Outcome-based Definition of the Lower Limit of Normal in Spirometry: A Study of 26,000 Young Adult Men.

Rationale The definition of the lower limit of normal (LLN) of spirometric variables is not well established. Objectives To investigate the relationship between spirometric abnormalities defined with different thresholds of the LLN and clinical outcomes, and to explore the possibility of using different LLN thresholds according to the pre-test probability of disease. Methods We studied the associations between pre-bronchodilator spirometric abnormalities (FEV1 < LLN, FVC < LLN, airflow obstruction, spirometric restriction) defined with different thresholds of the LLN (10th, 5th, 2.5th, 1st percentile) and multiple outcomes (prevalence of spirometric abnormalities, respiratory symptoms, all-cause and respiratory mortality) in 26,091 30-46 years old men who participated in a general population survey in Norway in 1988-1990 and were followed for 26 years. Analyses were performed with both local and GLI-2012 reference equations, stratified by pre-test risk (presence or absence of respiratory symptoms), and adjusted for age, BMI, smoking, and education. Results In the total population, the prevalence of airflow obstruction was 11.6% with GLI-LLN10, 11.0% with Local-LLN5, 6.1% with GLI-LLN5, 7.6% with Local-LLN2.5, and 3.5% with GLI-LLN2.5. The prevalence of spirometric restriction was 5.9% with GLI-LLN10, 5.2% with Local-LLN5, and 2.8% with GLI-LLN5. Increasingly lower thresholds of the LLN were associated with increasingly higher odds of respiratory symptoms and hazard of mortality for all spirometric abnormalities with both reference equations. Spirometric abnormalities defined with Local-LLN2.5 in asymptomatic subjects were associated with lower hazard of all-cause mortality (hazard ratio 1.50 (1.15, 1.95, 95% confidence intervals) for FEV1 < LLN) than those defined with Local-LLN5 in the general population (1.67 (1.50, 1.87) for FEV1 < LLN) and symptomatic subjects (1.67 (1.46, 1.91) for FEV1 < LLN). Overall, prevalence of spirometric abnormalities and associations with outcomes obtained with Local-LLN5 were comparable to those obtained with GLI-LLN10, and those obtained with Local-LLN2.5 to GLI-LLN5. Conclusions There is a relationship between statistically-based thresholds of the LLN of spirometric variables and clinical outcomes. Different thresholds of the LLN may be used in different risk subgroups of subjects, but the choice of the threshold needs to be evaluated together with the choice of reference equations.

Reduced lung function and cause-specific mortality: A population-based study of Norwegian men followed for 26 years.

BACKGROUND AND AIM: Reduced lung function is associated with increased mortality, but it is unclear how different spirometric patterns are related to specific deaths. Aim of this study was to investigate these associations in a large general population cohort. METHODS: The study population consisted of 26,091 men aged 30-46 years from the Pneumoconiosis Survey of Western Norway conducted in 1988-1990 with follow-up on date and cause of death for 26 years. Cox proportional hazard models were used to estimate the association between baseline FEV1, FVC, obstructive (OSP) and restrictive spirometric pattern (RSP) (z-scores calculated according to GLI-2012 equations) and mortality (European 2012 shortlist classification (E-2012)), after adjustment for age, body mass index, smoking habits, and education. RESULTS: In total, 2462 (9%) subjects died. A predominant reduction of FEV1 (and OSP) were associated with respiratory non-cancer (E-8) (HR for one unit FEV1 z-score decrease 2.29 (95% CI 1.90, 2.77) and lung cancer mortality (E-2.1.8) (1.27(1.12, 1.44)). A similar reduction of FEV1 and FVC (and RSP) were associated with diabetes (E-4.1) (FEV1 2.21(1.67, 2.92), FVC 2.41(1.75, 3.32)), cerebrovascular (E-7.3) (1.52(1.21, 1.91), 1.54(1.19, 1.98)), ischemic heart disease (E-7.1) (1.22(1.10, 1.35), 1.21(1.08, 1.36)), neurological (E-6.3) (1.56(1.21, 2.01), 1.61(1.22, 2.13)), suicide (E-17.2) (1.37(1.13, 1.65), 1.29(1.04, 1.59)) and hematological cancer mortality (E-2.1.19-21) (1.29(1.05, 1.58), (1.26(1.00, 1.58)). No association was found between reduced lung function and mortality due to accidents, alcohol abuse, digestive and genitourinary cancer. CONCLUSIONS: Spirometric obstruction was mainly related to pulmonary mortality. Spirometric restriction was mainly related to extra-pulmonary mortality.

