The total-breath method yields higher values of DLCO and TLC than the conventional method.

BACKGROUND: The 2017 ATS/ERS technical standard for measuring the single-breath diffusing capacity (DLCO) proposed the "rapid-gas-analyzer" (RGA) or, equivalently, "total-breath" (TB) method for the determination of total lung capacity (TLC). In this study, we compared DLCO and TLC values estimated using the TB and conventional method, and how estimated TLC using these two methods compared to that determined by body plethysmography. METHOD: A total of 95 people with COPD (GOLD grades 1-4) and 23 healthy subjects were studied using the EasyOne Pro (ndd Medical Technologies, Switzerland) and Master Screen Body (Vyaire Medical, Höchberg, Germany). RESULTS: On average the TB method resulted in higher values of DLCO (mean ± SD Δ = 0.469 ± 0.267; 95%CI: 0.420; 0.517 mmol*min-1*kPa-1) and TLC (Δ = 0.495 ± 0.371; 95%CI: 0.427; 0.562 L) compared with the conventional method. In healthy subjects the ratio between TB and conventional DLCO was close to one. TLC estimated using both methods was lower than that determined by plethysmography. The difference was smaller for the TB method (Δ = 1.064 ± 0.740; 95%CI: 0.929; 1.199 L) compared with the conventional method (Δ = 1.558 ± 0.940; 95%CI: 1.387; 1.739 L). TLC from body plethysmography could be estimated as a function of TB TLC and FEV1 Z-Score with an accuracy (normalized root mean square difference) of 9.1%. CONCLUSION: The total-breath method yielded higher values of DLCO and TLC than the conventional analysis, especially in subjects with COPD. TLC from the total-breath method can also be used to estimate plethysmographic TLC with better accuracy than the conventional method. The study is registered under clinicaltrial.gov NCT04531293.

A new approach for the detection of obesity-related airway obstruction in lung-healthy individuals.

BACKGROUND: Subjects with obesity show an increased prevalence of airway obstruction but it is not clear in each case whether this reflects genuine lung disease. Via intentional increase in end-expiratory lung volume we studied the detection of obesity-induced airway obstruction in lung-healthy obese subjects. METHODS: The primary study population comprised 66 lung-healthy obese subjects and 23 normal weight subjects. Measurements were performed in a body plethysmograph allowing for recording and quantification of breathing loops in terms of specific airway resistance at both normal and intentionally elevated end-expiratory lung volume. The change in volume was documented by a shutter maneuver. RESULTS: The voluntary increase of lung volume led to a significant reduction of expiratory airway resistance in 11 of the 66 obese subjects. This reduction could be quantified by a change of total expiratory resistance (sRtEX) of >1 kPa*s but was also clearly visible in the breathing loops. sRtEX showed the largest change among all resistance parameters. The loops of normal weight subjects remained virtually unaffected by the change in lung volume. Moreover, those of 5 obese patients with COPD who were measured for comparison partially showed a reduction of resistance but airway obstruction remained. CONCLUSION: The proposed breathing maneuver was simple to perform and allowed for a quantitative and qualitative detection of obesity-induced airway obstruction. This might help in reducing the likelihood of misdiagnosis and overtreatment of obese patients.

Prediction of lung emphysema in COPD by spirometry and clinical symptoms: results from COSYCONET.

BACKGROUND: Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. METHODS: We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George's Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. RESULTS: When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. CONCLUSIONS: Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933 .

The role of clinical signs and spirometry in the diagnosis of obstructive airway diseases: a systematic analysis adapted to general practice settings.

