Publications by authors named "Ashraf Fawzy"

35 Publications

Randomized Clinical Trial of Air Cleaners to Improve Indoor Air Quality and COPD Health: Results of the CLEAN AIR STUDY.

Am J Respir Crit Care Med 2021 Aug 27. Epub 2021 Aug 27.

Johns Hopkins University Bloomberg School of Public Health, 25802, Department of Environmental Health and Engineering, Baltimore, Maryland, United States.

Rationale: Indoor particulate matter is associated with worse COPD outcomes. It remains unknown whether reductions of indoor pollutants improve respiratory morbidity.

Methods: Eligible former smokers with moderate-severe COPD received active or sham portable HEPA air cleaners and followed for six months in this blinded randomized controlled trial. The primary outcome was six-month change in Saint George's Respiratory Questionnaire (SGRQ). Secondary outcomes were exacerbation risk, respiratory symptoms, rescue medication use and 6MWD. Intention to treat analysis included all subjects and per protocol analysis included adherent participants (greater than 80% use of air cleaner).

Main Results: 116 participants were randomized of which 84.5% completed study. There was no statistically significant difference in total SGRQ score, but the active filter group had greater reduction in SGRQ symptom subscale (ß -7.7 [95% CI, -15.0 to -0.37]) and respiratory symptoms (BCSS, ß -0.8 [95% CI, -1.5 to -0.1); and lower rate of moderate exacerbations (IRR 0.32 [95% CI, 0.12-0.91]) and rescue medication use (IRR 0.54 [95% CI, 0.33-0.86]) compared to sham group (all p<0.05). In per protocol analysis, there was statistically significant difference in primary outcome between the active filter vs. sham group (SGRQ β-4.76 [95% CI, -9.2 to -0.34]) and in moderate exacerbation risk, BCSS and 6MWD. Participants spending more time indoors were more likely to have treatment benefit.

Conclusions: This is the first environmental intervention study conducted among former smokers with COPD showing potential health benefits of portable HEPA air cleaners, particularly among those with greater adherence and spending a greater time indoors. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02236858.
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http://dx.doi.org/10.1164/rccm.202103-0604OCDOI Listing
August 2021

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

ERJ Open Res 2021 Jul 26;7(3). Epub 2021 Jul 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.
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http://dx.doi.org/10.1183/23120541.00068-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311135PMC
July 2021

Metformin Use and Risk of Asthma Exacerbation Among Asthma Patients with Glycemic Dysfunction.

J Allergy Clin Immunol Pract 2021 Jul 19. Epub 2021 Jul 19.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address:

Background: Diabetes is associated with worse asthma morbidity. Metformin, which treats diabetes, may have a role among patients with asthma and glycemic dysfunction.

Objective: To determine the association between metformin use and asthma exacerbations among patients with diabetes.

Methods: We queried the Johns Hopkins electronic health record from April 1, 2013, to May 31, 2018. Adults with asthma and diabetes were followed from first hemoglobin A1c (HbA1c) test to an asthma-related systemic corticosteroid prescription, emergency department (ED) visit, or hospitalization. Multivariable Cox models estimated time to each outcome associated with metformin use, modeled as either time-invariant (status at HbA1c testing) or time-dependent (based on fill data). Mediation of results by HbA1c was assessed. Sensitivity analysis was performed by propensity score matching.

Results: The cohort comprised 1749 adults with asthma and diabetes. Metformin use at entry was associated with a lower hazard of asthma-related ED visits (adjusted hazard ratio [aHR], 0.40; 95% CI, 0.22-0.75) but not steroid prescription (aHR, 0.89; 95% CI, 0.70-1.13) or hospitalization (aHR, 0.38; 95% CI, 0.13-1.12). HbA1c did not mediate the association with ED visits. With metformin exposure modeled as time-dependent, metformin use was additionally associated with lower hazard of asthma-related hospitalization (aHR, 0.30; 95% CI, 0.09-0.93). Results were consistent within a subcohort of 698 metformin users matched 1:1 to nonusers by propensity score.

Conclusions: Metformin use, independent of glycemic control and obesity, was associated with lower hazard of asthma-related ED visits and hospitalizations. Metformin may have benefit in patients with asthma and glycemic dysfunction.
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http://dx.doi.org/10.1016/j.jaip.2021.07.007DOI Listing
July 2021

Polycythemia is Associated with Lower Incidence of Severe COPD Exacerbations in the SPIROMICS Study.

Chronic Obstr Pulm Dis 2021 Jul;8(3):326-335

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States.

Secondary polycythemia has long been recognized as a consequence of chronic pulmonary disease and hypoxemia and is associated with lower mortality and fewer hospitalizations among individuals with chronic obstructive pulmonary disease (COPD)-prescribed long-term oxygen therapy. This study investigates the association of polycythemia with COPD severity, phenotypic features, and respiratory exacerbations in a contemporary and representative sample of individuals with COPD. Current and former smokers with COPD (forced expiratory volume in 1 second [FEV] to forced vital capacity [FVC] ratio <70%) without a history of hematologic/oncologic disorders were selected from the SubPopulations and InteRmediate Outcomes Measures In COPD Study (SPIROMICS), a multi-center observational cohort. Participants with polycythemia (hemoglobin ≥15g/dL [females] or ≥17g/dL [males]), were compared to individuals without anemia (hemoglobin ≥12g/dL [females] or ≥13g/dL [males]). Cross-sectional outcomes including percent predicted FEV, respiratory symptoms, quality of life, exercise tolerance, and percentage and distribution of emphysema (voxels<-950 Hounsfield units [HU] at total lung capacity) were evaluated using linear or logistic regression. Longitudinal acute exacerbation of COPD (AECOPD) and severe AECOPD (requiring an emergency department visit or hospitalization) were assessed using zero-inflated negative binomial models. Among 1261 participants, 148 (11.7%) had polycythemia. Average follow-up was 4.2±1.7 years and did not differ by presence of polycythemia. In multivariate analysis, compared to participants with normal hemoglobin, polycythemia was associated with a reduced rate of severe AECOPD (adjusted incidence rate ratio 0.57, 95% CI: 0.33-0.98), lower percent predicted FEV, lower resting oxygen saturation, increased upper to lower lobe ratio of emphysema, and a greater degree of emphysema, though the latter was attenuated after adjusting for lung function. There were no significant differences in total AECOPD, patient-reported outcomes, or exercise tolerance. These findings suggest that polycythemia, while associated with less favorable physiologic parameters, is not independently associated with symptoms, and is associated with fewer severe exacerbations. Future studies should explore the potentially protective role of increased hemoglobin beyond the correction of anemia.
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http://dx.doi.org/10.15326/jcopdf.2021.0216DOI Listing
July 2021

Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.

