Application of Global Lung Function Initiative Global Spirometry Reference Equations across a Large, Multicenter Pulmonary Function Lab Population.

Rationale: Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a "race-neutral" interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives: Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race and ethnicity using GLI Global in place of GLI-2012 reference equations. Methods: In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared with the existing GLI-2012 standard, stratified by self-reported race and ethnicity. Measurements and Main Results: Mean FEV1 and FVC percent predicted increased in the White and Northeast Asian groups and decreased in the Black, Southeast Asian, and mixed/other race groups. The prevalence of obstruction increased by 9.7% in the White group, and prevalences of possible restriction increased by 51.1% and 37.1% in the Black and Southeast Asian groups, respectively. Using GLI Global in a population with equal representation of all five race and ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in the frequency of abnormal spirometry test results (32.9%). Conclusions: The use of GLI Global reference equations will significantly impact spirometry interpretation. Although GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need to place these data within an appropriate clinical context.

Combined Pulmonary Fibrosis and Emphysema: A Narrative Review.

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity.

Adjusting diffusing capacity for anemia in patients undergoing allogeneic HCT: a comparison of two methodologies.

BACKGROUND: Diffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint. STUDY DESIGN: This is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis. RESULTS: Patients had normal spirometry (FEV1 99.7% [IQR: 89.4-109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9-94.1%) while Dinakara-DLCO 111.0% (97.3-124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV1, Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20). CONCLUSION: The ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT.

Use of a Viral Filter to Reduce Exposure to Exhaled Aerosol Does Not Affect Methacholine Dose Delivery During Bronchoprovocation Testing.

BACKGROUND: Methacholine challenge testing (MCT) is a common bronchoprovocation technique used to assess airway hyper-responsiveness. We previously demonstrated that the addition of a viral filter to the nebulizer exhalation limb substantially reduced expelled particles during MCT. Our aim was to evaluate whether this modification affects the delivered dose of methacholine. METHODS: A mechanical ventilator was connected to a lung simulator with breathing frequency 15 breaths/min, tidal volume 500 mL, inspiratory-expiratory ratio 1:1, with a sinusoidal waveform. We compared methacholine dose delivery using the Hudson Micro Mist or AeroEclipse II BAN nebulizers powered by either a dry gas source or a compressor system. A filter placed in line between the nebulizer and test lung was weighed before and after 1 min of nebulized methacholine delivery. Mean inhaled mass was measured with and without a viral filter on the exhalation limb. Dose delivery was calculated by multiplying the mean inhaled mass by the respirable fraction (particles < 5 µm) and inhalation time. Unpaired t test was used to compare methacholine dose delivery with and without viral filter placement. RESULTS: The addition of a viral filter did not significantly affect methacholine dose delivery across all devices tested. Using a 50-psi dry gas source, dose delivered with or without a viral filter did not differ with the Hudson (422.3 µg vs 282.0 µg, P = .11) or the AeroEclipse nebulizer (563.0 µg vs 657.6 µg, P = .59). Using the compressor, dose delivered with and without a viral filter did not differ with the Hudson (974.0 µg vs 868.0 µg, P = .03) or the AeroEclipse nebulizer (818.0 µg vs 628.5 µg, P = .42). CONCLUSIONS: The addition of a viral filter to the nebulizer exhalation limb did not affect methacholine dose during bronchoprovocation testing. Routine use of a viral filter should be considered to improve pulmonary function technician safety and infection control measures during the ongoing COVID-19 pandemic.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.

BACKGROUND: Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. METHODS: The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. RESULTS: We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. CONCLUSION: Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

Aerosol Generation and Mitigation During Methacholine Bronchoprovocation Testing: Infection Control Implications in the Era of COVID-19.