BACKGROUND: In general practice (GP), the diagnosis of obstructive airway diseases much relies on diagnostic questions, in view of the limited availability of lung function. We systematically assessed the relative importance of such questions for diagnosing asthma and chronic obstructive pulmonary disease (COPD), either without or with information from spirometry. METHODS: We used data obtained in a pulmonary practice to ensure the validity of diagnoses and assessments. Subjects with a diagnosis of COPD (n=260), or asthma (n=433), or other respiratory diseases (n=230), and subjects without respiratory diseases (n=364, controls) were included. The diagnostic questions comprised eight items, covering smoking history, self-attributed allergic rhinitis, dyspnea, cough, phlegm and wheeze. Optionally standard parameters of the flow-volume-curve were included. Decision trees for the diagnosis of COPD and asthma were constructed, moreover a probabilistic diagnostic network based on the results of path analyses describing the relationship between variables. RESULTS: In the decision trees, age, sex, current smoking, wheezing, dyspnea upon mild exertion, self-attributed allergic rhinitis, phlegm, forced expiratory volume in one second (FEV1), and expiratory flow rates were relevant, depending on the diagnostic comparison, while cough, dyspnea upon strong exertion and ex-smoker status were not relevant. In contrast, the probabilistic network for the diagnosis of COPD and asthma versus controls incorporated all diagnostic questions, i.e., dyspnea upon mild or strong exertion, current smoking, ex-smoking, wheezing, cough and phlegm but from spirometry only FEV1. Depending on the individual pattern, the probability for COPD could raise from 25% to 81%, while the diagnostic gain for asthma was lower. CONCLUSIONS: The study developed simple diagnostic algorithms for asthma and COPD that take into account the relative importance of clinical signs and history, as well as spirometric data if available. The diagnostic accuracy was especially high for COPD. These algorithms may be helpful as a starting point in the standardisation of diagnostic strategies in GP practices. TRIAL REGISTRATION: The study is registered under DRKS00013935 at German Clinical Trials Register (DRKS, Date of registration 01/03/2018).

Withdrawal of inhaled corticosteroids versus continuation of triple therapy in patients with COPD in real life: observational comparative effectiveness study.

BACKGROUND: Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. METHOD: Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. RESULTS: A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10-1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03-2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/µL. CONCLUSIONS: In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).

Effect of Inhaled Corticosteroid Withdrawal on Chronic Obstructive Pulmonary Disease Exacerbations in Patients Taking Triple Therapy at Baseline.

Purpose: In the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, inhaled corticosteroid (ICS) withdrawal in patients with chronic obstructive pulmonary disease receiving triple therapy (long-acting ß2-agonist+long-acting muscarinic antagonist+ICS) did not change moderate/severe exacerbation risk. However, many patients were not taking triple therapy before study participation. This analysis was conducted to eliminate the impact of non-ICS users on WISDOM results by re-analyzing the data using only the subset of patients who were taking triple therapy at screening. Patients and Methods: The effect of ICS withdrawal on moderate/severe exacerbation risk in the subgroup of WISDOM patients taking triple therapy before enrolling in the study was evaluated in this post hoc analysis. Additionally, the effect of ICS withdrawal in patients with a history of ≥2 exacerbations in the previous year and various blood eosinophil counts was assessed. Results: Overall, 39.0% (n=970: ICS continuation, 479; ICS withdrawal, 491) of the WISDOM trial population were taking triple therapy at screening. Baseline characteristics were generally similar between groups. Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89-1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94-1.19]). However, in patients with a history of ≥2 exacerbations, exacerbation risk (HR [95% CI]) increased nominally with blood eosinophil count from 1.07 [0.81-1.41] (≥100 cells/µL) to 1.45 [0.58-3.60] (≥400 cells/µL). Conclusion: Consistent with results from the overall WISDOM trial population, ICS withdrawal did not increase exacerbation risk in patients taking triple therapy at screening. Patients with a history of frequent exacerbations and higher blood eosinophil counts could benefit from continuation of ICS-based therapy.

Blood eosinophils as a biomarker of future COPD exacerbation risk: pooled data from 11 clinical trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation and chronic inflammation. Predicting exacerbations of COPD, which contribute to disease progression, is important to guide preventative treatment and improve outcomes. Blood eosinophils are a biomarker for patient responsiveness to inhaled corticosteroids (ICS); however, their effectiveness as a predictive biomarker for COPD exacerbations is unclear. METHODS: This post hoc analysis pooled data from 11 Boehringer Ingelheim-sponsored Phase III and IV randomised COPD studies with similar methodologies. Exacerbation data were collected from these studies, excluding patients from the ICS withdrawal arm of the WISDOM® study. Patients were grouped according to their baseline blood eosinophil count, baseline ICS use and number of exacerbations in the year prior to each study. RESULTS: Exacerbation rate data and baseline eosinophil count were available for 22,125 patients; 45.6% presented with a baseline blood eosinophil count of ≤ 150 cells/µL, 34.3% with 150-300 cells/µL and 20.1% with > 300 cells/µL. The lowest exacerbation rates were observed in patients with ≤ 150 cells/µL, with small increases in exacerbation rate observed with increasing eosinophil count. When stratified by exacerbation history, the annual rate of exacerbations for patients with 0 exacerbations in the previous year increased in line with increasing eosinophil counts (0.38 for ≤ 150 cells/µL, 0.39 for 150-300 cells/µL and 0.44 for > 300 cells/µL respectively). A similar trend was identified for patients with one exacerbation in the previous year, 0.62, 0.66 and 0.67 respectively. For patients with ≥ 2 exacerbations, exacerbation rates fluctuated between 1.02 (≤ 150 cells/µL) to 1.10 (150-300 cells/µL) and 1.07 (> 300 cells/µL). Higher exacerbation rates were noted in patients treated with ICS at baseline (range 0.75 to 0.82 with increasing eosinophil count) compared with patients not on ICS (range 0.45 to 0.49). CONCLUSION: We found no clinically important relationship between baseline blood eosinophil count and exacerbation rate. Hence, the current analysis does not support the use of blood eosinophils to predict exacerbation risk; however, previous exacerbation history was found to be a more reliable predictor of future exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00168844 , NCT00168831 , NCT00387088 , NCT00782210 , NCT00782509 , NCT00793624 , NCT00796653 , NCT01431274 , NCT01431287 , NCT02296138 and NCT00975195 .

