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1.  Impaired Nuclear Translocation of the Glucocorticoid Receptor in Corticosteroid-Insensitive Airway Smooth Muscle in Severe Asthma 
Rationale: Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA.
Objectives: We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies.
Measurements and Main Results: GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10−7 M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α–induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α–induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA.
Conclusions: Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB–dependent gene promoters, may underlie CS insensitivity of severe asthma.
PMCID: PMC4299627  PMID: 25411910
airway smooth muscle; asthma; corticosteroid insensitivity; glucocorticoid receptor; nuclear translocation
2.  Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma 
Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from SA patients.
We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n=10), severe (n=8) and non-severe asthma (N-SA; n=8) were cultured from endobronchial biopsies.
Measurements and Main Results
GR expression in ASMC from SA and N-SA was reduced compared to that from healthy subjects by 49% (p<0.01). While baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10−7 M) in SA was 60% of that measured in either healthy or N-SA. TNF-α induced greater NF-κB (p65) mRNA expression in ASMC from SA (5.6 vs 2.0-fold; p<0.01), whereas baseline and TNFα-induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, while not modulating TNFα-induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA group, but this suppressive effect was impaired in SA.
Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NFκB-dependent gene promoters, may underlie CS insensitivity of severe asthma.
PMCID: PMC4299627  PMID: 25411910
airway smooth muscle; asthma; corticosteroid insensitivity; glucocorticoid receptor; nuclear translocation; CCL11
3.  Predicting the Outcome of Therapy for Pulmonary Tuberculosis 
Patients vary considerably in their response to treatment of pulmonary tuberculosis. Although several studies have indicated that adverse outcomes are more likely in those patients with delayed sputum sterilization, few tools are available to identify those patients prospectively. In this study, multivariate models were developed to predict the response to therapy in a prospectively recruited cohort of 42 HIV-uninfected subjects with drug-sensitive tuberculosis. The cohort included 2 subjects whose initial response was followed by drug-sensitive relapse. The total duration of culture positivity was best predicted by a model that included sputum M. tuberculosis antigen 85 concentration on Day 14 of therapy, days-to-positive in BACTEC on Day 30, and the baseline radiographic extent of disease (R = 0.63). A model in which quantitative AFB microscopy replaced BACTEC also performed adequately (R = 0.58). Both models predicted delayed clearance of bacilli in both relapses (> 85th percentile of all subjects) using information collected during the first month of therapy. Stratification of patients according to anticipated response to therapy may allow TB treatment to be individualized, potentially offering superior outcomes and greater efficiency in resource utilization, and aiding in the conduct of clinical trials.
PMCID: PMC4752200  PMID: 10764293
4.  Longevity and Determinants of Protective Humoral Immunity after Pandemic Influenza Infection 
Rationale: Antibodies to influenza hemagglutinin are the primary correlate of protection against infection. The strength and persistence of this immune response influences viral evolution and consequently the nature of influenza epidemics. However, the durability and immune determinants of induction of humoral immunity after primary influenza infection remain unclear.
Objectives: The spread of a novel H1N1 (A[H1N1]pdm09) virus in 2009 through an unexposed population offered a natural experiment to assess the nature and longevity of humoral immunity after a single primary influenza infection.
Methods: We followed A(H1N1)pdm09-seronegative adults through two influenza seasons (2009–2011) as they developed A(H1N1)pdm09 influenza infection or were vaccinated. Antibodies to A(H1N1)pdm09 virus were measured by hemagglutination-inhibition assay in individuals with paired serum samples collected preinfection and postinfection or vaccination to assess durability of humoral immunity. Preexisting A(H1N1)pdm09-specific multicytokine-secreting CD4 and CD8 T cells were quantified by multiparameter flow cytometry to test the hypothesis that higher frequencies of CD4+ T-cell responses predict stronger antibody induction after infection or vaccination.
Measurements and Main Results: Antibodies induced by natural infection persisted at constant high titer for a minimum of approximately 15 months. Contrary to our initial hypothesis, the fold increase in A(H1N1)pdm09-specific antibody titer after infection was inversely correlated to the frequency of preexisting circulating A(H1N1)pdm09-specific CD4+IL-2+IFN-γ−TNF-α− T cells (r = −0.4122; P = 0.03).