Am J Respir Crit Care Med 2021 Sep;204(6):651-666

Division of Pulmonary and Critical Care Medicine and.

Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects and/or were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism and ; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (-0.92%; 95% confidence interval [CI], -1.7% to -0.14%;  = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L;  = 0.01). Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.
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http://dx.doi.org/10.1164/rccm.202012-4510OCDOI Listing
September 2021

Emphysema Progression and Lung Function Decline Among Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockade Users in the COPDGene Cohort.

Chest 2021 May 21. Epub 2021 May 21.

Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, MD.

Background: Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV progression in current smokers.

Research Question: Is use of ACEi and ARB associated with less progression of emphysema and FEV decline among individuals with COPD or baseline emphysema?

Methods: Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume <-950 Hounsfield units [HU]), 15th percentile of the attenuation histogram (attenuation [in HU] below which 15% of voxels are situated plus 1,000 HU), and lung function decline over 5 years between ACEi and ARB users and nonusers in those with spirometry-confirmed COPD, as well as all participants and those with baseline emphysema. Effect modification by smoking status also was investigated.

Results: Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV % predicted, 0.83; 95% CI, -0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema.

Interpretation: Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline.

Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.05.007DOI Listing
May 2021

Association of Triglyceride-Glucose Index and Lung Health: A Population-Based Study.

Chest 2021 Sep 8;160(3):1026-1034. Epub 2021 Apr 8.

Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX.

Background: Metabolic syndrome and insulin resistance are associated with worsened outcomes of chronic lung disease. The triglyceride-glucose index (TyG), a measure of metabolic dysfunction, is associated with metabolic syndrome and insulin resistance, but its relationship to lung health is unknown.

Research Question: What is the relationship of TyG to respiratory symptoms, chronic lung disease, and lung function?

Study Design And Methods: This study analyzed data from the National Health and Nutrition Examination Survey from 1999 to 2012. Participants included fasting adults age ≥ 40 years (N = 6,893) with lung function measurements in a subset (n = 3,383). Associations of TyG with respiratory symptoms (cough, phlegm production, wheeze, and exertional dyspnea), chronic lung disease (diagnosed asthma, chronic bronchitis, and emphysema), and lung function (FEV, FVC, and obstructive or restrictive spirometry pattern) were evaluated, adjusting for sociodemographic variables, comorbidities, and smoking. TyG was compared vs insulin resistance, represented by the homeostatic model assessment of insulin resistance (HOMA-IR), and vs the metabolic syndrome.

Results: TyG was moderately correlated with HOMA-IR (Spearman ρ = 0.51) and had good discrimination for metabolic syndrome (area under the receiver-operating characteristic curve, 0.80). A one-unit increase in TyG was associated with higher odds of cough (adjusted OR [aOR], 1.28; 95% CI, 1.06-1.54), phlegm production (aOR, 1.20; 95% CI, 1.01-1.43), wheeze (aOR, 1.18; 95% CI, 1.03-1.35), exertional dyspnea (aOR, 1.21; 95% CI, 1.07-1.38), and a diagnosis of chronic bronchitis (aOR, 1.21; 95% CI, 1.02-1.43). TyG was associated with higher relative risk of a restrictive spirometry pattern (adjusted relative risk ratio, 1.45; 95% CI, 1.11-1.90). Many associations were maintained with additional adjustment for HOMA-IR or metabolic syndrome.

Interpretation: TyG was associated with respiratory symptoms, chronic bronchitis, and a restrictive spirometry pattern. Associations were not fully explained by insulin resistance or metabolic syndrome. TyG is a satisfactory measure of metabolic dysfunction with relevance to pulmonary outcomes. Prospective study to define TyG as a biomarker for impaired lung health is warranted.
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http://dx.doi.org/10.1016/j.chest.2021.03.056DOI Listing
September 2021

Metformin use and respiratory outcomes in asthma-COPD overlap.

Respir Res 2021 Feb 26;22(1):70. Epub 2021 Feb 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, 1830 E. Monument St. 5th Floor, Baltimore, MD, 21205, USA.

Background: Metformin is associated with improved respiratory outcomes in asthma; however, metformin in COPD and asthma-COPD overlap (ACO) remains unexplored.

Objective: To determine the association between metformin use and respiratory outcomes in COPD and ACO.

Study Design And Methods: Participants with COPD (FEV1/FVC < 0.70) in the Genetic Epidemiology of COPD study (COPDGene®) were categorized as ACO (n = 510), defined as concurrent physician-diagnosed asthma before age 40 years, or COPD alone (n = 3459). We estimated the association of baseline metformin use with (1) rate of total and severe respiratory exacerbations during follow-up, (2) cross-sectional St. George's Respiratory Questionnaire (SGRQ) score, six-minute walk distance (6MWD), and post-bronchodilator FEV1 percent predicted (FEV1pp), and (3) 5-year change in SGRQ, 6MWD, and FEV1pp. We also examined change in SGRQ, 6MWD and FEV1pp among participants who initiated metformin during follow-up (n = 108) compared to persistent metformin non-users (n = 2080). Analyses were adjusted for sociodemographic factors, medications, and comorbidities.

Results: Among participants with ACO, metformin use was associated with lower rate of total (adjusted incidence rate ratio [aIRR] 0.3; 95% confidence interval [95%CI] 0.11, 0.77) and severe exacerbations (aIRR 0.29; 95%CI 0.10, 0.89). Among participants with COPD alone, there was no association between metformin use with total (aIRR 0.98; 95%CI 0.62, 1.5) or severe exacerbations (aIRR 1.3; 95% CI 0.68, 2.4) (p-interaction < 0.05). Metformin use was associated with lower baseline SGRQ score (adjusted mean difference [aMD] - 2.7; 95%CI - 5.3, - 0.2) overall. Metformin initiation was associated with improved SGRQ score (aMD -10.0; 95% CI - 18.7, - 1.2) among participants with ACO but not COPD alone (p-interaction < 0.05). There was no association between metformin use and 6MWD or FEV1pp in any comparison.

Conclusions: Metformin use was associated with fewer respiratory exacerbations and improved quality of life among individuals with ACO but not COPD alone. Results suggest a potential role for metformin in ACO which requires further prospective study.

Trial Registry: NCT00608764.
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http://dx.doi.org/10.1186/s12931-021-01658-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908718PMC
February 2021

Hypogammaglobulinemia in COPD: Treatable Phenotype or Surrogate Marker?

