Early lung function abnormalities in acromegaly.

BACKGROUND: Acromegaly is an insidious disorder caused by a pituitary growth hormone (GH)-secreting adenoma resulting in high circulating levels of GH and insulin-like growth factor I (IGF-I). Respiratory disorders are common complications in acromegaly, and can severely impact on quality of life, eventually affecting mortality. OBJECTIVES: The present study aimed to explore structural and functional lung alterations of acromegalic subjects. METHODS: We enrolled 10 consecutive patients (M/F: 5/5) affected by acromegaly. In all patients, magnetic resonance imaging (MRI) revealed the presence of pituitary tumor. All patients underwent clinical, lung functional, biological, and radiological assessments. Ten healthy age-matched subjects also served as controls. RESULTS: No statistically significant differences in lung function were detected between acromegalic and healthy subjects (p ≥ 0.05 for all analyses). However, the diffusing capacity for CO (TLCO) was significantly lower in the acromegalic group than in healthy subjects (TLCO% predicted: 78.1 ± 16 vs. 90 ± 6 %, respectively, p = 0.04; KCO% predicted: 77 ± 16 vs. 93 ± 5 %, p = 0.02, respectively). None of the lung function parameters correlated with duration of the disease, or with inflammatory marker of the airways. In acromegalics, biological (exhaled NO concentrations) and imaging (total lung volume, TLV, and mean lung density, MLD) evaluations were within normal values. The TLV measured by HRCT was 3540 ± 1555 ml in acromegalics, and the MLD was -711 ± 73 HU. None of the lung functional, radiological, and biological findings correlated with GH or IGF-I levels, and no correlation was found with duration of disease. CONCLUSIONS: In the current study, lung function evaluation allowed to detect early involvement of lung parenchyma, as assessed by TLCO and KCO, even in the absence of parenchymal density alterations of the lung by HRCT. These findings suggest to routinely include the carbon monoxide diffusing capacity in the lung function assessment for an early intervention in acromegaly.

Allergen sensitizations in southern Italy: a 5-year retrospective study in allergic respiratory patients.

The assessment of the distribution of allergen skin test sensitizations is highly recommended for the optimal management of allergic respiratory conditions. We aimed at evaluating the distribution of allergen sensitizations in individuals with asthma and/or rhinitis in the Southern region of ltaly, and at exploring whether changes in the frequency of allergen sensitizations occurred after a 5-year period. Demographic data and skin prick test sensitizations to allergens from asthmatics and/or rhinitis attending the Division of Respiratory Diseases, University of Palermo, Italy in 2005 (Phase 1) and in 2010 (Phase 2) were extrapolated and retained for analysis. A total of 2033 allergic respiratory patients were included (1002 in Phase 1 and 1031 in Phase 2). In both investigations, the most prevalent allergen sensitization was towards Parietaria; however, a significant reduction in the rate of prevalence after 5 years was recorded (from 60% to 48% of skin test positive patients, p < 0.0001). Up to one out of two subjects showed sensitization to dust mites in both Phases. Interestingly, Cypress pollen sensitization almost doubled from Phase 1 (17%) to Phase 2 (29%; p < 0.0001). Overall, the mean number of skin test sensitizations for each patient increased from 2.7 +/- 1.6 in Phase 1 to 3.1 + 1.8 in Phase 2 (p < 0.0001). The present findings confirm the prevalent role of Parietaria sensitization in the allergic population of the Mediterranean area of Southern Italy, and document the increase of Cypress sensitization. These observations could contribute to a proper management of chronic allergic respiratory conditions in this region.

Validation of lung densitometry threshold at CT for the distinction between senile lung and emphysema in elderly subjects.

