Longitudinal Imaging-Based Clusters in Former Smokers of the COPD Cohort Associate with Clinical Characteristics: The SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).

PURPOSE: Quantitative computed tomography (qCT) imaging-based cluster analysis identified clinically meaningful COPD former-smoker subgroups (clusters) based on cross-sectional data. We aimed to identify progression clusters for former smokers using longitudinal data. PATIENTS AND METHODS: We selected 472 former smokers from SPIROMICS with a baseline visit and a one-year follow-up visit. A total of 150 qCT imaging-based variables, comprising 75 variables at baseline and their corresponding progression rates, were derived from the respective inspiration and expiration scans of the two visits. The COPD progression clusters identified were then associated with subject demography, clinical variables and biomarkers. RESULTS: COPD severities at baseline increased with increasing cluster number. Cluster 1 patients were an obese subgroup with rapid progression of functional small airway disease percentage (fSAD%) and emphysema percentage (Emph%). Cluster 2 exhibited a decrease of fSAD% and Emph%, an increase of tissue fraction at total lung capacity and airway narrowing over one year. Cluster 3 showed rapid expansion of Emph% and an attenuation of fSAD%. Cluster 4 demonstrated severe emphysema and fSAD and significant structural alterations at baseline with rapid progression of fSAD% over one year. Subjects with different progression patterns in the same cross-sectional cluster were identified by longitudinal clustering. CONCLUSION: qCT imaging-based metrics at two visits for former smokers allow for the derivation of four statistically stable clusters associated with unique progression patterns and clinical characteristics. Use of baseline variables and their progression rates enables identification of longitudinal clusters, resulting in a refinement of cross-sectional clusters.

Erratum: Structural and Functional Features on Quantitative Chest Computed Tomography in the Korean Asian versus the White American Healthy Non-Smokers.

This corrects the article on p. 20 in vol. 1236, PMID: 31270987.

The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.

Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial.Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations.Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1.Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007).Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.

Structural and Functional Features on Quantitative Chest Computed Tomography in the Korean Asian versus the White American Healthy Non-Smokers.

OBJECTIVE: Considering the different prevalence rates of diseases such as asthma and chronic obstructive pulmonary disease in Asians relative to other races, Koreans may have unique airway structure and lung function. This study aimed to investigate unique features of airway structure and lung function based on quantitative computed tomography (QCT)-imaging metrics in the Korean Asian population (Koreans) as compared with the White American population (Whites). MATERIALS AND METHODS: QCT data of healthy non-smokers (223 Koreans vs. 70 Whites) were collected, including QCT structural variables of wall thickness (WT) and hydraulic diameter (Dh) and functional variables of air volume, total air volume change in the lung (ΔVair), percent emphysema-like lung (Emph%), and percent functional small airway disease-like lung (fSAD%). Mann-Whitney U tests were performed to compare the two groups. RESULTS: As compared with Whites, Koreans had smaller volume at inspiration, ΔVair between inspiration and expiration (p < 0.001), and Emph% at inspiration (p < 0.001). Especially, Korean females had a decrease of ΔVair in the lower lobes (p < 0.001), associated with fSAD% at the lower lobes (p < 0.05). In addition, Koreans had smaller Dh and WT of the trachea (both, p < 0.05), correlated with the forced expiratory volume in 1 second (R = 0.49, 0.39; all p < 0.001) and forced vital capacity (R = 0.55, 0.45; all p < 0.001). CONCLUSION: Koreans had unique features of airway structure and lung function as compared with Whites, and the difference was clearer in female individuals. Discriminating structural and functional features between Koreans and Whites enables exploration of inter-racial differences of pulmonary disease in terms of severity, distribution, and phenotype.

Heterogeneous burden of lung disease in smokers with borderline airflow obstruction.

BACKGROUND: The identification of smoking-related lung disease in current and former smokers with normal FEV1 is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV1/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group. METHODS: We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV1 and FEV1/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV1/FVC criteria thresholds. RESULTS: The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV1 and FEF25-75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV1/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality. CONCLUSIONS: Ever-smokers with normal FEV1 and FEV1/FVC <  0.70 but > LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone.