BACKGROUND: Methacholine bronchoprovocation or challenge testing (MCT) is commonly performed to assess airway hyper-responsiveness in the setting of suspected asthma. Nebulization is an aerosol-generating procedure, but little is known about the risks of MCT in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. We aimed to quantify and characterize aerosol generation during MCT by using different delivery methods and to assess the impact of adding a viral filter. METHODS: Seven healthy subjects performed simulated MCT in a near particle-free laboratory space with 4 different nebulizers and with a dosimeter. Two devices continuously sampled the ambient air during the procedure, which detected ultrafine particles, from 0.02-1 µm, and particles of sizes 0.3, 0.5, 1.0, 2.0, 5.0, and 10 µm, respectively. Particle generation was compared among all the devices, with and without viral filter placement. RESULTS: Ultrafine-particle generation during simulated MCT was significant across all the devices. Ultrafine-particle (0.02-1 µm) concentrations decreased 77%-91% with the addition of a viral filter and varied significantly between unfiltered (P < .001) and filtered devices (P < .001). Ultrafine-particle generation was lowest when using the dosimeter with filtered Hudson nebulizer (1,258 ± 1,644 particle/mL). Ultrafine-particle concentrations with the filtered nebulizer devices using a compressor were higher than particle concentrations detected when using the dosimeter: Monaghan (3,472 ± 1,794 particles/mL), PARI (4,403 ± 2,948), Hudson (6,320 ± 1,787) and AirLife (9,523 ± 5,098). CONCLUSIONS: The high particle concentrations generated during MCT pose significant infection control concerns during the COVID-19 pandemic. Particle generation during MCT was significantly reduced by using breath-actuated delivery and a viral filter, which offers an effective mitigation strategy.

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Pulse Oximetry Is Insensitive for Detection of Hepatopulmonary Syndrome in Patients Evaluated for Liver Transplantation.

Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2 ), arterial blood gas, spirometry, and contrast-enhanced echocardiography (CE). HPS was defined as an alveolar-arterial gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%-25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c-statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51-0.66). An SpO2 <96%, recommended by practice guidelines as a threshold to require further testing, had low sensitivity (28%; 95% CI, 18%-28%). The c-statistic of SpO2 in discriminating HPS with a partial pressure of oxygen (PaO2 ) <60 mm Hg (eligible for LT exception points) was 0.76 (95% CI, 0.46-1.00). An SpO2 cutoff of <96% had higher sensitivity for detecting HPS with PaO2 <60 mm Hg (71%; 95% CI, 38%-100%) but was still inadequate. Conclusion: Pulse oximetry is not sufficiently sensitive to screen for HPS in LT candidates. Arterial blood gas and CE are required in LT candidates for diagnosis of HPS.

COPD Guidelines: A Review of the 2018 GOLD Report.

Global Strategy for the Diagnosis, Management, and Prevention of COPD 2018 is a consensus report published periodically since 2001 by an international panel of health professionals from respiratory medicine, socioeconomics, public health, and education comprising the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The GOLD documents endeavor to incorporate latest evidence and expert consensus and are intended for use as "strategy documents" for implementation of effective care for chronic obstructive lung disease (COPD) on a global level. The GOLD 2018 report defines COPD as a "common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities, usually caused by significant exposure to noxious particles or gases," with the criteria of "persistent respiratory symptoms" being a new and controversial inclusion since 2017. With the availability of newer pharmacotherapy options, treatment recommendations are made on the basis of a review of the latest literature and directed by symptom burden and health care utilization. Apart from the change in definition, a major shift in the recommendations is the exclusion of severity of airflow limitation as one of the major factors in guiding therapy. We review the salient features of the GOLD 2018 document and provide commentary on features that merit further discussion based on our clinical experience and practice as well as literature review current as of February 2018.

Pulmonary Function Tests for the Generalist: A Brief Review.

One of the frequent reasons patients see their primary care physicians is for the symptom of dyspnea. Among the objective tests to quantify this symptom is the pulmonary function test, which includes several different studies: spirometry with flow-volume loop, lung volumes, and diffusing capacity of lung for carbon monoxide. The results may indicate both respiratory and nonrespiratory disorders, including helping in the diagnosis of cardiac or neuromuscular diseases. This review, intended for the generalist, describes common findings of pulmonary function tests and provides a road map for interpretation.

ß-Blocker Therapy and Clinical Outcomes in Patients with Moderate Chronic Obstructive Pulmonary Disease and Heightened Cardiovascular Risk. An Observational Substudy of SUMMIT.

