Melinda Carter

Inflammatory Markers at Hospital Discharge Predict Subsequent Mortality after Pneumonia and Sepsis

RATIONALE Survivors of hospitalization for community-acquired pneumonia (CAP) are at increased risk of cardiovascular events, repeat infections, and death in the following months but the cause is unknown. OBJECTIVES To investigate whether persistent inflammation, defined as elevating circulating inflammatory markers at hospital discharge, is associated with subsequent outcomes. METHODS Prospective cohort study at 28 sites. MEASUREMENTS AND MAIN RESULTS We used standard criteria to define CAP and the National Death Index to determine all-cause and cause-specific 1-year mortality. At hospital discharge, 1,799 subjects (77.5%) were alive and vital signs had returned to normal in 1,512 (87%) subjects. The geometric means (+/-SD) for circulating IL-6 and IL-10 concentrations were 6.9 (+/-1) pg/ml and 1.2 (+/-1.1) pg/ml. At 1 year, 307 (17.1%) subjects had died. Higher IL-6 and IL-10 concentrations at hospital discharge were associated with an increased risk of death, which gradually fell over time. Using Grays survival model, the associations were independent of demographics, comorbidities, and severity of illness (for each log-unit increase, the range of adjusted hazard ratios [HRs] for IL-6 were 1.02-1.46, P < 0.0001, and for IL-10 were 1.17-1.44, P = 0.01). The ranges of HRs for each log-unit increase in IL-6 and IL-10 concentrations among subjects who did and did not develop severe sepsis were 0.95-1.27 and 1.07-1.55, respectively. High IL-6 concentrations were associated with death due to cardiovascular disease, cancer, infections, and renal failure (P = 0.008). CONCLUSIONS Despite clinical recovery, many patients with CAP leave hospital with ongoing subclinical inflammation, which is associated with an increased risk of death.

Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival

While sepsis is a leading cause of acute kidney injury in critically ill patients, the relationship between immune response and acute kidney injury in less severely ill patients with infection is not known. Here we studied the epidemiology, 1-year mortality, and immune response associated with acute kidney injury in 1836 hospitalized patients with community-acquired severe and non-severe pneumonia. Acute kidney injury developed in 631 patients of whom 329 had severe and 302 had non-severe sepsis. Depending on the subgroup classification, 16-25% of the patients with non-severe pneumonia also developed acute kidney injury. In general, patients with acute kidney injury were older, had more comorbidity, and had higher biomarker concentrations (interleukin-6, tumor necrosis factor, D-dimer) even among patients without severe sepsis. The risk of death associated with acute kidney injury varied when assessed by Grays survival model and after adjusting for differences in age, gender, ethnicity, and comorbidity. This risk was significantly higher immediately after hospitalization but gradually fell over time in the overall cohort and in those with non-severe pneumonia. A significantly higher risk of death (hazard ratio 1.29) was also present in those never admitted to an intensive care unit. Hence acute kidney injury is common even among patients with non-severe pneumonia and is associated with higher immune response and an increased risk of death.

Urinary Biomarkers and Renal Recovery in Critically Ill Patients with Renal Support

BACKGROUND AND OBJECTIVES Despite significant advances in the epidemiology of acute kidney injury (AKI), prognostication remains a major clinical challenge. Unfortunately, no reliable method to predict renal recovery exists. The discovery of biomarkers to aid in clinical risk prediction for recovery after AKI would represent a significant advance over current practice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted the Biological Markers of Recovery for the Kidney study as an ancillary to the Acute Renal Failure Trial Network study. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AKI and received renal replacement therapy (RRT) in the intensive care unit. We explored whether levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary hepatocyte growth factor (uHGF), urinary cystatin C (uCystatin C), IL-18, neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9, and urine creatinine could predict subsequent renal recovery. RESULTS We defined renal recovery as alive and free of dialysis at 60 days from the start of RRT. Patients who recovered had higher uCystatin C on day 1 (7.27 versus 6.60 ng/mg·creatinine) and lower uHGF on days 7 and 14 (2.97 versus 3.48 ng/mg·creatinine; 2.24 versus 3.40 ng/mg·creatinine). For predicting recovery, decreasing uNGAL and uHGF in the first 14 days was associated with greater odds of renal recovery. The most predictive model combined relative changes in biomarkers with clinical variables and resulted in an area under the receiver-operator characteristic curve of 0.94. CONCLUSIONS We showed that a panel of urine biomarkers can augment clinical risk prediction for recovery after AKI.