Association between lipid-A-producing oral bacteria of different potency and fractional exhaled nitric oxide in a Norwegian population-based adult cohort.

BACKGROUND: Lipid A is the primary immunostimulatory part of the lipopolysaccharide (LPS) molecule. The inflammatory response of LPS varies and depends upon the number of acyl chains and phosphate groups in lipid A which is specific for a bacterial species or strain. Traditional LPS quantification assays cannot distinguish between the acylation degree of lipid A molecules, and therefore little is known about how bacteria with different inflammation-inducing potencies affect fractional exhaled nitric oxide (FeNO). We aimed to explore the association between pro-inflammatory hexa- and less inflammatory penta-acylated LPS-producing oral bacteria and FeNO as a marker of airway inflammation. METHODS: We used data from a population-based adult cohort from Norway (n = 477), a study center of the RHINESSA multi-center generation study. We applied statistical methods on the bacterial community- (prediction with MiRKAT) and genus-level (differential abundance analysis with ANCOM-BC) to investigate the association between the oral microbiota composition and FeNO. RESULTS: We found the overall composition to be significantly associated with increasing FeNO levels independent of covariate adjustment, and abundances of 27 bacterial genera to differ in individuals with high FeNO vs. low FeNO levels. Hexa- and penta-acylated LPS producers made up 2.4% and 40.8% of the oral bacterial genera, respectively. The Bray-Curtis dissimilarity within hexa- and penta-acylated LPS-producing oral bacteria was associated with increasing FeNO levels independent of covariate adjustment. A few single penta-acylated LPS producers were more abundant in individuals with low FeNO vs. high FeNO, while hexa-acylated LPS producers were found not to be enriched. CONCLUSIONS: In a population-based adult cohort, FeNO was observed to be associated with the overall oral bacterial community composition. The effect of hexa- and penta-acylated LPS-producing oral bacteria was overall significant when focusing on Bray-Curtis dissimilarity within each of the two communities and FeNO levels, but only penta-acylated LPS producers appeared to be reduced or absent in individuals with high FeNO. It is likely that the pro-inflammatory effect of hexa-acylated LPS producers is counteracted by the dominance of the more abundant penta-acylated LPS producers in this population-based adult cohort involving mainly healthy individuals.

Period and cohort effects: consequences on spirometric lung function in Norway during the 20th century.

Background and aim: Several factors can influence measured lung function over time. The aim of this study was to investigate period and cohort effects on spirometric measures in a large general population sample in Norway during the 20th century, using Global Lung Function Initiative (GLI-2012) equations as a reference. Methods: 36 466 subjects (born 1894-1969) from four cross-sectional surveys conducted between 1965 and 1999 were included, with harmonised data on smoking habits, respiratory symptoms, lung diseases, education and spirometry. Changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) z-scores in healthy subjects across surveys were explored to investigate period effects. Linear mixed-effects models of FEV1 and FVC z-scores on birth cohort, with survey as random effect, were used to investigate cohort effects, both in subjects of the total population and in healthy ones. Results: Relatively higher FEV1 and FVC z-scores in healthy subjects were found in the first survey (1965-1970) compared to the more recent ones (1988-1999), suggesting period effects. FEV1 and FVC z-scores increased significantly with birth cohort from 1894 to 1935, after adjustment for covariates. A more stable trend of FEV1 and FVC z-scores with birth cohort was evidenced for subjects born more recently (1945-1969). Conclusions: An increase of lung function with year of birth was observed in Norwegian subjects during the first half of the 20th century. The impact of period effects on lung function decreased from 1965 to 1999.

Should Perfusion Scintigraphy Be Performed to Follow Patients with Acute Pulmonary Embolism? If So, When?

