Author s response to reviews Title: Asthma control and severe exacerbations in patients with moderate or severe asthma in Jilin Province, China: a multicenter cross-sectional survey Authors: Bing-di Yan (13504402490@163.com) Shan-shan Meng (mengshanshan0101@163.com) Jin Ren (renjin1980@163.com) Zheng Lv (28861541@qq.com) Qing-hua Zhang (ninozqh@126.com) Jin-yan Yu (yujinyan1988@163.com) Rong Gao (happygaorong@163.com) Chang-min Shi (scmchangchun@sina.com) Chun-feng Wu (feng1218@sohu.com) Chun-lin Liu (774902072@qq.com) Jie Zhang (doctorzhangj@sina.com) Zhong-sen Ma (13331770808@163.com) Jing Liu (liujing020901@163.com) Version: 1 Date: 17 Jul 2016 Author s response to reviews: Reviewer #1: The paper reports interesting data on asthma exacerbations in a follow-up in China, adding important information on treatment adhesion and socio economical aspects in the analyzed region. Anyway I think AA need to improve the paper, particularly on statistical analysis. M&M
Does AA mean allergic asthma (or atopic asthma)? I agree with that AA is an important factor for the analysis of asthma exacerbation. We reviewed the medical records of patients and supplemented the atopic status (with clear allergic history or positive specific IgE or positive skin prick test) of patients. We found that 567 (36.67%) patients had atopic status (data was shown in table2 line 6), but atopic status of patients was not risk factor for severe asthma exacerbation in the follow-up period (data was shown in table4, line 27). Patients enrolled: did they were "consecutively" enrolled? Please specify. Yes, the asthmatic patients were enrolled consecutively depending on the following inclusion criteria in five hospitals in this multi-center, cross-sectional study. The revise was shown in page 5 line 6-7. page 5 line 28: 5 grade 1: do you intend 5 hospital with grade 1? Please modify to permit a better comprehension of the text. Thanks for checking carefully. In fact, we intend 5 hospitals with grade 3. The comprehension and revise was shown in page 6, line4 and page 6, line 9-10. page 7 line 59: month was... on regular review (better use control) We think that it is easy to confuse with asthma control (grades of asthma control), so regular review had been used here. Univariate and multivariate analysis: it is not clear in the table 4 and 5 what analysis was performed. Do you control for age and sex? I suggest to report data on univariate analysis and then multivariate analysis considering in the model age and sex (or adjusting for them). This is a good question. In fact, we had performed a univariate analysis firstly to filtrate the significant risk factors for severe asthma exacerbation (Data was shown in table4). And then a
multivariate analysis was conducted using binary logistic regression (Forward: LR), with the significant factors identified from the univariate analysis(data was shown in table 5). The effect of sex had been excluded in univariate analysis (table 4, line 15), and Older>60 years old was risk factor for severe exacerbation of asthma in univariate analysis (table 4, line 16), but it became insignificant in multivariate analysis with P>0.05. That is the reason that age and sex was not shown in table 5. It would be interesting to insert in the statistical analysis the role of different occupations and atopic status (if available). We have supplemented the statistical analysis about the role of different occupations and atopic status by univariate analysis.( The revise was shown in table 4 line 20-23 and line 27). Tables: in the title you report N (%) than in the text of the table you report data as 67/4.33 Thanks for checking carefully. It has been modified to N / %. (The revise was shown in table1-3 ) Discussion: I suggest to improve discussion on the need that important drugs for asthma treatments must be free to permit to all patients to avoid the worsening of the disease and the recurrent exacerbations. The adherence to the therapy is a crucial point in every countries, also where drugs are available for free for patients with low income. These aspects need to be better discussed. Our study revealed that lower income and education, and medical insurance with low reimbursement ratio were main risk factors for poor adherence of asthma treatment, and 71.48 % of patients stopped the therapy of ICS/(ICS+LABA)/(ICS+LAMA) ahead of schedule, because of expensive price of medicines. So reduced out-of-pocket expenses or free drugs may improve medication adherence from the government level. Otherwise, 45.89% of asthma patients used other drugs to instead of ICS/(ICS+LABA)/(ICS+LAMA), for example theophylline, which has been recently shown to have anti-inflammatory effects in asthma at lower concentrations, is used commonly in China for cheaper price. Meanwhile, some traditional Chinese medicine had been used irregularly. So a multi-center, cross-sectional study about certain cheaper drugs for asthma control to improve adherence to self-administered medications should be designed well in further.