Chest 2020 10;158(4):1296-1297

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2020.05.560DOI Listing
October 2020

Clinical Phenotypes of Atopy and Asthma in COPD: A Meta-analysis of SPIROMICS and COPDGene.

Chest 2020 12 23;158(6):2333-2345. Epub 2020 May 23.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies.

Research Question: What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)?

Study Design And Methods: Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis.

Results: The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes.

Interpretation: Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.
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http://dx.doi.org/10.1016/j.chest.2020.04.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768932PMC
December 2020

Association of Long-term Ambient Ozone Exposure With Respiratory Morbidity in Smokers.

JAMA Intern Med 2020 01;180(1):106-115

Department of Medicine, Johns Hopkins University, Baltimore, Maryland.

Importance: Few studies have investigated the association of long-term ambient ozone exposures with respiratory morbidity among individuals with a heavy smoking history.

Objective: To investigate the association of historical ozone exposure with risk of chronic obstructive pulmonary disease (COPD), computed tomography (CT) scan measures of respiratory disease, patient-reported outcomes, disease severity, and exacerbations in smokers with or at risk for COPD.

Design, Setting, And Participants: This multicenter cross-sectional study, conducted from November 1, 2010, to July 31, 2018, obtained data from the Air Pollution Study, an ancillary study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). Data analyzed were from participants enrolled at 7 (New York City, New York; Baltimore, Maryland; Los Angeles, California; Ann Arbor, Michigan; San Francisco, California; Salt Lake City, Utah; and Winston-Salem, North Carolina) of the 12 SPIROMICS clinical sites. Included participants had historical ozone exposure data (n = 1874), were either current or former smokers (≥20 pack-years), were with or without COPD, and were aged 40 to 80 years at baseline. Healthy persons with a smoking history of 1 or more pack-years were excluded from the present analysis.

Exposures: The 10-year mean historical ambient ozone concentration at participants' residences estimated by cohort-specific spatiotemporal modeling.

Main Outcomes And Measures: Spirometry-confirmed COPD, chronic bronchitis diagnosis, CT scan measures (emphysema, air trapping, and airway wall thickness), 6-minute walk test, modified Medical Research Council (mMRC) Dyspnea Scale, COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), postbronchodilator forced expiratory volume in the first second of expiration (FEV1) % predicted, and self-report of exacerbations in the 12 months before SPIROMICS enrollment, adjusted for demographics, smoking, and job exposure.

Results: A total of 1874 SPIROMICS participants were analyzed (mean [SD] age, 64.5 [8.8] years; 1479 [78.9%] white; and 1013 [54.1%] male). In adjusted analysis, a 5-ppb (parts per billion) increase in ozone concentration was associated with a greater percentage of emphysema (β = 0.94; 95% CI, 0.25-1.64; P = .007) and percentage of air trapping (β = 1.60; 95% CI, 0.16-3.04; P = .03); worse scores for the mMRC Dyspnea Scale (β = 0.10; 95% CI, 0.03-0.17; P = .008), CAT (β = 0.65; 95% CI, 0.05-1.26; P = .04), and SGRQ (β = 1.47; 95% CI, 0.01-2.93; P = .048); lower FEV1% predicted value (β = -2.50; 95% CI, -4.42 to -0.59; P = .01); and higher odds of any exacerbation (odds ratio [OR], 1.37; 95% CI, 1.12-1.66; P = .002) and severe exacerbation (OR, 1.37; 95% CI, 1.07-1.76; P = .01). No association was found between historical ozone exposure and chronic bronchitis, COPD, airway wall thickness, or 6-minute walk test result.

Conclusions And Relevance: This study found that long-term historical ozone exposure was associated with reduced lung function, greater emphysema and air trapping on CT scan, worse patient-reported outcomes, and increased respiratory exacerbations for individuals with a history of heavy smoking. The association between ozone exposure and adverse respiratory outcomes suggests the need for continued reevaluation of ambient pollution standards that are designed to protect the most vulnerable members of the US population.
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http://dx.doi.org/10.1001/jamainternmed.2019.5498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902160PMC
January 2020

COPDGene 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis 2019 Nov;6(5):384-399

Northeastern University, Boston, Massachusetts.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.

Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.

Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.

Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020846PMC
November 2019

Association of Metformin Initiation and Risk of Asthma Exacerbation. A Claims-based Cohort Study.

Ann Am Thorac Soc 2019 12;16(12):1527-1533

Division of Pulmonary and Critical Care Medicine.

Diabetes and metabolic syndrome have been associated with worsened asthma control. Metformin improves insulin resistance and metabolic function. Experimental studies suggest that metformin may improve pathologic features of asthma, but evidence of clinical benefit is limited. To determine if treatment with metformin in a cohort of individuals with asthma and diabetes is associated with lower risk of asthma exacerbation. A 6-year retrospective cohort of individuals over age 18 with asthma and diabetes was assembled from a national administrative claims database. New users of metformin were matched to nonusers by propensity score on the basis of demographic, comorbidity, and medication-use characteristics. An exacerbation was defined as an asthma-related hospitalization, emergency department visit, or filling of a systemic corticosteroid prescription within 14 days of an asthma-related ambulatory visit. Cox proportional hazards estimated the change in hazard of asthma exacerbation associated with metformin initiation. In a cohort of 23,920 individuals with asthma and diabetes, metformin initiation was associated with lower hazard of asthma exacerbation (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86-0.98), driven by lower hazards of asthma-related emergency department visits (HR, 0.81; 95% CI, 0.74-0.88) and hospitalization (HR, 0.67; 95% CI, 0.50-0.91), without differences in corticosteroid use (HR, 0.96; 95% CI, 0.86-1.03). In an administrative cohort of individuals with asthma and diabetes, metformin initiation was associated with a lower hazard of asthma-related emergency department visits and hospitalizations. These findings suggest a possible benefit of metformin in more severe asthma exacerbations. Investigation within cohorts with more detailed participant characterization is necessary.
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http://dx.doi.org/10.1513/AnnalsATS.201812-897OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956833PMC
December 2019

Clinical Epidemiology of COPD: Insights From 10 Years of the COPDGene Study.

Chest 2019 08 30;156(2):228-238. Epub 2019 May 30.

Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO. Electronic address:

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap.
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http://dx.doi.org/10.1016/j.chest.2019.04.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198872PMC
August 2019

Association of platelet count with all-cause mortality and risk of cardiovascular and respiratory morbidity in stable COPD.

Respir Res 2019 May 8;20(1):86. Epub 2019 May 8.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1830 E. Monument St. 5th Floor, Baltimore, MD, USA.