Genuair®/Pressair® Inhaler in COPD: The Patient Perspective.

This article reviews the latest data pertaining to the Genuair®/Pressair® device, a breath-actuated, multi-dose dry-powder inhaler with a two-step inhalation process, which is marketed for the delivery of aclidinium alone or in combination with formoterol for long-term maintenance bronchodilation treatment in chronic obstructive pulmonary disease. It contains multiple feedback mechanisms to guide effective use, and safety features to avoid double-dosing or attempted use when empty. In addition to describing the design of Genuair®, the article will provide an update on inhaler operability and performance, focusing on recent patient preference and satisfaction studies. The evidence suggests that patients find Genuair® easy to use, with patients requiring less training and making fewer inhalation errors than with other inhalers, and that patient satisfaction with the device is high.

[Therapy control of COPD by Eosinophilic Granulocytes?] / Therapiesteuerung der COPD durch eosinophile Granulozyten?

Symptomatic patients with COPD reporting about repeated exacerbations in their history (group D according to GOLD recommendations) are treated with dual bronchodilation (LAMA/LABA) with potential benefits from additional ICS. Eosinophils in peripheral blood are considered as potential biomarkers to predict exacerbations. > 300 cells/µL or 4 % of eosinophils in peripheral blood are recommended to treat the patients with additional ICS. In clinical practice, about 10 - 15 % of patients with COPD are classified as group D according to GOLD. < 20 % have increased eosinophils in peripheral blood. Thus, ICS therapy should be restricted to a minority of patients with COPD.

Spirometric changes during exacerbations of COPD: a post hoc analysis of the WISDOM trial.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with loss of lung function and poor outcomes for patients. However, there are limited data on the time course of changes in forced expiratory volume in 1 s (FEV1) preceding the first reported symptom and after the start of an exacerbation. METHODS: WISDOM was a multinational, randomized, double-blind, active-controlled, 52-week study in patients with severe-to-very severe COPD. Patients received triple therapy (long-acting muscarinic antagonist and long-acting ß2-agonist/inhaled corticosteroid [ICS]) for 6 weeks, and were randomized to continue triple therapy or stepwise withdrawal of the ICS (dual bronchodilator group). After suitable training, patients performed daily spirometry at home using a portable, battery-operated spirometer. In the present post hoc analysis, patients who continued to perform daily home spirometry and completed at least one measurement per week for a 56-day period before and after the start of a moderate or severe exacerbation were included. Missing values were imputed by linear interpolation (intermittent), backfilling (beginning) or carry forward (end). Exacerbation onset was the first day of a reported symptom of exacerbation. RESULTS: Eight hundred and eighty-eight patients in the WISDOM study had a moderate/severe exacerbation after the complete ICS withdrawal visit; 360 of them contributed at least one FEV1 measure per week for the 8 weeks before and after the event and are included in this analysis. Mean daily FEV1 began to decline from approximately 2 weeks before the onset of symptoms of an exacerbation, dropping from 0.907 L (mean Days - 56 to - 36 before the exacerbation) to 0.860 L on the first day of the exacerbation. After the exacerbation, mean FEV1 improved but did not return to pre-exacerbation levels (mean Days 36-56 after the exacerbation, 0.875 L). The pattern of FEV1 changes around exacerbations was similar in the triple therapy and dual bronchodilator groups, and a similar pattern was seen in moderate and severe exacerbations when analysed separately. CONCLUSIONS: Mean lung function starts to decline prior to the first reported symptoms of an exacerbation, and does not recover to pre-exacerbation levels 8 weeks after the event. TRIAL REGISTRATION: WISDOM (ClinicalTrials.gov number, NCT00975195 ).

