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  • Extracellular Mitochondrial DNA is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-07
    Changwan Ryu; ; Mridu Gulati; Jose Herazo-Maya; Yonglin Chen; Awo Osafo-Addo; Caitlin Brandsdorfer; Julia Winkler; Christina Blaul; Jaden Faunce; Hongyi Pan; Tony Woolard; Argyrios Tzouvelekis; Danielle E Antin-Ozerkis; Jonathan T Puchalski; Martin Slade; Anjelica L Gonzalez; Daniel F Bogenhagen; Varvara Kirillov; Carol Feghali-Bostwick; Kevin Gibson; Kathleen Lindell; Raimund I. Herzog; Charles S Dela Cruz; Wajahat Mehal; Naftali Kaminski; Erica L Herzog; Glenda Trujillo

    Rationale: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of alpha smooth muscle actin (αSMA) expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor beta-1 (TGFβ1), and mechanical influences such as local tissue stiffness. While IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA) have not been identified in IPF. Objectives: We aimed to define an association between mtDNA and fibroblast responses in IPF. Methods: We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGFβ1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, and in plasma samples from two longitudinal IPF cohorts and demographically-matched controls. Measurements and Main Results Exposure to mtDNA augments αSMA expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGFβ1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival. Conclusions: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

  • A Phase 2 Randomized Controlled Study of Tralokinumab in Subjects with Idiopathic Pulmonary Fibrosis
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-08
    Joseph M Parker; Ian N Glaspole; Lisa H Lancaster; Tarik J Haddad; Dewei She; Stephanie L. Roseti; Jon P Fiening; Ethan P Grant; Chris M Kell; Kevin R Flaherty

    Rationale: Interleukin (IL)-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease. Objectives: Investigate efficacy and safety of tralokinumab, a human anti–IL-13 monoclonal antibody, in subjects with mild to moderate IPF. Methods: Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent-predicted forced vital capacity (FVC) in the intention to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median. Measurements and Main Results: The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor 800 mg met the primary endpoint; least-squares mean difference [95% CI] percent-predicted FVC from baseline to Week 52: –1.77 [–4.13, 0.59] (P = 0.140) and –1.41 [–3.73, 0.91] (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent-predicted FVC ≥10% at Week 52 was numerically greater for tralokinumab-treated subjects, compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, 800 mg, and placebo were cough (17.5%, 30.5%, 22.8%), IPF progression and exacerbation (21.1%, 16.9%, 22.8%), and upper respiratory tract infection (17.5%, 20.3%, 12.3%), respectively. Conclusions: Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01629667.

  • Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-08
    Marloes van den Berg; Pleuni E. Hooijman; Albertus Beishuizen; Monique C. de Waard; Marinus A. Paul; Koen J. Hartemink; Hieronymus W.H. van Hees; Michael W Lawlor; Lorenza Brocca; Roberto Bottinelli; Maria A. Pellegrino; Ger J.M. Stienen; Leo M. A. Heunks; Rob C.I. Wüst; Coen AC Ottenheijm

    RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity, duration of hospital stay and health care costs. The mechanisms underlying diaphragm weakness are unknown, but might include mitochondrial dysfunction and oxidative stress. OBJECTIVES: We hypothesized that weakness of diaphragm muscle fibers in critically ill patients is accompanied by impaired mitochondrial function, structure, and increased markers of oxidative stress. METHODS: To test these hypotheses, we studied contractile force, mitochondrial function, and mitochondrial structure in diaphragm muscle fibers. Fibers were isolated from diaphragm biopsies of thirty-six mechanically ventilated critically ill patients and compared to those isolated from biopsies of twenty-seven patients with suspected early-stage lung malignancy (controls). MEASUREMENTS AND MAIN RESULTS: Diaphragm muscle fibers from critically ill patients displayed significant atrophy and contractile weakness, but lacked impaired mitochondrial respiration and increased levels of oxidative stress markers. Mitochondrial energy status and morphology were not altered, despite a lower content of fusion proteins. CONCLUSIONS: Critically ill patients have manifest diaphragm muscle fiber atrophy and weakness, in the absence of mitochondrial dysfunction and oxidative stress. Thus, mitochondrial dysfunction and oxidative stress do not play a causative role in the development of atrophy and contractile weakness of the diaphragm in critically ill patients.

