Factors Associated with Mortality and Graft Failure in Liver Transplants: A Hierarchical Approach

Background

Liver transplantation has received increased attention in the medical field since the 1980s following the introduction of new immunosuppressants and improved surgical techniques. Currently, transplantation is the treatment of choice for patients with end-stage liver disease, and it has been expanded for other indications. Liver transplantation outcomes depend on donor factors, operating conditions, and the disease stage of the recipient. A retrospective cohort was studied to identify mortality and graft failure rates and their associated factors. All adult liver transplants performed in the state of São Paulo, Brazil, between 2006 and 2012 were studied.

Methods and Findings

A hierarchical Poisson multiple regression model was used to analyze factors related to mortality and graft failure in liver transplants. A total of 2,666 patients, 18 years or older, (1,482 males; 1,184 females) were investigated. Outcome variables included mortality and graft failure rates, which were grouped into a single binary variable called negative outcome rate. Additionally, donor clinical, laboratory, intensive care, and organ characteristics and recipient clinical data were analyzed. The mortality rate was 16.2 per 100 person-years (py) (95% CI: 15.1–17.3), and the graft failure rate was 1.8 per 100 py (95% CI: 1.5–2.2). Thus, the negative outcome rate was 18.0 per 100 py (95% CI: 16.9–19.2). The best risk model demonstrated that recipient creatinine ≥ 2.11 mg/dl [RR = 1.80 (95% CI: 1.56–2.08)], total bilirubin ≥ 2.11 mg/dl [RR = 1.48 (95% CI: 1.27–1.72)], Na⁺ ≥ 141.01 mg/dl [RR = 1.70 (95% CI: 1.47–1.97)], RNI ≥ 2.71 [RR = 1.64 (95% CI: 1.41–1.90)], body surface ≥ 1.98 [RR = 0.81 (95% CI: 0.68–0.97)] and donor age ≥ 54 years [RR = 1.28 (95% CI: 1.11–1.48)], male gender [RR = 1.19(95% CI: 1.03–1.37)], dobutamine use [RR = 0.54 (95% CI: 0.36–0.82)] and intubation ≥ 6 days [RR = 1.16 (95% CI: 1.10–1.34)] affected the negative outcome rate.

Conclusions

The current study confirms that both donor and recipient characteristics must be considered in post-transplant outcomes and prognostic scores. Our data demonstrated that recipient characteristics have a greater impact on post-transplant outcomes than donor characteristics. This new concept makes liver transplant teams to rethink about the limits in a MELD allocation system, with many teams competing with each other. The results suggest that although we have some concerns about the donors features, the recipient factors were heaviest predictors for bad outcomes.     

Hospital Admission following Acute Kidney Injury in Kidney Transplant Recipients Is Associated with a Negative Impact on Graft Function after 1-Year

The incidence and outcomes of acute kidney injury (AKI) in kidney transplantation are poorly known. Retrospective cohort analysis was performed on the data of all patients (≥3 months after transplantation and ≥16 years of age) admitted to the hospital due to medical or surgical complications from 2007 to 2010. We analyzed 458 kidney transplant recipients, 55.2% men, median age 49 (IQR, 36–58) years, median of 12.5 (IQR, 3–35) months after kidney transplantation; admitted to the hospital due to medical or surgical complications. Most of the patients received a kidney from a deceased donor (62.2%), the primary cause for hospital admission was infection (60.7%) and 57 (12.4%) individuals were diagnosed with acute rejection (AR). The incidence of AKI was 82.3%: 31.9% stage 1, 29.3% stage 2 and 21.2% stage 3. Intensive care unit (ICU) admission (OR 8.90, 95% CI: 1.77–44.56 p = 0.008), infection (OR 5.73, 95% CI: 2.61–12.56, p<0.001) and the use of contrast media (OR 9.34, 95% CI: 2.04–42.70, p = 0.004) were the independent risk factors for AKI development. The mortality rate was 2.1% and all patients who died were diagnosed with AKI. Even after the exclusion of AR cases, at the end of 12 months, the individuals with AKI exhibited higher percent changes in creatinine values when compared with individuals without AKI (9.1% vs. -4.3%; p<0.001). According to KDIGO system, we found a high incidence of AKI among the complications of renal transplantation. As in other scenarios, AKI was associated with renal function loss at 1-year after the hospital discharge.     

