Committee Report

Criteria for the Assessment of Reversibility in Airways Obstruction: Report of the Committee on Emphysema American College of Chest Physicians

The relationship between bronchodilator responsiveness and eosinophilic airway inflammation has not been well documented in COPD. It has been investigated in this retrospective study. This issue has grown in importance due to increasing interest in the asthma-COPD overlap syndrome.

264 stable COPD patients with no past history of asthma were retrospectively analyzed. Correlation analyses between FEV₁ reversibility and sputum eosinophil levels were conducted. Sputum eosinophil levels were dichotomized using FEV₁ reversibility cut-off points (>0.4 L and >15% vs. >0.2 L and >12%) and compared. The effectiveness of FEV₁ reversibility to predict sputum eosinophilia (>3%) was analyzed with a logistic regression and a ROC analysis.

82 (31.1%) patients with higher FEV₁ reversibility values (0.14 vs. 0.11 L, P=.01) presented sputum eosinophilia. FEV₁ reversibility was weakly correlated with the sputum eosinophil level (r = 0.162, P=.008). Patients with FEV₁ > 0.4 L and >15% increment had higher sputum eosinophil levels (6.11 vs. 1.02%, P=.049) whereas the level did not differ when dichotomized by FEV₁ increment >0.2 L and >12%. Very positive FEV₁ reversibility (>0.4 L and >15%) predicted sputum eosinophilia after adjustment forage, baseline FEV₁ and FVC (OR: 4.262, P=.029). In the ROC analysis, the AUC was 0.58 (P=.034), and FEV₁ increment > 0.4 L and >15% had a positive predictive value of 63.6% and an overall accuracy of 70.1%.

FEV₁ reversibility was weakly correlated with sputum eosinophil levels in COPD. Positive FEV₁ reversibility (>0.4 L and >15%) is moderately successful in predicting sputum eosinophilia (>3%).

La relación entre la reactividad al broncodilatador y la inflamación eosinofílica de la vía aérea no está bien documentada en la EPOC y se ha investigado en este estudio retrospectivo. Esta cuestión ha adquirido mayor importancia debido al creciente interés que despierta el fenotipo mixto asma-EPOC.

Se analizó retrospectivamente a 264 pacientes con EPOC estable y sin antecedentes de asma. Se efectuaron análisis de correlación entre la reversibilidad del FEV₁ y las concentraciones de eosinófilos en esputo, que se compararon una vez dicotomizadas en función de diferentes puntos de corte de la reversibilidad del FEV₁ (> 0,4 l y > 15% vs. > 0,2 l y > 12%). La utilidad de la reversibilidad del FEV₁ para predecir la eosinofilia del esputo (> 3%) se evaluó mediante una regresión logística y un análisis de la curva ROC.

En los 82 pacientes (31,1%) que presentaban eosinofilia del esputo, la reversibilidad del FEV₁ fue mayor (0,14 vs. 0., 1 l, p = 0,01). La reversibilidad del FEV₁ se correlacionó débilmente con la concentración de eosinófilos en esputo (r = 0,162, p = 0,008). Los pacientes con incrementos del FEV₁ > 0,4 l y > 15% mostraron mayores concentraciones de eosinófilos en el esputo (6,11 vs. 1,02%, p = 0,049), aunque las concentraciones no difirieron tras dicotomizarlas de acuerdo a un incremento del FEV₁ > 0,2 l y > 12%. Tras ajustarla en función de la edad, el FEV₁ inicial y la FVC, la reversibilidad del FEV₁ muy alta (> 0,4 l y > 15%) continuó siendo significativa para predecir la eosinofilia del esputo (OR: 4,262, p = 0,029). El análisis de la curva ROC mostró que el valor predictivo positivo de un AUC de 0,58 (p = 0,034) y un incremento del FEV₁ > 0,4 l y > 15% es del 63,6%, con una precisión total del 70,1%.

En pacientes con EPOC, la reversibilidad del FEV₁ se correlacionó débilmente con las concentraciones de eosinófilos en esputo. Una reversibilidad del FEV₁ muy alta (> 0,4l y > 15%) puede predecir la eosinofilia del esputo (> 3%), pero su rendimiento es modesto.

Recommendations on interpreting tests of bronchodilator responsiveness (BDR) are conflicting. We investigated the dependence of BDR criteria on sex, age, height, ethnicity, and severity of respiratory impairment.

