a higher CI of BSI. IAT resulted in considerably less consumption of cefotaxime, but also carbapenem and glycopeptide antibiotics. We conclude that the proposed procedure of IAT replacing SAP is safe and feasible. Larger patient numbers are needed to confirm a possible benefit of IAT on GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epidemiology, Risk Factors and Outcome of Bacterial, Fungal, and Viral Infections in Pediatric Allogeneic and Autologous Hematopoietic Stem Cell Transplantation Recipients

Objectives Infection remains a major cause of morbidity and mortality after hematopoietic stem cell transplant (HSCT). With recent changes in transplant practices, such as the increasing use of alternative donors and T-cell depletion, how various risk factors interplay and affect the timeline of infections have not been well elucidated in children. While the epidemiology and risk factors for viral infections post-HSCT were well described for cytomegalovirus (CMV) and Epstein-Barr virus (EBV), the corresponding information on human herpes virus 6 (HHV-6), adenovirus (ADV) and BK virus (BKV) infection in children is limited. This study aims to review comprehensively the epidemiology, risk factors and outcome of bacterial, viral and fungal infections after contemporary HSCT to inform future infection prophylaxis strategies. Method We retrospectively reviewed the first 100 consecutive HSCT for malignant and non-malignant diseases from April 2019 to October 2021 in the only pediatric HSCT center in Hong Kong. The incidences were recorded and risk factors were analyzed for bacterial, viral and fungal infections and infection-related mortality. Results The vast majority of the allogeneic transplant recipients (69/74, 93.2%) had infections after HSCT, amongst which bacterial, viral and fungal infection rate was 35.1%, 90.5% and 9.5% respectively. In contrast, only 30.8% (8/26) of autologous transplant recipients had infections, and their respective rate of bacterial, viral and fungal infection was 19.2%, 15.4% and 3.8%. HHV-6 and BKV typically occurred early after HSCT, ADV and varicella zoster virus (VZV) thereafter, and CMV and EBV throughout the entire 2.5-year observation period. The cumulative incidences of HHV-6 and BKV were significantly higher in patients receiving umbilical cord blood (UCB) or haploidentical stem cell transplant (p = 0.0001; p <0.0001, respectively) when compared with matched sibling (MSD) or matched unrelated donor (MUD) transplant (Figure 1 and 2). Ex vivo T-cell depletion was a general risk factor for viral infection with HHV-6 (HR = 3.03), BKV (HR = 3.36), CMV (HR = 4.45) and EBV (HR = 7.15); all p < 0.02. Cancer in second- compared with first-complete remission was a risk factor for bacterial infection in multivariate analyses (OR = 6.0, 95% CI = 1.12-32.2, p = 0.037). Patients with gut graft-versus-host disease were at risk for fungal infections (OR = 12.3, 95% CI = 1.33-114.4, p = 0.027). The infection-related mortality (IRM) rate was 10%, which occurred only in allogeneic HSCT patients with hematological malignancies receiving cord blood (n = 4) or haploidentical HSCT (n = 6). History of bacterial infection after HSCT was associated with an increased risk of IRM (HR = 4.13, 95% CI = 1.05-16.3, p = 0.042). Conclusion Not all HSCT recipients are of equal risk to infections and IRM. Our findings in pediatric patients after contemporary HSCT support both time-dependent and risk-adapted measures against infective complications to improve transplant outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incompleteness of health-related quality of life assessments before left ventricular assist device implant: A novel quality metric.

Improved health-related quality of life (HRQOL) is an important outcome following durable left ventricular assist device (LVAD) implant. However, half of pre-implant HRQOL data are incomplete in The Society of Thoracic Surgeons' Intermacs registry. Pre-implant HRQOL incompleteness may reflect patient status or hospital resources to capture HRQOL data. We hypothesized that pre-implant HRQOL incompleteness predicts 90 day outcomes and serves as a novel quality metric. Risk factors for pre-implant HRQOL (EQ-5D-5L visual analog scale; 12-item Kansas City Cardiomyopathy Questionnaire "KCCQ") incompleteness were examined by stepwise logistic modeling. Direct standardization method was used to calculate adjusted incompleteness rates using a mixed effects logistic model. Hospitals were dichotomized as low or high based on median adjusted incompleteness rates. Andersen-Gill models were used to associate pre-implant HRQOL adjusted incompleteness rate with adverse events within 90 day post-implant. The study cohort included 14,063 patients receiving a primary LVAD (4/2012-8/2017). HRQOL incompleteness at high-rate hospitals was more often due to administrative reasons (risk difference, EQ-5D: 10.1%; KCCQ-12: 11.6%) and less likely due to patient reasons (risk difference, EQ-5D: -8.9%; KCCQ-12: -11.4%). A 10% increase in the adjusted pre-implant EQ-5D incompleteness rate was significantly associated with higher risk of infection-related mortality (HR: 1.09), infection (HR: 1.05), and renal dysfunction (HR: 1.03). A 10% increase in the adjusted pre-implant KCCQ-12 incompleteness rate was significantly associated with higher risk of infection (HR: 1.04). Hospital adjusted pre-implant HRQOL incompleteness was predictive of 90-day post-implant outcomes and may serve as a novel quality metric.