BACKGROUND AND AIMS: An ageing lung is characterised by distal airspace enlargement without alveolar wall destruction: therefore the anatomical distinction between senile lung and emphysema is clear-cut. In clinical settings the definition of precise boundaries between normalcy and pathology is more difficult with the risk of overdiagnosis. CT is an important diagnostic advancement in the field of COPD. Most methods for the evaluation of emphysema are based on the detection and measurement of areas characterised by a density level below a threshold assumed to characterize parenchymal destruction. METHODS: Our retrospective study included 47 healthy subjects (65-91 years), 36 never smokers and 11 former smokers. As a reference sample we recruited 9 patients with emphysema (69-81 years). Thoracic scan was performed by single slice spiral CT and acquired without contrast enhancement. For each scan and on both lungs we sampled eighteen regions of interest in the upper, middle and lower field. Mean lung density (MLD) and lower limit of normal (LLN) of density distribution were calculated. RESULTS: MLD for the whole study sample was -846 +/- 41 HU. -901 HU was the LLN of density distribution in the study sample. No significant correlation was noted between age and MLD. In the emphysematous sample the average lung density was -946 +/- 18 HU. The mean coefficient of variation was 3% in the healthy sample and 2% in the emphysematous one. The difference between groups was significant (p < 0.0001). In one healthy subject only we measured a value slightly below the threshold reported in literature for conventional CT; no emphysematous value fell above the LLN. CONCLUSIONS: This study highlights the fact that in the elderly the threshold level of lung density commonly adopted in diagnostic algorithms of emphysema is fully applicable. When applying this method to older subjects the risk of misinterpreting areas of physiologic non-destructive reduction of density as emphysema is low.

Ageing and COPD affect different domains of nutritional status: the ECCE study.

Chronic obstructive pulmonary disease (COPD) and ageing may contribute to malnutrition. We aimed to explore whether COPD and ageing determine malnutrition in different manners. 460 stable COPD outpatients (376 males and 84 females) from the Extrapulmonary Consequences of COPD in the Elderly (ECCE) study database were investigated (age 75.0±5.9 yrs; forced expiratory volume in 1 s 54.7±18.3% predicted). Nutritional status was evaluated using the Mini Nutritional Assessment® (MNA) questionnaire. From the MNA, three scores exploring the domains of the nutritional status were calculated: body composition, energy intake and body functionality scores. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages were negatively correlated with five MNA items exploring mobility, patient's perception of own nutrition and health status, and arm and calf circumferences (lowest Spearman's rho (rs)=-0.011; highest p=0.039). GOLD stages were independently correlated with body composition and body functionality scores (model r2=0.073). Age was negatively correlated with four MNA items exploring loss of appetite, fluid intake, mobility and autonomy in daily life (lowest rs=-0.013; highest p=0.030). Age was independently correlated with body functionality score (model r2=0.037). Severe COPD and ageing are independent and probably concurrent conditions leading to malnutrition. The MNA questionnaire allows a valuable insight into the complexity of components of nutritional status and may provide useful clues for treatment strategies.

Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma.

BACKGROUND: Airway inflammation in asthma involves both large and small airways, and the combination of inhaled corticosteroids (ICS) and long acting beta-2 agonists (LABA) is the mainstay of therapy. Available inhaled combinations differ in terms of drug delivery to the lung and the ability to reach small airways. AIM: To evaluate whether treatment with an extra-fine inhaled combination provides additional effects vs a nonextra-fine combination on airway function. METHODS: After a 1- to 4-week run-in period, patients with asthma were randomized to a double blind, double dummy, 12-week treatment with either extra-fine beclomethasone/formoterol (BDP/F) 400/24 microg daily or fluticasone propionate/salmeterol (FP/S) 500/100 microg daily. Methacholine (Mch) bronchoprovocation challenge and single breath nitrogen (sbN2) test were performed. RESULTS: Thirty patients with asthma (15 men), mean age 43, mean forced expiratory volume in the first second (FEV(1)) 71.4% of predicted, were included. A significant increase (P < 0.01) versus baseline was observed in predose FEV(1) in both BDP/F and FP/S groups (0.37 +/- 0.13 l and 0.36 +/- 0.12 l, respectively). PD(20)FEV(1) Mch improved significantly from 90.42 (+/-30.08) microg to 432.41 (+/-122.71) microg in the BDP/F group (P = 0.01) but not in the FP/S group. A trend toward improvement vs baseline was observed for BDP/F in closing capacity (CC), whereas no differences were recorded in other sbN(2) test parameters. CONCLUSION: The findings of this pilot study suggest that an extra-fine inhaled combination for the treatment of asthma has beneficial effects on both large and small airways function as expressed by Mch and sbN(2) tests.

The Gene-Environment Interactions in Respiratory Diseases (GEIRD) Project.

