Author's response to reviews

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1 Author's response to reviews Title: Vital capacity and inspiratory capacitiy as additional parameters to evaluate bronchodilator response in asthmatics patients: a cross section study Authors: Karen S Azevedo (karensodre@hotmail.com) Ronir R Luiz (ronir@iesc.ufrj.br) Patricia RM Rocco (prmrocco@biof.ufrj.br) Marcus B Conde (marcusconde@hucff.ufrj.br) Version: 2 Date: 28 June 2012 Author's response to reviews: see over

2 June 28 th, 2012 Dear Prof. Timothy Shipley MS: : Vital capacity and inspiratory capacity as additional parameters to evaluate bronchodilator response in asthmatics patients: a cross section study. Thank you very much for the opportunity to revise our submission to BMC Pulmonary Medicine. The text has been carefully revised according to the reviewers suggestions. We would like to express our gratitude to the assessors; their thorough work really helped us improve the manuscript. We hope that in its present form the paper can be accepted for publication in BMC Pulmonary Medicine. Karen S. Azevedo, MD. Chief, Laboratory of Pulmonary Function Test Institute of Thoracic Diseases Federal University of Rio de Janeiro Tel/fax: marcusconde@hucff.ufrj.br

3 Reviewer 1: Reviewer's report Title: Vital capacity and inspiratory capacitiy as additional parameters to evaluate bronchodilator response in asthmatics patients: a cross section study Version: 1 Date: 13 March 2012 Reviewer: Christophe Delclaux Reviewer's report: The aim of this study was to evaluate the usefulness of vital capacity and inspiratory capacity to evaluate bronchodilator response in asthma patients with persistent airflow obstruction. Clearly, the evaluation of bronchodilator response deserves to be studied in these patients. Thank you very much for your comments. Major comments 1. Why were the patients divided into two small groups, based on non consensual cutoff levels of FEV1? The ATS/ERS consensus defines severity of any spirometric abnormality based on the FEV1: Mild <70, Moderate 60 69, Moderately severe 50 59, Severe and Very severe <35% predicted. The authors should at least justify their choice based on a pathophysiological background. We agree with your comment. However, we divided the patients into 2 groups based on GINA (2006, the year we started collect these data) that classified severity based on clinics data and on cut-off levels of FEV1: moderate (60%<FEV1<80%) and severe (FEV1 60%). Furthermore, it has already been suggested that higher degree of obstruction is associated with more hyperinflation and consequently an increase volume response after bronchodilators. Based on this aforementioned we analyzed if the response in VC and IC was more intense in patients with severe obstruction compared to moderate. We justified our choice in the test, as suggested by the reviewer. 2. The effect of treatments on resting dyspnea is a difficult issue. Most patients with severe obstruction do not complain of resting dyspnea usually, and it has been shown that perceived effect of treatment is mainly related to the increase in forced inspiratory flows (Taube C, AJRCCM, 2000). I m surprised by the baseline resting values of Borg scores given in Table 2 that seems quite elevated (VAS instead of Borg?, please clarify). The authors state that the gold standard for clinical bronchodilator response was 6MWD # 50 meters or at least 30 meters associated with a reduction greater than 2 points in the Borg scale score. They would better state that they defined clinical bronchodilator response as because in ref 23 the distance was 54 meters (95% CI: 37 to 71 m) and the ref 5 is not available in PubMed. Moreover, the well-demonstrated learning effect of 6MWT should have been at least discussed (ideally patients should have two 6MWT before bronchodilation, this limitation should be discussed). Tel/fax: marcusconde@hucff.ufrj.br

4 We agree with the reviewer that the effect of treatments on resting dyspnea is a difficult issue. In fact, in patients with severe airway obstruction it has been reported that FEV1 presents a lack of sensitivity to evaluated improvement of dyspnea and exercise tolerance. Baseline resting dyspnea was evaluated using Borg score (0 to 10). In order to evaluate the clinical bronchodilator response in the 6WT, we used the ATS statement (ref 20: 6MWD > 50 meters corrected in the text) associated to criterions tested on ref 5. This journal is available in PubMed since 2006 as J Bras Pneumol. The ATS statement refers that practice test is not needed in most clinical settings and that the reproducibility of the 6MWD is excellent. The manuscript was modified to better clarify this point. 3. Statistical analyses: Since Mann-Whitney test was used for quantitative data, it suggests that variables were not normally distributed. Spearman rank correlation would be preferred (instead of Pearson) and expression of the results as median [interquartile] would have been better. The effect of bronchodilation on pulmonary function tests would be evaluated using Wilcoxon test. It seems to me quite useless to compare the results of the two groups since these two groups have been selected based on their level of obstruction. I apologize for this mistake. Indeed, Spearman rank correlation test was used instead of Pearson. Tables 1/2/3 are now modified and data presented as median (interquartile). Additionally, the information regarding the effect of the bronchodilator on pulmonary function tests are now added. There were significant changes in VC, IC, FVC, FEV1, 6WTD and Borg Scale in both groups and a significant change in RV/TLC in severe group (p values are now added in tables 2/3). 4. Table 3. The correlations tested are meaningless. For instance, if the RV/TLC ratio decreases after bronchodilation, an increase in VC is expected (the absence of correlation would be amazing! (one limitation is that absolute volumes were evaluated by dilution technique) (Table 4) The correlation between the variation in VC and RV/TLC ratio was 0.7 in severe group. Unfortunately we were not able to use plethysmograph when the study was performed. Minor comments 1. Airflow limitation definition: since patients up to 76 years were enrolled, it is important to ensure that all patients had airflow limitation. What was the criterion defining airflow limitation? Tel/fax: marcusconde@hucff.ufrj.br