Background: Platelet count is a prognostic indicator in the general population and elderly. Thrombocytosis during acute exacerbation of COPD (AECOPD) has been associated with mortality; however, the relationship between platelet count and mortality in stable COPD is unknown.

Methods: We performed post hoc secondary analysis on a subsample of 1797 patients in the Study to Understand Mortality and Morbidity in COPD (SUMMIT) who had blood samples drawn at baseline. Participants were current or former smokers, 40-80 years old with moderate COPD and history or increased risk of cardiovascular (CV) disease. The primary outcome was on and post-treatment all-cause mortality. Secondary outcomes included first-on-treatment moderate/severe AECOPD and on-treatment CV composite event (CV death, myocardial infarction, stroke, unstable angina and transient ischemic attack). Multivariable Cox proportional hazards models were used to investigate study endpoint associations with platelet count quintile grouping, continuous platelet count utilizing two-term fractional polynomials, and categories of low, normal and high platelet count (< 150, ≥150 to < 300, ≥300 × 10/L).

Results: Patients were followed for 2.3 ± 0.9 years for vital status and 1.6 ± 1.1 years for morbidity endpoints during which 105 (5.8%) died, 651 (36.2%) experienced AECOPD (159 with severe AECOPD) and 86 (4.8%) experienced a CV event. A U-shaped association between platelet count and all-cause mortality was observed. Compared to the third quintile group (Q3) of platelet count, risk of death was increased in the lowest quintile group (Q1; hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 0.93-3.23) and highest quintile group (Q5; HR: 1.66; 95%CI: 0.89-3.10), though point estimates were imprecise. Using clinical cutoffs, compared with normal platelet counts (≥150 to < 300 × 10/L), risk of all-cause mortality was nominally increased among patients with thrombocytopenia (HR: 1.46; 95%CI: 0.81-2.64) and high platelet count (HR: 1.66; 95%CI: 0.96-2.86). Compared with Q3, CV events were nominally increased for Q5 (HR: 1.71; 95%CI: 0.83-3.49) and Q1 (HR: 1.41; 95%CI: 0.70, 2.85). There was no association between platelet count and AECOPD.

Conclusions: In stable COPD platelet count demonstrated a U-shaped association with increased risk of 3-year all-cause mortality, though a platelet count level above or below which risk of mortality was increased could not be definitively identified.

Trial Registration: ClinicalTrials.gov NCT01313676 .
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http://dx.doi.org/10.1186/s12931-019-1059-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507019PMC
May 2019

Anemia and Adverse Outcomes in a Chronic Obstructive Pulmonary Disease Population with a High Burden of Comorbidities. An Analysis from SPIROMICS.

Ann Am Thorac Soc 2018 06;15(6):710-717

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine and.

Rationale: Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and associated with a significant burden of comorbidities. Although anemia is associated with adverse outcomes in COPD, its contribution to outcomes in individuals with other comorbid chronic diseases is not well understood.

Objectives: This study examines the association of anemia with outcomes in a large, well-characterized COPD cohort, and attempts to understand the contribution of anemia to outcomes and phenotypes in individuals with other comorbidities.

Methods: Participants with COPD from SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study) were analyzed in adjusted models to determine the associations of normocytic anemia with clinical outcomes, computed tomographic measures, and biomarkers. Analysis was additionally performed to understand the independence and possible interactions related to cardiac and metabolic comorbidities.

Results: A total of 1,789 individuals with COPD from SPIROMICS had data on hemoglobin, and of these 7.5% (n = 135) were found to have normocytic anemia. Anemic participants were older with worse airflow obstruction, a higher proportion of them were African Americans, and they had a higher burden of cardiac and metabolic comorbidities. Anemia was strongly associated with 6-minute walk distance (β, -61.43; 95% confidence interval [CI], -85.11 to -37.75), modified Medical Research Council dyspnea questionnaire (β, 0.27; 95% CI, 0.11-0.44), and St. George's Respiratory Questionnaire (β, 3.90; 95% CI, 1.09-6.71), and these adjusted associations were stronger among those with two or more cardiac and metabolic comorbidities. Anemia was associated with higher levels of serum C-reactive protein, soluble receptor for advanced glycosylation end-products, and epithelial cadherin-1, findings that persisted when in those with a high burden of comorbidities.

Conclusions: Anemia is associated with worse exercise capacity, greater dyspnea, and greater disease severity among adults with COPD, particularly among those with comorbid chronic cardiac and metabolic diseases. The biomarkers found in anemic individuals suggest inflammation, lung tissue injury, and oxidative stress as possible pathways for the adverse correlations of anemia with outcomes in COPD; however, substantial further study is required to better understand these potential mechanisms. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).
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http://dx.doi.org/10.1513/AnnalsATS.201708-687OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207135PMC
June 2018

Aspirin Use and Respiratory Morbidity in COPD: A Propensity Score-Matched Analysis in Subpopulations and Intermediate Outcome Measures in COPD Study.

Chest 2019 03 26;155(3):519-527. Epub 2018 Dec 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD. Electronic address:

Background: Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown.

Methods: Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV/FVC < 70%). Acute exacerbations of COPD (AECOPD) were prospectively ascertained through quarterly structured telephone questionnaires up to 3 years and categorized as moderate (symptoms treated with antibiotics or oral corticosteroids) or severe (requiring ED visit or hospitalization). Aspirin users were matched one-to-one with nonusers, based on propensity score. The association of aspirin use with total, moderate, and severe AECOPD was investigated using zero-inflated negative binomial models. Linear or logistic regression was used to investigate the association with baseline respiratory symptoms, quality of life, and exercise tolerance.

Results: Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (β, -2.2; 95% CI, -4.1 to -0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (β, -1.1; 95% CI, -1.9 to -0.2) but not 6-min walk distance (β, 0.7 m; 95% CI, -14.3 to 15.6).

Conclusions: Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding.

Trial Registry: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2018.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414789PMC
March 2019

Lower serum IgA is associated with COPD exacerbation risk in SPIROMICS.

PLoS One 2018 12;13(4):e0194924. Epub 2018 Apr 12.

Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Background: Decreased but measurable serum IgA levels (≤70 mg/dL) have been associated with risk for infections in some populations, but are unstudied in COPD. This study tested the hypothesis that subnormal serum IgA levels would be associated with exacerbation risk in COPD.

Methods: Data were analyzed from 1,049 COPD participants from the observational cohort study SPIROMICS (535 (51%) women; mean age 66.1 (SD 7.8), 338 (32%) current smokers) who had baseline serum IgA measured using the Myriad RBM biomarker discovery platform. Exacerbation data was collected prospectively (mean 944.3 (SD 281.3) days), and adjusted linear, logistic and zero-inflated negative binomial regressions were performed.