Conclusions: The longevity of protective humoral immunity after influenza infection has important implications for influenza transmission dynamics and vaccination policy, and identification of its predictive cellular immune correlate could guide vaccine development and evaluation.
PMCID: PMC4351579  PMID: 25506631
pandemic influenza; immunology; antibodies; T cells; epidemiology
5.  Nocturnal Asthma and the Importance of Race/Ethnicity and Genetic Ancestry 
Rationale: Nocturnal asthma is a common presentation and is associated with a more severe form of the disease. However, there are few epidemiologic studies of nocturnal asthma, particularly in minority populations.
Objectives: To identify factors associated with nocturnal asthma, including the contribution of self-identified race/ethnicity and genetic ancestry.
Methods: The analysis included individuals from the Study for Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) cohort. Nocturnal asthma symptoms were assessed by questionnaire. Genome-wide genotype data were used to estimate genetic ancestry in a subset of African American participants. Logistic regression was used evaluate the association of various factors with nocturnal asthma, such as self-identified race/ethnicity and genetic ancestry.
Measurement and Main Results: The study comprised 3,380 African American and 1,818 European Americans individuals with asthma. After adjusting for other potential explanatory variables, including controller medication use, African Americans were more than twice as likely (odds ratio, 2.56; 95% confidence interval, 2.24–2.93) to report nocturnal asthma when compared with European American individuals. Among the subset of African American participants with genome-wide genotype data (n = 1,040), estimated proportion of African ancestry was also associated with an increased risk of nocturnal asthma (P = 0.007). Differences in lung function explained a small, but statistically significant (P = 0.02), proportion of the relationship between genetic ancestry and nocturnal asthma symptoms.
Conclusions: Both self-identified race/ethnicity and African ancestry appear to be independent predictors of nocturnal asthma. The mechanism by which genetic ancestry contributes to population-level differences in nocturnal asthma appears to be largely independent of lung function.
PMCID: PMC4226040  PMID: 24937318
asthma; nocturnal symptoms; race/ethnicity; lung function; genetic ancestry
6.  Pseudomonas aeruginosa In Vitro Phenotypes Distinguish Cystic Fibrosis Infection Stages and Outcomes 
Rationale: Pseudomonas aeruginosa undergoes phenotypic changes during cystic fibrosis (CF) lung infection. Although mucoidy is traditionally associated with transition to chronic infection, we hypothesized that additional in vitro phenotypes correlate with this transition and contribute to disease.
Objectives: To characterize the relationships between in vitro P. aeruginosa phenotypes, infection stage, and clinical outcomes.
Methods: A total of 649 children with CF and newly identified P. aeruginosa were followed for a median 5.4 years during which a total of 2,594 P. aeruginosa isolates were collected. Twenty-six in vitro bacterial phenotypes were assessed among the isolates, including measures of motility, exoproduct production, colony morphology, growth, and metabolism.
Measurements and Main Results: P. aeruginosa phenotypes present at the time of culture were associated with both stage of infection (new onset, intermittent, or chronic) and the primary clinical outcome, occurrence of a pulmonary exacerbation (PE) in the subsequent 2 years. Two in vitro P. aeruginosa phenotypes best distinguished infection stages: pyoverdine production (31% of new-onset cultures, 48% of intermittent, 69% of chronic) and reduced protease production (31%, 39%, and 65%, respectively). The best P. aeruginosa phenotypic predictors of subsequent occurrence of a PE were mucoidy (odds ratio, 1.75; 95% confidence interval, 1.19–2.57) and reduced twitching motility (odds ratio, 1.43; 95% confidence interval, 1.11–1.84).
Conclusions: In this large epidemiologic study of CF P. aeruginosa adaptation, P. aeruginosa isolates exhibited two in vitro phenotypes that best distinguished early and later infection stages. Among the many phenotypes tested, mucoidy and reduced twitching best predicted subsequent PE. These phenotypes indicate potentially useful prognostic markers of transition to chronic infection and advancing lung disease.