The role of genetic and environmental factors, as well as their interaction, in the natural history of asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD) is largely unknown. This is mainly due to the lack of large-scale analytical epidemiological/genetic studies aimed at investigating these 3 respiratory conditions simultaneously. The GEIRD project is a collaborative initiative designed to collect information on biomarkers of inflammation and oxidative stress, individual and ecological exposures, diet, early-life factors, smoking habits, genetic traits and medication use in large and accurately defined series of asthma, allergic rhinitis and COPD phenotypes. It is a population-based multicase-control design, where cases and controls are identified through a 2-stage screening process (postal questionnaire and clinical examination) in pre-existing cohorts or new samples of subjects. It is aimed at elucidating the role that modifiable and genetic factors play in the occurrence, persistence, severity and control of inflammatory airway diseases, by way of the establishment of a historical multicentre standardized databank of phenotypes, contributed by and openly available to international epidemiologists. Researchers conducting population-based surveys with standardized methods may contribute to the public-domain case-control database, and use the resulting increased power to answer their own scientific questions.

The role of small airways in monitoring the response to asthma treatment: what is beyond FEV1?

The definition of asthma has evolved from that of an episodic disease characterized by reversible airways constriction to a chronic inflammatory disease of the airways, with at least partially reversible airway constriction. Increasing evidence supports the notion that small and large airways play a central role in asthma pathophysiology with regard to inflammation, remodeling and symptoms. The contribution of the distal airways to the asthma phenotype carries implications for the delivery of inhaled medications to the appropriate areas of the lung and for the monitoring of the response to asthma treatment. Asthma control is evaluated on the basis of symptoms, lung function and exacerbations. However, evidence suggests that dissociation between lung function and respiratory symptoms, quality of life and airway inflammation exists. In this study, common spirometric parameters offer limited information with regard to the peripheral airways, and it is therefore necessary to move beyond FEV(1). Several functional parameters and inflammatory markers, which are discussed in the present study, can be employed to evaluate distal lung function. In this study, extrafine formulations deliver inhaled drugs throughout the bronchial tree (both large and small airways) and are effective on parameters that directly or indirectly measure air trapping/airway closure.

Non-invasive diagnosis in a case of bronchopulmonary sequestration and proposal of diagnostic algorithm.

The case of a 43-year-old woman with intralobar pulmonary sequestration, Pryce type one, is presented. The medical history was characterised by recurrent bronchopneumonia, productive cough with purulent sputum and hemoptysis in the last three years. Diagnosis was made by CT angiography: multiplanar, maximum intensity projection and volume rendering reconstructions were visualised. A volume reduction of middle and lower lobe with multiple cyst-like bronchiectasis was detected and no evident relationship with tracheobronchial tree was pointed out. Reconstructions aimed at evaluating bronchial structures demonstrated no patency of middle and lower lobar bronchi. The study carried out after contrast medium infusion in arterial phase showed a vascular disorder characterised by an accessory arterial branch arising from the upper portion of thoracic aorta which, after moving caudally to pulmonary hilus with a tortuous course, supplied the atelectatic parenchyma. No anomalous venous drainage was detected. The patient underwent surgery with resection of two pulmonary lobes. CT compares favourably with other alternative imaging technique for pulmonary sequestration as multiplanar reconstructions allow not only the detection of supplying vessel, but also the accurate description of heterogeneous characteristics of the mass and adjacent structures. Finally an imaging-based diagnostic algorhithm is proposed.

A rare case of pedunculated bronchial hemangioma.

We describe a rare case of pedunculated endobronchial hemangioma observed in a 60-years-old patient complaining of chronic productive cough and accessional dyspnea which had been progressively worsening over 20 years. The lesion was first noticed at fiberoptic bronchoscopy; then computed tomography scan was performed and integrated with tridimensional reconstruction techniques. Pathology showed the picture of a vascular neoplasm, compatible with capillary hemangioma. The lesion was submitted to laser-assisted endoscopic removal in order to relieve the obstruction, leading to remission of symptoms.

Validation of FEV6 in the elderly: correlates of performance and repeatability.