Results: Mean IgA was 269.1 mg/dL (SD 150.9). One individual had deficient levels of serum IgA (<7 mg/dL) and 25 (2.4%) had IgA level ≤70 mg/dL. Participants with IgA ≤70 mg/dL were younger (62 vs. 66 years, p = 0.01) but otherwise similar to those with higher IgA. In adjusted models, IgA ≤70 mg/dL was associated with higher exacerbation incidence rates (IRR 1.71, 95% CI 1.01-2.87, p = 0.044) and greater risk for any severe exacerbation (OR 2.99, 95% CI 1.30-6.94, p = 0.010). In adjusted models among those in the lowest decile (<120 mg/dL), each 10 mg/dL decrement in IgA (analyzed continuously) was associated with more exacerbations during follow-up (β 0.24, 95% CI 0.017-0.46, p = 0.035).

Conclusions: Subnormal serum IgA levels were associated with increased risk for acute exacerbations, supporting mildly impaired IgA levels as a contributing factor in COPD morbidity. Additionally, a dose-response relationship between lower serum IgA and number of exacerbations was found among individuals with serum IgA in the lowest decile, further supporting the link between serum IgA and exacerbation risk. Future COPD studies should more comprehensively characterize immune status to define the clinical relevance of these findings and their potential for therapeutic correction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896903PMC
July 2018

Association of thrombocytosis with COPD morbidity: the SPIROMICS and COPDGene cohorts.

Respir Res 2018 01 26;19(1):20. Epub 2018 Jan 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 1830 E Monument St. 5th Floor, Baltimore, MD, 21287, USA.

Background: Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown. This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity.

Methods: Participants with COPD were included from two multi-center observational studies (SPIROMICS and COPDGene). Cross-sectional associations of thrombocytosis (platelet count ≥350 × 10/L) with AECOPD during prior year (none vs. any), exertional dyspnea (modified Medical Research Council (mMRC) score ≥ 2), COPD Assessment Test (CAT) score ≥ 10, six-minute-walk distance (6MWD), and St. George Respiratory questionnaire (SGRQ) were modeled using multivariable logistic or linear regression. A pooled effect estimate for thrombocytosis was produced using meta-analysis of data from both studies.

Results: Thrombocytosis was present in 124/1820 (6.8%) SPIROMICS participants and 111/2185 (5.1%) COPDGene participants. In meta-analysis thrombocytosis was associated with any AECOPD (adjusted odds ratio [aOR] 1.5; 95% confidence interval [95% CI]: 1.1-2.0), severe AECOPD (aOR 1.5; 95% CI: 1.1-2.2), dyspnea (mMRC ≥ 2 aOR 1.4; 95% CI: 1.0-1.9), respiratory symptoms (CAT ≥ 10 aOR 1.6; 95% CI: 1.1-2.4), and higher SGRQ score (β 2.7; 95% CI: 0.5, 5). Thrombocytosis was also associated with classification into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D (aOR 1.7 95% CI: 1.2-2.4).

Conclusions: Thrombocytosis was associated with higher likelihood of prior exacerbation and worse symptoms. Platelet count, a commonly measured clinical assay, may be a biomarker for moderate-severe COPD symptoms, guide disease classification and intensity of treatment. Future longitudinal studies investigating the role of platelets in COPD progression may be warranted.

Trial Registration: ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene).
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http://dx.doi.org/10.1186/s12931-018-0717-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787242PMC
January 2018

Safety and efficacy of taurolidine/urokinase versus taurolidine/heparin as a tunneled catheter lock solution in hemodialysis patients: a prospective, randomized, controlled study.

Nephrol Dial Transplant 2018 04;33(4):619-626

Nephrology Department, Hamad Medical Corp., Doha, Qatar.

Background: Taurolidine citrate with heparin (Taurolock/Hep) is a promising central venous catheter lock solution. Despite its universal use among our hemodialysis patients, the prevalence of catheter malfunction was high. We aimed to compare Taurolock/Hep and taurolidine citrate with urokinase (Taurolock/U) as a catheter lock solution in order to identify whether either solution could reduce catheter-related dysfunction.

Methods: In this prospective, randomized, controlled trial, patients were randomized to receive either Taurolock/Hep or Taurolock/U and were followed for 6 months. Episodes of acute catheter thrombosis, requirement of recombinant tissue plasminogen activator (rt-PA) and incidence of catheter-related blood stream infection (CRBSI) were recorded, along with dialysis adequacy (Kt/V), blood flow rates (BFRs) and adverse events.

Results: There were 93 inclusions (85 patients) in the Taurolock/Hep group and 84 inclusions in the Taurolock/U group (79 patients). Three catheters were removed in the Taurolock/Hep group because of acute thrombosis, while no catheter was removed for the same reason in the Taurolock/U group. The total number of all-causes catheter exchange (acute thrombosis and CRBSI) was significantly lower in Taurolock/U group (P = 0.028). rt-PA was used significantly less often in the Taurolock/U group than in the Taurolock/Hep group (P = 0.006). Moreover, higher BFR and Kt/V were noted in the Taurolock/U group than in the Taurolock/Hep group, although the differences were not uniformly significant.

Conclusion: Taurolock/U is a safe and effective tunneled dialysis catheter lock solution, with a low rate of catheter exchange.
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http://dx.doi.org/10.1093/ndt/gfx187DOI Listing
April 2018

Impact of Physical Activity on Reporting of Childhood Asthma Symptoms.

Lung 2017 12 15;195(6):693-698. Epub 2017 Sep 15.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

This study aims to determine the impact of physical activity on asthma symptom reporting among children living in an inner city. Among 147 children aged 5-12 years with physician-diagnosed asthma, we assessed asthma symptoms using twice-daily diaries and physical activity using the physical activity questionnaire for children during three 8-day periods (baseline, 3 and 6 months). Linear, logistic, and quasi-poisson regression models were used to determine the association between physical activity and asthma symptoms; adjusting for age, sex, race, BMI, caregiver's education, asthma severity, medication use, and season. A 1-unit increase in PAQ score was significantly associated with reporting more nocturnal symptoms [risk ratio (RR): 1.03; 95% CI 1.00-1.06], daytime symptoms (RR: 1.04; 95% CI 1.00-1.09), being bothered by asthma (RR: 1.05; 95% CI 1.00-1.09), and trouble breathing (RR: 1.05; 95% CI 1.00-1.10). Level of physical activity should be taken into account in clinical management of asthma and epidemiological studies of asthma symptom burden.
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http://dx.doi.org/10.1007/s00408-017-0049-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674113PMC
December 2017

Association Between Hospital Case Volume of Sepsis, Adherence to Evidence-Based Processes of Care and Patient Outcomes.