Effects of hemoadsorption on cytokine removal and short-term survival in septic rats.

Objective:A broad-spectrum immune-regulating therapy could be beneficial in the treatment of sepsis. Our previous studies have shown that a hemoadsorption device (CytoSorb) removes both pro- and anti-inflammatory cytokines and improves survival in experimental endotoxemia. We sought to determine whether hemoadsorption can also be effective in the treatment of sepsis. Design:Randomized controlled laboratory experiment. Setting:University laboratory. Interventions:Rats were subjected to cecal ligation and puncture (CLP) and 20 hrs later were randomized to receive either hemoadsorption or sham treatment using an arterial-venous circuit. Hemoadsorption was accomplished using a cartridge containing Cytosorb beads. Blood was drawn for cytokine measurements and mean arterial pressure (MAP) was continuously monitored. Cytokines were measured via multiplex bead immunoassays. Survival time was observed for 9 hours after the intervention and assessed by Kaplan–Meier statistics. The overall survival in each group was compared using Fishers exact test. Finally, we used a Cox proportional-hazards model to examine the effects of cytokine removal on survival time. Measurements and Main Results:Baseline plasma cytokine concentrations and MAP were similar between hemoadsorption and sham-treated groups. However, the concentrations of tumor necrosis factor, interleukin (IL)-1β, IL-6, and IL-10 were significantly lower after hemoadsorption compared to the sham group. Six hours after treatment ended, IL-6 and IL-10 concentrations were still lower in hemoadsorption group. MAP was significantly better in hemoadsorption compared to sham-treated animals (p < .05). Finally, mean survival time was significantly longer (720 vs. 381 min, p < .05, Mann–Whitney test), and overall survival was significantly better (11/17 vs. 2/16, p < .01) with hemoadsorption compared to sham. Combined reduction in both IL-6 and IL-10 was associated with a significantly decreased risk of death (hazard ratio, .11, p = .005). Conclusion:Hemoadsorption reduced circulating cytokines, improved MAP, and resulted in better short-term survival in CLP-induced septic rats.

Plasma neutrophil gelatinase-associated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia

Although plasma neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for early detection of acute kidney injury, its ability to predict recovery is unknown. Using RIFLE criteria to define kidney injury, we tested whether higher plasma NGAL concentrations on the first day of RIFLE-F would predict failure to recover in a post hoc analysis of a multicenter, prospective, cohort study of patients with community-acquired pneumonia. Recovery was defined as alive and not requiring renal replacement therapy during hospitalization or having a persistent RIFLE-F classification at hospital discharge. Median plasma NGAL concentrations were significantly lower among the 93 of 181 patients who recovered. Plasma NGAL alone predicted failure to recover with an area under the receiver operating characteristic curve of 0.74. A clinical model using age, serum creatinine, pneumonia severity, and nonrenal organ failure predicted failure to recover with area under the curve of 0.78. Combining this clinical model with plasma NGAL concentrations did not improve prediction. The reclassification of risk of renal recovery, however, significantly improved by 17% when plasma NGAL was combined with the clinical model. Thus, in this cohort of patients with pneumonia-induced severe acute kidney injury, plasma NGAL appears to be a useful biomarker for predicting renal recovery.