Serum alkaline phosphatase and infection-related mortality in hemodialysis patients: ten-year outcomes of the Q-cohort study.

High serum alkaline phosphatase (ALP) levels are associated with excess all-cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the long-term relationship between serum ALP levels and infection-related mortality remains unclear. A total of 3502 maintenance HD patients were registered in the Q-Cohort Study, an observational cohort study in Japan. The primary outcome was infection-related mortality during a 10-year follow-up period. The covariate of interest was serum ALP levels at baseline. The association between serum ALP levels and infection-related mortality was calculated using a Cox proportional hazards model and a Fine-Gray subdistribution hazards model with non-infection-related death as a competing risk. During the follow-up period, 446 patients died of infection. According to their baseline serum ALP levels, the patients were categorized into sex-specific quartiles (Q1-Q4). Compared with patients in the lowest serum ALP quartile (Q1), those in the highest quartile (Q4) had a significantly higher multivariable-adjusted hazard ratio (HR) of 1.70 [95% confidence interval (CI) 1.24-2.32] for infection-related mortality. Furthermore, the HR for every 50U/L increase in serum ALP levels was 1.24 (95% CI 1.12-1.36) for infection-related mortality. These associations remained consistent in the competing risk model: subdistribution HR, 1.47; 95% CI 1.07-2.03 for Q4 compared with Q1. Higher serum ALP levels were significantly associated with a higher risk of infection-related mortality in patients undergoing HD.

Soluble suppression of tumorigenesis-2 is a strong predictor of all-cause, cardiovascular and infection-related mortality risk in haemodialysis patients with diabetes mellitus

ABSTRACTBackgroundSoluble suppression of tumorigenesis-2 (sST2) is a strong prognostic biomarker of cardiovascular (CV) disease. End-stage kidney disease (ESKD) patients are at high risk of CV events and infections. Herein we investigated the utility of sST2 to predict all-cause and cause-specific mortality in haemodialysis (HD) patients with diabetes mellitus.MethodssST2 concentrations were measured in plasma samples of 1196 participants of the German Diabetes and Dialysis (4D) study who had type 2 diabetes mellitus and received maintenance HD for ESKD. Hazard ratios (HRs) for prespecified, adjudicated endpoints were determined according to sST2 levels at baseline by multivariate Cox proportional hazards analysis.ResultsParticipants (mean age 66 years, 54% male) had a median sST2 concentration of 25 ng/mL and were followed up for 4 years. After adjustment for possible confounders, participants with sST2 concentrations in the highest (>32.6 ng/mL) compared with the lowest (<20.1 ng/mL) quartile exhibited a 2-fold higher all-cause mortality risk {[HR 2.06 95% confidence interval (CI) 1.61–2.61]; P < .001}. High sST concentrations (fourth versus first quartile) were strongly associated with the risk of cardiac death [HR 2.29 (95% CI 1.55–3.39); P < .001]. Analysis of individual components of cardiac causes of death showed an increased risk of sudden death [HR 2.24 (95% CI 1.33–3.77); P < .001], death due to myocardial infarction [HR 2.12 (95% CI 0.9–5.0); P = .087] and heart failure [HR 3.34 (95% CI 1.15–9.75); P = .027] in participants with sST2 levels in the highest compared with the lowest quartile. Likewise, participants with the highest sST2 levels had an increased risk of fatal stroke [HR 1.92 (95% CI 1.17–3.14); P = .009] and fatal infections [HR 2.01 (95% CI 1.2–3.37); P = .008]. In contrast to fatal CV events, sST2 was not associated with the risk of non-fatal myocardial infarction [HR 0.68 (95% CI 0.41–1.12); P = .132] or non-fatal stroke [HR 1.28 (95% CI 0.64–2.53); P = .485].ConclusionsIn HD patients with diabetes mellitus, high concentrations of sST2 were strongly and independently associated with an increased risk of all-cause mortality, CV mortality and death due to infection but not non-fatal CV events.