Crit Care Med 2017 Jun;45(6):980-988

1Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA. 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 3The Pulmonary Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA. 4Evans Center for Implementation and Improvement Sciences, Department of Medicine, Boston University School of Medicine, Boston, MA.

Objectives: We sought to explore potential mechanisms underlying hospital sepsis case volume-mortality associations by investigating implementation of evidence-based processes of care.

Design: Retrospective cohort study. We determined associations of sepsis case volume with three evidence-based processes of care (lactate measurement during first hospital day, norepinephrine as first vasopressor, and avoidance of starch-based colloids) and assessed their role in mediation of case volume-mortality associations.

Setting: Enhanced administrative data (Premier, Charlotte, NC) from 534 U.S. hospitals.

Subjects: A total of 287,914 adult patients with sepsis present at admission between July 2010 and December 2012 of whom 58,045 received a vasopressor for septic shock during the first 2 days of hospitalization.

Interventions: None.

Measurements And Main Results: Among patients with sepsis, 1.9% received starch, and among patients with septic shock, 68.3% had lactate measured and 64% received norepinephrine as initial vasopressor. Patients at hospitals with the highest case volume were more likely to have lactate measured (adjusted odds ratio quartile 4 vs quartile 1, 2.8; 95% CI, 2.1-3.7) and receive norepinephrine as initial vasopressor (adjusted odds ratio quartile 4 vs quartile 1, 2.1; 95% CI, 1.6-2.7). Case volume was not associated with avoidance of starch products (adjusted odds ratio quartile 4 vs quartile 1, 0.73; 95% CI, 0.45-1.2). Adherence to evidence-based care was associated with lower hospital mortality (adjusted odds ratio, 0.81; 95% CI, 0.70-0.94) but did not strongly mediate case volume-mortality associations (point estimate change ≤ 2%).

Conclusions: In a large cohort of U.S. patients with sepsis, select evidence-based processes of care were more likely implemented at high-volume hospitals but did not strongly mediate case volume-mortality associations. Considering processes and case volume when regionalizing sepsis care may maximize patient outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000002409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433897PMC
June 2017

Hemodialysis delivery, dialysis dose achievement, and vascular access types in hemodialysis patients from the Gulf Cooperation Council countries enrolled in the dialysis outcomes and practice patterns study phase 5 (2012-2015).

Saudi J Kidney Dis Transpl 2016 11;27(6 Suppl 1):S42-50

List of Study Group in Acknowledgment.

The prospective observational Dialysis Outcomes and Practice Patterns Study (DOPPS) was initiated in late 2012 in national samples of hemodialysis (HD) units (n = 41 study sites) in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates). For many years, guidelines have recommended single pool Kt/V ≥1.2 as the minimum adequate dose for chronic HD patients. Here, we report initial DOPPS results regarding HD practices related to dialysis dose achievement in the GCC. A total of 928 adult HD patients were included in this analysis from 41 centers representing all six GCC countries. Baseline descriptive statistics (e.g., mean, standard deviation, median, interquartile range, or percentage) were calculated for the study sample. Results were weighted according to the fraction of HD patients sampled within each participating study site. Mean age varied between 51 years in Bahrain, Oman, and Saudi Arabia, 55 years in the United Arab Emirates (UAE) and Kuwait, and 62 years in Qatar. Mean body mass index (BMI) was the lowest in Oman patients (23.9 kg/m 2 , but the remaining GCC countries had mean BMIs of 25.7-28.9 kg/m 2 and substantial fractions of overweight patients. Median dialysis vintage ranged from 1.52 years in Kuwait to 3.52 years in Oman. Mean treatment time per session varied from 202 min in Saudi Arabia to 230 min in Qatar while mean blood flow rate (BFR) ranged between 267 mL/min in Oman and 310 mL/min in Saudi Arabia. Interdialytic weight gain varied considerably among GCC countries between 3.1 and 4.0 kg. Central venous catheter use was high among GCC countries, ranging from 29% in Oman to 56% in Kuwait, with other countries averaging 30-40% catheter use. Data were available only for 50-76% of patients in four GCC countries (Kuwait, Qatar, Saudi Arabia, and UAE) for calculating single pool Kt/V to indicate dialysis adequacy. When calculated for patients with vintage >1 year and dialyzing three times per week, mean single pool Kt/V was highest in Qatar and the UAE (1.50-1.51), intermediate in Kuwait (1.35), and lowest in Saudi Arabia (1.29). A higher risk of mortality was observed for patients having a single pool Kt/V <1.2 (vs. ≥1.2) [hazard ratio (HR) = 1.71, 95% confidence interval [CI]: 1.01-2.92]. Achievement of Kt/V in the GCC, although lower than in other DOPPS regions such as Europe/ANZ and North America, was similar to that in Japan. Japan and the GCC also share the practice of having a lower blood volume filtered per HD session per kg body weight. These findings suggest that increasing mean BFR and treatment time in the GCC, along with reducing catheter use, would substantially increase overall achievement of Kt/V >1.2 in the GCC, and hence, may improve survival. These mortality findings will need to be confirmed with up-coming GCC-DOPPS 6 analysis.
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http://dx.doi.org/10.4103/1319-2442.194889DOI Listing
November 2016

Identifying Vasopressor and Inotrope Use for Health Services Research.

Ann Am Thorac Soc 2016 Mar;13(3):414-8

1 Department of Medicine, Boston Medical Center, and.

Rationale: Identifying vasopressor and inotrope (vasopressor) use from administrative claims data may provide an important resource to study the epidemiology of shock.

Objectives: Determine accuracy of identifying vasopressor use using International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) coding.

Methods: Using administrative data enriched with pharmacy billing files (Premier, Inc., Charlotte, NC), we identified two cohorts: adult patients admitted with a diagnosis of sepsis from 2010 to 2013 or pulmonary embolism (PE) from 2008 to 2011. Vasopressor administration was obtained using pharmacy billing files (dopamine, dobutamine, epinephrine, milrinone, norepinephrine, phenylephrine, vasopressin) and compared with ICD-9-CM procedure code for vasopressor administration (00.17). We estimated performance characteristics of the ICD-9-CM code and compared patients' characteristics and mortality rates according to vasopressor identification method.