5 This is a very important point. Thank you for your comment. In the current study, we used the recommendations of GINA that considered FEV1 values below 80% to define function abnormality in patient with asthma. If we used the ATS/ERS consensus, [obstruction definition (FEV1/VC < 5 th percentile of predicted)] 2 patients did not fulfill the criterion for airflow limitation, although they had FEV1 values below 80%, respectively 79 an 69%. 2. Table 1: treatments should be given according to usual criteria, ICS, short-acting beta-agonists, long-acting, etc. Modified accordingly. 3. Table 1: X-Ray (normal/abnormal): it seems to me not useful since a normal X-Ray is expected in asthmatic patients Modified accordingly. 4. Table 1: 6-min walk distance should be given Overall the results should be simplified and should focus on the main results. : The results of 6-min walk test are now presented in a separate table (Table 3). Level of interest: An article of limited interest Quality of written English: Acceptable Statistical review: Yes, and I have assessed the statistics in my report. Declaration of competing interests: I declare that I have no competing interests Reviewer 2: Reviewer's report Title: Vital capacity and inspiratory capacitiy as additional parameters to evaluate bronchodilator response in asthmatics patients: a cross section study Version: 1 Date: 2 May 2012 Reviewer: Claudio Tantucci Reviewer's report: In a population of stable asthmatic patients with persistent airflow obstruction, after adequate wash out from bronchodilators, the Authors assessed the acute changes of FEV1 and FVC, but also those of IC and VC and their respective relationships with Tel/fax: marcusconde@hucff.ufrj.br

6 exercise capacity (m) and dyspnea (VAS) during a 6-minute walking test (6MWT) after the administration of 400 mcg of salbutamol (MDI). Despite a mild increment of FEV1, they found a significant and clinically relevant increase in FVC and VC in the group of patients with more severe baseline airway obstruction. Changes in VC were related to RV/TLC changes and were in agreement with improved exertional dyspnea. Thank you very much for your comments. General comments It is well known that in chronic asthma characterized by airway remodeling and mostly in severe chronic asthma where peripheral airways are more markedly involved, the acute change in FEV1 (so called flow response) although statistically significant often does not reach the cut-off for a positive broncho-reversibility test after SA bronchodilator. In contrast, a statistically significant and clinically positive acute change in FVC (so called volume response) after SA bronchodilator can be found in these patients: a functional behavior similar to that observed in most COPD patients. This is exactly what was found by the Authors who, in addition, showed similar changes in VC. No doubt that VC changes are more closely related to RV(plethysmographic) and RV/TLC (plethysmographic) ratio changes than FVC changes. The lung volume measurements performed by the Authors using a dilutional multibreath method and referred only in terms of TLC and RV/TLC ratio before and after bronchodilator, especially in patients with severe obstruction, are always difficult to interpret (because these volumes can decrease or increase), as well as their relationship with the changes of VC or FVC. Thank you very much for your comments. The variation of the RV/TCL ratio to analyze the rank correlation was used due to two reasons. First, the RV/TLC has been considered the static lung volume that was better correlated with the variation in spirometric parameters. Second, changes in TCL have not been expected after the bronchodilator in patients with asthma. Based on our data, the variation in TLC after the bronchodilator was not significant (p=0.80 in group 1 e p=0.38 in group 2 - additional data Table 2). Furthermore, the median values of TLC were normal in the 2 groups, both before and after bronchodilator. Reviewer The acute IC changes after bronchodilator are more interesting. In average, they seem significant (?) in the group with more severe asthma, but perhaps are not clinically relevant according to the predefined cut-off (?) in each patient. In any case the IC changes do not agree with the exertional dyspnea improvement, while the VC changes do. This is surprising and more than the agreement I would like to see the correlation between #VC and #IC vs #VAS. Tel/fax: marcusconde@hucff.ufrj.br

7 This is a very important point. In fact, IC presented significant changes in both moderate (p value = 0.02) and severe (p value < 0.01) patients. These data are not added in Table 2. Additionally the IC median values were different between the 2 groups (lower in severe obstruction patients both before and after bronchodilator). The correlation between VC and IC vs VAS was analyzed according to your suggestion and a poor correlation between VC and VAS (0.35) was found in severe obstruction patients. Additionally, we found a poor correlation between IC and VAS (0.28). These data were added in the text (results). Reviewer: Specific comments Background I wouldn t say that bronchodilators are the drug of choice for asthma management! This sentence is now modified according to your suggestion. Methods The technique used to measure lung volumes should be detailed in the Method section. The technique is now described in Method section. Which is the criterion for defining a positive bronchodilator FEV1 response: 12 % of predicted value or 12 % of baseline value plus 200 ml? Please, specify. The criterion for defining a positive bronchodilator FEV1 response is 12% of baseline value plus 200ml (ATS/ERS/2005). The text is now corrected. Results The RV values should be added in the Table 2. Modified as suggested. In Table 2 also the significance between pre- and post-bronchodilator values should be written for the different variables in both groups of asthmatics. Tel/fax: marcusconde@hucff.ufrj.br

8 Modified as suggested. Again, I would like to see the correlation between #VC and #IC vs #VAS shown in a figure. Modified as suggested. Level of interest: An article whose findings are important to those with closely related research interests Quality of written English: Needs some language corrections before being published Statistical review: No, the manuscript does not need to be seen by a statistician. Declaration of competing interests: I declare that I have no competing interests. Tel/fax: marcusconde@hucff.ufrj.br