Readmissions after Hospitalization for Heart Failure,Acute Myocardial Infarction,or Pneumonia among Young and Middle-Aged Adults: A Retrospective Observational Cohort Study

Background

Patients aged ≥65 years are vulnerable to readmissions due to a transient period of generalized risk after hospitalization. However, whether young and middle-aged adults share a similar risk pattern is uncertain. We compared the rate, timing, and readmission diagnoses following hospitalization for heart failure (HF), acute myocardial infarction (AMI), and pneumonia among patients aged 18–64 years with patients aged ≥65 years.

Methods and Findings

We used an all-payer administrative dataset from California consisting of all hospitalizations for HF (n = 206,141), AMI (n = 107,256), and pneumonia (n = 199,620) from 2007–2009. The primary outcomes were unplanned 30-day readmission rate, timing of readmission, and readmission diagnoses. Our findings show that the readmission rate among patients aged 18–64 years exceeded the readmission rate in patients aged ≥65 years in the HF cohort (23.4% vs. 22.0%, p<0.001), but was lower in the AMI (11.2% vs. 17.5%, p<0.001) and pneumonia (14.4% vs. 17.3%, p<0.001) cohorts. When adjusted for sex, race, comorbidities, and payer status, the 30-day readmission risk in patients aged 18–64 years was similar to patients ≥65 years in the HF (HR 0.99; 95%CI 0.97–1.02) and pneumonia (HR 0.97; 95%CI 0.94–1.01) cohorts and was marginally lower in the AMI cohort (HR 0.92; 95%CI 0.87–0.96). For all cohorts, the timing of readmission was similar; readmission risks were highest between days 2 and 5 and declined thereafter across all age groups. Diagnoses other than the index admission diagnosis accounted for a substantial proportion of readmissions among age groups <65 years; a non-cardiac diagnosis represented 39–44% of readmissions in the HF cohort and 37–45% of readmissions in the AMI cohort, while a non-pulmonary diagnosis represented 61–64% of patients in the pneumonia cohort.

Conclusion

When adjusted for differences in patient characteristics, young and middle-aged adults have 30-day readmission rates that are similar to elderly patients for HF, AMI, and pneumonia. A generalized risk after hospitalization is present regardless of age. Please see later in the article for the Editors'' Summary     

Human Papillomavirus Vaccine Uptake among Individuals with Systemic Inflammatory Diseases

ObjectivesThe human papillomavirus (HPV) vaccine is safe and efficacious in patients with systemic inflammatory diseases (SID) who have higher rates of persistent HPV infection. We compared HPV vaccine uptake among SID and non-SID patients.MethodsUsing a U.S. insurance claims database (2006–2012), we identified individuals 9–26 years with ≥2 SID diagnosis codes ≥7 days apart with ≥12 months of continuous enrollment prior to the second code (index date). We matched SID patients by age, sex and index date to randomly selected non-SID subjects and selected those with ≥24 months of post-index date continuous follow-up. We also identified a non-SID subcohort with ≥1 diagnosis code for asthma. We defined initiation as ≥1 HPV vaccination claim after 2007, and completion as 3 claims. We used multivariable logistic regression to assess uptake in females 11–26 years comparing SID, non-SID and asthma cohorts, adjusting for demographics, region, comorbidities, and healthcare utilization.ResultsWe identified 5,642 patients 9–26 years with SID and 20,643 without. The mean age was 18.1 years (SD 4.9). We identified 1,083 patients with asthma; the mean age was 17.2 (SD 5.1). Among females, 20.6% with SID, 23.1% without SID and 22.9% with asthma, received ≥1 HPV vaccine. In our adjusted models, the odds of receipt of ≥1 vaccine was 0.87 times lower in SID (95% CI 0.77–0.98) compared to non-SID and did not differ for 3 vaccines (OR 1.03, 95% CI 0.83–1.26). The odds of initiation and completion were not statistically different between SID and non-SID asthma cohorts.ConclusionsIn this nationwide cohort, HPV vaccine uptake was extremely low. Despite the heightened risk of persistent HPV infection among those with SID, no increase in HPV vaccine uptake was observed. Public health efforts to promote HPV vaccination overall are needed, and may be particularly beneficial for those at higher risk.     

Prevalence and Predictors of Early Cardiovascular Events after Kidney Transplantation: Evaluation of Pre-Transplant Cardiovascular Work-Up

Introduction

Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up.

Material and Method

In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed.

Results

Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06–4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04–3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 –5.96], p = 0.03). Pre-transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients.     

