MinJae Lee

The Impact of Tumor Necrosis Factor α Inhibitors on Radiographic Progression in Ankylosing Spondylitis

OBJECTIVE To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS). METHODS All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model. RESULTS TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching. CONCLUSION Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.

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.

Plasma MicroRNAs as Novel Biomarkers for Endometriosis and Endometriosis-Associated Ovarian Cancer

Purpose: Endometriosis, a largely benign, chronic inflammatory disease, is an independent risk factor for endometrioid and clear cell epithelial ovarian tumors. We aimed to identify plasma miRNAs that can be used to differentiate patients with endometriosis and ovarian cancer from healthy individuals. Experimental Design: We conducted a two-stage exploratory study to investigate the use of plasma miRNA profiling to differentiate between patients with endometriosis, patients with endometriosis-associated ovarian cancer (EAOC), and healthy individuals. In the first stage, using global profiling of more than 1,000 miRNAs via reverse transcriptase quantitative PCR (RT-qPCR) in a 20-patient initial screening cohort, we identified 23 candidate miRNAs, which are differentially expressed between healthy controls (n = 6), patients with endometriosis (n = 7), and patients with EAOC (n = 7) based on the fold changes. In the second stage, the 23 miRNAs were further tested in an expanded cohort (n = 88) of healthy individuals (n = 20), endometriosis (n = 33), EAOC (n = 14), and serous ovarian cancer cases (SOC; n = 21, included as controls). Results: We identified three distinct miRNA signatures with reliable differential expression between healthy individuals, patients with endometriosis, and patients with EAOC. When profiled against the control SOC category, our results revealed different miRNAs, suggesting that the identified signatures are reflective of disease-specific pathogenic mechanisms. This was further supported by the fact that the majority of miRNAs differentially expressed in human EAOCs were mirrored in a double transgenic mouse EAOC model. Conclusion: Our study reports for the first time that distinct plasma miRNA expression patterns may serve as highly specific and sensitive diagnostic biomarkers to discriminate between healthy, endometriosis, and EAOC cases. Clin Cancer Res; 19(5); 1213–24. ©2013 AACR.

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.

Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study

BACKGROUND Bacterial meningitis continues to be a substantial cause of morbidity and mortality, but the epidemiological trends after adjunctive dexamethasone recommendations are unknown in the USA. We aimed to describe the changing patterns among the most common bacterial causes in the USA after conjugate vaccination and to assess the association between adjunctive dexamethasone and mortality. METHODS For this population-based observational study, we searched information available from hospital discharges about incidence and inpatient mortality for the most important causes of community and nosocomial bacterial meningitis based on International Classification of Diseases coding across all hospitals in the USA between 1997 and 2010 with the HealthCare Cost Utilization Project (HCUP) network database. We calculated incidences according to US Census Bureau data and used a negative binomial regression model to evaluate the significance of changes over time. We assessed mortality from pneumococcus for three periods 1997-2001 (baseline), 2002-04 (transition years), and 2005-08 (after corticosteroid recommendations were available). FINDINGS Streptococcus pneumoniae incidence fell from 0·8 per 100 000 people in 1997, to 0·3 per 100 000 people by the end of 2010 (RR 0·3737, 95% CI 0·1825-0·7656). Mortality from pneumococcal meningitis decreased between 2005 (0·049 per 100 000 people) and 2008 (0·024 per 100 000 people) compared with between 2002 (0·073 per 100 000 people) and 2004 (0·063 per 100 000 people; RR 0·5720, 95% CI 0·4303-0·7582). The incidence of Neisseria meningitidis infection decreased from 0·721 per 100 000 people in 1997, to 0·123 per 100 000 people in 2010 (RR 0·1386, 95% CI 0·048-0·4284), which has placed this pathogen close to common bacterial causes of nosocomial meningitis such as staphylococcus and Gram-negative bacteria and to Haemophilus influenzae. INTERPRETATION S pneumoniae continues to be the leading identifiable cause of bacterial meningitis in the USA, but with a significant decrease in incidence and mortality associated with the introduction of conjugated vaccines and a mortality decrease that is associated with the introduction of recommendations for use of adjunctive dexamethasone for pneumococcal meningitis. FUNDING National Center for Research Resources.