PMCID: PMC4226041  PMID: 24937177
epidemiology; risk factors; exacerbation; pulmonary function; mucoid Pseudomonas aeruginosa
7.  miR-31 Dysregulation in Cystic Fibrosis Airways Contributes to Increased Pulmonary Cathepsin S Production 
Rationale: Cathepsin S (CTSS) activity is increased in bronchoalveolar lavage (BAL) fluid from patients with cystic fibrosis (CF). This activity contributes to lung inflammation via degradation of antimicrobial proteins, such as lactoferrin and members of the β-defensin family.
Objectives: In this study, we investigated the hypothesis that airway epithelial cells are a source of CTSS, and mechanisms underlying CTSS expression in the CF lung.
Methods: Protease activity was determined using fluorogenic activity assays. Protein and mRNA expression were analyzed by ELISA, Western blotting, and reverse-transcriptase polymerase chain reaction.
Measurements and Main Results: In contrast to neutrophil elastase, CTSS activity was detectable in 100% of CF BAL fluid samples from patients without Pseudomonas aeruginosa infection. In this study, we identified epithelial cells as a source of pulmonary CTSS activity with the demonstration that CF airway epithelial cells express and secrete significantly more CTSS than non-CF control cells in the absence of proinflammatory stimulation. Furthermore, levels of the transcription factor IRF-1 correlated with increased levels of its target gene CTSS. We discovered that miR-31, which is decreased in the CF airways, regulates IRF-1 in CF epithelial cells. Treating CF bronchial epithelial cells with a miR-31 mimic decreased IRF-1 protein levels with concomitant knockdown of CTSS expression and secretion.
Conclusions: The miR-31/IRF-1/CTSS pathway may play a functional role in the pathogenesis of CF lung disease and may open up new avenues for exploration in the search for an effective therapeutic target.
PMCID: PMC4226050  PMID: 24940638
protease; microRNA; cystic fibrosis; epithelium
8.  Wnt Coreceptor Lrp5 Is a Driver of Idiopathic Pulmonary Fibrosis 
Rationale: Wnt/β-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown.
Objectives: To determine whether the Wnt coreceptor Lrp5 drives pulmonary fibrosis in mice and is predictive of disease severity in humans.
Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-β. We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF).
Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of β-catenin signaling by the small molecular inhibitor of β-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-β production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-β, Lrp5 null mice were not protected against lung fibrosis induced by TGF-β.
Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-β signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.
PMCID: PMC4226053  PMID: 24921217
lung fibrosis; Wnt/β-catenin signaling; peripheral blood mononuclear cell
9.  Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis 
Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.
Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.
Methods: We conducted a longitudinal cohort study in 2012–2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology
Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m2; P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, −53.8 mmol/L; 95% confidence interval, −57.7 to −49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.
Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
PMCID: PMC4226057  PMID: 24927234
cystic fibrosis; CFTR modulator; ivacaftor; Pseudomonas aeruginosa; pH
10.  Dysregulation of Claudin-5 in HIV-induced Interstitial Pneumonitis and Lung Vascular Injury. Protective Role of Peroxisome Proliferator–activated Receptor-γ 
Rationale: HIV-1–induced interstitial pneumonitis (IP) is a serious complication of HIV-1 infection, characterized by inflammation and cellular infiltration in lungs, often leading to respiratory failure and death. The barrier function of the pulmonary endothelium is caused in part by tight junction (TJ) proteins, such as claudin-5. Peroxisome proliferator–activated receptor (PPAR)-γ is expressed in lung tissues and regulates inflammation. We hypothesize that HIV-1 induces vascular lung injury, and HIV-1–mediated damage of the pulmonary endothelium and IP is associated with dysregulation of PPAR-γ.
Objectives: Investigate the effects of HIV-1 infection on the pulmonary microvasculature and the modulatory effects of the PPAR-γ ligands.
Methods: Using human lung tissues, we demonstrated down-regulation of claudin-5 (marker of pulmonary barrier integrity), down-regulation of PPAR-γ transcription, and expression in lung tissues of HIV-1–infected humans with IP.
Measurements and Main Results: Human lung microvascular endothelial cells expressed the TJ proteins claudin-5, ZO-1, and ZO-2; HIV-1 decreased TJ proteins expression and induced nuclear factor-κB promoter activity, which was reversed by PPAR-γ agonist. Using two murine HIV/AIDS models, we demonstrated decreased claudin-5 expression and increased macrophage infiltration in the lungs of HIV-1–infected animals. Activation of PPAR-γ prevented HIV-1–induced claudin-5 down-regulation and significantly reduced viremia and pulmonary macrophage infiltration.