Mortality in solid organ transplant recipients with COVID-19: More than meets the eye

Mortality in solid organ transplant recipients with COVID-19: More than meets the eye

Pre-infection HDL-cholesterol levels and mortality among elderly patients infected with SARS-CoV-2

Background and aimsLow HDL-cholesterol (HDLc) concentration is associated with a greater risk of infection-related mortality. We wanted to evaluate the relationship between pre-infection HDLc levels and mortality among older patients infected with SARS-Cov-2. MethodsThis is a population-based, cohort study, comprising all individuals residing in Madrid (Spain) born before 1 January 1945, and alive on 31 December 2019. Demographic, clinical, and analytical data were obtained from the primary care electronic clinical records. Confirmed SARS-CoV-2 infection was defined as a positive result in the RT-qPCR or in the antigen test. A death from COVID-19 was defined as that registered in the hospital chart, or as any death occurring in the 15 days following a confirmed SARS-CoV-2 infection. Data on infection, hospitalization, or death due to SAR-CoV-2 were collected from 1 March 2020 through 31 December 2020. ResultsOf the 593,342 individuals comprising the cohort, 36,966 had a SARS-CoV-2 infection during 2020, and at least one HDLc measurement in the previous five years. Among them, 9689 (26.2%) died from COVID-19. After adjustment for age and sex, the relative risk (95% confidence interval) of COVID-19 death across increasing quintiles of HDLc was 1.000, 0.896 (0.855–0.940), 0.816 (0.776–0.860), 0.758 (0.719–0.799), and 0.747 (0.708–0.787). The association was maintained after further adjustment for comorbidities, statin treatment and markers of malnutrition. While in females this association was linear, in males it showed a U-shaped curve. ConclusionsIn older subjects, a higher HDLc measured before SARS-CoV-2 infection was associated with a lower risk of death.

Association of serum globulin with all-cause mortality in incident hemodialysis patients.

Serum globulin is a major component of total protein and can be elevated in inflammatory disease states. While inflammation is common in hemodialysis patients and associated with mortality and morbidity, the association between serum globulin and mortality has never been examined in hemodialysis patients. In a retrospective cohort of 104 164 incident hemodialysis patients treated by a large dialysis organization from 2007 to 2011, we explored the association between baseline serum globulin, albumin: globulin (A:G) ratio and serum protein levels and all-cause, cardiovascular and infection-related mortality with adjustments for demographic variables and laboratory markers of malnutrition and inflammation using Cox proportional hazards models. Patients with a globulin concentration >3.8g/dL had a higher all-cause and infection-related mortality risk {hazard ratio [HR] 1.11 [95% confidence interval (CI) 1.06-1.16] and HR 1.28 [95% CI 1.09-1.51], respectively} in the fully adjusted model when compared with the reference group of 3.0-<3.2g/dL. In addition, patients with an A:G ratio <0.75had a 45% higher all-cause mortality hazard [HR 1.45 (95% CI 1.38-1.52)] and patients with total serum protein <5.5g/dLhad a 34% higher risk of death [1.34 (95% CI 1.27-1.42)] when compared with the reference (A:G ratio 1.05-<1.15 and total serum protein 6.5-<7g/dL). Among incident hemodialysis patients, a higher globulin level was associated with a higher mortality risk independent of other markers of malnutrition and inflammation, including albumin. A lower A:G ratio and serum protein was also associated with a higher mortality hazard. The mechanisms that contribute to elevated serum globulin should be further explored.

Cigarette Smoking and Risk of Infection-Related Mortality: A Cohort Study.