BACKGROUND: Forced expiratory volume in 6 s (FEV6) has been proposed as a more easily measurable parameter than forced vital capacity (FVC) to diagnose airway disease using spirometry. A study was undertaken to estimate FEV6 repeatability, to identify correlates of a good quality FEV6 measurement and of volumetric differences between FEV6 and FVC in elderly patients. METHODS: 1531 subjects aged 65-100 years enrolled in the SA.R.A project (a cross-sectional multicentre non-interventional study) were examined. FEV6 was measured on volume-time curves that achieved satisfactory start-of-test and end-of-test criteria. Correlates of FEV6 achievement were assessed by logistic regression. RESULTS: Valid FEV6 and FVC measurements were obtained in 82.9% and 56.9%, respectively, of spirometric tests with an acceptable start-of-test criterion. Female sex, older age, lower educational level, depression, cognitive impairment and lung restriction independently affected the achievement of FEV6 measurement. Good repeatability (difference between the best two values <150 ml) was found in 91.9% of tests for FEV6 and in 86% for FVC; the corresponding figures in patients with airway obstruction were 94% and 78.4%. Both FEV6 and FVC repeatability were affected by male sex and lower education. Male sex, airway obstruction and smoking habit were independently associated with greater volumetric differences between FEV6 and FVC. CONCLUSIONS: In elderly patients, FEV6 measurements are more easily achievable and more reproducible than FVC although 1/6 patients in this population were unable to achieve them.

Rapidly progressive organising pneumonia associated with cytomegalovirus infection in a patient with psoriasis.

A 63-year-old woman experienced progressive respiratory distress and psoriatic plaques. The radiographic images showed diffuse interstitial infiltrates. The surgical open lung biopsy revealed an obliteration of the alveolar spaces by plugs of connective tissue distributed within the terminal bronchioles, alveolar ducts and spaces. No relevant cause was determined, and she was diagnosed with idiopathic organising pneumonia. The patient was discharged with oral glucocorticosteroid and supplemental oxygen therapy. One month later, the patient's pulmonary status had progressively worsened, and she was re-admitted. She required higher oxygen concentrations and mechanical ventilation. Pharmacological therapy included high-dose steroids and cyclophosphamide. Serological assays revealed high antibodies titers (both IgM and IgG) to cytomegalovirus. Therefore, ganciclovir was added to the regimen. Despite the therapy, she died as a result of the disease. The review of the current literature on the topic is also presented.

A new questionnaire specifically designed for patients affected by chronic obstructive pulmonary disease; The Italian Health Status Questionnaire.

The aim of this study was to develop a specific and valid questionnaire for Italian COPD patients, living on the north or the south of Italy-which are two culturally distinct areas. The project consisted in three steps: (1) initial item set generation to identify items relevant to both genders, all ages and both regions; (2) item reduction including tests of regional specificity; (3) tests of internal validity using item-response theory using Rasch one-parameter modelling. Ninty-six COPD patients (mean aged 69 yr; 78 Male) completed the original set of 124 items of the Italian Health Status Questionnaire (IHSQ). Item reduction was carried out using an established standardised approach employing classical psychometric test theory. The internal construct validity of the 47 items that survived this process were tested to determine whether they constituted a unidimensional construct "impaired health due to COPD" using Rasch analysis. This showed that the questionnaire had very good psychometric properties, with an excellent Person Separation Index of 0.95 and no evidence of bias due to item-trait interaction (chi104(2)=127.1, P=n.s.). The combination of classical test theory and modern item-response methodology has produced a questionnaire with excellent measurement properties suitable for COPD patients whether from the north or south of Italy.

Small airways function and molecular markers in exhaled air in mild asthma.

BACKGROUND: Several studies suggest that the periphery of the lung is the major site of inflammation in asthma. Fractional exhaled nitric oxide (Feno) and 8-isoprostane have been proposed as biomarkers of inflammation and oxidative stress. We therefore hypothesised that small airway dysfunction in asthma is of inflammatory origin that can be detected by molecular markers in exhaled air. To test this hypothesis, we examined the relationship of Feno and 8-isoprostane in exhaled air with small airways function as assessed by the single breath nitrogen test. METHODS: Sixteen patients (14 women) with mild atopic asthma (forced expiratory volume in 1 second >80% predicted) of mean (SD) age 23.0 (5.5) years participated in a cross sectional study. Feno was recorded by chemiluminescence and 8-isoprostane was measured by ELISA in concentrated exhaled breath condensate. The slope of phase III (deltaN2) and the closing volume (CV) were assessed from the single breath washout curve. RESULTS: The median Feno level was 30.4 ppb (range 10.1-82.8), the median 8-isoprostane concentration in exhaled breath condensate was 2.2 pg/ml (range 1.6-2.7), and the mean (SD) deltaN2 value was 1.1 (0.4)% N2/l. Feno was positively associated with deltaN2 (r(s) = 0.54, p = 0.032) while 8-isoprostane was inversely correlated with FEV1% predicted (rs= -0.58; p = 0.017) and CV as a percentage of vital capacity (rs= 0.58; p = 0.019). CONCLUSIONS: Feno and 8-isoprostane in exhaled air are associated with small airways function in mild asthma. This suggests that these markers reflect small airway inflammation and favours a role for them as disease markers that is complementary to spirometry in the monitoring of patients with asthma.