Measurements And Main Results: Using either pharmacy data or the ICD-9-CM procedure code, 29% of 541,144 patients in the sepsis cohort and 5% of 81,588 patients in the PE cohort were identified as receiving a vasopressor. In the sepsis cohort, the ICD-9-CM procedure code had low sensitivity (9.4%; 95% confidence interval, 9.2-9.5), which increased over time. Results were similar in the PE cohort (sensitivity, 5.8%; 95% confidence interval, 5.1-6.6). The ICD-9-CM code exhibited high specificity in the sepsis (99.8%) and PE (100%) cohorts. However, patients identified as receiving vasopressors by ICD-9-CM code had significantly higher unadjusted in-hospital mortality, had more acute organ failures, and were more likely hospitalized in the Northeast and West.

Conclusions: The ICD-9-CM procedure code for vasopressor administration has low sensitivity and selects for higher severity of illness in studies of shock. Temporal changes in sensitivity would likely make longitudinal shock surveillance using ICD-9-CM inaccurate.
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http://dx.doi.org/10.1513/AnnalsATS.201508-487BCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015715PMC
March 2016

Risk factors for loss to follow-up prior to ART initiation among patients enrolling in HIV care with CD4+ cell count ≥200 cells/μL in the multi-country MTCT-Plus Initiative.

BMC Health Serv Res 2015 Jun 25;15:247. Epub 2015 Jun 25.

Epidemiology and Biostatistics Program, CUNY School of Public Health, New York, NY, USA.

Background: In resource-limited settings, many HIV-infected patients are lost to follow-up (LTF) before starting ART; risk factors among those not eligible for ART at enrollment into care are not well described.

Methods: We examined data from 4,278 adults (3,613 women, 665 men) enrolled in HIV care through March 2007 in the MTCT-Plus Initiative with a CD4 count ≥200 cells/mm(3) and WHO stage ≤ 2 at enrollment. Patients were considered LTF if > 12 months elapsed since their last clinic visit. Gender-specific Cox regression models were used to assess LTF risk factors.

Results: The proportion LTF was 8.2 % at 12 months following enrollment, and was higher among women (8.4 %) than men (7.1 %). Among women, a higher risk of LTF was associated with younger age (adjusted hazard ratio [AHR]15-19/30+: 2.8, 95 % CI:2.1-3.6; AHR20-24/30+:1.9, 95 % CI:1.7-2.2), higher baseline CD4 count (AHR350-499/200-349:1.5; 95 % CI:1.0-2.1; AHR500+/200-349:1.5; 95 % CI:1.0-2.0), and being pregnant at the last clinic visit (AHR:1.9, 95 % CI:1.4-2.5). Factors associated with a lower risk of LTF included, employment outside the home (AHR:0.73, 95 % CI:0.59-0.90), co-enrollment of a family/household member (AHR:0.40, 95 % CI:0.26-0.61), and living in a household with ≥4 people (AHR:0.74, 95 % CI:0.64-0.85). Among men, younger age (AHR15-19/30+: 2.1, 95 % CI:1.2-3.5 and AHR30-34/35+:1.5, 95 % CI:1.0-2.4) had a higher risk of LTF. Electricity in the home (AHR:0.61, 95 % CI:0.41-0.91) and living in a household with ≥4 people (AHR:0.58, 95 % CI:0.39-0.85) had a lower risk of LTF.

Conclusions: Socio-economic status and social support may be important determinants of retention in patients not yet eligible for ART. Among women of child-bearing age, strategies around sustaining HIV care during and after pregnancy require attention.
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http://dx.doi.org/10.1186/s12913-015-0898-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480451PMC
June 2015

Practice Patterns and Outcomes Associated With Choice of Initial Vasopressor Therapy for Septic Shock.

Crit Care Med 2015 Oct;43(10):2141-6

1Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA. 2Data Coordinating Center, Boston University School of Public Health, Boston, MA. 3The Pulmonary Center, Division of Pulmonary and Critical Care Medicine, Boston University School of Medicine, Boston, MA.

Objectives: Clinical guidelines recommend norepinephrine as initial vasopressor of choice for septic shock, with dopamine suggested as an alternative vasopressor in selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia. We sought to determine practice patterns and outcomes associated with vasopressor selection in a large, population-based cohort of patients with septic shock that allows for assessment of outcomes in clinically important subgroups.

Design: We performed a retrospective cohort study to determine factors associated with choice of dopamine as compared with norepinephrine as initial vasopressor for patients with septic shock. We used propensity score matching to compare risk of hospital mortality based on initial vasopressor. We performed multiple sensitivity analyses using alternative methods to address confounding and hospital-level clustering. We investigated interaction between vasopressor selection and mortality in clinical subgroups based on arrhythmia and cardiovascular risk.

Setting: Enhanced administrative data (Premier, Charlotte, NC) from 502 U.S. hospitals during the years 2010-2013.

Subjects: A total of 61,122 patients admitted with septic shock who received dopamine or norepinephrine as initial vasopressor during the first 2 days of hospitalization.

Interventions: None.

Measurements And Main Results: Norepinephrine (77.6%) was the most frequently used initial vasopressor during septic shock. Dopamine was preferentially selected by cardiologists, in the Southern United States, at nonteaching hospitals, for older patients with more cardiovascular comorbidities and was used less frequently over time. Patients receiving dopamine experienced greater hospital mortality (propensity-matched cohort: n = 38,788; 25% vs 23.7%; odds ratio, 1.08; 95% CI, 1.02-1.14). Sensitivity analyses showed similar results. Subgroup analyses showed no evidence for effect modification based on arrhythmia risk or underlying cardiovascular disease.

Conclusions: In a large population-based sample of patients with septic shock in the United States, use of dopamine as initial vasopressor was associated with increased mortality among multiple clinical subgroups. Areas where use of dopamine as initial vasopressor is more common represent potential targets for quality improvement intervention.
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http://dx.doi.org/10.1097/CCM.0000000000001149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094367PMC
October 2015

Standard continuous ambulatory peritoneal dialysis therapy provides similar initial T-Kt/V regardless of the patient's peritoneal membrane transporter category: Single-center experience.

Saudi J Kidney Dis Transpl 2014 Jul;25(4):788-92

Nephrology Section, Internal Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.

