Robert A. Oster

Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (Transnet)

BACKGROUND Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. METHODS The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. RESULTS During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. CONCLUSIONS We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Standard versus High-Dose CVVHDF for ICU-Related Acute Renal Failure

The effect of dosage of continuous venovenous hemodiafiltration (CVVHDF) on survival in patients with acute renal failure (ARF) is unknown. In this study, 200 critically ill patients with ARF were randomly assigned to receive CVVHDF with prefilter replacement fluid at an effluent rate of either 35 ml/kg per h (high dosage) or 20 ml/kg per h (standard dosage). The primary study outcome, survival to the earlier of either intensive care unit discharge or 30 d, was 49% in the high-dosage arm and 56% in the standard-dosage arm (odds ratio 0.75; 95% confidence interval 0.43 to 1.32; P = 0.32). Among hospital survivors, 69% of those in the high-dosage arm recovered renal function compared with 80% of those in the standard-dosage arm (P = 0.29); therefore, a difference in patient survival or renal recovery was not detected between patients receiving high-dosage or standard-dosage CVVHDF.

Factors Associated with Mortality in Transplant Patients with Invasive Aspergillosis

BACKGROUND Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA. METHODS Transplant patients from 23 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression. RESULTS Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA, and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition, and central nervous system disease were poor prognostic indicators, whereas prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death. CONCLUSIONS There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.

Outcomes of critically ill children requiring continuous renal replacement therapy

PURPOSE Acute kidney injury in the pediatric intensive care unit (PICU) is associated with significant morbidity, with continued mortality greater than 50%. Previous studies have described an association between percentage of fluid overload (%FO) less than 20% and improved survival. We reviewed our continuous renal replacement therapy (CRRT) experience to evaluate for factors associated with mortality as well as secondary outcomes. MATERIALS AND METHODS This is a retrospective chart review of pediatric CRRT intensive care unit patients from January 2000 to September 2005. RESULTS Seventy-six admissions required CRRT during the study period. Overall survival was 55.3%. Median patient age was 5.8 years (range, 0-18.9). Median %FO at the time of CRRT initiation was 7.3% in survivors vs 22.3% in nonsurvivors (P = .0001). Presence of sepsis was significantly associated with mortality (P = .0001). All nonsurvivors had multiple organ dysfunction syndrome (MODS); only 69% of survivors had MODS (P = .0003). For survivors, there was a significant relationship between %FO and time to renal recovery (P = .0038). Greater %FO was also associated with significantly prolonged days of mechanical ventilation (P = .0180), PICU stay (P = .0425), and duration of hospitalization (P = .0123). CONCLUSIONS For patients with acute kidney injury who require CRRT, the presence of sepsis, MODS, and FO greater than 20% at the time of CRRT initiation are significantly associated with higher mortality. In addition, we report that duration of mechanical ventilation, PICU stay, hospitalization, and time to renal recovery were all significantly prolonged for survivors who had FO greater than 20%.

Effect of Diet With and Without Exercise Training on Markers of Inflammation and Fat Distribution in Overweight Women

The independent effects of exercise and weight loss on markers of inflammation (MOI) in obese individuals have not been clearly characterized. The objectives of this study were to: (i) identify the independent effects of exercise and weight loss on MOI and (ii) determine whether changes in MOI were associated with changes in fat distribution. Subjects were 126 healthy, premenopausal women, BMI 27–30 kg/m2. They were randomized to one of three groups: diet only, diet + aerobic‐, or diet + resistance training until a BMI <25 kg/m2 was achieved. Fat distribution was measured with computed tomography, and body composition with dual‐energy X‐ray absorptiometry. Serum concentrations of tumor necrosis factor (TNF)‐α, soluble TNF receptor 1 (sTNF‐R1), soluble TNF receptor 2 (sTNF‐R2), C‐reactive protein (CRP), and interleukin (IL)‐6 were assessed. Results of repeated‐measures ANOVA indicated a significant effect of time on MOI, such that MOI decreased with weight loss. Results of mixed‐model analysis indicated that adjusting for intra‐abdominal adipose tissue (IAAT) and total fat mass explained the decreases in TNF‐α and sTNF‐R1, whereas only total fat mass explained the decreases in sTNF‐R2, IL‐6, and CRP. In conclusion, weight loss was associated with decreases in MOI. The effect of weight loss appeared to be mediated by changes in total fat mass or IAAT. Addition of exercise did not alter the response, suggesting that weight loss has a more profound impact for reducing MOI in overweight women than exercise.