  • Adverse Heart-lung Interactions in Ventilator-induced Lung Injury
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-10
    Bhushan H Katira; Regan E Giesinger; Doreen Engelberts; Diana Zabini; Alik Kornecki; Gail Otulakowski; Takeshi Yoshida; Wolfgang M Kuebler; Patrick J McNamara; Kim A Connelly; Brian P Kavanagh

    RATIONALE: The original in vivo study of ventilator-induced lung injury by Webb and Tierney (1974) reported that high VT with zero PEEP caused overwhelming lung injury, subsequently shown by others to be due to lung shear stress. OBJECTIVE: To reproduce the lung injury and edema in the ‘Webb and Tierney’ study and investigate the mechanism. METHODS: Sprague-Dawley rats (≈400 g) received mechanical ventilation for 60 min according to the protocol of Webb and Tierney (14/0, 30/0, 45/10, 45/0 cmH2O). Additional series of experiments (20 min duration, to ensure all animals survived) were studied to assess permeability (4/group), echocardiography (4/group), and right and left ventricular pressure (5 and 4/group, respectively). MEASUREMENTS AND MAIN RESULTS: The original Webb & Tierney results were replicated in terms of lung/body weight ratio (45/0 > 45/10 ≈ 30/0 ≈ 14/0; P<0.05), and histology. In 45/0, pulmonary edema was overt and rapid, with survival less than 30 min. In 45/0 (but not 45/10), there was an increase in microvascular permeability, cyclical abolition of preload, and progressive dilation of the right ventricle. While left ventricular end-diastolic pressure decreased in 45/10, it increased in 45/0. CONCLUSIONS: In a classic model of VILI high peak pressure (and zero PEEP) causes respiratory swings (obliteration during inspiration) in RV filling and pulmonary perfusion, and ultimate RV failure and dilation. Pulmonary edema was due to increased permeability, augmented by a modest (approximately 40%) increase in hydrostatic pressure. The mechanism of cor pulmonale is uncertain but might be due to pulmonary microvascular injury from cyclic interruption/exaggeration of flow.

  • miR-542 Promotes Mitochondrial Dysfunction and SMAD Activity and is Raised in ICU Acquired Weakness
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-15
    Roser Farre Garros; Richard Paul; Martin Connolly; Amy Lewis; Benjamin E Garfield; S Amanda Natanek; Susannah Bloch; Vincent Mouly; Mark J Griffiths; Michael I Polkey; Paul R Kemp

    Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.

  • Recommended Reading from University Hospital Cleveland Fellows
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-16
    Amy Attaway; Mirna Ayache; Shrey Velani; Joanne McKell

    We review three recent and very interesting articles that have come out in the literature that made us reconsider certain aspects of asthma. These studies ask us whether a biologic is emerging that can be used in patients with normal IgE and no evidence of eosinophilia, if late onset asthma is associated with cardiovascular disease, and finally how different types of environmental exposures can influence the development of asthma in farming cultures.