Conclusions: HIV-induced IP is associated with injury to the lung vascular endothelium, with decreased TJ and PPAR-γ expression, and increased pulmonary macrophage infiltration. PPAR-γ ligands abrogated these effects. Thus, regulation of PPAR-γ can be a therapeutic approach against HIV-1–induced vascular damage and IP in infected humans. Removal of Expression of Concern: Issues leading to the previous expression of concern for this article have been resolved after further revisions and editorial review. No further concerns exist.
PMCID: PMC4226025  PMID: 22345580
pulmonary endothelium; tight junction proteins; HIV/AIDS; macrophages; PBMC
11.  T-Regulatory Cells and Programmed Death 1+ T Cells Contribute to Effector T-Cell Dysfunction in Patients with Chronic Obstructive Pulmonary Disease 
Rationale: Previous studies from our laboratory have shown that peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) prone to exacerbations with nontypeable Haemophilus influenzae have impaired responses to lipoprotein P6. We hypothesized that an underlying immunosuppressive network could be responsible for the defective antibacterial immunity observed in these patients. We evaluated T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and exhausted T effector cells (programmed death 1 [PD-1]+) in patients with COPD, because these cells are known to play a pivotal role in suppressing immune responses.
Objectives: We performed an in-depth characterization of Tregs, T effector cells, and MDSC in COPD and correlated their levels and function with disease severity.
Methods: Treg, effector T cell, and MDSC frequency from patients with COPD and healthy subjects’ PBMCs were analyzed by flow cytometry. Treg immunosuppressive capacity was measured by in vitro suppression assay. The frequency of interferon-γ producing T cells and T-cell proliferation were measured after blocking CTLA-4 and PD-1. Plasma proinflammatory and immunosuppressive cytokine levels were measured.
Measurements and Main Results: Significantly increased levels of Tregs, MDSC, and PD-1+ exhausted effector T cells were present in patients with COPD compared with healthy subjects. Tregs from patients with COPD suppressed P6-specific T-cell proliferation to a greater extent than Tregs from healthy subjects. Plasma levels of Treg-generated cytokines, IL-10, and transforming growth factor-β were elevated. Blockade of CTLA-4 resulted in significant augmentation of T-cell IFN-γ production in patients with COPD.
Conclusions: Functionally suppressive Tregs, MDSCs, and exhausted PD-1+ T cells contribute to effector T-cell dysfunction in COPD.
PMCID: PMC4226027  PMID: 24825462
Foxp3+ Tregs; myeloid-derived suppressor cells; cytokines; lung function; T effector cells
12.  An Aberrant Leukotriene A4 Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease 
Rationale: Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated.
Objectives: We investigated changes to the leukotriene A4 hydrolase (LTA4H)–proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD.
Methods: A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis. Two human cohorts were used to analyze changes to the LTA4H–PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA4H aminopeptidase activity were detected by mass spectroscopy, LTA4H amounts were detected by ELISA, and acrolein was detected by Western blot.
Measurements and Main Results: Mice exposed to cigarette smoke developed emphysema with increased PGP, neutrophilic inflammation, and selective inhibition of LTA4H aminopeptidase, which ordinarily degrades PGP. We recapitulated these findings in smokers with and without COPD. PGP and AcPGP are closely associated with cigarette smoke use. Once chronic inflammation is established, changes to LTA4H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA4H and inhibits aminopeptidase activity to the same extent as cigarette smoke.
Conclusions: These results demonstrate a novel pathway of aberrant regulation of PGP/AcPGP, suggesting this inflammatory pathway may be intimately involved in disease progression in the absence of ongoing cigarette smoke exposure. We highlight a mechanism by which acrolein potentiates neutrophilic inflammation through selective inhibition of LTA4H aminopeptidase activity.
Clinical trial registered with (NCT 00292552).
PMCID: PMC4226028  PMID: 24874071
COPD; inflammation; PGP; leukotriene A4 hydrolase; acrolein
13.  Update in Lung Transplantation 2013 
Research in pulmonary transplantation is actively evolving in quality and scope to meet the challenges of a growing population of lung allograft recipients. In 2013, research groups leveraged large publicly available datasets in addition to multicenter research networks and single-center studies to make significant contributions to our knowledge and clinical care in the areas of donor use, clinical transplant outcomes, mechanisms of rejection, infectious complications, and chronic allograft dysfunction.