BDR test data were available from clinical patients in the Netherlands, New Zealand, and the United States (n = 15,278; female subjects, 51.7%) and from surveys in Canada, Norway, and five Latin-American countries (n = 16,250; female subjects, 54.7%). BDR calculated according to FEV₁, FVC, and FEV₁/FVC was expressed as absolute change, a percentage of the baseline level (% baseline), a percentage of the predicted value (% predicted), and z score.

Change (Δ) in FEV₁ and FVC, in milliliters, was unrelated to the baseline value but was biased toward age, height, sex, and level of airways obstruction; ΔFEV₁ was significantly lower in African Americans. In 1,106 subjects with low FEV₁ (200-1,621 mL) the FEV₁ increased by 12% to 44.7% relative to baseline but < 200 mL. Expressing BDR as a percentage of the predicted value or as a z score attenuated the bias and made the 200-mL criterion redundant, but reduced positive responses by half. ΔFEV₁ % baseline increased with the level of airflow obstruction but decreased with severe obstruction when expressed as z scores or % predicted; ΔFVC, however expressed, increased with the level of airflow obstruction.

Expressing FEV₁ responsiveness as % baseline spuriously suggests that responsiveness increases with the severity of respiratory impairment. Expressing change in FEV₁ or FVC as % predicted or as z scores eliminates this artifact and renders the required 200-mL minimum increase redundant. In severe airways obstruction ΔFVC should be critically evaluated as an index of clinically important relief of hyperinflation, with implications for bronchodilator drug trials.

Consensus on how best to express bronchodilator reversibility (BDR) is lacking. We tested different BDR criteria against the null hypotheses that BDR should show no sex or size bias. To determine the best criterion for defining BDR, we hypothesized that clinically important BDR should be associated with better survival in respiratory patients compared with that of patients without BDR.

We used the first BDR test of 4,231 patients who had known subsequent survival status (50.8% male sex; mean age, 60.9 years; mean survival, 5.2 years [range, 0.1-16.5 years]). BDR for FEV₁ was expressed as absolute change, % baseline change, and change as % predicted FEV₁.

Having BDR defined from absolute change was biased toward men (male to female ratio, 2.70) and toward those with larger baseline FEV₁. BDR defined by % change from baseline was biased toward those with lower baseline values. BDR defined by % predicted had no sex or size bias. Multivariate Cox regression found those with FEV₁ BDR > 8% predicted (33% of the subjects) had an optimal survival advantage (hazard ratio, 0.56; 95% CI, 0.45-0.69) compared with those with FEV₁ BDR ≤ 8% predicted. The survival of those with FEV₁ BDR > 8% predicted was not significantly different from that of those with FEV₁ BDR > 14% predicted but was significantly better than that of those with FEV₁ BDR < 0.

We have shown that expressing FEV₁ BDR as % predicted avoids sex and size bias. FEV₁ BDR > 8% predicted showed optimal survival advantage and may be the most appropriate criterion to define clinically important reversibility.

Bronchodilator response has been noted in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response to β₂ agonists resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely to be far more common than is symptomatic bronchoconstriction with β₂ agonists, but no systematic studies have been done. We assessed the prevalence of paradoxical response in current and former smokers with and without COPD, and its radiological correlates and clinical implications.

Non-Hispanic white and African-American patients (aged 45–80 years) from a large multicentre study COPDGene were classified into two groups on the basis of a paradoxical response, defined as at least a 12% and 200 mL reduction in forced expiratory volume in 1 sec (FEV₁) or forced vital capacity (FVC), or both, after administration of a shortacting β₂ agonist (180 μg salbutamol).