The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia

The cytokine, macrophage migration inhibitory factor (MIF), is encoded in a functionally polymorphic locus and subjects with high‐expression MIF alleles are at an increased risk of inflammatory disease. Severe sepsis is the leading cause of death in intensive care units, and the prevailing hypothesis is that an excessive innate response contributes to its pathogenesis. To assess if MIF alleles influence the clinical course of infection, we conducted a case‐ control study to assess susceptibility and a parallel inception cohort study of community‐acquired pneumonia (CAP) to assess risk of severe sepsis and 90‐d mortality. Two distinct polymorphisms in the MIF promoter were analyzed: a G/C transition at —173 and a CATT repeat at —794. The frequency of both polymorphisms was similar in the CAP cohort (n=1739) and controls (n=639);however, the 90‐d mortality was lower for the high‐expression C allele (P=0.003). This association remained significant after adjusting for demographics, comorbid conditions, and disease severity score [hazard ratio = 0.64 (0.44‐0.91), P=0.01]. The hazard ratio was similar in different geographic subcohorts, and the association remained significant after adjusting for false discovery. These data indicate that polymorphisms associated with higher MIF expression may have a beneficial effect in community‐acquired pneumonia.— Yende, S., Angus, D. C., Kong, L., Kel‐ lum, J. A., Weissfeld, L., Ferrell, R., Finegold, D., Carter, M., Leng, L., Peng, Z.‐Y., Bucala, R. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from communityacquired pneumonia. FASEB J. 23, 2403–2411 (2009)

Increased plasma interleukin-6 in donors is associated with lower recipient hospital-free survival after cadaveric organ transplantation

Objectives:Brain death induces a massive inflammatory response. However, the influence of this inflammatory response on organ procurement, transplantation, and recipient outcome is unknown. We describe the inflammatory response characteristics in brain-dead organ donors and examine associations with organ transplantation and recipient survival. We test the hypothesis that increased inflammatory response is associated with fewer organs transplanted and decreased recipient survival. Design:Prospective, observational, cohort study. Setting:Two large intensive care units of tertiary care university hospitals in the United States. Patients:We recruited 30 consecutive brain-dead organ donors and 78 recipients between April 11, 2004, and November 23, 2004; recipients were followed through May 2005. Following declaration of brain death, we collected data on donor demographics, mechanism of brain death, number of organs procured and transplanted, and recipient characteristics. Plasma cytokines (tumor necrosis factor, interleukin-6, interleukin-10) were measured in donors at baseline following study enrollment, every hour for the first 4 hrs, and immediately before organ procurement for transplantation. Interventions:None. Measurements and Main Results:We examined the relationships among clinical characteristics, demographics, and cytokine response in donors and their influence on organ procurement and transplantation using multivariable regression and recipient’s 6-month hospital-free survival using a Cox proportional hazards regression. One hundred-eighteen organs were procured from 30 donors, and 91 (77%) were transplanted (mean of three organs transplanted per donor). All cytokines were increased following brain death. Older age in donors was significantly associated with lower number of organs transplanted (p < .001). Higher plasma interleukin-6 concentrations in donors before organ procurement was significantly associated with lower 6-month hospital-free survival in recipients (hazard ratio 1.77; 95% confidence interval, 1.17–2.69, p < .007). Conclusions:Among brain-dead organ donors, older age donors contribute fewer organs for transplantation, and increased donor interleukin-6 level before organ procurement is associated with lower recipient six-month hospital-free survival.

Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis

The effect of extracorporeal blood purification on clinical outcomes in sepsis is assumed to be related to modulation of plasma cytokine concentrations. To test this hypothesis directly, we treated rats that had a cecal ligation followed by puncture (a standard model of sepsis) with a modest dose of extracorporeal blood purification that did not result in acute changes in a panel of common cytokines associated with inflammation (TNF-α, IL-1β, IL-6, and IL-10). Pre- and immediate post-treatment levels of these cytokines were unchanged compared to the sham therapy of extracorporeal circulation without blood purifying sorbent. The overall survival to 7 days, however, was significantly better in animals that received extracorporeal blood purification compared to those with a sham procedure. This panel of common plasma cytokines along with alanine aminotransferase and creatinine was significantly lower 72 h following extracorporeal blood purification compared to sham-treated rats. Thus, the effects of this procedure on organ function and survival do not appear to be due solely to immediate changes in the usual measured circulating cytokines. These results may have important implications for the design and conduct of future trials in sepsis including defining alternative targets for extracorporeal blood purification and other therapies.