PMCID: PMC4226029  PMID: 24983218
lung transplantation; donor; rejection; infection; bronchiolitis obliterans syndrome
14.  Increased 1-Year Healthcare Use in Survivors of Severe Sepsis 
Rationale: Hospitalizations for severe sepsis are common, and a growing number of patients survive to hospital discharge. Nonetheless, little is known about survivors’ post-discharge healthcare use.
Objectives: To measure inpatient healthcare use of severe sepsis survivors compared with patients’ own presepsis resource use and the resource use of survivors of otherwise similar nonsepsis hospitalizations.
Methods: This is an observational cohort study of survivors of severe sepsis and nonsepsis hospitalizations identified from participants in the Health and Retirement Study with linked Medicare claims, 1998–2005. We matched severe sepsis and nonsepsis hospitalizations by demographics, comorbidity burden, premorbid disability, hospitalization length, and intensive care use.
Measurements and Main Results: Using Medicare claims, we measured patients’ use of inpatient facilities (hospitals, long-term acute care hospitals, and skilled nursing facilities) in the 2 years surrounding hospitalization. Severe sepsis survivors spent more days (median, 16 [interquartile range, 3–45] vs. 7 [0–29]; P < 0.001) and a higher proportion of days alive (median, 9.6% [interquartile range, 1.4–33.8%] vs. 1.9% [0.0–7.9%]; P < 0.001) admitted to facilities in the year after hospitalization, compared with the year prior. The increase in facility-days was similar for nonsepsis hospitalizations. However, the severe sepsis cohort experienced greater post-discharge mortality (44.2% [95% confidence interval, 41.3–47.2%] vs. 31.4% [95% confidence interval, 28.6–34.2%] at 1 year), a steeper decline in days spent at home (difference-in-differences, −38.6 d [95% confidence interval, −50.9 to 26.3]; P < 0.001), and a greater increase in the proportion of days alive spent in a facility (difference-in-differences, 5.4% [95% confidence interval, 2.8–8.1%]; P < 0.001).
Conclusions: Healthcare use is markedly elevated after severe sepsis, and post-discharge management may be an opportunity to reduce resource use.
PMCID: PMC4226030  PMID: 24872085
patient outcomes assessment; hospitalization; patient readmission; skilled nursing facility; healthcare facilities
15.  Adiposity, Fractional Exhaled Nitric Oxide, and Asthma in U.S. Children 
Rationale: Whether allergic airway inflammation mediates the association between overweight or obesity and childhood asthma is unknown.
Objectives: To examine adiposity, asthma, and fractional exhaled nitric oxide (FeNO) in U.S. children.
Methods: Cross-sectional study of indicators of adiposity or obesity, FeNO (a biomarker of eosinophilic airway inflammation), and asthma in 2,681 children aged 6–17 years in the 2007–2010 National Health and Nutrition Examination Survey. Adiposity measures included body mass index (BMI), percent body fat (PBF), and waist circumference (WC).
Measurements and Main Results: BMI, PBF, and WC were associated with asthma among children with low FeNO (odds ratio, 1.54–1.68; P < 0.01), but not among children with increased FeNO. Among children without asthma, BMI, PBF, and WC were associated with higher FEV1 and FVC, and lower FEV1/FVC. Among children with asthma and a high FeNO, all adiposity indicators were associated with decreased FEV1/FVC (β = −1.5% to −1.7% per z score) but not with FEV1 or FVC. Higher BMI or PBF was associated with worse asthma severity or control in children with asthma and increased FeNO, but not in children with asthma and low FeNO. Similar results were obtained in a secondary multivariate analysis of overweight or obesity (defined as BMI ≥85th percentile) and asthma or indicators of asthma severity or control, stratified by FeNO level.
Conclusions: Adiposity indicators are associated with asthma in children with low FeNO. Among children with asthma, adiposity indicators are associated with worse asthma severity or control in those with high FeNO.