  • Microbial Lineages in Sarcoidosis: A Metagenomic Analysis Tailored for Low Microbial Content Samples
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-28
    ; Abigail P. Lauder; Casey E. Hofstaedter; Young Hwang; Ayannah S. Fitzgerald; Ize Imai; Wojciech Biernat; Bartłomiej Rękawiecki; Hanna Majewska; Anna Dubaniewicz; Leslie A Litzky; Michael D. Feldman; Kyle Bittinger; Milton D Rossman; Karen C. Patterson; Frederic D. Bushman; Ronald G Collman

    Rationale: The etiology of sarcoidosis is unknown, but microbial agents are suspected as triggers. Objective: We sought to identify bacterial, fungal or viral lineages in specimens from sarcoidosis patients enriched relative to controls using metagenomic DNA sequencing. Since DNA from environmental contamination contributes disproportionately to samples with low authentic microbial content, we developed improved methods for filtering environmental contamination. Methods: We analyzed specimens from sarcoidosis subjects (n=93), non-sarcoidosis control subjects (n=72) and various environmental controls (n=150). Sarcoidosis specimens consisted of two independent sets of formalin-fixed, paraffin-embedded lymph node biopsies, bronchoalveolar lavage (BAL), Kveim reagent, and fresh granulomatous spleen from a sarcoidosis patient. All specimens were analyzed by bacterial 16S and fungal ITS rRNA gene sequencing. In addition, BAL was analyzed by shotgun sequencing of fractions enriched for viral particles, and Kveim and spleen were subjected to whole-genome shotgun sequencing. Measurements and Main Results: In one tissue set, fungi in the Cladosporiaceae family were enriched in sarcoidosis compared to non-sarcoidosis tissues; in the other tissue set, we detected enrichment of several bacterial lineages in sarcoidosis, but not Cladosporiaceae. BAL showed limited enrichment of Aspergillus fungi. Several microbial lineages were detected in Kveim and spleen, including Cladosporium. No microbial lineage was enriched in more than one sample type after correction for multiple comparisons. Conclusions: Metagenomic sequencing revealed enrichment of microbes in single types of sarcoidosis samples, but limited concordance across sample types. Statistical analysis accounting for environmental contamination was essential to avoiding false positives.

  • S1PR3 Signaling Drives Bactericidal Killing and is Required for Survival in Bacterial Sepsis
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-29
    JinChao Hou; QiXing Chen; XiaoLiang Wu; DongYan Zhao; Hadas Reuveni; Tamar Licht; MengLong Xu; Hu Hu; Andreas Hoeft; Shmuel A. Ben-Sasson; Qiang Shu; XiangMing Fang

    Rationale: Efficiently eliminating pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. Objectives: To investigate the role of S1PR3 in antibacterial immunity during sepsis. Methods: Loss and gain of function experiments were performed using cell and murine models. S1PR3 levels were determined in septic patients and healthy volunteers. Measurements and Main Results: S1PR3 protein levels were upregulated in macrophages upon bacterial stimuli. S1pr3-/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3-/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. The loss of S1PR3 led to markedly decreased bactericidal killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated macrophage bactericidal function and improved the survival in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3-/- macrophages due to impaired recruitment of the vacuolar protein sorting 34 to the phagosomes. In addition, the S1RP3 expression levels were elevated in monocytes from septic patients. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status and preferable outcomes. Conclusions: S1PR3 signaling drives bactericidal killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.

  • Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function Through Macrophage Immunomodulation
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-30
    Gareth R. Willis; Angeles Fernandez-Gonzalez; Jamie Anastas; Sally H Vitali; Xianlan Liu; Maria Ericsson; April Kwong; S. Alex Mitsialis; Stella Kourembanas