Feasibility study of cytokine removal by hemoadsorption in brain-dead humans.

Background:Inflammatory cytokines occur in the circulation and in the tissues after brain death and have been associated with dysfunction of donor organs before and after transplantation. Objective:To determine the feasibility of removing cytokines using a hemoadsorption device. Design:Two-center, randomized, open-label, feasibility study in which brain-dead subjects were randomized to two treatment groups. Setting:Two U.S. academic hospitals. Participants:Eight brain-dead subjects deemed unsuitable for organ donation by respective organ procurement organizations. Main Outcome Measures:After obtaining consent from families, subjects were treated with hemoadsorption for 4 hrs using CytoSorb. Effects on cytokines (tumor necrosis factor, interleukin [IL]-6, and IL-10) were assessed both across the device and in the plasma over time. Feasibility for cytokine removal was assessed using objective criteria. Results:Cytokine removal across the CytoSorb device ranged from 4% to 30% and was not significantly different from 1 hr to 4 hrs. Overall removal was greatest for IL-6, 28% (p = .006), and least for tumor necrosis factor, 8.5% (p = .13). Plasma concentrations of both IL-6 and tumor necrosis factor, but not IL-10, were significantly reduced after the first hour of therapy; mean differences were −13% ± 7% for IL-6 (p = .039), −23% ± 9% for tumor necrosis factor (p = .02), and −2% ± 7% of IL-10 (p = 23). However, plasma concentrations for all three cytokines increased over time and were above baseline by the end of the intervention. No adverse effects of therapy were observed. However, removal of cortisol and triiodothyronine was similar to removal of cytokines. Conclusions:Hemoadsorption for removal of cytokines in brain-dead subjects is feasible. Evaluation of possible clinical benefit will require controlled trials in actual donors. However, the significant capacity for cytokine removal and absence of adverse events suggest that such trials are warranted.

Prevalence and Significance of Coagulation Abnormalities in Community-Acquired Pneumonia

Coagulation abnormalities are common in severe pneumonia and sepsis, yet little is known about the presence of coagulopathy or its significance in patients with lesser illness severity. We examined coagulation abnormalities in 939 subjects hospitalized with community-acquired pneumonia (CAP) in 28 US hospitals, hypothesizing that abnormalities would increase with illness severity and poor outcomes. We measured plasma coagulation markers (D-dimer, plasminogen activator inhibitor (PAI), antithrombin, factor IX, and thrombin-antithrombin complex (TAT)) at the time of patient presentation to the emergency department and daily during the first wk of hospitalization. Day-1 clinical laboratory test results for international normalized ratio, activated partial thromboplastin time, and platelet count were recorded from the medical record. In our cohort, 32.5% of patients developed severe sepsis and 11.1% died by d 90. Day-1 coagulation abnormalities were common, especially for D-dimer (80.6%) and TAT (36.0%), and increased with illness severity and poor outcomes. However, abnormalities also occurred in those patients who never developed organ dysfunction and differences between groups were modest. The proportion of patients with abnormalities changed over time, yet the magnitude of change was small and not always in the direction of normality. Many patients remaining in the hospital continued to manifest coagulation abnormalities on d 7, especially for D-dimer (86.5%) and TAT (36.9%). In conclusion, coagulation abnormalities were common and persistent in CAP patients, even among the least ill. These findings underscore the complexity of the coagulation response to infection and may offer insights into coagulation-based therapeutics in clinical sepsis trials.