Genome-wide association study of lung function and clinical implication in heavy smokers.

BACKGROUND: The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD. METHODS: Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers. RESULTS: A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10- 8) and FEV1 (p = 2.1 × 10- 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10- 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P <  2.2 × 10- 16). CONCLUSIONS: This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function. Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers. The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity. Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.

Sleep disruption as a predictor of quality of life among patients in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS).

Study Objectives: Sleep quality is poor among patients with chronic obstructive pulmonary disease (COPD), and studies show that sleep disturbance is associated with low overall quality of life in this population. We evaluated the impact of patient-reported sleep quality and sleep apnea risk on disease-specific and overall quality of life within patients with COPD enrolled in the SPIROMICS study, after accounting for demographics and COPD disease severity. Methods: Baseline data from 1341 participants [892 mild/moderate COPD (FEV1 ≥ 50% predicted); 449 severe COPD (FEV1 < 50%)] were used to perform three nested (blocks) regression models to predict quality of life (Short Form-12 mental and physical components and St. George's Respiratory Questionnaire). Dependent measures used for the nested regressions included the following: Block1: demographics and smoking history; Block 2: disease severity (forced expiratory volume 1 s; 6 min walk test); Block 3: risk for obstructive sleep apnea (OSA; Berlin questionnaire); and Block 4: sleep quality (Pittsburgh Sleep Quality Index [PSQI]). Results: Over half of participants with COPD reported poor sleep quality (Mean PSQI 6.4 ± 3.9; 50% with high risk score on the Berlin questionnaire). In all three nested regression models, sleep quality (Block 4) was a significant predictor of poor quality of life, over and above variables included in blocks 1-3. Conclusions: Poor sleep quality represents a potentially modifiable risk factor for poor quality of life in patients with COPD, over and above demographics and smoking history, disease severity, and risk for OSA. Improving sleep quality may be an important target for clinical interventions. Clinical Trial: SPIROMICS. Clinical Trial URL: http://www2.cscc.unc.edu/spiromics/. Clinical Trial Registration: ClinicalTrials.gov NCT01969344.

Decreased Lung Function and All-Cause Mortality in HIV-infected Individuals.

RATIONALE: Human immunodeficiency virus (HIV) infection is associated with pulmonary disease and worse lung function, but the relationship of lung function with survival in HIV is unknown. OBJECTIVES: To determine whether lung function is associated with all-cause mortality in HIV-infected individuals. METHODS: HIV-infected participants from cohorts in three locations underwent pre- and post-bronchodilator spirometry and determination of single-breath diffusing capacity of the lung for carbon monoxide (DlCO) in 2008-2009, computed tomographic (CT) scanning of the chest for quantitative emphysema and airway measures, and echocardiography for estimated left ventricular systolic and diastolic function and tricuspid regurgitant velocity. Bivariate analysis and multivariable Cox proportional hazards models were used to determine whether decreased lung function was independently associated with increased all-cause mortality. Models were adjusted for covariates including age, sex, body mass index, smoking status, self-reported hepatitis C status, HIV viral levels, CD4+ T-cell counts, hemoglobin, antiretroviral therapy, and illicit drug use. RESULTS: Overall, 396 HIV-infected participants underwent pulmonary function testing. Thirty-two participants (8%) died during a median follow-up period of 69 months. A post-bronchodilator FEV1-to-FVC ratio less than 0.7 (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.10-5.58) and a DlCO less than 60% (HR, 2.28; 95% CI, 1.08-4.82) were independently associated with worse mortality. Also, hepatitis C (HR, 2.68; 95% CI, 1.22-5.89) and baseline plasma HIV RNA level (HR per ln RNA copies/ml, 1.50; 95% CI, 1.22-1.86) were associated with mortality in HIV-infected participants. The only CT or echocardiographic measure associated with greater mortality in univariate analysis was greater wall thickness of medium-sized airways (HR for wall area percent, 1.08; 95% CI, 1.00-1.18; P = 0.051), but none of the CT or echocardiogram measures were associated with mortality in multivariable analysis. CONCLUSIONS: Airflow obstruction and impaired diffusing capacity appear to be associated with all-cause mortality in HIV-infected persons over an average of 6 years of follow-up. These data highlight the importance of lung dysfunction in HIV-infected persons and should be confirmed in larger cohorts and with extended follow-up periods. Clinical trial registered with www.clinicaltrials.gov (NCT00869544, NCT01326572).