RATIONALE: Cardiovascular disease is a common comorbidity in patients with chronic obstructive pulmonary disease. Although ß-blockers can be used safely in patients with chronic obstructive pulmonary disease, concerns remain regarding safety and efficacy interactions in patients using concomitant inhaled long-acting ß-agonists. OBJECTIVES: To compare the differential effects of long-acting ß-agonist or inhaled corticosteroid use on clinical outcomes in patients with heightened cardiovascular risk treated and not treated with ß-blockers. METHODS: We examined data from 16,485 participants in the SUMMIT study (Study to Understand Mortality and Morbidity in COPD) who were randomized to once-daily inhaled fluticasone furoate, vilanterol, fluticasone furoate/vilanterol combination, or placebo and examined the associations between treatment allocation and lung function, chronic obstructive pulmonary disease exacerbations, cardiovascular events, and all-cause mortality, stratified by baseline ß-blocker therapy. RESULTS: Baseline ß-blocker therapy was used by 31% (n = 5,159) of SUMMIT participants. There was no evidence of an interaction between baseline ß-blocker therapy and the association between inhaled treatments and forced expiratory volume in 1 second at 3 months (P = 0.27), 6 months (P = 0.14), or 12 months (P = 0.33). The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the vilanterol-alone group were 58 ml (95% confidence interval, 38-78) in those receiving baseline ß-blocker therapy and 51 ml (95% confidence interval, 38-65) in those not receiving baseline ß-blocker therapy. The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the combination fluticasone furoate/vilanterol group were 85 ml (95% confidence interval, 65-105) in those receiving baseline ß-blocker therapy and 68 ml (95% confidence interval, 54-82) in those not receiving baseline ß-blocker therapy. Overall, there was no evidence of interaction by randomized treatment, including vilanterol alone or in combination with fluticasone furoate, for chronic obstructive pulmonary disease exacerbations (P = 0.18), cardiovascular composite events (P = 0.33), and all-cause mortality (P = 0.41). CONCLUSIONS: There is no evidence to suggest that baseline ß-blocker therapy reduces the respiratory benefits or increases the cardiovascular risk of inhaled long-acting ß-agonists in patients with chronic obstructive pulmonary disease and heightened cardiovascular risk. Clinical trial registered with www.clinicaltrials.gov (NCT01313676).

Clinical Impact of Intrapulmonary Vascular Dilatation in Candidates for Liver Transplant.

BACKGROUND: Intrapulmonary vascular dilatations (IPVD) frequently are detected in patients with liver disease by the delayed appearance of microbubbles at contrast-enhanced echocardiography. IPVD with an elevated alveolar-arterial (A-a) gradient define hepatopulmonary syndrome (HPS); however, the importance of IPVD in the absence of abnormal gas exchange is unknown. We aimed to determine the clinical impact of IPVD in patients with liver disease. METHODS: We performed a cross-sectional study within the Pulmonary Vascular Complications of Liver Disease 2 Study, a multicenter, prospective cohort study of patients being evaluated for liver transplant. We excluded patients with obstructive or restrictive lung disease, HPS, or intracardiac shunting. We compared patients with and those without IPVD. RESULTS: Forty-six patients with IPVD and 81 patients without IPVD were included. Patients with IPVD were more likely to have autoimmune hepatitis and less likely to have cryptogenic cirrhosis and hepatocellular carcinoma. Patients with IPVD had higher Child-Pugh scores (6 [interquartile range (IQR), 5-7] vs 5 [IQR, 4-7]; P = .04), possibly higher Model for End-Stage Liver Disease scores (14.5 [IQR, 11.6-15.8] vs 12.2 [IQR, 9.4-15.5]; P = .06), higher PaO2 levels (97.9 [IQR, 92.0-103.0] vs 89.0 [IQR, 82.0-96.9] mm Hg; P < .001), and lower A-a gradients (9.9 [IQR, 6.2-13.5] vs 14.9 [IQR, 9.0-21.8] mm Hg; P < .001). Symptoms and quality of life were similar between the groups. CONCLUSIONS: Autoimmune hepatitis and increased liver disease severity were associated with the presence of IPVD, which was characterized by higher PaO2 levels. Future studies to better characterize IPVD pathogenesis and the relationship of IPVD to HPS are warranted.

Chronic obstructive pulmonary disease as a risk factor for ventricular arrhythmias independent of left ventricular function.