Recipient-Related Risk Factors for Graft Failure and Death in Elderly Kidney Transplant Recipients

Background

Elderly patients with end-stage renal disease have become the fastest growing population of kidney transplant candidates in recent years. However, the risk factors associated with long-term outcomes in these patients remain unclear.

Methods

We retrospectively analyzed 166 recipients aged 60 years or older who underwent primary deceased kidney transplantation between 2002 and 2013 in our center. The main outcomes included 1-, 3- and 5-year patient survival as well as overall and death-censored graft survival. The independent risk factors affecting graft and patient survival were analyzed using Cox regression analysis.

Results

The 1-, 3-, 5-year death-censored graft survival rates were 93.6%, 89.4% and 83.6%, respectively. Based on the Cox multivariate analysis, panel reactive antibody (PRA)>5% [hazard ratio (HR) 4.295, 95% confidence interval (CI) 1.321–13.97], delayed graft function (HR 4.744, 95% CI 1.611–13.973) and acute rejection (HR 4.971, 95% CI 1.516–16.301) were independent risk factors for graft failure. The 1-, 3-, 5-year patient survival rates were 84.8%, 82.1% and 77.1%, respectively. Longer dialysis time (HR 1.011 for 1-month increase, 95% CI 1.002–1.020), graft loss (HR 3.501, 95% CI 1.559–7.865) and low-dose ganciclovir prophylaxis (1.5 g/d for 3 months) (HR 3.173, 95% CI 1.063–9.473) were risk factors associated with patient death.

Conclusions

The five-year results show an excellent graft and patient survival in elderly kidney transplant recipients aged ≥60 years. PRA>5%, delayed graft function, and acute rejection are risk factors for graft failure, while longer duration of dialysis, graft loss and low-dose ganciclovir prophylaxis are risk factors for mortality in elderly recipients. These factors represent potential targets for interventions aimed at improving graft and patient survival in elderly recipients.     

The International Heart Transplant Survival Algorithm (IHTSA): A New Model to Improve Organ Sharing and Survival

Background

Heart transplantation is life saving for patients with end-stage heart disease. However, a number of factors influence how well recipients and donor organs tolerate this procedure. The main objective of this study was to develop and validate a flexible risk model for prediction of survival after heart transplantation using the largest transplant registry in the world.

Methods and Findings

We developed a flexible, non-linear artificial neural networks model (IHTSA) and classification and regression tree to comprehensively evaluate the impact of recipient-donor variables on survival over time. We analyzed 56,625 heart-transplanted adult patients, corresponding to 294,719 patient-years. We compared the discrimination power with three existing scoring models, donor risk index (DRI), risk-stratification score (RSS) and index for mortality prediction after cardiac transplantation (IMPACT). The accuracy of the model was excellent (C-index 0.600 [95% CI: 0.595–0.604]) with predicted versus actual 1-year, 5-year and 10-year survival rates of 83.7% versus 82.6%, 71.4% – 70.8%, and 54.8% – 54.3% in the derivation cohort; 83.7% versus 82.8%, 71.5% – 71.1%, and 54.9% – 53.8% in the internal validation cohort; and 84.5% versus 84.4%, 72.9% – 75.6%, and 57.5% – 57.5% in the external validation cohort. The IHTSA model showed superior or similar discrimination in all of the cohorts. The receiver operating characteristic area under the curve to predict one-year mortality was for the IHTSA: 0.650 (95% CI: 0.640–0.655), DRI 0.56 (95% CI: 0.56–0.57), RSS 0.61 (95% CI: 0.60–0.61), and IMPACT 0.61 (0.61–0.62), respectively. The decision-tree showed that recipients matched to a donor younger than 38 years had additional expected median survival time of 2.8 years. Furthermore, the number of suitable donors could be increased by up to 22%.

Conclusions

We show that the IHTSA model can be used to predict both short-term and long-term mortality with high accuracy globally. The model also estimates the expected benefit to the individual patient.     