Interferon-induced depression: prevalence and management.

BACKGROUND: Interferon-induced depression ranges from 0 to 50%. Interferon schedule and a history of psychiatric illnesses are not enough to predict who will develop symptoms and who will not. AIMS: To assess the prevalence of depression during interferon therapy; to test whether Minnesota Multiphasic Personality Inventory is useful in clinical practice for the early identification of patients at risk of depression; whether and how the depression can be cured. PATIENTS: One hundred and eighty-five patients treated with interferon and ribavirin for chronic hepatitis C. METHODS: Before therapy, all patients underwent a Minnesota Multiphasic Personality Inventory and a clinical examination, specifically for the identification of depressive symptoms. RESULTS: Thirty-one patients developed a psychiatric disorder, 11 of them requiring treatment with anti-depressant drugs. Among the 18 patients with Minnesota Multiphasic Personality Inventory positive tests, 16 developed a psychiatric disorder, 8 of them a severe disorder (sensitivity of 0.58; 0.73 for severe disorders). Among the 154 who did not develop psychiatric side effects, 152 had a negative Minnesota Multiphasic Personality Inventory (specificity: 0.99). Severe psychiatric disorders were successfully treated with anti-depressant drugs. CONCLUSIONS: Psychiatric side effects are easy to see during interferon therapy. A psychiatric evaluation should be considered on all patients before treatment. If depression develops, it should be treated aggressively, and selective serotonin re-uptake inhibitors are the anti-depressants of choice.

Airway hyperresponsiveness in the elderly: prevalence and clinical implications.

Airway hyperresponsiveness is associated with an increased risk of developing respiratory symptoms. The assessment of airway hyperresponsiveness can provide valuable information regarding the natural course of respiratory diseases. However, little information is available for populations of more advanced age, and data are conflicting. It was assessed whether age influences the occurrence of airway hyperresponsiveness by reviewing those studies that specifically addressed this issue, and attempting to identify the factors responsible for discrepancies between studies. Eighteen studies, published between 1983 and 2002, are included in this review. Overall, the results of the analysis are in favour of a positive association between age and airway hyperresponsiveness, the prevalence of which appears to increase in the elderly. The most important determinants were reduced lung function, probably due to geometric factors, and a history of smoking, primarily because of the length of exposure, although acute effects were also demonstrated. Atopy should also be considered as an independent determinant of airway hyperresponsiveness in the elderly population. In addition, inflammatory and neuronal mechanisms could be involved. Finally, the role of sex requires further investigation. Assessing the impact of age on the occurrence of airway hyperresponsiveness has important implications: the age-associated alterations to the lung provide a model for evaluating the contribution of structural changes to the pathogenesis of airway hyperresponsiveness. From a clinical standpoint, evaluation of the magnitude of airway hyperresponsiveness could permit the early identification of individuals who are at risk, even at more advanced age. Assessment of airway hyperresponsiveness in the aged should be considered as an additional tool in the diagnostic work-up in the subset of elderly subjects with long-term smoking exposure and/or documented atopy.

Airway remodelling assessed by sputum and high-resolution computed tomography in asthma and COPD.