PMCID: PMC4226031  PMID: 24922361
asthma; airway inflammation; adiposity; obesity; NHANES
16.  Disparities in Pulmonary Function in Healthy Children across the Indian Urban–Rural Continuum 
Rationale: Marked socioeconomic health-care disparities are recognized in India, but lung health inequalities between urban and rural children have not been studied.
Objectives: We investigated whether differences exist in spirometric pulmonary function in healthy children across the Indian urban–rural continuum and compared results with those from Indian children living in the UK.
Methods: Indian children aged 5 to 12 years were recruited from Indian urban, semiurban, and rural schools, and as part of the Size and Lung Function in Children study, London. Anthropometric and spirometric assessments were undertaken.
Measurements and Main Results: Acceptable spirometric data were obtained from 728 (58% boys) children in India and 311 (50% boys) UK-Indian children. As an entire group, the India-resident children had significantly lower z FEV1 and z FVC than UK-Indian children (P < 0.0005), when expressed using Global Lung Function Initiative–2012 equations. However, when India-resident children were categorized according to residence, there were no differences in z FEV1 and z FVC between Indian-urban and UK-Indian children. There were, however, significant reductions of ∼0.5 z scores and 0.9 z scores in both FEV1 and FVC (with no difference in FEV1/FVC) in Indian-semiurban and Indian-rural children, respectively, when compared with Indian-urban children (P < 0.0005). z Body mass index, socioeconomic circumstances, tobacco, and biomass exposure were individually significantly associated with z FEV1 and z FVC (P < 0.0005).
Conclusions: The presence of an urban–rural continuum of lung function within a specific ethnic group emphasizes the impact of environmental factors on lung growth in emerging nations such as India, which must be taken into account when developing ethnic-specific reference values or designing studies to optimize lung health.
PMCID: PMC4299630  PMID: 25412016
children; urban; rural; socioeconomic circumstances; ethnic differences in lung function
17.  Impact of GeneXpert MTB/RIF on Patients and Tuberculosis Programs in a Low-Burden Setting. A Hypothetical Trial 
Rationale: Guidelines recommend routine nucleic-acid amplification testing in patients with presumed tuberculosis (TB), but these tests have not been widely adopted. GeneXpert MTB/RIF (Xpert), a novel, semiautomated TB nucleic-acid amplification test, has renewed interest in this technology, but data from low-burden countries are limited.
Objectives: We sought to estimate Xpert’s potential clinical and public health impact on empiric treatment, contact investigation, and housing in patients undergoing TB evaluation.
Methods: We performed a prospective, cross-sectional study with 2-month follow-up comparing Xpert with standard strategies for evaluating outpatients for active pulmonary TB at the San Francisco Department of Public Health TB Clinic between May 2010 and June 2011. We calculated the diagnostic accuracy of standard algorithms for initial empiric TB treatment, contact investigation, and housing in reference to three Mycobacterium tuberculosis sputum cultures, as compared with that of a single sputum Xpert test. We estimated the incremental diagnostic value of Xpert, and the hypothetical reductions in unnecessary treatment, contact investigation, and housing if Xpert were adopted to guide management decisions.
Measurements and Main Results: A total of 156 patients underwent Xpert testing. Fifty-nine (38%) received empiric TB treatment. Thirteen (8%) had culture-positive TB. Xpert-guided management would have hypothetically decreased overtreatment by 94%, eliminating a median of 44 overtreatment days (interquartile range, 43–47) per patient and 2,169 total overtreatment days (95% confidence interval, 1,938–2,400) annually, without reducing early detection of TB patients. We projected similar benefits for contact investigation and housing.
Conclusions: Xpert could greatly reduce the frequency and impact of unnecessary empiric treatment, contact investigation, and housing, providing substantial patient and programmatic benefits if used in management decisions.