Risk and Outcome after Ablation of Isthmus-Dependent Atrial Flutter in Elderly Patients

MethodsA total of 1187 patients with a mean age 65±12 years consecutively referred for AFL ablation were retrospectively analyzed in the study.Results445 (37.5%) patients were aged ≥70 (range 70 to 93) among which 345 were aged 70 to 79 years (29.1%) and 100 were aged ≥80 (8.4%). In multivariable analysis, AFL-related rhythmic cardiomyopathy and presentation with 1/1 AFL were less frequent (respectively adjusted OR = 0.44, 0.27–0.74, p = 0.002 and adjusted OR = 0.29, 0.16–0.52, p<0.0001). AFL ablation-related major complications were more frequent in patients ≥70 although remained lower than 10% (7.4% in ≥70 vs. 4.2% in <70, adjusted OR = 1.74, 1.04–2.89, p = 0.03). After 2.1±2.7 years, AFL recurrence was less frequent in patients ≥70 (adjusted OR = 0.54, 0.37–0.80, p = 0.002) whereas atrial fibrillation (AF) occurrence was as frequent in the 70–79 and ≥80 age subsets. As expected, cardiac mortality was higher in older patients. Patients aged ≥80 also had a low probability of AFL recurrence (5.0%) and AF onset (19.0%).ConclusionsOlder patients represent 37.5% of patients referred for AFL ablation and displayed a <10% risk of ablation-related complications. Importantly, AFL recurrences were less frequent in patients ≥70 while AF occurrence was as frequent as in patients <70. Similar observations were made in patients ≥80 years. AFL ablation appears to be safe and efficient and should not be ruled out in elderly patients.     

Mortality Predictors in Renal Transplant Recipients with Severe Sepsis and Septic Shock

Introduction

The growing number of renal transplant recipients in a sustained immunosuppressive state is a factor that can contribute to increased incidence of sepsis. However, relatively little is known about sepsis in this population. The aim of this single-center study was to evaluate the factors associated with hospital mortality in renal transplant patients admitted to the intensive care unit (ICU) with severe sepsis and septic shock.

Methods

Patient demographics and transplant-related and ICU stay data were retrospectively collected. Multiple logistic regression was conducted to identify the independent risk factors associated with hospital mortality.

Results

A total of 190 patients were enrolled, 64.2% of whom received kidneys from deceased donors. The mean patient age was 51±13 years (males, 115 [60.5%]), and the median APACHE II was 20 (16–23). The majority of patients developed sepsis late after the renal transplantation (2.1 [0.6–2.3] years). The lung was the most common infection site (59.5%). Upon ICU admission, 16.4% of the patients had ≤1 systemic inflammatory response syndrome criteria. Among the patients, 61.5% presented with ≥2 organ failures at admission, and 27.9% experienced septic shock within the first 24 hours of ICU admission. The overall hospital mortality rate was 38.4%. In the multivariate analysis, the independent determinants of hospital mortality were male gender (OR = 5.9; 95% CI, 1.7–19.6; p = 0.004), delta SOFA 24 h (OR = 1.7; 95% CI, 1.2–2.3; p = 0.001), mechanical ventilation (OR = 30; 95% CI, 8.8–102.2; p<0.0001), hematologic dysfunction (OR = 6.8; 95% CI, 2.0–22.6; p = 0.002), admission from the ward (OR = 3.4; 95% CI, 1.2–9.7; p = 0.02) and acute kidney injury stage 3 (OR = 5.7; 95% CI,1.9–16.6; p = 0.002).

Conclusions

Hospital mortality in renal transplant patients with severe sepsis and septic shock was associated with male gender, admission from the wards, worse SOFA scores on the first day and the presence of hematologic dysfunction, mechanical ventilation or advanced graft dysfunction.     

Pre-Transplant Depression Is Associated with Length of Hospitalization,Discharge Disposition,and Survival after Liver Transplantation

Depression after liver transplantation has been associated with decreased survival, but the effects of pre-transplant depression on early and late post-transplant outcomes remain incompletely evaluated. We assessed all patients who had undergone single-organ liver transplantation at a single center over the prior 10 years. A diagnosis of pre-transplant depression, covariates, and the outcomes of interest were extracted from the electronic medical record. Potential covariates included demographics, etiology and severity of liver disease, comorbidities, donor age, graft type, immunosuppression, and ischemic times. In multivariable models adjusting for these factors, we evaluated the effect of pre-transplant depression on transplant length of stay (LOS), discharge disposition (home vs. facility) and long-term survival. Among 1115 transplant recipients with a median follow-up time of 5 years, the average age was 56±11 and MELD was 12±9. Nineteen percent of the study population had a history of pre-transplant depression. Pre-transplant depression was associated with longer LOS (median = 19 vs. 14 days, IRR = 1.25, CI = 1.13,1.39), discharge to a facility (36% vs. 25%, OR 1.70,CI = 1.18,2.45), and decreased survival (HR = 1.54,CI = 1.14,2.08) in this cohort, accounting for other potential confounders. In conclusion, pre-transplant depression was significantly associated with longer transplant length of stay, discharge to a facility, and mortality in this cohort.     