Variability in objective and subjective measures affects baseline values in studies of patients with COPD.

RATIONALE: Understanding the reliability and repeatability of clinical measurements used in the diagnosis, treatment and monitoring of disease progression is of critical importance across all disciplines of clinical practice and in clinical trials to assess therapeutic efficacy and safety. OBJECTIVES: Our goal is to understand normal variability for assessing true changes in health status and to more accurately utilize this data to differentiate disease characteristics and outcomes. METHODS: Our study is the first study designed entirely to establish the repeatability of a large number of instruments utilized for the clinical assessment of COPD in the same subjects over the same period. We utilized SPIROMICS participants (n = 98) that returned to their clinical center within 6 weeks of their baseline visit to repeat complete baseline assessments. Demographics, spirometry, questionnaires, complete blood cell counts (CBC), medical history, and emphysema status by computerized tomography (CT) imaging were obtained. RESULTS: Pulmonary function tests (PFTs) were highly repeatable (ICC's >0.9) but the 6 minute walk (6MW) was less so (ICC = 0.79). Among questionnaires, the Saint George's Respiratory Questionnaire (SGRQ) was most repeatable. Self-reported clinical features, such as exacerbation history, and features of chronic bronchitis, often produced kappa values <0.6. Reported age at starting smoking and average number of cigarettes smoked were modestly repeatable (kappa = 0.76 and 0.79). Complete blood counts (CBC) variables produced intraclass correlation coefficients (ICC) values between 0.6 and 0.8. CONCLUSIONS: PFTs were highly repeatable, while subjective measures and subject recall were more variable. Analyses using features with poor repeatability could lead to misclassification and outcome errors. Hence, care should be taken when interpreting change in clinical features based on measures with low repeatability. Efforts to improve repeatability of key clinical features such as exacerbation history and chronic bronchitis are warranted.

Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts.

RATIONALE: Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux. OBJECTIVES: To determine the value of adding blood biomarkers to clinical variables to predict exacerbations. METHODS: Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis. MEASUREMENTS AND MAIN RESULTS: Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations. CONCLUSIONS: Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.

BACKGROUND: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide. METHODS: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129. FINDINGS: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019). INTERPRETATION: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. FUNDING: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

Novel relationships of markers of monocyte activation and endothelial dysfunction with pulmonary dysfunction in HIV-infected persons.

OBJECTIVE: Chronic obstructive pulmonary disease is a common comorbidity in HIV, with prevalence and severity of disease incompletely explained by risk factors such as smoking and age. Unique HIV-associated factors, including microbial translocation, monocyte activation, and endothelial dysfunction, have been described in other comorbidities, but have not been investigated in relation to pulmonary abnormalities in HIV. This study assessed the relationship of these pathologic processes to pulmonary function in HIV-infected and uninfected individuals and determined if relationships were unique to HIV. DESIGN: Longitudinal observational study. METHODS: Total 274 participants completed pulmonary function testing. Markers of inflammation (IL-6, IL-8, and TNFα), microbial translocation (lipopolysaccharide, sCD14), monocyte activation (sCD163, sCD14, and IL-2 receptor), and endothelial dysfunction (endothelin-1) were measured at baseline. Cross-sectional and longitudinal analyses were performed, adjusting for pertinent covariates. RESULTS: In HIV-infected individuals, higher IL-6 and endothelin-1 associated with worse forced expiratory volume in one second (FEV1) percentage-predicted, and higher sCD163 associated with worse FEV1/forced vital capacity. IL-6, TNFα, lipopolysaccharide, sCD163, IL-2 receptor, and endothelin-1 associated with diffusing impairment. sCD163 and endothelin-1 interacted with HIV status in relationship to pulmonary function. In HIV-infected individuals only, baseline endothelin-1 was associated with lower FEV1, and sCD163 and endothelin-1 were associated with lower diffusing capacity during follow-up. CONCLUSION: Circulating markers of HIV-associated humoral abnormalities are associated with airflow obstruction and diffusing impairment and baseline measures of monocyte activation and endothelial dysfunction associate with lower pulmonary function over time in HIV-infected persons. These findings suggest mechanisms of the disproportionate burden of chronic obstructive pulmonary disease in HIV-infected persons.