Cigarette smoking is a leading cause of death worldwide and is associated with various diseases. However, studies addressing its impact on infection-related deaths are limited. This study examined the relationship between smoking and infection-related mortality. A cohort of 583 034 South Korean adults who underwent annual or biennial health examinations were followed up for infection-related deaths using national records. Cox proportional hazards regression assessed hazard ratios (HRs) and 95% confidence intervals (CIs) for infection-related mortality. The median follow-up was 9.1 years (maximum 18 years), and 335 infection-related deaths were identified. Current smoking, but not former smoking, was positively associated with an increased risk of infection-related mortality. After adjusting for possible confounders, the multivariable-adjusted HRs (95% CIs) for infection-related mortality comparing former and current smokers with never smokers were 0.94 (0.68-1.30) and 1.45 (1.05-2.02), respectively; and those for infection-related mortality by number of pack-years comparing 10-19.9 and ≥20 pack-years to <10 pack-years were 1.26 (0.81-1.96) and 1.47 (1.03-2.09), respectively, while those comparing 10-19 and ≥20 cigarettes/day to <10 cigarettes/day were 1.35 (0.86-2.11) and 1.54 (1.13-2.11), respectively (p for trend <.05). Individuals with ≥20 pack-years had a 2.06 times greater risk of infection-related mortality when changes in smoking status and confounders during follow-up were updated in the analysis as time-varying covariates. Current smoking status, intensity, and pack-years were associated with an increased risk of infection-related death, with the highest risk of infection-related mortality found consistently in individuals with ≥20 pack-years. In this large-scale cohort study of relatively young and middle-aged South Korean adults, current smoking, smoking intensity, and pack-years were associated with an increased risk of death due to infections; in particular, a significantly increased risk of infection-related mortality was consistently found in individuals with ≥20 pack-years. When appropriate, infection-related mortality should be included in smoking-attributable mortality burdens, and effective smoking control measures should be considered to improve infection-related mortality.

Outcomes among Hospitalized Chronic Kidney Disease Patients with COVID-19.

Patients with CKD ha ve impaired immunity, increased risk of infection-related mortality, and worsened COVID-19 outcomes. However, data comparing nondialysis CKD and ESKD are sparse. Patients with COVID-19 admitted to three hospitals in the New York area, between March 2 and August 27, 2020, were retrospectively studied using electronic health records. Patients were classified as those without CKD, those with nondialysis CKD, and those with ESKD, with outcomes including hospital mortality, ICU admission, and mortality rates. Of 3905 patients, 588 (15%) had nondialysis CKD and 128 (3%) had ESKD. The nondialysis CKD and ESKD groups had a greater prevalence of comorbidities and higher admission D-dimer levels, whereas patients with ESKD had lower C-reactive protein levels at admission. ICU admission rates were similar across all three groups (23%-25%). The overall, unadjusted hospital mortality was 25%, and the mortality was 24% for those without CKD, 34% for those with nondialysis CKD, and 27% for those with ESKD. Among patients in the ICU, mortality was 56%, 64%, and 56%, respectively. Although patients with nondialysis CKD had higher odds of overall mortality versus those without CKD in univariate analysis (OR, 1.58; 95% CI, 1.31 to 1.91), this was no longer significant in fully adjusted models (OR, 1.11; 95% CI, 0.88 to 1.40). Also, ESKD status did not associate with a higher risk of mortality compared with non-CKD in adjusted analyses, but did have reduced mortality when compared with nondialysis CKD (OR, 0.57; 95% CI, 0.33 to 0.95). Mortality rates declined precipitously after the first 2 months of the pandemic, from 26% to 14%, which was reflected in all three subgroups. In a diverse cohort of patients with COVID-19, we observed higher crude mortality rates for patients with nondialysis CKD and, to a lesser extent, ESKD, which were not significant after risk adjustment. Moreover, patients with ESKD appear to have better outcom es than those with nondialysis CKD.

POS-633 TRENDS IN MORTALITY AMONG PERITONEAL DIALYSIS PATIENTS ACROSS TIME PERIODS: THE IMPACT OF PERITONEAL DIALYSIS-RELATED PERITONITIS