It is not known whether sputum elastase, metalloproteinase (MMP)-9 and tissue-inhibitor metalloproteinase (TIMP)-1 are related to structural changes of the airways, as assessed by high-resolution computed tomography (HRCT) scan. The relationships between these markers and the magnitude of structural changes of the airways in asthma and chronic obstructive pulmonary disease (COPD) were assessed. Induced sputum and HRCT scan were performed in 30 asthmatics (14 mild and 16 severe) and in 12 patients with COPD. A greater extent of HRCT scan abnormalities was found in COPD than in severe and mild asthmatics. HRCT scan abnormalities correlated with the degree of airway obstruction in COPD and in severe asthma. HRCT scan abnormalities also correlated with the levels of sputum elastase both in COPD and in severe asthma. HRCT scan abnormalities were associated with sputum MMP-9/TIMP-1 ratio in mild asthma, severe asthma and COPD. In conclusion, this study demonstrates that sputum elastase and the metalloproteinase-9/tissue-inhibitor metalloproteinase-1 ratio are associated with the magnitude of high-resolution computed tomography scan abnormalities of the airways in asthma and chronic obstructive pulmonary disease, and suggests that the levels of these markers reflect the extent of structural changes of the airways.

Monitoring response to treatment in asthma management: food for thought.

Asthma is a chronic inflammatory disorder of the airways that is characterized by episodic symptoms. In this regard, asthma management has classically involved periodic re-assessment by the health-care provider, during which therapy is altered mainly based on clinical and physiological parameters, such as assessment of symptoms, spirometry and peak expiratory flow monitoring. In this context, various markers of airway inflammation (e.g. eosinophils in the induced sputum, nitric oxide in the exhaled air) have been proposed to assess the severity of asthma and to adjust the therapy accordingly. The evaluation of airway hyper-responsiveness with different stimuli has also been suggested as a new tool to monitor asthma. However, the lack of definite relationships between airway inflammation and asthmatic symptoms strongly limit the use of markers of asthma severity in the clinical setting. Therefore, the need of new tools to assess the severity of asthma is raised. The ideal measurement employed to establish the proper asthmatic therapy should be safe, non-invasive, easy to perform, reproducible and accurate, and have the capability to monitor the changes induced by the therapeutic interventions. A careful review of the available techniques, and the evaluation of their sensitivity and specificity in the clinical setting is warranted.

Effect of age and asthma duration upon elastase and alpha1-antitrypsin levels in adult asthmatics.

In asthmatic subjects an imbalance between elastase and alpha1-antitrypsin (alpha1-PI) exists. This study aims to evaluate whether ageing per se affects the levels of elastase. Both young and elderly asthmatics with comparable severity and duration of disease, as well as young and elderly healthy subjects, underwent an induced sputum procedure to measure levels of elastase and alpha1-PI. The percentage of sputum neutrophils and eosinophils was higher in young and elderly asthmatics than in young and elderly controls. The levels of both total and active elastase were significantly higher in young and elderly asthmatics than in young and elderly controls, and directly correlated with the percentage of neutrophils. In addition, in both young and elderly asthmatics the levels of total and active elastase were negatively correlated with forced expiratory volume in one second values, but positively correlated with the duration of the disease. This study indicates that ageing per se does not necessarily lead to a progressive elastase/alpha1-antitrypsin imbalance in asthma, and suggests that an important variable in the development of airway remodelling in both young and elderly asthmatics is represented by the duration of the disease.

Do GOLD stages of COPD severity really correspond to differences in health status?

The purpose of this study was to assess whether different stages of chronic obstructive pulmonary disease (COPD) severity defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria correlate with meaningful differences in health status. A total of 381 COPD patients, aged 73+/-6 yrs, were classified in the five GOLD stages. Disease-specific (St George Respiratory Questionnaire (SGRQ)) and generic indexes of health status were measured in all patients. Multivariate analysis of covariance or Kruskal Wallis tests were used to compare health status indexes across the spectrum of GOLD stages of COPD severity. GOLD stages of COPD severity significantly differed in SGRQ components and Barthel's index, but not in the indexes assessing cognitive and affective status and quality of sleep. The largest variation in health status was observed at the transition from stage IIa to stage IIb, while there were no other significant differences between consecutive stages. Both female sex and comorbidity were associated with a greater impact of COPD on the health status. In conclusion, the upper limit of stage IIb (forced expiratory volume in one second of 49%) marks a threshold for dramatic worsening of health status. Progression of chronic obstructive pulmonary disease severity from stage 0 to stage IIa does not correspond to any meaningful difference in health status.