PMCID: PMC4226012  PMID: 24869625
tuberculosis; diagnosis; health care quality assurance; operations research; public health
18.  Investigating the Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Bacterial Lung Infection 
Lower respiratory tract infections (LRTIs) are a persistent and pervasive public health problem worldwide. Pneumonia and other LRTIs will be among the leading causes of death in adults, and pneumonia is the single largest cause of death in children. LRTIs are also an important cause of acute lung injury and acute exacerbations of chronic obstructive pulmonary disease. Because innate immunity is the first line of defense against pathogens, understanding the role of innate immunity in the pulmonary system is of paramount importance. Pattern recognition molecules (PRMs) that recognize microbial-associated molecular patterns are an integral component of the innate immune system and are located in both cell membranes and cytosol. Toll-like receptors and nucleotide-binding oligomerization domain–like receptors (NLRs) are the major sensors at the forefront of pathogen recognition. Although Toll-like receptors have been extensively studied in host immunity, NLRs have diverse and important roles in immune and inflammatory responses, ranging from antimicrobial properties to adaptive immune responses. The lung contains NLR-expressing immune cells such as leukocytes and nonimmune cells such as epithelial cells that are in constant and close contact with invading microbes. This pulmonary perspective addresses our current understanding of the structure and function of NLR family members, highlighting advances and gaps in knowledge, with a specific focus on immune responses in the respiratory tract during bacterial infection. Further advances in exploring cellular and molecular responses to bacterial pathogens are critical to develop improved strategies to treat and prevent devastating infectious diseases of the lung.
PMCID: PMC4226013  PMID: 24707903
lung; bacterial infection; nucleotide-binding oligomerization domain–like receptors; inflammasome
19.  Endothelial Progenitor Cells and a Stromal Cell–derived Factor-1α Analogue Synergistically Improve Survival in Sepsis 
Rationale: Endothelial progenitor cells (EPCs) have been associated with human sepsis but their role is incompletely understood. Stromal cell–derived factor (SDF)-1α facilitates EPC recruitment and is elevated in murine sepsis models. Previous studies have demonstrated that the SDF-1α analog CTCE-0214 (CTCE) is beneficial in polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice.
Objectives: We hypothesized that exogenously administered EPCs are also beneficial in CLP sepsis and that CTCE provides synergistic benefit.
Methods: Mice were subjected to CLP and administered EPCs at varying doses, CTCE, or a combination of the two. Mouse survival, plasma miRNA expression, IL-10 production, and lung vascular leakage were determined. The in vitro effect of CTCE on miRNA expression and EPC function were determined.
Measurements and Main Results: Survival was improved with EPC therapy at a threshold of 106 cells. In coculture studies, EPCs augmented LPS-induced macrophage IL-10 production. In vivo EPC administration in sepsis increased plasma IL-10, suppressed lung vascular leakage, attenuated liver and kidney injury, and augmented miR-126 and -125b expression, which regulate endothelial cell function and/or inflammation. When subthreshold numbers of EPCs were coadministered with CTCE in CLP mice they synergistically improved survival. We demonstrated that CTCE recruits endogenous EPCs in septic mice. In in vitro analysis, CTCE enhanced EPC proliferation, angiogenesis, and prosurvival signaling while inhibiting EPC senescence. These cellular effects were, in part, explained by the effect of CTCE on miR-126, -125b, -34a, and -155 expression in EPCs.
Conclusions: EPCs and CTCE represent important potential therapeutic strategies in sepsis.
PMCID: PMC4226015  PMID: 24707934
endothelial progenitor cell; sepsis; CTCE; microRNA
20.  Outcomes and Statistical Power in Adult Critical Care Randomized Trials 
Rationale: Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits.
Objectives: Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials.
Methods: One hundred forty-six ICU-based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied.
Measurement and Main Results: Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%.
Conclusions: ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates.
PMCID: PMC4226016  PMID: 24786714
intensive care unit; critical care; intensive care; randomized clinical trial; randomized controlled trial
21.  The Nonallergic Asthma of Obesity. A Matter of Distal Lung Compliance 
Rationale: The pathogenesis of asthma in obesity is poorly understood, but may be related to breathing at low lung volumes.
Objectives: To determine if lung function in obese patients with asthma and control subjects would respond differently to weight loss.
Methods: Lung function was evaluated by conventional clinical tests and by impulse oscillometry in female late-onset, nonallergic patients with asthma and control subjects before, and 12 months after, bariatric surgery.