Seven-Day Mortality Can Be Predicted in Medical Patients by Blood Pressure,Age, Respiratory Rate,Loss of Independence,and Peripheral Oxygen Saturation (the PARIS Score): A Prospective Cohort Study with External Validation

Background

Most existing risk stratification systems predicting mortality in emergency departments or admission units are complex in clinical use or have not been validated to a level where use is considered appropriate. We aimed to develop and validate a simple system that predicts seven-day mortality of acutely admitted medical patients using routinely collected variables obtained within the first minutes after arrival.

Methods and Findings

This observational prospective cohort study used three independent cohorts at the medical admission units at a regional teaching hospital and a tertiary university hospital and included all adult (≥15 years) patients. Multivariable logistic regression analysis was used to identify the clinical variables that best predicted the endpoint. From this, we developed a simplified model that can be calculated without specialized tools or loss of predictive ability. The outcome was defined as seven-day all-cause mortality. 76 patients (2.5%) met the endpoint in the development cohort, 57 (2.0%) in the first validation cohort, and 111 (4.3%) in the second. Systolic blood Pressure, Age, Respiratory rate, loss of Independence, and peripheral oxygen Saturation were associated with the endpoint (full model). Based on this, we developed a simple score (range 0–5), ie, the PARIS score, by dichotomizing the variables. The ability to identify patients at increased risk (discriminatory power and calibration) was excellent for all three cohorts using both models. For patients with a PARIS score ≥3, sensitivity was 62.5–74.0%, specificity 85.9–91.1%, positive predictive value 11.2–17.5%, and negative predictive value 98.3–99.3%. Patients with a score ≤1 had a low mortality (≤1%); with 2, intermediate mortality (2–5%); and ≥3, high mortality (≥10%).

Conclusions

Seven-day mortality can be predicted upon admission with high sensitivity and specificity and excellent negative predictive values.     

Severity of COVID-19 among solid organ transplant recipients in Canada, 2020–2021: a prospective,multicentre cohort study

Background:Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe COVID-19 outcomes among recipients of organ transplants across Canada.Methods:We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen.Results:A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (n = 190), compared with not needing (n = 319), supplemental oxygen included age (median 62.6 yr, interquartile range [IQR] 52.5–69.5 yr v. median 55.5 yr, IQR 47.5–66.5; p < 0.001) and number of comorbidities (median 3, IQR 2–3 v. median 2, IQR 1–3; p < 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (n = 48) were more likely to have severe disease with a high mortality rate (n = 15, 31.3%) compared with recipients of other organ transplants, including kidney (n = 48, 14.8%), heart (n = 1, 4.4%), liver (n = 9, 11.4%) and kidney–pancreas (n = 3, 12.0%) transplants (p = 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02–1.07) and number of comorbidities (OR 1.63, 95% CI 1.30–2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly.Interpretation:Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.

Recipients of solid organ transplants take life-long immunosuppressive agents to prevent rejection. In Canada, an estimated 3000 transplant procedures are performed annually and 40 000 people are living with a transplant. Early studies from Europe and the United States suggested that transplant recipients were at greater risk of severe COVID-19, with a two- to fivefold greater mortality than the general population.^1–3 It is unclear whether the increased risk is owing to multiple comorbidities, immunosuppression or a combination of both factors.Initial trials of therapeutics for SARS-CoV-2, including remdesivir, dexamethasone and tocilizumab, did not formally include transplant recipients.^4–6 Similarly, pivotal studies of the SARS-CoV-2 vaccines did not include immunocompromised populations.^7,8 Therefore, the use of COVID-19 therapeutics and SARS-CoV-2 vaccines in the transplant population has been extrapolated from the general population. Commonly used COVID-19 therapies such as dexamethasone and tocilizumab may place transplant recipients at risk of over-immunosuppression, which may result in secondary infections. In addition, withdrawal of standard immunosuppression may result in organ rejection.Previous cohort studies of transplant recipients with COVID-19 have primarily focused on the early phase of the pandemic, when therapeutics and vaccinations were limited.^2,9,10 These have generally been single-centre studies with short-term follow-up. Canadian data may differ from that of other countries owing to differences in timing and strategy of vaccine rollouts, as well as use and availability of certain therapeutics. Moreover, current data are limited with regard to longer-term outcomes of COVID-19 in transplant recipients up to 90 days postinfection, especially for the development of graft rejection.We sought to determine factors associated with severe COVID-19 outcomes, to estimate the impact of available therapeutics on COVID-19 severity and to determine whether disease severity changed over the course of the pandemic among recipients of solid organ transplants from 9 centres in Canada.     