Factors associated with abnormal spirometry among HIV-infected individuals.

OBJECTIVE: HIV-infected individuals are susceptible to development of chronic lung diseases, but little is known regarding the prevalence and risk factors associated with different spirometric abnormalities in this population. We sought to determine the prevalence, risk factors and performance characteristics of risk factors for spirometric abnormalities among HIV-infected individuals. DESIGN: Cross-sectional cohort study. METHODS: We analyzed cross-sectional US data from the NHLBI-funded Lung-HIV consortium - a multicenter observational study of heterogeneous groups of HIV-infected participants in diverse geographic sites. Logistic regression analysis was performed to determine factors statistically significantly associated with spirometry patterns. RESULTS: A total of 908 HIV-infected individuals were included. The median age of the cohort was 50 years, 78% were men and 68% current smokers. An abnormal spirometry pattern was present in 37% of the cohort: 27% had obstructed and 10% had restricted spirometry patterns. Overall, age, smoking status and intensity, history of Pneumocystis infection, asthma diagnosis and presence of respiratory symptoms were independently associated with an abnormal spirometry pattern. Regardless of the presence of respiratory symptoms, five HIV-infected participants would need to be screened with spirometry to diagnose two individuals with any abnormal spirometry pattern. CONCLUSIONS: Nearly 40% of a diverse US cohort of HIV-infected individuals had an abnormal spirometry pattern. Specific characteristics including age, smoking status, respiratory infection history and respiratory symptoms can identify those at risk for abnormal spirometry. The high prevalence of abnormal spirometry and the poor predictive capability of respiratory symptoms to identify abnormal spirometry should prompt clinicians to consider screening spirometry in HIV-infected populations.

Medicare Payment Policy Creates Incentives For Long-Term Care Hospitals To Time Discharges For Maximum Reimbursement.

Long-term care hospitals are postacute care facilities for patients requiring extended hospital-level care. These facilities are reimbursed by Medicare under a prospective payment system with a short-stay outlier policy, which results in substantially lower payments for patients discharged before a diagnosis-related group-specific short-stay threshold. Using Medicare data, we examined the impact of the short-stay policy on lengths-of-stay and Medicare reimbursement among patients in long-term care hospitals who require prolonged mechanical ventilation. After accounting for case-mix and facility-level differences, we found that discharges for reasons other than death in the period 2005-10 were most likely to occur on the day of or immediately after the short-stay threshold; this held true regardless of facility ownership. In contrast, live discharges in 2002­the year before the prospective payment system started phasing out cost-based payment­were evenly distributed around the day that later became the short-stay threshold. Our findings confirm that the short-stay outlier payment policy created a strong financial incentive for long-term care hospitals to time patient discharges to maximize Medicare reimbursement. The results suggest that the new very-short-stay policy implemented in December 2012 could have a similar effect.

Topographic diversity of the respiratory tract mycobiome and alteration in HIV and lung disease.