Patients were recruited from January, 2008, to June, 2011. 9986 (96%) of 10 364 patients enrolled in the COPDGene study were included in the analysis population (mean age 59·6 years [SD 9·0]). Paradoxical response was noted in 453 (5%) of 9986 patients and the frequency was similar in patients with COPD (198 [4%] of 4439) and smokers without airflow obstruction (255 [5%] of 5547). Compared with white patients, a paradoxical response was twice as common in African-American patients (227 [7%] of 3282 vs 226 [3%] of 6704; p<0·0001). In the multivariate analyses, African-American ethnic origin (adjusted odds ratio 1·89, 95% CI 1·50–2·39; p<0·0001), less emphysema (0·96, 0·92–0·99; p=0·023), and increased wall-area percentage of the segmental airways (1·04, 1·01–1·08; p=0·023) were independently associated with a paradoxical response. A paradoxical response was independently associated with worse dyspnoea (adjusted β for Modified Medical Research Council Dyspnoea Scale 0·12 [95% CI 0·00 to 0·24]; p=0·05), lower 6 min walk distance (−45·8 [–78·5 to −13·2]; p=0·006), higher Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index (0·31 [0·19 to 0·43]; p<0·0001), and a greater frequency of severe exacerbations (increased by a factor of 1·35, 1·00–1·81; p=0·048).

Paradoxical response to β₂ agonists is associated with respiratory morbidity and is more common in African-Americans. These findings might have implications for the use of β₂agonists in some patients.

National Institutes of Health.

Although some studies show that IL-22 and IL-25 play critical roles in the pathogenesis of asthma, little is known about the systemic production of these cytokines. The aim of this study was to assay IL-22 and IL-25 in serum, in mitogen-activated whole blood (WB), and in mitogen-activated peripheral blood mononuclear cell (PBMC) cultures of patients with severe asthma.

In this cross-sectional study, a questionnaire was prepared to determine the severity of asthma. Through the questionnaire, information including clinical signs, clinical symptoms, and past medical history were acquired. Information collected allowed all patients who were active or ex-smokers to be excluded. A trained observer assessed airway reversibility, peak flowmetry, and spirometry in the remaining patients. Twenty-one patients and simultaneously, twenty age- and sex-matched healthy controls were selected. Sterile blood (10 ml) was taken from each study participant. Sera were isolated and anticoagulant blood used for WB and PBMC cultures and haematological tests. Phytohaemagglutinin and lipopolysaccharide (LPS) were used to activate WB and PBMC. The data from these two groups were compared using Student's t-test.

Although the total white blood cell count was elevated in the asthmatic group, other haematological indices, including IL-22 and IL-25 levels in the asthmatic group were not significantly (p > 0.05) different from controls.

The levels of IL-22 and IL-25 in patients with severe asthma are no higher than those of non-asthmatic individuals. Any major role for IL-22 and IL-25 in severe asthma is likely to be localised to the lungs and bronchial tissues.

La espirometría es la principal prueba de función pulmonar, y resulta imprescindible para la evaluación y el seguimiento de las enfermedades respiratorias. Su utilidad trasciende el ámbito de la neumología, adquiere una creciente importancia en atención primaria e incluso se han descrito aplicaciones fuera del campo de las enfermedades respiratorias. Por ello, este documento pretende servir de apoyo a todos los profesionales de la salud que utilicen la espirometría, proporcionando recomendaciones basadas en las mejores evidencias científicas disponibles.

Se propone una actualización de las indicaciones y contraindicaciones de la prueba. El documento establece recomendaciones sobre los requerimientos necesarios para los espirómetros convencionales y los equipos portátiles de oficina, así como sobre las medidas de higiene y de control de calidad de los espirómetros. Se definen los parámetros espirométricos que deben ser considerados, la realización de las maniobras, los criterios de aceptabilidad y repetibilidad de las medidas y su control de calidad. También se establece una propuesta para la presentación de los resultados y se recomienda una evaluación e interpretación acorde a la información generada en los últimos años. Por último, se consideran las líneas de adaptación e integración de la espirometría en el campo de las nuevas tecnologías.

Spirometry is the main pulmonary function test and is essential for the evaluation and monitoring of respiratory diseases. Its utility transcends the field of Respiratory Medicine, is becoming increasingly important in primary care and applications have even been described outside the field of respiratory diseases. This document is therefore intended to serve as support for all health professionals who use spirometry, providing recommendations based on the best scientific evidence available.

An update of the indications and contraindications of the test is proposed. The document sets out recommendations on the requirements necessary for conventional spirometers and portable office equipment, as well as on spirometer hygiene and quality control measures. Spirometric parameters that must be considered, performance of manoeuvres, criteria for acceptability and repeatability of measurements and their quality control are defined. A proposal is also established for presentation of the results and an evaluation and interpretation is proposed according to information generated in recent years. Finally, lines of adaptation and integration of spirometry in the field of new technologies are considered.