Physical Activity and Fatigue in Patients with Sarcoidosis.

BACKGROUND: Little is known about physical activity in daily life among patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. METHODS: In patients with sarcoidosis, we measured physical activity (steps per day) by accelerometry (SenseWear Armband) for 1 week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walking distance [6MWD]), health-related quality of life (St George's Respiratory Questionnaire [SGRQ]), generic quality of life (12-Item Short-Form Health Survey [SF-12]), and fatigue (Multidimensional Fatigue Inventory [MFI-20]). RESULTS: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73% predicted, mean FVC 91% predicted, mean 6MWD 525 m, mean steps per day 7,490), of whom n = 14 (25%) had severe fatigue. The MFI-20 subscales "reduced activity" and "physical fatigue" were weakly associated with steps per day on a bivariate level (Spearman ρ = -0.274 and ρ = -0.277, respectively; p < 0.05), while the other subscales and the total score were not. 6MWD, SGRQ score, and SF-12 (physical health) score showed stronger associations with steps per day in bivariate analyses (Pearson r = 0.499, r = -0.386, and r = 0.467, respectively; p < 0.01), and were independent predictors of steps per day in multivariate linear regression analyses adjusting for confounders (p < 0.05). In ROC curve analyses, 6MWD, SGRQ score, and SF-12 (physical health) score properly identified sedentary patients (steps per day <5,000; AUROC 0.90, 0.81, and 0.80, respectively; p < 0.01). Fatigue was less predictive (MFI-20 subscale "general fatigue," AUROC 0.70; p = 0.03). CONCLUSION: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling.

Triple Therapy in COPD: What We Know and What We Don't.

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.

Brain Activation during Perception and Anticipation of Dyspnea in Chronic Obstructive Pulmonary Disease.

Background: Dyspnea is the impairing cardinal symptom in COPD, but the underlying brain mechanisms and their relationships to clinical patient characteristics are widely unknown. This study compared neural responses to the perception and anticipation of dyspnea between patients with stable moderate-to-severe COPD and healthy controls. Moreover, associations between COPD-specific brain activation and clinical patient characteristics were examined. Methods: During functional magnetic resonance imaging, dyspnea was induced in patients with stable moderate-to-severe COPD (n = 17) and healthy control subjects (n = 21) by resistive-loaded breathing. Blocks of severe and mild dyspnea were alternating, with each block being preceded by visually cued anticipation phases. Results: During the perception of increased dyspnea, both patients and controls showed comparable brain activation in common dyspnea-relevant sensorimotor and cortico-limbic brain regions. During the anticipation of increased dyspnea, patients showed higher activation in hippocampus and amygdala than controls which was significantly correlated with reduced exercise capacity, reduced health-related quality of life, and higher levels of dyspnea and anxiety. Conclusions: This study suggests that patients with stable moderate-to-severe COPD show higher activation in emotion-related brain areas than healthy controls during the anticipation, but not during the actual perception of experimentally induced dyspnea. These brain activations were related to important clinical characteristics and might contribute to an unfavorable course of the disease via maladaptive psychological and behavioral mechanisms.

What can we learn from pulmonary function testing in heart failure?

Pulmonary diseases frequently coexist in heart failure (HF), thus posing diagnostic and therapeutic challenges to cardiologists evaluating patients with overlapping symptoms and implementing recommended HF treatments. There is a growing body of evidence suggesting that pulmonary function testing might provide useful information for the best management of these patients. The availability of portable devices, allowing the measurement of spirometry and lung diffusion capacity for carbon monoxide outside of hospital-based pulmonary lung function laboratories, provides an opportunity for a more widespread use of these measures in the cardiology community, but their interpretation can be challenging. In this work, after a brief review of the methodologies, we discuss the interpretation of pulmonary function testing in patients with HF alone or associated with pulmonary diseases, and its contribution in differentiating cardiac and pulmonary symptoms and preventing acute cardiac decompensation. In addition, we examined recent evidence suggesting how the use of pulmonary function testing may provide independent prognostic information in HF patients with and without pulmonary disorders, and help therapeutic decisions to fill the treatment gap that still exists in HF patients with concomitant pulmonary diseases.

Prognosis and longitudinal changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. METHODS: We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). RESULTS: During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively. CONCLUSION: While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.