BACKGROUND: The association between chronic obstructive pulmonary disease (COPD) and sudden cardiac death has not been fully elucidated. OBJECTIVE: The purpose of this study was to investigate whether decreased left ventricular ejection fraction (LVEF) can explain the increased rate of ventricular tachycardia (VT) in COPD. METHODS: This retrospective study included consecutive adult patients who underwent pulmonary function testing (PFT), Holter monitoring, and transthoracic echocardiography. COPD was correlated with the frequency of VT in a multivariate analysis that adjusted for known confounders including LVEF. Long-term all-cause mortality of patients with COPD and VT was examined. RESULTS: Of the 6351 patients included in this study (age 66 ± 15 years; 48% woman; 92% Caucasian, LVEF 59% ± 12%), 2800 (44%) had PFT indicative of COPD. VT was nearly twice as likely to occur during Holter monitoring in COPD patients (13% vs 23%; P <.001), and the severity of COPD correlated with the risk of VT (21% vs 28% vs 37% for mild-moderate, severe, and very severe COPD; P <.001). COPD and VT remained independently associated (P <.001) even after adjusting for LVEF, demographics, and comorbidities (age, sex, body mass index, hypertension, chronic kidney disease, coronary artery disease, cancer history, diabetes mellitus). COPD was associated with all-cause mortality independently of LVEF (P <.001). CONCLUSION: COPD patients are at higher risk for VT and mortality. This may not be fully attributed to the confounding effect of systolic heart failure measured by LVEF. Further studies are needed to explore the mechanistic interactions between VT and COPD in order to determine whether antiarrhythmic strategies would apply especially to patients with severe COPD.

The "Complex Restrictive" Pulmonary Function Pattern: Clinical and Radiologic Analysis of a Common but Previously Undescribed Restrictive Pattern.

BACKGROUND: Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV1 are reduced to a similar degree. This pattern is called "simple restriction" (SR). In contrast, we commonly observe a pattern in which FVC percent predicted (pp) is disproportionately reduced relative to TLCpp. This pattern is termed "complex restriction" (CR), and we attempted to characterize its clinical, radiologic, and physiologic features. METHODS: This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLCpp-FVCpp ≤ 10%, and CR was stratified into four classes based on TLCpp-FVCpp discrepancy: Class 1 CR, TLCpp-FVCpp > 10% and ≤ 15%; Class 2 CR, TLCpp-FVCpp > 15% and ≤20%; Class 3 CR, TLCpp-FVCpp > 20% and ≤ 25%; and Class 4 CR, TLCpp-FVCpp > 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed. RESULTS: Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m2 or < 18.5 kg/m2, diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension (P < .0001, < .0001, < .001, .004, .0008, .002, .008, .009, .053, and .01, respectively) and a lower prevalence of interstitial lung disease (P < .0001). CONCLUSIONS: CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.

Effect of beta-blockers on exacerbation rate and lung function in chronic obstructive pulmonary disease (COPD).

BACKGROUND: Beta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have been wary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern for bronchospasm, but retrospective studies have shown that cardio-selective beta-blockers are safe in COPD and possibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of the medication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbation rates and longitudinal measures of lung function in two well-characterized COPD cohorts. METHODS: We retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPE trial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primary endpoints were exacerbation rates per person-year and change in spirometry over time in association with beta blocker use. RESULTS: Overall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statistically significant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiac comorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versus a rate of 1.71/person-year in patients not taking beta-blockers. In the STATCOPE cohort, patients taking beta-blockers had an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time. CONCLUSION: We found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomes in study participants with moderate to severe COPD.

The sawtooth sign is predictive of obstructive sleep apnea.

BACKGROUND: The sawtooth sign in spirometry is associated with redundant upper airway tissue and snoring, but its predictive value for identifying obstructive sleep apnea (OSA) is disputed. We retrospectively assessed the predictive value of the spirometric sawtooth sign in terms of the odds ratio (OR) of association with a diagnosis of OSA compared to those without the sign. METHODS: Consecutive spirometry reports showing a sawtooth sign were identified from our laboratory. We identified 50 subjects with sawtooth sign and 100 control subjects without sawtooth sign, matched for age, BMI, and gender. The electronic medical record of each patient was queried for a diagnosis of OSA based on physician-reported diagnoses. RESULTS: Of the 50 subjects with sawtooth sign, 22 were found to have a current diagnosis of OSA (44%). Twenty-seven of the 100 controls (27%) also had OSA. From logistic regression analysis, sawtooth sign was associated with an increased likelihood of OSA (OR = 2.12, 95% C.I. 1.04 to 4.35). Similar results were obtained after adjustment for age, gender, pack years, and BMI (OR = 2.61, 95% C.I. 1.13 to 6.21). CONCLUSIONS: Patients with the sawtooth sign have greater odds of having a diagnosis of OSA compared with those without the sign. If prospectively evaluated, as a result of improved identification, we hypothesize that the sawtooth sign may show an even stronger association with OSA. This relatively common finding, which adds no cost to routine spirometry, may serve as an indicator for OSA workup for some individuals not already identified as having OSA.