    Rationale: Mesenchymal stem/stromal cell (MSC) therapies have shown promise in preclinical models of pathologies relevant to newborn medicine, such as bronchopulmonary dysplasia (BPD). We have reported that the therapeutic capacity of MSCs is comprised in their secretome, and demonstrated that the therapeutic vectors are exosomes produced by MSCs (MSC-exos). Objective: To assess efficacy of MSC-exo treatment in a pre-clinical model of BPD and to investigate mechanisms underlying MSC-exo therapeutic action. Methods: Exosomes were isolated from media conditioned by human MSC cultures. Newborn mice were exposed to hyperoxia (HYRX, 75% O2), treated with exosomes on postnatal day 4 (PN4) and returned to room air on PN7. Treated animals and appropriate controls were harvested on PN7, 14 or 42 for assessment of pulmonary parameters. Measurements and Main Results: HYRX-exposed mice presented with pronounced alveolar simplification, fibrosis, and pulmonary vascular remodeling, which was effectively ameliorated by MSC-exo treatment. Pulmonary function tests and assessment of pulmonary hypertension showed functional improvements following MSC-exo treatment. Lung mRNA sequencing demonstrated that MSC-exo treatment induced pleiotropic effects on gene expression associated with HYRX-induced inflammation and immune responses. MSC-exos modulate the macrophage phenotype fulcrum, suppressing the proinflammatory M1 state and augmenting an anti-inflammatory M2-like state, both in vitro and in vivo. Conclusion: MSC-exo treatment blunts hyperoxia-associated inflammation and alters the hyperoxic lung transcriptome. This results in alleviation of HYRX-induced BPD, improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling, and amelioration of pulmonary hypertension. The MSC exosome mechanism-of-action is associated with modulation of lung macrophage phenotype.

  • Airway Mucosal Host Defense is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-30
    Deepika Polineni; Hong Dang; Paul J. Gallins; Lisa C Jones; Rhonda G Pace; Jaclyn R. Stonebraker; Leah A. Commander; Jeanne E. Krenicky; Yi-Hui Zhou; Harriet Corvol; Garry R Cutting; Mitchell L Drumm; Lisa J Strug; Michael P Boyle; Peter R Durie; James F Chmiel; Fei Zou; Fred A. Wright; Wanda K O'Neal; Michael R Knowles

    Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that >50% of the variability reflects non-CFTR genetic variation; however the full extent of the pertinent genetic variation is not known. Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing “in vivo” CF airway epithelial gene expression, complemented with genome-wide association study (GWAS) data. Methods: Nasal mucosal RNA from 134 CF patients was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested. Measurements and Main Results: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA genes. Ion transport and CFTR processing pathways, and HLA genes, were identified across differential gene expression and GWAS signals. Conclusion: Transcriptomic analyses in CF airway epithelia, coupled to genomic (GWAS) analyses, highlights the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health.

  • Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-30
    Asawari Korde; Lei Jin; Jian-ge Zhang; Anuradha Ramaswamy; Buqu Hu; Saeed Kolahian; Brenda Juan Guardela; Jose Herazo-Maya; Jill M. Siegfried; Laura Stabile; Margaret A Pisani; Roy S Herbst; Naftali Kaminski; Jack A. Elias; Jonathan T Puchalski; Shervin S Takyar

    Rationale: VEGF down-regulates miR-1 in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. Objectives: To examine the clinical significance of miR-1 in NSCLC and its specific role in tumor endothelium. Method and measurements: MiR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used VE-cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRAS mutant/P53 knockout (KP) mice, lung-specific VEGF transgenic mice, Lewis lung carcinoma (LLC) xenografts, and primary endothelial cells were used to test the effects of miR-1. Results: In two cohorts of NSCLC patients, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of NSCLC patients. MiR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KRAS mutant P53 knockout (KP) mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 over-expression. Vector-mediated delivery or transgenic over-expression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of LLC xenografts, and decreased tracheal angiogenesis in VEGF transgenic mice. In endothelial cells, miR-1 level was regulated through PI3kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene (Mpl) was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. Conclusion: Endothelial miR-1 is downregulated in NSCLC tumors and controls tumor progression and angiogenesis.