Patients on continuous ambulatory peritoneal dialysis (CAPD) are routinely evaluated using the peritoneal equilibrium test (PET) to determine the best method for achieving target total dialysis clearance (T-Kt/V). In this study, we tested the hypothesis that standard CAPD prescription would achieve an initial T-Kt/V of more than 1.7 in all the patients regardless of their PET measurements. This is a retrospective study that included patients who started standard CAPD of four two-liter exchanges per day. The study included 118 patients; their mean age was 51.5 years with a standard deviation (SD) of 14.39 years. There were 83 males (70.3%) and 35 females (29.7%). PET and Kt/V were performed during the first four to six weeks of the study. The PET classified the patients into four categories: 24 (20.3%), high transporters; 65 (55.1%), high average; 28 (23.7%), low average; and one (0.8%), low transporter. Patients were then divided in two groups: Group 1 comprised of the high transporters while Group 2 included all the other patients. The T-Kt/V of the two groups was similar; in Group 1, it was 2.57 (± 1.17) and in Group 2 it was 2.50 (± 0.88) (P = 0.77). The T-Kt/V of patients with no residual renal function was also similar; in Group 1 and Group 2 it was 1.8 (± 0.29) and 1.97 (± 0.56), respectively (P = 0.45). All patients in our study who started on standard CAPD treatment had an adequate initial T-Kt/V. Thus, our data demonstrate that all patients with end-stage renal disease can safely begin standard CAPD without PET, which only needs to be performed if the patient encounters trouble in his/her T-Kt/V or fluid removal.
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http://dx.doi.org/10.4103/1319-2442.135004DOI Listing
July 2014

Erythropoietin-stimulating agents in the management of anemia of end-stage renal disease patients on regular hemodialysis: a prospective randomized comparative study from Qatar.

Hemodial Int 2015 Jan 3;19(1):33-43. Epub 2014 Jun 3.

Nephrology Division, Hamad General Hospital, Doha, Qatar.

Despite extensive use, to the best of our knowledge, no trial has simultaneously compared the three currently used erythropoietin-stimulating agents (ESAs) in a prospective manner in the treatment of anemia of end-stage renal disease patients. All hemodialysis patients in Qatar who were treated with short-acting epoetin alfa or beta have been screened. Eligible patients had been prospectively randomized, either to continue on the previous regimen of epoetin or to receive darbepoetin alfa or continuous erythropoietin receptor activator (CERA) for a total period of 40 weeks. All groups were assessed at the end of the study for safety and efficacy parameters. A total of 327 eligible patients were randomized. Mean hemoglobin concentration remained constant within the recommended target range (11-12 g/dL) throughout the study in the three studied groups. The percentage of patients who reached the target range was constantly above 50% in the second half of the study among CERA group patients who also had significantly lower mean number of dose adjustments as compared with the other two groups (P = 0.001). Similarly, the number of discontinuations of ESA among epoetin, darbepoetin, and CERA groups was 17, 19, and 9, respectively (P = 0.042). The frequencies of adverse events were similar in all groups. This study has specifically compared the effect of ESA type on the variability of serum hemoglobin levels in hemodialysis patients. Furthermore, it confirmed the efficacy and safety of once monthly CERA for maintaining tight hemoglobin control within recommended target ranges.
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http://dx.doi.org/10.1111/hdi.12181DOI Listing
January 2015

Expression of Snail transcription factor in prostatic adenocarcinoma in Egypt: correlation with Maspin protein expression and clinicopathologic variables.

Int J Clin Exp Pathol 2013 15;6(8):1558-66. Epub 2013 Jul 15.

Department of Pathology, Faculty of Medicine, Minia University, El-Minia, Egypt.

Background: Snail transcription factor and Maspin tumor suppressor serpin are involved in the regulation of progression, invasion and metastasis of many human malignancies. However, there is very limited data in the literature about their role in prostatic adenocarcinoma. The present study was designed to investigate Snail and Maspin expression, their interrelationship and their relationship to different clinicopathologic variables in clinically detectable prostatic adenocarcinoma.

Material And Methods: Tissue sections from 110 resected prostatic lesions distributed as 80 cases of prostatic adenocarcinoma and 30 cases of benign prostatic hyperplasia (BPH) were evaluated for Snail and Maspin proteins expression by immunohistochemistry.

Results: Snail protein expression was detected in 53.8% of prostatic adenocarcinomas versus none of BPH cases (p = < 0.001). A significant positive correlation of Snail expression to cancer grade (p = 0.015), lymph node metastasis (p = 0.026) and pTNM stage (p = 0.036). Maspin expression was detected in 36.6% of prostatic adenocarcinomas versus 93.3% of BPH cases (p = < 0.001). A significant negative correlation of Maspin expression to cancer grade (p = 0.007) and lymphovascular invasion (p = 0.017). Also detected was a significant negative relationship between Snail and Maspin expression in cancer cases under investigation (p = 0.002).

Conclusion: Snail immunohistochemical expression can be promising as a potential prognostic biomarker in prostatic adenocarcinoma since it was significantly associated with clinicopathologic variables of progressive disease. A potential role for Snail in regulating Maspin expression is suggested based on the finding of negative association between Snail and Maspin expression in prostatic adenocarcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726971PMC
March 2014

Bone density, body composition, and markers of bone remodeling in type 1 diabetic patients.

Scand J Clin Lab Invest 2011 Sep 8;71(5):387-93. Epub 2011 Apr 8.

Department of Pediatrics, National Research Center, Cairo, Egypt.

Objective: To assess bone mineral density (BMD), body composition by dual X-ray absorptiometry (DXA), and various biochemical markers of bone growth and resorption in a group of children with type 1 diabetes mellitus (T1DM).

Patients And Methods: The study included 47 patients with T1DM and 30 age- and sex-matched controls. Anthropometric measurements, biochemical markers for bone formation, bone resorption and DXA were done for all patients and controls.

Results: Of our diabetes patients, seven (16.7 %), three (7.3 %), and 17 (41.5%) met diagnostic criteria for osteopenia at the right femur, lumbar spine and total body, respectively. On the other hand, osteoporosis as defined by the WHO criteria was diagnosed in 21 patients (51.2%) at the total body by DXA. Lean body mass and lean fat ratio were lower, while, total fat mass, abdominal fat%, soft tissue fat mass%, and fat/lean ratio were higher in diabetics compared to controls. Also, our patients showed lower serum osteocalcin, osteoprotegerin, procollagen type 1, and higher urinary deoxypyridinoline. Pubertal (diabetics and controls) have higher BMD and BMC than prepubertal.

Conclusion: Diabetic patients had a low BMD after adjustment (Z score), low bone formation and high bone resorption markers. Diabetes control and increase in BMI leads to a decrease in the incidence of low bone mineral density. Diabetes causes an increase in body fat especially abdominal fat which leads to an increase in insulin resistance and decrease in lean mass.
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http://dx.doi.org/10.3109/00365513.2011.573574DOI Listing
September 2011
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