Association of Inhaled Corticosteroids with Incident Pneumonia and Mortality in COPD Patients; Systematic Review and Meta-Analysis.

BACKGROUND: Inhaled corticosteroids are commonly prescribed for patients with severe COPD. They have been associated with increased risk of pneumonia but not with increased pneumonia-associated or overall mortality. METHODS: To further examine the effects of inhaled corticosteroids on pneumonia incidence, and mortality in COPD patients, we searched for potentially relevant articles in PubMed, Medline, CENTRAL, EMBASE, Scopus, Web of Science and manufacturers' web clinical trial registries from 1994 to February 4, 2014. Additionally, we checked the included and excluded studies' bibliographies. We subsequently performed systematic review and meta-analysis of included randomized controlled trials and observational studies on the topic. RESULTS: We identified 38 studies: 29 randomized controlled trials and nine observational studies. The estimated unadjusted risk of pneumonia was increased in randomized trials: RR 1.61; 95% CI 1.35-1.93, p < 0.001; as well as in observational studies: OR 1.89; 95% CI 1.39-2.58, p < 0·001. Six randomized trials and seven observational studies were useful in estimating unadjusted risk of pneumonia -case-fatality: RR 0.91; 95% CI 0.52-1.59, p = 0.74; and OR 0.72; 95% CI 0.59-0.88, p = 0.001, respectively. Twenty-nine randomized trials and six observational studies allowed estimation of unadjusted risk of overall mortality: RR 0.95; 95% CI 0.85-1.05, p = 0.31; and OR 0.79; 95% CI 0.65-0.97, p = 0.02, respectively. CONCLUSIONS: Despite a substantial and significant increase in unadjusted risk of pneumonia associated with inhaled corticosteroid use, pneumonia fatality and overall mortality were found not to be increased in randomized controlled trials and were decreased in observational studies.

Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. A double effect of inhaled corticosteroids?

Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose-effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).

Relation of chronic obstructive pulmonary disease to atrial and ventricular arrhythmias.

Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality, yet the exact pathophysiological links remain unclear. Whether the presence and severity of COPD are associated with atrial or ventricular arrhythmias recorded on continuous electrocardiographic monitoring is unknown. We identified consecutive adult patients who underwent clinically indicated pulmonary function testing as well as 24-hour Holter monitoring at the Mayo Clinic, Rochester, from 2000 to 2009. Demographic data and relevant co-morbidities were gathered from the electronic medical record; severity of COPD was classified according to the GOLD classification, and arrhythmias were classified in concordance with the current clinical guidelines. From 7,441 patients who were included (age 64±16 years, 49% woman, 92% Caucasian), COPD was diagnosed in 3,121 (41.9%). Compared with those without COPD, the presence and severity of COPD were associated with increased likelihood of atrial fibrillation/atrial flutter (AF/AFL; 23.3% vs 11.0%, respectively, p<0.0001), nonsustained ventricular tachycardia (NSVT; 13.0% vs 5.9%, respectively, p<0.0001), and sustained ventricular tachycardia (0.9% vs 1.6%, respectively, p<0.0001). COPD remained a significant predictor of AF/AFL and NSVT (p<0.0001 and p<0.0001, respectively) after adjusting for age, gender, tobacco use, obesity, hypertension, coronary artery disease, heart failure, diabetes, anemia, cancer, chronic kidney disease, and rate/rhythm control medications. In conclusion, the independent association between the presence and severity of COPD and arrhythmias (AF/AFL and NSVT) provides further insight into the markedly increased cardiovascular mortality of patients with COPD. Further studies should explore which anti-arrhythmic strategies would best apply to the patients with COPD.