  • Effect of Telemedicine Education and Telemonitoring on CPAP Adherence: The Tele-OSA Randomized Trial
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-08-31
    Dennis Hwang; Jeremiah W Chang; Adam V Benjafield; ; Colleen Kelly; Kendra A Becker; Joseph B Kim; Rosa R Woodrum; Joanne Liang; Stephen F Derose

    Rationale– Automated telemedicine interventions could potentially improve adherence to continuous positive airway pressure therapy (CPAP). Objective–Examining the effects of telemedicine-delivered obstructive sleep apnea (OSA) education and CPAP telemonitoring with automated patient feedback messaging on CPAP adherence. Methods–This 4-arm, randomized, factorial-design clinical trial enrolled 1455 patients (51.0% women, age 49.1±12.5 years) referred for suspected OSA. 956 underwent home sleep apnea testing and 556 were prescribed CPAP. Two telemedicine interventions were implemented: (a) web-based OSA education (Tel-Ed); (b) CPAP telemonitoring with automated patient feedback (Tel-TM). Patients were randomized to (1) Usual Care, (2) Tel-Ed added, (3) Tel-TM added, or (4) Tel-Ed and Tel-TM added (Tel-Both). Measurements–Primary endpoint was 90-day CPAP usage. Secondary endpoints included attendance to OSA evaluation, and change in Epworth Sleepiness Scale score. Main Results– CPAP average daily use at 90 days was 3.8±2.5, 4.0±2.4, 4.4±2.2 and 4.8±2.3 hours in Usual Care, Tel-Ed, Tel-TM and Tel-Both groups. Usage was significantly higher in the Tel-TM and Tel-Both groups versus Usual Care (p=0.0002 for both) but not for Tel-Ed (p=0.10). Medicare adherence rates were 53.5%, 61.0%, 65.6% and 73.2% in Usual Care, Tel-Ed, Tel-TM and Tel-Both groups (Tel-Both vs Usual Care, p=0.001; Tel-TM vs Usual Care, p=0.003; Tel-Ed vs Usual Care, p=0.07). Telemedicine education improved clinic attendance compared to no telemedicine education (show rate 68.5% vs 62.7%; p=0.02). Conclusions–The use of CPAP telemonitoring with automated feedback messaging improved 90-day adherence in OSA patients. Telemedicine-based education did not significantly improve CPAP adherence but did increase clinic attendance for OSA evaluation. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02279901.

  • Chronic Obstructive Pulmonary Disease in Hispanics: A 9-Year Update
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Alejandro Díaz; Bartolomé Celli; Juan C. Celedón

    Hispanics are the largest minority in the U.S., now encompassing 56.6 million people. A Hispanic or Latino is an individual whose ancestry can be traced to Spain or territories previously under Spanish control. The Hispanic population in the U.S. and Latin America is very diverse for country of origin, nativity, and racial ancestry. Over the last nine years, our knowledge of COPD in Hispanics has improved, due to a better understanding of differences in COPD burden and risk factors across Hispanic subgroups, development of subgroup-specific spirometry reference equations, genetic studies, and better knowledge of barriers and needs in the diagnosis and management of COPD in the Hispanic population. Despite this progress, much remains to be done. The ongoing HCHS/SOL study, combined with future observational studies and clinical trials including sufficient numbers of well-characterized Hispanic subjects, are needed to draw firm conclusions about the etiology and management of COPD in Hispanic subgroups. Such Hispanic-focused studies should improve our understanding of the “omics” of COPD, the impact of variables correlated with racial ancestry on COPD and lung function (e.g., are spirometry reference equations that account for racial ancestry proportions superior to those developed for self-reported members of Hispanic subgroups?), the burden of ACOS, the use of non-tobacco products, and effective smoking cessation interventions in this ethnic group. Increasing health insurance coverage, together with culturally sensitive policies to address healthcare barriers (i.e. language proficiency, low health literacy, non-adherence to therapy, and patient beliefs), should help improve the care of Hispanic patients with COPD.

  • Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype in Asthma
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Elizabeth A. Kelly; Stephane Esnault; Lin Ying Liu; Michael D. Evans; Mats W Johansson; Sameer Mathur; Deane F Mosher; Loren C Denlinger; Nizar N. Jarjour

    Rationale: Mepolizumab, an interleukin-5 blocking antibody, reduces exacerbations in severe eosinophilic asthma patients. Mepolizumab arrests eosinophil maturation; however, the functional phenotype of eosinophils that persist in the blood and airway after administration of interleukin-5 neutralizing antibodies has not been reported. Objective: To determine the effect of anti-IL-5 antibody on the numbers and phenotypes of allergen-induced circulating and airway eosinophils. Methods: Airway inflammation was elicited in mild allergic asthma participants by segmental allergen challenge before and one month after a single intravenous 750 milligram dose of mepolizumab. Eosinophils were examined in blood, bronchoalveolar lavage, and endobronchial biopsies forty-eight hours after challenge. Measurements and Main Results: Segmental challenge without mepolizumab induced a rise in circulating eosinophils, bronchoalveolar lavage eosinophilia, and eosinophil peroxidase deposition in bronchial mucosa. Interleukin-5 neutralization before allergen challenge abolished the allergen-induced rise in circulating eosinophils and expression of interleukin-3 receptor; whereas, airway eosinophilia and eosinophil peroxidase deposition were blunted but not eliminated. Before mepolizumab treatment, bronchoalveolar lavage eosinophils had more surface interleukin-3 and granulocyte-monocyte colony-stimulating factor receptors, CD69, CD44, and CD23 and decreased interleukin-5 and eotaxin receptors than blood eosinophils. This activation phenotype indicated by bronchoalveolar lavage eosinophil surface markers, as well as the release of eosinophil peroxidase by eosinophils in the bronchial mucosa was maintained after mepolizumab. Conclusions: Mepolizumab reduced airway eosinophil numbers, but had limited effect on airway eosinophil activation markers suggesting these cells retain functionality. This observation may explain why interleukin-5 neutralization reduces but does not completely eradicate asthma exacerbations. Clinical trial registration available at www.clinicaltrials.gov, ID NCT00802438.

  • Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction After Lung Transplant
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-05
    Edward Cantu; Joshua M Diamond; Yoshikazu Suzuki; Jared Lasky; Christian Schaufler; Brian Lim; Rupal Shah; Mary Porteous; ; Steven M. Kawut; Scott M. Palmer; Laurie D Snyder; Matthew G Hartwig; Vibha N. Lama; Sangeeta Bhorade; Christian Bermudez; Maria Crespo; John McDyer; Keith Wille; Jonathan Orens; Pali D Shah; Ann Weinacker; David Weill; David Wilkes; David Roe; Chadi Hage; Lorraine B. Ware; Scarlett L Bellamy; Jason D Christie

    Rationale: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. Objective: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. Methods: Data from the Lung Transplant Outcomes Group multi-centered cohort was used to compare variations to the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. Main Results: 1,179 subjects from 10 centers were enrolled from 2007-2012. Median length of follow-up was 4 years (IQR [2.4; 5.9]). No mortality differences were noted between No PGD (Grade 0) and Mild PGD (Grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours – p<0.001). Biomarker divergent discrimination was superior when collapsing Grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. Conclusions: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

  • Effects of a Telephone- and Web-based Coping Skills Training Program Compared to an Education Program for Survivors of Critical Illness and Their Family Members: A Randomized Clinical Trial
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-05
    Christopher E Cox; Catherine L Hough; Shannon S. Carson; Douglas B White; Jeremy M. Kahn; Maren K. Olsen; Derek M Jones; Tamara J Somers; Sarah A. Kelleher; Laura S. Porter