RATIONALE: Microbiome studies typically focus on bacteria, but fungal species are common in many body sites and can have profound effects on the host. Wide gaps exist in the understanding of the fungal microbiome (mycobiome) and its relationship to lung disease. OBJECTIVES: To characterize the mycobiome at different respiratory tract levels in persons with and without HIV infection and in HIV-infected individuals with chronic obstructive pulmonary disease (COPD). METHODS: Oral washes (OW), induced sputa (IS), and bronchoalveolar lavages (BAL) were collected from 56 participants. We performed 18S and internal transcribed spacer sequencing and used the neutral model to identify fungal species that are likely residents of the lung. We used ubiquity-ubiquity plots, random forest, logistic regression, and metastats to compare fungal communities by HIV status and presence of COPD. MEASUREMENTS AND MAIN RESULTS: Mycobiomes of OW, IS, and BAL shared common organisms, but each also had distinct members. Candida was dominant in OW and IS, but BAL had 39 fungal species that were disproportionately more abundant than in the OW. Fungal communities in BAL differed significantly by HIV status and by COPD, with Pneumocystis jirovecii significantly overrepresented in both groups. Other fungal species were also identified as differing in HIV and COPD. CONCLUSIONS: This study systematically examined the respiratory tract mycobiome in a relatively large group. By identifying Pneumocystis and other fungal species as overrepresented in the lung in HIV and in COPD, it is the first to determine alterations in fungal communities associated with lung dysfunction and/or HIV, highlighting the clinical relevance of these findings. Clinical trial registered with www.clinicaltrials.gov (NCT00870857).

Differences between attendings' and fellows' perceptions of futile treatment in the intensive care unit at one academic health center: implications for training.

PURPOSE: Knowing when patients are too ill to benefit from intensive care is essential for clinicians to recommend aggressive or palliative care as appropriate. To explore prognostic ability among critical care fellows, the authors compared fellows' and attendings' assessments of futile critical care and evaluated factors associated with assessments. METHOD: Thirty-six attendings and 14 fellows in intensive care units at the University of California, Los Angeles, were surveyed daily for three months (December 2011-March 2012) to identify patients perceived as receiving futile treatment. Frequency of futile treatment assessments and reasons listed by attendings versus fellows were compared. Predictors of futile treatment assessments by provider type were assessed using multivariate probit models. RESULTS: Attendings made 6,897 assessments on 1,125 patients; fellows made 4,407 assessments on 773 patients. Fellows assessed 161 (20.8%) patients as receiving futile treatment, compared with attendings (123 [10.9%] patients, P<.001), and listed fewer reasons that treatment was futile (P<.001). Fellows were more likely to assess a patient as receiving futile treatment by the second day, whereas attendings took four days. Patients assessed as receiving futile treatment by fellows were less likely than patients so assessed by attendings to die in the hospital (51% versus 68%, P=.003) and within six months (62% versus 85%, P<.001). CONCLUSIONS: Fellows made earlier assessments and judged more patients to be receiving futile treatment than attendings, and their assessments were less predictive of mortality, suggesting that assessment of treatment appropriateness develops with experience.

Acute bronchodilator responses decline progressively over 4 years in patients with moderate to very severe COPD.

BACKGROUND: We previously reported a progressive decline in absolute responses of FEV1 and FVC to a near-maximal dose of 2 different short-acting bronchodilators over 4 years. Since varying host factors and the method of expressing the response may impact the time trend of acute bronchodilator responses, we now examined the potential influence of salient host characteristics on changes in bronchodilator responses over time expressed in different ways. METHODS: As part of the 4-year, placebo-controlled Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, pre- and post-bronchodilator spirometry was performed at baseline and 1 month and every 6 months thereafter. Post-bronchodilator values for FEV1 and FVC were analyzed for subjects completing at least the 1 year visit (Placebo - N = 2463; Tiotropium - N = 2579), stratified by GOLD stage, age, gender and smoking status and expressed as absolute, relative (%) and % predicted changes from pre-bronchodilator values. Annual changes in bronchodilator response were estimated using linear mixed effects models. RESULTS: For all subjects analyzed, FEV1 and FVC bronchodilator responses showed progressive and highly significant (p < 0.0001) declines over 4 years. Declines were generally larger in patients with severe/very severe than mild/moderate airflow obstruction, in older patients (≥65 yrs) and in former than continuing smokers. CONCLUSION: Acute FEV1 and FVC responses to bronchodilators decline significantly over time in COPD patients, whether expressed as absolute, relative or % predicted changes, potentially impacting on the clinical responses to bronchodilator therapy as well as on the annual rate of decline in post-bronchodilator lung function. Clinicaltrials.gov number: NCT00144339.

Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts.

BACKGROUND: Several lung diseases are increasingly recognized as comorbidities with HIV; however, few data exist related to the spectrum of respiratory symptoms, diagnostic testing, and diagnoses in the current HIV era. The objective of the study is to determine the impact of HIV on prevalence and incidence of respiratory disease in the current era of effective antiretroviral treatment. METHODS: A pulmonary-specific questionnaire was administered yearly for three years to participants in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS). Adjusted prevalence ratios for respiratory symptoms, testing, or diagnoses and adjusted incidence rate ratios for diagnoses in HIV-infected compared to HIV-uninfected participants were determined. Risk factors for outcomes in HIV-infected individuals were modeled. RESULTS: Baseline pulmonary questionnaires were completed by 907 HIV-infected and 989 HIV-uninfected participants in the MACS cohort and by 1405 HIV-infected and 571 HIV-uninfected participants in the WIHS cohort. In MACS, dyspnea, cough, wheezing, sleep apnea, and incident chronic obstructive pulmonary disease (COPD) were more common in HIV-infected participants. In WIHS, wheezing and sleep apnea were more common in HIV-infected participants. Smoking (MACS and WIHS) and greater body mass index (WIHS) were associated with more respiratory symptoms and diagnoses. While sputum studies, bronchoscopies, and chest computed tomography scans were more likely to be performed in HIV-infected participants, pulmonary function tests were no more common in HIV-infected individuals. Respiratory symptoms in HIV-infected individuals were associated with history of pneumonia, cardiovascular disease, or use of HAART. A diagnosis of asthma or COPD was associated with previous pneumonia. CONCLUSIONS: In these two cohorts, HIV is an independent risk factor for several respiratory symptoms and pulmonary diseases including COPD and sleep apnea. Despite a higher prevalence of chronic respiratory symptoms, testing for non-infectious respiratory diseases may be underutilized in the HIV-infected population.

The opportunity cost of futile treatment in the ICU*.

OBJECTIVE: When used to prolong life without achieving a benefit meaningful to the patient, critical care is often considered "futile." Although futile treatment is acknowledged as a misuse of resources by many, no study has evaluated its opportunity cost, that is, how it affects care for others. Our objective was to evaluate delays in care when futile treatment is provided. DESIGN: For 3 months, we surveyed critical care physicians in five ICUs to identify patients that clinicians identified as receiving futile treatment. We identified days when an ICU was full and contained at least one patient who was receiving futile treatment. For those days, we evaluated the number of patients waiting for ICU admission more than 4 hours in the emergency department or more than 1 day at an outside hospital. SETTING: One health system that included a quaternary care medical center and an affiliated community hospital. PATIENTS: Critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Boarding time in the emergency department and waiting time on the transfer list. Thirty-six critical care specialists made 6,916 assessments on 1,136 patients of whom 123 were assessed to receive futile treatment. A full ICU was less likely to contain a patient receiving futile treatment compared with an ICU with available beds (38% vs 68%, p < 0.001). On 72 (16%) days, an ICU was full and contained at least one patient receiving futile treatment. During these days, 33 patients boarded in the emergency department for more than 4 hours after admitted to the ICU team, nine patients waited more than 1 day to be transferred from an outside hospital, and 15 patients canceled the transfer request after waiting more than 1 day. Two patients died while waiting to be transferred. CONCLUSIONS: Futile critical care was associated with delays in care to other patients.