This investigation evaluated the changes of pulmonary perfusion at 4 different points of follow-up within 1 y in patients with pulmonary embolism (PE) and the factors predictive of complete or incomplete recovery of pulmonary perfusion. Methods: Patients with symptomatic PE underwent perfusion lung scintigraphy and blood gas analysis within 48 h from clinical presentation, after 1 wk, and after 1, 6, and 12 mo; echocardiography was performed at baseline and after 6 and 12 mo. All perfusion lung scintigraphy scans were examined by 2 expert nuclear medicine physicians with a scoring method that attributed a score of 0, 0.5, or 1 for extension (maximum score, 18) to the presence of perfusion defects (PD), both at baseline and on each follow-up scan. Results: Among 183 patients who completed 1 y of follow-up, the median baseline PD score was 8.2; it decreased significantly at each follow-up time point until 6 mo (P < 0.001). Median baseline alveolar-arterial difference in oxygen partial pressure (PA-aO2) was 50.9 and decreased significantly up to 1 mo (P < 0.001); median pulmonary artery systolic pressure (PAsP) was 45.9 mm Hg and decreased significantly until 12 mo (P < 0.001). A correlation was found between PD and both PA-aO2 (P < 0.05) and PAsP (P < 0.05). We found a correlation between PD ≠ 0 and PAsP ≥ 40 mm Hg at 12 mo (P < 0.05); in 6 (3.3%) of these patients such a correlation was still present after 24 mo, suggesting they could develop chronic thromboembolic pulmonary hypertension. Low baseline PD (odds ratio, 0.80; P < 0.0001) and high 1-wk percent recovery (odds ratio, 1.04; P < 0.0001) were predictive factors of complete 6-mo recovery. Conclusion: Perfusion scintigraphy may be useful to follow patients with PE. The follow-up should consist of 3 steps: the baseline examination, which reflects the severity of PE; the scan at 1 wk, which indicates the early amount of reperfusion; and the scan at 6 mo, which demonstrates the maximum attainable recovery. Patients with incomplete recovery and persistence of pulmonary hypertension on the 24-mo control should be further studied for possible development of chronic thromboembolic pulmonary hypertension.

Chronic Obstructive Pulmonary Disease: Pulmonary Function and CT Lung Attenuation Do Not Show Linear Correlation.

PURPOSE: To determine whether the relationship between pulmonary function and computed tomographic (CT) lung attenuation in chronic obstructive pulmonary disease (COPD), which is traditionally described with single univariate and multivariate statistical models, could be more accurately described with a multiple model estimation approach. MATERIALS AND METHODS: The study was approved by the local ethics committee. All participants provided written informed consent. The prediction of the percentage area with CT attenuation values less than -950 HU at inspiration (%LAA-950insp) and less than -910 HU at expiration (%LAA-910exp) obtained with single univariate and multivariate models was compared with that obtained with a multiple model estimation approach in 132 patients with COPD. RESULTS: At univariate analysis, %LAA-950insp and %LAA-910exp values higher than the mean value of this cohort (19.1% and 22.0%) showed better correlation with percentage of predicted diffusing capacity of lung for carbon monoxide (Dlco%) than with airflow obstruction (forced expiratory volume in 1 second [FEV1]/vital capacity [VC]). Conversely, %LAA-950insp and %LAA-910exp values lower than the mean value were correlated with FEV1/VC but not with Dlco%. Multiple model estimation performed with two multivariate regressions, each selecting the most appropriate functional variables (FEV1/VC for mild parenchymal destruction, Dlco% and functional residual capacity for severe parenchymal destruction), predicted better than single multivariate regression both %LAA-950insp (R(2) = 0.75 vs 0.46) and %LAA-910exp (R(2) = 0.83 vs 0.63). CONCLUSION: The relationship between pulmonary function data and CT densitometric changes in COPD varies with the level of lung attenuation impairment. The nonlinear profile of this relationship is accurately predicted with a multiple model estimation approach.

Pulmonary function and sputum characteristics predict computed tomography phenotype and severity of COPD.