    Rationale: Many survivors of critical illness and their family members experience significant psychological distress after discharge. Objectives: To compare effects of a coping skills training (CST) program with an education program on patient and family psychological distress. Methods: In this 5-center clinical trial, adult patients who received mechanical ventilation >48 hours and one family member of each patient were randomized to six weekly CST telephone sessions plus access to a study website or a critical illness education program. Measurements and Main Results: The primary outcome was the patient Hospital Anxiety and Depression Scale (HADS) at 3 months. Secondary outcomes included 3- and 6-month HADS subscales and the Impact of Events Scale-Revised. Among the 175 patients randomized to CST (n=86) or education (n=89), there was no significant difference between CST and education in either 3-month HADS scores (difference 1.3 [95% CI: -0.9, 3.4], p=0.24) or secondary patient and family outcomes. In pre-specified analyses, among patients with high baseline distress (n=60), CST recipients had greater improvement in 6-month HADS score (difference -4.6, [95% CI: -8.6, -0.6], p=0.02) than education. Among patients ventilated >7 days (n=47), education recipients had greater improvement in 3-month HADS score (difference -4.0 [95% CI: -8.1,-0.05] p=0.047) than CST. Conclusions: CST did not improve psychological distress symptoms compared to an education program. However, CST improved symptoms of distress at 6 months among patients with high baseline distress while the education program improved distress at 3 months among those ventilated for >7 days. Future efforts to address psychological distress among critical illness survivors should target high-risk populations. Clinical trial registration available at www.clinicaltrials.gov, ID NCT0198325

  • Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    ; ; Hennie Geldenhuys; Nicole Bilek; Simbarashe Mabwe; Deborah Abrahams; Lebohang Makhethe; Mzwandile Erasmus; Alana Keyser; Asma Toefy; Yolundi Cloete; Frances Ratangee; Thomas Blauenfeldt; Morten Ruhwald; Gerhard Walzl; Bronwyn Smith; Andre G. Loxton; Willem A. Hanekom; Jason R. Andrews; Maria D. Lempicki; Ruth Ellis; Ann M. Ginsberg; Mark Hatherill;

    Rationale: Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (Mtb) infection, which predisposes individuals to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability.

  • High-Dose Vitamin D3 during Tuberculosis Treatment in Mongolia. A Randomized Controlled Trial
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Davaasambuu Ganmaa; Baatar Munkhzul; Wafaie Fawzi; Donna Spiegelman; Walter C. Willett; Purev Bayasgalan; Erkhembayar Baasansuren; Burneebaatar Buyankhishig; Sereeter Oyun-Erdene; David A. Jolliffe; Theodoros Xenakis; Sabri Bromage; Barry R. Bloom; Adrian R. Martineau

    Rationale: Existing trials of adjunctive vitamin D in the treatment of pulmonary tuberculosis (PTB) are variously limited by small sample sizes, inadequate dosing regimens, and high baseline vitamin D status among participants. Comprehensive analyses of the effects of genetic variation in the vitamin D pathway on response to vitamin D supplementation are lacking.

  • A Comparative Analysis of Pulmonary and Critical Care Medicine Guideline Development Methodologies
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Noah C. Schoenberg; Alan F. Barker; John Bernardo; Robin R. Deterding; Jerrold J. Ellner; Dean R. Hess; Neil R. MacIntyre; Fernando J. Martinez; Kevin C. Wilson

    Rationale: The Institute of Medicine (IOM) standards for guideline development have had unintended negative consequences. A more efficient approach is desirable.

  • Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    ; ; Cecilia A. Hinojosa; Nilam J. Soni; Antonio Anzueto; Bettina L. Babu; Norberto Gonzalez-Juarbe; Alejandro H. Rodriguez; Alejandro Jimenez; James D. Chalmers; Stefano Aliberti; Oriol Sibila; Vicki T. Winter; Jacqueline J. Coalson; Luis D. Giavedoni; Charles S. Dela Cruz; Grant W. Waterer; Martin Witzenrath; Norbert Suttorp; Peter H. Dube; Carlos J. Orihuela

    Rationale: Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae can invade the myocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia.