The Presence of a Matrix-Derived Neutrophil Chemoattractant in Bronchiolitis Obliterans Syndrome after Lung Transplantation

Lung transplantation is a therapeutic modality frequently used in end-stage lung disease. Unfortunately, lung transplant recipients have poor clinical outcomes, often due to the development of bronchiolitis obliterans syndrome (BOS). This process is often characterized by the pathologic findings of obliterative bronchiolitis: neutrophil influx and extracellular matrix remodeling leading to luminal obstruction and airway inflammation. The molecular mechanisms underlying BOS are poorly understood and disease-specific biomarkers are lacking. We report that in addition to increased levels of IL-8, the level of the neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in BOS patient bronchoalveolar lavage (BAL) fluid. The enzymes responsible for generating PGP, matrix metalloproteases 8 and -9 and prolyl endopeptidase, are also elevated in these samples. Together, IL-8 and PGP account for most of the neutrophil chemoattractant capacity seen in BOS BAL fluid. Using specific neutralizing Abs to both IL-8 and PGP, we demonstrate that PGP is a prominent neutrophil chemoattractant found in BAL fluid from individuals at the time of diagnosis of BOS. These findings highlight the influence of a matrix-derived neutrophil chemoattractant in posttransplantation BOS and provide opportunities for the development of unique diagnostics and therapeutics to potentially improve disease outcomes.

Fasting and postprandial markers of inflammation in lean and overweight children

BACKGROUND Overweight children have greater circulating concentrations of markers of inflammation (MOI) than do lean children. Whether adiposity influences the postprandial MOI response is unknown. OBJECTIVE We aimed to evaluate the relations of fasting and postprandial MOI with total and regional adiposity and insulin sensitivity in children. DESIGN Fifty-nine children aged 7-12 y were assessed for C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptor-2 (sTNF-R2) in the fasted state and after a mixed meal. Insulin sensitivity, body composition, and abdominal adipose tissue distribution were assessed with a frequently sampled intravenous-glucose-tolerance test, dual-energy X-ray absorptiometry, and computed tomography, respectively. RESULTS Central adipose measures were not independently associated with fasting MOI, although they were independently inversely associated with the postprandial sTNF-R2 response (r = -0.30 to -0.37, P = 0.02-0.006). The inverse association between intraabdominal adipose tissue and the postprandial CRP response was nearly significant (r = -0.27, P = 0.05). Insulin sensitivity was not associated with fasting or postprandial CRP or sTNF-R2; however, there was a positive relation between insulin sensitivity and fasting IL-6 (r = 0.27, P = 0.03), which was attenuated after adjustment for lean body mass (r = 0.25, P = 0.08). CONCLUSIONS Excess adiposity is associated with both fasting and postprandial MOI. The postprandial MOI response may be influenced by central adiposity in children. The positive association of insulin sensitivity with IL-6 warrants further study.

Plasma TGF-β1 in pediatric cystic fibrosis: Potential biomarker of lung disease and response to therapy

Transforming growth factor beta‐1 (TGF‐β1) is an important genetic modifier of lung disease severity in cystic fibrosis (CF), yet the mechanism behind this disease association remains unknown. Initial steps in the investigation of the relationship between TGF‐β1 and CF lung disease include determining the most appropriate available biospecimen for TGF‐β1 protein measurement.

Meta-analysis of cancer risk in folic acid supplementation trials

Several reports suggest that folate has a procarcinogenic effect. Folate has a unique role because its coenzymes are needed for de novo purine and thymine nucleotide biosynthesis. Antifolates, such as methotrexate, are used in cancer treatment. Using a meta-analysis weighted for the duration of folic acid (pteroylglutamic acid) supplementation, we analyzed the cancer incidence of six previously published large prospective folic acid-supplementation trials in men and women. These articles were carefully selected from over 1100 identified using PubMed search. Our analyses suggest that cancer incidences were higher in the folic acid-supplemented groups than the non-folic acid-supplemented groups (relative risk=1.21 [95% confidence interval: 1.05-1.39]). Folic acid-supplementation trials should be performed with careful monitoring of cancer incidence. Solid monitoring systems to detect side effects, including increase in cancer risk, should be established before the initiation of folic acid supplementation trials.

Predictors of response and relapse in a cohort of adults with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a single-institution experience.

BACKGROUND: Thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome (TTP‐HUS) is a diagnosis of exclusion when a patient presents with the sine qua non findings of thrombocytopenia and microangiopathic hemolytic anemia without an identifiable cause. Although most patients respond to therapeutic plasma exchange (TPE), a significant number of patients relapse. The aim was to determine if clinical, laboratory, and/or treatment features could predict response and/or relapse.