Airway obstruction and parenchymal destruction underlie phenotype and severity in chronic obstructive pulmonary disease (COPD). We aimed to predict, by clinical and pulmonary function data, the predominant type and severity of pathological changes quantitatively assessed by computed tomography (CT). Airway wall thickness (AWT-Pi10) and percentage of lung area with X-ray attenuation values <-950 HU (%LAA-950) were measured in 100 (learning set) out of 473 COPD outpatients undergoing clinical and functional evaluation. Original CT measurements were translated by principal component analysis onto a plane with the novel coordinates CT1 and CT2, depending on the difference (prevalent mechanism of airflow limitation) and on the sum (severity) of AWT-Pi10 and %LAA-950, respectively. CT1 and CT2, estimated in the learning set by cross-validated models of clinical and functional variables, were used to classify 373 patients in the testing set. A model based on diffusing capacity of the lung for carbon monoxide, total lung capacity and purulent sputum predicted CT1 (r = 0.64; p<0.01). A model based on forced expiratory volume in 1 s/vital capacity, functional residual capacity and purulent sputum predicted CT2 (r = 0.77; p<0.01). Classification of patients in the testing set obtained by model-predicted CT1 and CT2 reflected, according to correlations with clinical and functional variables, both COPD phenotype and severity. Multivariate models based on pulmonary function variables and sputum purulence classify patients according to overall severity and predominant phenotype of COPD as assessed quantitatively by CT.

BODE-index, modified BODE-index and ADO-score in chronic obstructive pulmonary disease: relationship with COPD phenotypes and CT lung density changes.

COPD is a heterogeneous disorder whose assessment is going to be increasingly multidimensional. Grading systems such as BODE (Body-Mass Index, Obstruction, Dyspnea, Exercise), mBODE (BODE modified in grading of walked distance), ADO (Age, Dyspnea, Obstruction) are proposed to assess COPD severity and outcome. Computed tomography (CT) is deemed to reflect COPD lung pathologic changes. We studied the relationship of multidimensional grading systems (MGS) with clinically determined COPD phenotypes and CT lung density. Seventy-two patients underwent clinical and chest x-ray evaluation, pulmonary function tests (PFT), 6-minute walking test (6MWT) to derive: predominant COPD clinical phenotype, BODE, mBODE, ADO. Inspiratory and expiratory CT was performed to calculate mean lung attenuation (MLA), relative area with density below-950 HU at inspiration (RAI(-950)), and below -910 HU at expiration (RAE(-910)). MGS, PFT, and CT data were compared between bronchial versus emphysematous COPD phenotype. MGS were correlated with CT data. The prediction of CT density by means of MGS was investigated by direct and stepwise multivariate regression. MGS did not differ in clinically determined COPD phenotypes. BODE was more closely related and better predicted CT findings than mBODE and ADO; the better predictive model was obtained for CT expiratory data; stepwise regression models of CT data did not include 6MWT distance; the dyspnea score MRC was included only to predict RA-950 and RA-910 which quantify emphysema extent. BODE reflect COPD severity better than other MGS, but not its clinical heterogeneity. 6MWT does not significantly increase BODE predictivity of CT lung density changes.

Explorative data analysis techniques and unsupervised clustering methods to support clinical assessment of Chronic Obstructive Pulmonary Disease (COPD) phenotypes.

Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death worldwide and represents one of the major causes of chronic morbidity. Cigarette smoking is the most important risk factor for COPD. In these patients, the airflow limitation is caused by a mixture of small airways disease and parenchyma destruction, the relative contribution of which varies from person to person. The twofold nature of the pathology has been studied in the past and according to some authors each patient should be classified as presenting a predominantly bronchial or emphysematous phenotype. In this study we applied various explorative analysis techniques (PCA, MCA, MDS) and recent unsupervised clustering methods (KHM) to study a large dataset, acquired from 415 COPD patients, to assess the presence of hidden structures in data corresponding to the different COPD phenotypes observed in clinical practice. In order to validate our methods, we compared the results obtained from a training set of 415 patients with lung density data acquired in a test set of 93 patients who underwent HRCT (High Resolution Computerized Tomography).