As the global burden of chronic kidney disease continues to increase, so does the need for a cost-effective renal replacement therapy. Peritoneal dialysis (PD) offers several advantages in end-stage renal disease but infectious peritonitis (IP) remains one of the most serious and life threatening complications of PD. The purpose of this study is to assess the prevalence and to evaluate the impact of peritonitis on patient mortality and technique survival with respect to duration of follow-up. We conducted a twenty seven years retrospective study from 1990 till december 2017 in the nephrology department, Fattouma Bourguiba University Hospital (Monastir, Tunisia). The rate of peritonitis, the causative organisms as well as the patient's outcome after its occurrence have been analyzed. We used the Cox regression model to assess whether peritonitis has a negative impact on mortality. The 476 episodes of IP were identified in 206 patients. The mean age of our patients was 45.8.1±16.8 years [11–86] (male to female: sex ratio M/F=2.43). The peritonitis rate (months × patients/peritonitis) was 17.6 (0.68 episode per year). Time to occurrence of peritonitis from the start of peritoneal exchange was 14.53±14 months. Gram-positive cocci (GC+) were involved in 54.7% of microbiologically proven IP cases presented mostly by Staphylococcus aureus. Gram-negative bacilli (GB-) ranked second (37.7%) represented mainly by Pseudomonas. The peritonitis was the main influencing factor on the technique survival causing ultrafiltration failure (p=0.02). The median survival of the DP technique was 68 months (95%, CI [47, 90]). After adjusting for confounders, peritonitis was independently associated with 95% increased risk of all-cause mortality and near 4-fold increased risk of infection-related mortality (hazard ratio, 4.98; 95% confidence interval: 2.47–8.86). Further analyses showed that peritonitis strongly influenced mortality in patients dialysed within the first 2 years. Peritonitis was independently associated with higher risk of all-cause and infection-related mortality in peritoneal dialysis patients, and its impact on technique survival was determinate. Despite the gradual decrease of its rate over periods, peritonitis remains frequent in our center and calls for optimization of means of prevention.

Outcomes of Infection and Risk of Mortality in Liver Transplant Patients with Simultaneous Splenectomy

PurposeThe purpose of this study was to compare the outcomes of infection between liver transplant patients with and without simultaneous splenectomy. MethodsWe retrospectively analyzed the records of 211 patients who underwent liver transplantation in the Tri-Service General Hospital from 2012 to 2017. The frequency of blood cultures obtained after liver transplantation; incidence of bacteremia, pathogens, and complications; and overall survival rates were compared between the groups. ResultsOne hundred thirty-three of 211 patients underwent liver transplantation without simultaneous splenectomy. There were no significant differences in the frequency of blood cultures obtained after liver transplantation (non-splenectomy group and splenectomy group: 63% and 62%, respectively); incidences of bacteremia after liver transplantation (21% and 21%, respectively), repeat bacteremia (39% and 35%, respectively), cytomegalovirus infection (4% and 3%, respectively), herpes infection (6% and 7%, respectively), and fungal infection (3% and 3%, respectively); and overall survival rate between the two groups. However, there was a significant difference in infection-related deaths between the groups. Simultaneous splenectomy and episodes of antibody-related rejection were significant risk factors associated with infection-related death in multivariate analyses. ConclusionAlthough simultaneous splenectomy does not increase the incidence of infection, simultaneous splenectomy definitely carries risks of infection-related mortality in liver transplantation.

Association of kidney transplantation with mortality on hemodialysis after graft failure.

Although a substantial number of patients return to dialysis after kidney transplant failure, it remains controversial whether transplant-failure patients have a higher mortality risk than transplant-naïve patients on dialysis who have never undergone kidney transplantation. We compared outcomes of transplant-failure and transplant-naïve patients on hemodialysis. Data from the Japanese National Dialysis Registry (2012-2013) were analyzed, including 220,438 prevalent hemodialysis patients. Multivariable Cox models were used to compare all-cause, cardiovascular, and infection-related mortality during 1-year follow-up between transplant-failure and transplant-naïve patients. Multiple imputation and propensity score matching were utilized as sensitivity analyses. During 209,377 patient-years of follow-up, 18,648 all-cause deaths (8.5% of all patients), 7700 cardiovascular deaths (41% of all-cause deaths), and 3806 infection-related deaths (20% of all-cause deaths) were observed. Adjusted hazard ratios [95% confidence intervals] for all-cause, cardiovascular, and infection-related deaths among transplant-failure patients were 0.81 [0.59-1.11], 0.54 [0.30-0.98], and 1.54 [0.92-2.59], respectively. Sensitivity analyses using multiple imputation and propensity score matching yielded similar results. This Japanese cohort study suggested that a cardiovascular mortality risk of transplant-failure patients could be significantly lower than that of transplant-naïve patients, while there might be a trend toward a higher infection-related mortality risk in transplant-failure patients. However, this retrospective, single-country study can introduce an immortal time bias in transplant-failure patients, and limit the external validity. Further prospective studies are warranted to improve the comparability of outcomes between transplant-failure and transplant-naïve patients, and to examine worldwide the generalizability of the potential cardiovascular benefit of kidney transplantation even after returning to dialysis.