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 pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: Analysis of two multicentre cohort studies

Background Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear. Methods A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined. Measurements included the mortality rate within the first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumour necrosis factor, interleukin 6, interleukin 10), coagulation (Factor IX, thrombin–antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1 and D-dimer) and cell surface markers (CD120a, CD120b, human leucocyte antigen (HLA)-DR, Toll-like receptor-2 and Toll-like receptor-4). Results In GenIMS, diabetes increased the mortality rate within the first year after CAP (unadjusted HR 1.41, 95% CI 1.12 to 1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR 1.3, 95% CI 1.03 to 1.65, p=0.02). In Health ABC, diabetes increased the mortality rate within the first year following CAP hospitalisation, but not after hospitalisation for non-infectious illnesses (significant interaction for diabetes and reason for hospitalisation (p=0.04); HR for diabetes on mortality over the first year after CAP 1.87, 95% CI 0.76 to 4.6, p=0.16, and after non-infectious hospitalisation 1.16, 95% CI 0.8 to 1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels, in the emergency department and during the first week. Those with diabetes had a higher risk of acute kidney injury during hospitalisation (39.3% vs 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs 26.8% and 10.4% vs 4.5%, p=0.03). Conclusions Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.

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.

Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy

BACKGROUND Survivors of critical illness complicated by acute kidney injury requiring renal replacement therapy (RRT) are at an increased risk of dialysis dependence and death but the mechanisms are unknown. METHODS In a multicenter, prospective, cohort study of 817 critically ill patients receiving RRT, we examined association between Day 1 plasma inflammatory [interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-18; macrophage migration inhibitory factor (MIF) and tumor necrosis factor]; apoptosis [tumor necrosis factor receptor (TNFR)-I and TNFR-II and death receptor (DR)-5]; and growth factor (granulocyte macrophage colony stimulating factor) biomarkers and renal recovery and mortality at Day 60. Renal recovery was defined as alive and RRT independent. RESULTS Of 817 participants, 36.5% were RRT independent and 50.8% died. After adjusting for differences in demographics, comorbid conditions; premorbid creatinine; nephrotoxins; sepsis; oliguria; mechanical ventilation; RRT dosing; and severity of illness, increased concentrations of plasma IL-8 and IL-18 and TNFR-I were independently associated with slower renal recovery [adjusted hazard ratio (AHR) range for all markers, 0.70-0.87]. Higher concentrations of IL-6, IL-8, IL-10 and IL-18; MIF; TNFR-I and DR-5 were associated with mortality (AHR range, 1.16-1.47). In an analysis of multiple markers simultaneously, increased IL-8 [AHR, 0.80, 95% confidence interval (95% CI) 0.70-0.91, P < 0.001] and TNFR-I (AHR, 0.63, 95% CI 0.50-0.79, P < 0.001) were associated with slower recovery, and increased IL-8 (AHR, 1.26, 95% CI 1.14-1.39, P < 0.001); MIF (AHR, 1.18, 95% CI 1.08-1.28, P < 0.001) and TNFR-I (AHR, 1.26, 95% CI 1.02-1.56, P < 0.03) were associated with mortality. CONCLUSIONS Elevated plasma concentrations of inflammatory and apoptosis biomarkers are associated with RRT dependence and death. Our data suggest that future interventions should investigate broad-spectrum immune-modulation to improve outcomes.

The relationship of hypovitaminosis D and IL-6 in preeclampsia

OBJECTIVE Vitamin D deficiency has been linked to the pathogenesis of preeclampsia. Given the demonstrated antiinflammatory function of vitamin D in multiple organ systems including trophoblast cells and placenta, we hypothesized that vitamin D deficiency contributes to the development of preeclampsia through increased inflammation, as indicated by elevated interleukin (IL)-6 concentrations. STUDY DESIGN Plasma samples from a large preeclampsia cohort study were examined in 100 preeclamptic and 100 normotensive pregnant women. Comparisons of vitamin D and IL-6 concentrations used Student t test and χ(2) test or their nonparametric counterparts. A logistic regression model assessed the association among vitamin D, IL-6 concentrations, and preeclampsia risk. RESULTS The mean concentration of 25-hydroxyvitamin D was 49.4 ± 22.6 nmol/L in normotensives and 42.3 ± 17.3 nmol/L in preeclamptic women (P = .01). The median (interquartile range: Q1, Q3) concentrations of IL-6 were 2.0 (1.3, 3.4) pg/mL and 4.4 (2.2, 10.0) pg/mL in the control and preeclampsia groups, respectively (P < .01). We observed a significant association between IL-6 elevation and preeclampsia (odds ratio, 4.4; 95% confidence interval, 1.8-10.8; P < .01) and between vitamin D deficiency and preeclampsia (odds ratio, 4.2; 95% confidence interval, 1.4-12.8; P = .04). However, there was no association between vitamin D deficiency and IL-6 elevation. CONCLUSION Third-trimester IL-6 elevation and vitamin D deficiency were independently associated with the risk of preeclampsia. We found no evidence to support the hypothesis that vitamin D deficiency alters the pathogenesis of preeclampsia by activation of inflammation as assessed by IL-6 concentration.