  • Assessing the Generalizability of the National Lung Screening Trial: Comparison of Patients with Stage 1 Disease
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Nichole T. Tanner; Lin Dai; Brett C. Bade; Mulugeta Gebregziabher; Gerard A. Silvestri

    Rationale: The findings of the NLST (National Lung Screening Trial) are the basis for screening high-risk individuals according to age and smoking history. Although screening is covered for eligible Medicare beneficiaries, the generalizability of the NLST in the elderly population has been questioned.

  • Volume-controlled Ventilation Does Not Prevent Injurious Inflation during Spontaneous Effort
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Takeshi Yoshida; Susumu Nakahashi; Maria Aparecida Miyuki Nakamura; Yukiko Koyama; Rollin Roldan; Vinicius Torsani; Roberta R. De Santis; Susimeire Gomes; Akinori Uchiyama; Marcelo B. P. Amato; Brian P. Kavanagh; Yuji Fujino

    Rationale: Spontaneous breathing during mechanical ventilation increases transpulmonary pressure and Vt, and worsens lung injury. Intuitively, controlling Vt and transpulmonary pressure might limit injury caused by added spontaneous effort.

  • Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    So Young Park; Sanjeeb Shrestha; Young-Jin Youn; Jun-Kyu Kim; Shin-Yeong Kim; Hyun Jung Kim; So-Hee Park; Won-Gyun Ahn; Shin Kim; Myung Goo Lee; Ki-Suck Jung; Yong Bum Park; Eun-Kyung Mo; Yousang Ko; Suh-Young Lee; Younsuck Koh; Myung Jae Park; Dong-Keun Song;

    Rationale: Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined.

  • Applying Precision Medicine to Trial Design Using Physiology. Extracorporeal CO2 Removal for Acute Respiratory Distress Syndrome
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    ; Marcelo B. P. Amato;

    In clinical trials of therapies for acute respiratory distress syndrome (ARDS), the average treatment effect in the study population may be attenuated because individual patient responses vary widely. This inflates sample size requirements and increases the cost and difficulty of conducting successful clinical trials. One solution is to enrich the study population with patients most likely to benefit, based on predicted patient response to treatment (predictive enrichment). In this perspective, we apply the precision medicine paradigm to the emerging use of extracorporeal CO2 removal (ECCO2R) for ultraprotective ventilation in ARDS. ECCO2R enables reductions in tidal volume and driving pressure, key determinants of ventilator-induced lung injury. Using basic physiological concepts, we demonstrate that dead space and static compliance determine the effect of ECCO2R on driving pressure and mechanical power. This framework might enable prediction of individual treatment responses to ECCO2R. Enriching clinical trials by selectively enrolling patients with a significant predicted treatment response can increase treatment effect size and statistical power more efficiently than conventional enrichment strategies that restrict enrollment according to the baseline risk of death. To support this claim, we simulated the predicted effect of ECCO2R on driving pressure and mortality in a preexisting cohort of patients with ARDS. Our computations suggest that restricting enrollment to patients in whom ECCO2R allows driving pressure to be decreased by 5 cm H2O or more can reduce sample size requirement by more than 50% without increasing the total number of patients to be screened. We discuss potential implications for trial design based on this framework.

  • Computed Tomography Measure of Lung at Risk and Lung Function Decline in Chronic Obstructive Pulmonary Disease
    Am. J. Respir. Crit. Care Med. (IF 13.204) Pub Date : 2017-09-01
    Surya P. Bhatt; Sandeep Bodduluri; Eric A. Hoffman; John D. Newell Jr.; Jessica C. Sieren; Mark T. Dransfield; Joseph M. Reinhardt

    Rationale: The rate of decline of lung function is greater than age-related change in a substantial proportion of patients with chronic obstructive pulmonary disease, even after smoking cessation. Regions of the lung adjacent to emphysematous areas are subject to abnormal stretch during respiration, and this biomechanical stress likely influences emphysema initiation and progression.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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