Host Factors and Biomarkers Associated with Poor Outcomes in Adults with Invasive Pneumococcal Disease

BackgroundInvasive pneumococcal disease (IPD) causes considerable morbidity and mortality. We aimed to identify host factors and biomarkers associated with poor outcomes in adult patients with IPD in Japan, which has a rapidly-aging population.MethodsIn a large-scale surveillance study of 506 Japanese adults with IPD, we investigated the role of host factors, disease severity, biomarkers based on clinical laboratory data, treatment regimens, and bacterial factors on 28-day mortality.ResultsOverall mortality was 24.1%, and the mortality rate increased from 10.0% in patients aged ˂50 years to 33.1% in patients aged ≥80 years. Disease severity also increased 28-day mortality, from 12.5% among patients with bacteraemia without sepsis to 35.0% in patients with severe sepsis and 56.9% with septic shock. The death rate within 48 hours after admission was high at 54.9%. Risk factors for mortality identified by multivariate analysis were as follows: white blood cell (WBC) count <4000 cells/μL (odds ratio [OR], 6.9; 95% confidence interval [CI], 3.7–12.8, p < .001); age ≥80 years (OR, 6.5; 95% CI, 2.0–21.6, p = .002); serum creatinine ≥2.0 mg/dL (OR, 4.5; 95% CI, 2.5–8.1, p < .001); underlying liver disease (OR, 3.5; 95% CI, 1.6–7.8, p = .002); mechanical ventilation (OR, 3.0; 95% CI, 1.7–5.6, p < .001); and lactate dehydrogenase ≥300 IU/L (OR, 2.4; 95% CI, 1.4–4.0, p = .001). Pneumococcal serotype and drug resistance were not associated with poor outcomes.ConclusionsHost factors, disease severity, and biomarkers, especially WBC counts and serum creatinine, were more important determinants of mortality than bacterial factors.     

Statin Treatment and Mortality in Community-Dwelling Frail Older Patients with Diabetes Mellitus: A Retrospective Observational Study

Background

Older adults are often excluded from clinical trials. Decision making for administration of statins to older patients with diabetes mellitus (DM) is under debate, particularly in frail older patients with comorbidity and high mortality risk. We tested the hypothesis that statin treatment in older patients with DM was differentially effective across strata of mortality risk assessed by the Multidimensional Prognostic Index (MPI), based on information collected with the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA).

Methods

In this retrospective observational study, we estimated the mortality risk in 1712 community-dwelling subjects with DM ≥ 65 years who underwent a SVaMA evaluation to establish accessibility to homecare services/nursing home admission from 2005 to 2013 in the Padova Health District, Italy. Mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) risk of mortality at baseline and propensity score-adjusted hazard ratios (HR) of three-year mortality were calculated according to statin treatment.

Results

Higher MPI-SVaMA scores were associated with lower rates of statin treatment (MPI-SVaMA-1 = 39% vs MPI-SVaMA-2 = 36% vs MPI-SVaMA-3 = 24.9%. p<0.001) and higher three-year mortality (MPI-SVaMA-1 = 12.9% vs MPI-SVaMA-2 = 24% vs MPI-SVaMA-3 = 34.4%, p<0.001). After adjustment for propensity score quintiles, statin treatment was significantly associated with lower three-year mortality irrespective of MPI-SVaMA group (interaction test p = 0.303). HRs [95% confidence interval (CI)] were 0.19 (0.14–0.27), 0.28 (0.21–0.36), and 0.26 (0.20–0.34) in the MPI-SVaMA-1, MPI-SVaMA-2, and MPI-SVaMA-3 groups, respectively. Subgroup analyses showed that statin treatment was also beneficial irrespective of age. HRs (95% CI) were 0.21 (0.15–0.31), 0.26 (0.20–0.33), and 0.26 (0.20–0.35) among patients aged 65–74, 75–84, and ≥ 85 years, respectively (interaction test p=0.812).