Measurements and Main Results: Patients with asthma (n = 10) had significantly lower FEV1 (79.8 ± 10.6 vs. 95.5 ± 7.0%) and FVC (82.4 ± 13.2 vs. 93.7 ± 8.9%) compared with control subjects (n = 13). There were no significant differences in FRC or TLC at baseline. Twelve months after surgery, control subjects had significant increases in FEV1 (95.5 ± 7.0 to 100.7 ± 5.9), FVC (93.6 ± 8.9 to 98.6 ± 8.3%), FRC (45.4 ± 18.5 to 62.1 ± 15.3%), and TLC (84.8 ± 15.0 to 103.1 ± 15.3%), whereas patients with asthma had improvement only in FEV1 (79.8 ± 10.6 to 87.2 ± 11.5). Control subjects and patients with asthma had a significantly different change in respiratory system resistance with weight loss: control subjects exhibited a uniform decrease in respiratory system resistance at all frequencies, whereas patients with asthma exhibited a decrease in frequency dependence of resistance. Fits of a mathematical model of lung mechanics to these impedance spectra suggest that the lung periphery was more collapsed by obesity in patients with asthma compared with control subjects.
Conclusions: Weight loss decompresses the lung in both obese control subjects and patients with asthma, but the more pronounced effects of weight loss on lung elastance suggest that the distal lung is inherently more collapsible in people with asthma.
PMCID: PMC4226017  PMID: 24821412
bariatric surgery; forced oscillation technique; impedance; lung volume
22.  Predictors of Chronic Obstructive Pulmonary Disease Exacerbation Reduction in Response to Daily Azithromycin Therapy 
Rationale: Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown.
Objectives: To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care.
Methods: Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use.
Measurements and Main Results: Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71–1.38; P = 0.95).
Conclusions: Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers.
Clinical trial registered with (NCT0011986 and NCT00325897).
PMCID: PMC4226018  PMID: 24779680
chronic obstructive pulmonary disease; exacerbation; quality of life; azithromycin
23.  Genotype–Phenotype Correlations for Infants and Children with ABCA3 Deficiency 
Rationale: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private.
Objectives: To determine genotype–phenotype correlations for recessive ABCA3 mutations.
Methods: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as “null,” whereas missense, predicted splice site mutations, and insertion/deletions were classified as “other.” We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other.
Measurements and Main Results: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001).
Conclusions: Genotype–phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.
PMCID: PMC4226019  PMID: 24871971
surfactant; childhood interstitial lung disease; neonatal respiratory distress
24.  Effectiveness of Motivational Interviewing to Reduce Head Start Children’s Secondhand Smoke Exposure. A Randomized Clinical Trial 
Rationale: Secondhand smoke exposure (SHSe) is a significant modifiable risk for respiratory health in children. Although SHSe is declining overall, it has increased for low-income and minority populations. Implementation of effective SHSe interventions within community organizations has the potential for significant public health impact.
Objectives: To evaluate the effectiveness of motivational interviewing (MI) delivered in the context of a SHS education reduction initiative within Head Start to reduce preschool children’s SHSe.
Methods: A total of 350 children enrolled in Baltimore City Head Start whose caregivers reported a smoker living in the home were recruited. Caregivers were randomized to MI + education or education alone. Assessments were conducted at baseline, 3, 6, and 12 months.
Measurements and Main Results: The primary outcome measure was household air nicotine levels measured by passive dosimeters. Secondary outcomes included child salivary cotinine, self-report of home smoking ban (HSB), and smoking status. Participants in the MI + education group had significantly lower air nicotine levels (0.29 vs. 0.40 mg), 17% increase in prevalence of caregiver-reported HSBs, and a 13% decrease in caregiver smokers compared with education-alone group (all P values < 0.05). Although group differences in salivary cotinine were not significant, among all families who reported having an HSB, salivary cotinine and air nicotine levels declined in both groups (P < 0.05).
Conclusions: MI may be effective in community settings to reduce child SHSe. More research is needed to identify ways to tailor interventions to directly impact child SHSe and to engage more families to make behavioral change.
Clinical trial registered with (NCT 00927264).
PMCID: PMC4226021  PMID: 24821270
secondhand smoke; preschool children; community engaged research; randomized controlled trial
25.  IL-33–Dependent Type 2 Inflammation during Rhinovirus-induced Asthma Exacerbations In Vivo 
Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation.
Objectives: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway.
Methods: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade.
Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33.
Conclusions: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33–responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.
PMCID: PMC4299647  PMID: 25350863
ILC2; infection; Th2; virus

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