The revise was shown in page12, line 19-22 and page 13, line1-9. Reviewer #2: Follow-up data on asthma control, asthma medication and severe asthma exacerbation revealed that only 8.66% of the patients kept in touch with physicians and reviewed regularly. The percentage of patients taking a pulmonary function test, utilizing PFM and writing in an asthma diary regularly were 7.87%, 3.60% and 5.29%, respectively. Only 38.47% of the patients took ICS/(ICS+LABA)/(ICS+LAMA) regularly for longer than 3 months after discharge regardless of whether they had received asthma education or low. Adherence to treatment is very low and unsatisfactory. What is the reason for this poor performance?a poor education to the management of asthma?a poor education to regular treatment?medical insurance?difficult access to drugs and structures? voluntary choice of the patients do not take drugs and not to go to the visits? Above questions are very good. The reasons mentioned above may lead to poor adherence of asthma treatment. Our study revealed that lower income and education, medical insurance with low reimbursement ratio, female, older>60 years old, and following up irregularly were risk factors for usage of ICS/(ICS+LABA)/(ICS+LAMA)3 months (Data was shown in table 6). And from the answers of patients, we found that 71.48% of patients stopped the therapy of ICS/(ICS+LABA)/(ICS+LAMA) ahead of schedule, because of expensive price of medicines, and 46.62% of patients stopped the therapy, because that they felt subjectively their symptoms had been controlled (Data was shown in table 3 line 14-19). Associate Editor's comments Reviewer #3: Major points: 1) I suggest to focalize on asthma control and exacerbations avoiding any data/comment/table on ACOS. The "several features usually associated in COPD" (page 7, line 45) has not been described in the text. Thanks for the suggestion. Data, comment and table on ACOS have been deleted.
2) In Table 1 no data are reported concerning the etiology of asthma (atopy, infection,...) in the hospedalized patients, so the role of etiological agents has not been evaluated as a risk factor of exacerbations at the follow-up. As a minor point I suggest also to modify the range of "Age" in order to evaluate the prevalence of patients according to similar number of years-old. We reviewed the medical records of patients and supplemented the atopic status (with clear allergic history or positive specific IgE or positive skin prick test) of patients. We found that 567 (36.67%) patients had atopic status (data was shown in table2 line 6), but atopic status of patients was not risk factor for severe asthma exacerbations in the follow-up period (data was shown in table4, line 27). The pneumonia, which reflected partly infection in lung, was analysis in table2, line 20 and table 4, line 29. For the suggest of range of age, would it be better to divide adult asthma patients into 20 years old, 20-40 years old, 41-60 years old, 61-80 years old and >80 years old? In this study, 70 patients older than 80 years old were enrolled (data was shown in table 1, line 6-7), but only 23 patients finished the following up. Because of the higher missing rate of patients with older than 80 years old, we analyzed the effect of aging (older than 60 years old) to severe asthma exacerbations and poor adherence of medicine. (data was shown in table 4 line 16 and table 6 line 6). Minor point: Figure 1, legend: please specify when ACT was measured. We test ACT in the middle and end of the follow up year, and get the mean value, which is better to reflect the level of asthma control in the whole year. (The revise was shown in figure legend). In Table 4 are reported risk factors for severe asthma exacerbation during the follow-up (12 months) and risk factors for application of ICS/LABA/LAMA in the following 3 months (547 cases). I suggest to delete the second section of the Table focusing on the main results (some reported risk factors are the same...). The Author have considered occupation or pollution or the season of exacerbation of asthma (i.e winter due to infection; spring-summer due to atopy). The effect of the center has been considered as a risk factor? Thanks for the suggestion, we had thought to delete the second part of table 4, but we need still the table to answer the questions from Reviewer #2. So, we put this section on table 6.( or as supplementary table 1, if it is more suitable for the journal). The effect of occupation on severe asthma exacerbation had been analyzed in table4 (shown in table 4 line 20-23). We had supplemented the atopic status (with clear allergic history or positive
specific IgE or positive skin prick test) of patients. We found that 567 (36.67%) patients had atopic status (data was shown in table2 line 6), but atopic status of patients was not risk factor for severe asthma exacerbations in the follow-up period (data was shown in table4, line 27). The comorbidity of pneumonia, which reflected partly infection in lung, was not associated with severe asthma exacerbations in the follow-up period (data was shown in table2, line 20 and table 4, line 29). It is difficult to evaluate the effect of season and airway infection on severe asthma exacerbation each time, because we collected the data of severe asthma exacerbations of patients in follow up visit per three months retrospectively, but not immediately when the acute exacerbations happened. And some information in detail was not complete because the hospitalization and emergency department visit of patients were not in original hospitals sometimes. Otherwise, it is difficult to evaluate the infection situation each time, due to the partly abuse of antibiotics in China. Thus, increasing the frequency of follow-up visits and establishing the network of hospitals with different grades would be solutions (the revise was shown in page14, line 1-13). At last, the effect of the center on severe asthma exacerbations of patients in follow-up period was not significant (p>0.05) with Chi-squared test.