Conclusions

Statin treatment was significantly associated with reduced three-year mortality independently of age and multidimensional impairment in community-dwelling frail older patients with DM.     

Excess Mortality Associated with Influenza among Tuberculosis Deaths in South Africa, 1999–2009

Background

Published data on the interaction between influenza and pulmonary tuberculosis (PTB) are limited. We aimed to estimate the influenza-associated mortality among individuals with PTB in South Africa from 1999–2009.

Methods

We modelled the excess influenza-associated mortality by applying Poisson regression models to monthly PTB and non-tuberculosis respiratory deaths, using laboratory-confirmed influenza as a covariate.

Results

PTB deaths increased each winter, coinciding with influenza virus circulation. Among individuals of any age, mean annual influenza-associated PTB mortality rate was 164/100,000 person-years (n = 439). The rate of non-tuberculosis respiratory deaths was 27/100,000 (n = 1125) for HIV-infected and 5/100,000 (n = 2367) for HIV-uninfected individuals of all ages. Among individuals aged <65 years, influenza-associated PTB mortality risk was elevated compared to influenza-associated non-tuberculosis respiratory deaths in HIV-infected (relative risk (RR): 5.2; 95% CI: 4.6–5.9) and HIV-uninfected individuals (RR: 61.0; CI: 41.4–91.0). Among individuals aged ≥65 years, influenza-associated PTB mortality risk was elevated compared to influenza-associated non-tuberculosis respiratory deaths in HIV-uninfected individuals (RR: 13.0; 95% CI: 12.0–14.0).

Conclusion

We observed an increased risk of influenza-associated mortality in persons with PTB compared to non-tuberculosis respiratory deaths. If confirmed in other settings, our findings may support recommendations for active inclusion of patients with TB for influenza vaccination and empiric influenza anti-viral treatment of patients with TB during influenza epidemics.     

Intentional Weight Loss and All-Cause Mortality: A Meta-Analysis of Randomized Clinical Trials

Background

Obesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality.

Methods

2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.

Results

Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30–46 kg/m², follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73–1.00). There was no evidence for heterogeneity of effect (Cochran’s Q = 5.59 (11 d.f.; p = 0.90); I² = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71–0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72–1.00).

Conclusions

In obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.     

Liver Stiffness by Transient Elastography Predicts Liver-Related Complications and Mortality in Patients with Chronic Liver Disease

Background

Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease.

Methods

In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic.

Results

Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0–23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10–19.9, 20–39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03–1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75–0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%).

Conclusions

Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients.     

Vitamin K Intake and Plasma Desphospho-Uncarboxylated Matrix Gla-Protein Levels in Kidney Transplant Recipients

Vitamin K is essential for activation of γ-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (n = 60) with stable renal function (creatinine clearance 61 [42–77] (median [interquartile range]) ml/min), who were 75 [35–188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, p = 0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.     

Liver Grafts for Transplantation from Donors with Diabetes: An Analysis of the Scientific Registry of Transplant Recipients Database

Patients with a history of diabetes mellitus (DM) have worse survival than those without DM after liver transplantation. However, the effect of liver grafts from DM donors on the post-transplantation survival of recipients is unclear. Using the Scientific Registry of Transplant Recipients database (2004–2008), 25,413 patients were assessed. Among them, 2,469 recipients received grafts from donors with DM. The demographics and outcome of patients were assessed. Patient survival was assessed using Kaplan–Meier methodology and Cox regression analyses. Recipients from DM donors experienced worse graft survival than recipients from non-DM donors (one-year survival: 81% versus 85%, and five-year survival: 67% versus 74%, P<0.001, respectively). Graft survival was significantly lower for recipients from DM donors with DM duration >5 years (P<0.001) compared with those with DM duration <5 years. Cox regression analyses showed that DM donors were independently associated with worse graft survival (hazard ratio, 1.11; 95% confidence interval, 1.02–1.19). The effect of DM donors was more pronounced on certain underlying liver diseases of recipients. Increases in the risk of graft loss were noted among recipients from DM donors with hepatitis-C virus (HCV) infection, whereas those without HCV experienced similar outcomes compared with recipients from non-DM donors. These data suggest that recipients from DM donors experience significantly worse patient survival after liver transplantation. However, in patients without HCV infection, using DM donors was not independently associated with worse post-transplantation graft survival. Matching these DM donors to recipients without HCV may be safe.