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BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay- per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 30, 2021 by guest. Protected copyright. BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017. Downloaded from BMJ Open Vitamin D status in tuberculosis patients with diabetes, pre- diabetes, and normal blood glucose in China ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2017-017557 Article Type: Research Date Submitted by the Author: 04-May-2017 Complete List of Authors: Zhao, Xin; Beijing Hospital, Laboratory Medicine Yuan, Yanli; Jilin Provincial Academy of Tuberculosis Control and Prevention, Director Office Lin, Yan; International Union Against Tuberculosis and Lung Disease, TB and HIV-China Zhang, Tiejuan; Jilin Provincial Academy of Tuberculosis Control and Prevention, Prevention and Treatment Ma, Jianjun; Jilin Provincial Academy of Tuberculosis Control and Prevention, Prevention and Treatment Kang, Wanli; Beijing Chest Hospital, Capital Medical University, Epidemiology; Beijing Tuberculosis and Thoracic Tumor Research Institute, Epidemiology Bai, Yunlong; Jilin Provincial Academy of Tuberculosis Control and http://bmjopen.bmj.com/ Prevention, Prevention and Treatment Wang, Yunlong; Meihekou City Tuberculosis Institute, Prevention and Treatment Shao, Hongshan; Dongfeng County Tuberculosis Institute, Treatment Dlodlo, Riitta; International Union Against Tuberculosis and Lung Diseases, TB and HIV Harries, Anthony; International Union against Tuberculosis and Lung Disease, TB and HIV; London School of Hygiene and Tropical Medicine <b>Primary Subject on September 30, 2021 by guest. Protected copyright. Infectious diseases Heading</b>: Secondary Subject Heading: Global health Keywords: Vitamin D, Tuberculosis < INFECTIOUS DISEASES, Diabetes, China For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017. Downloaded from Page 1 of 29 BMJ Open 1 1 2 3 Vitamin D status in tuberculosis patients with diabetes, pre-diabetes, 4 and normal blood glucose in China 5 6 7 Investigators and Institutions: 8 9 Xin Zhao1 10 11 2 12 Yanli Yuan 13 3 14 Yan Lin 15 For peer review only 16 Tiejuan Zhang2 17 18 Jianjun Ma 2 19 20 Wanli Kang4, 5 21 22 2 23 Yunlong Bai 24 6 25 Yunlong Wang 26 27 Hongshan Shao7 28 29 Riitta A. Dlodlo8 30 31 Anthony D. Harries9, 10 32 http://bmjopen.bmj.com/ 33 34 35 36 1 Beijing Hospital, Beijing, China 37 38 2Jilin Provincial Academy of Tuberculosis Control and Prevention, Changchun, China 39 40 3 International Union Against Tuberculosis and Lung Disease, Beijing, China on September 30, 2021 by guest. Protected copyright. 41 42 4 43 Beijing Chest Hospital, Capital Medical University, Beijing, China 44 5 45 Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China 46 47 6 Meihekou City Tuberculosis Institute, Meihekou, China 48 49 7 Dongfeng County Tuberculosis Institute, Dongfeng, China 50 51 8 52 International Union Against Tuberculosis and Lung Diseases, Bulawayo, Zimbabwe 53 9 54 International Union Against Tuberculosis and Lung Diseases, Paris, France 55 56 10 London School of Hygiene and Tropical Medicine, London, UK 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017. Downloaded from BMJ Open Page 2 of 29 2 1 2 3 Address for correspondence: 4 5 Professor Yan Lin, 6 7 6-1-151/152, No. 1 Xindonglu, Chaoyang District, Beijing 100600, China. 8 9 10 Telephone: +86 10 8532 1053; E-mail: [email protected] or 11 12 [email protected] 13 14 15 For peer review only 16 Details of Paper 17 18 19 Word Count of Abstract: 300 20 21 Word Count of the Full Paper: 2,614 22 23 References: 31 24 25 Tables: 4 26 27 Figures: 1 28 29 30 Short title: Vitamin D status in TB, pre-DM TB and DM-TB patients in China 31 32 Key words: Vitamin D; Tuberculosis; Diabetes, China http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 30, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017. Downloaded from Page 3 of 29 BMJ Open 3 1 2 3 ABSTRACT 4 5 OBJECTIVE: The association between tuberculosis (TB), diabetes (DM) and vitamin 6 7 D status is poorly characterised. We therefore: i) determined vitamin D status in TB 8 9 10 patients in relation to whether they had normal fasting blood glucose (FBG), pre-DM 11 12 or DM and ii) assessed whether baseline characteristics in TB patients with normal 13 14 FBG, pre-DM and DM status were associated with vitamin D deficiency. 15 For peer review only 16 METHOD: In TB patients consecutively attending six clinics or hospitals in China, 17 18 19 we measured 25 hydroxycholecalciferol [25-(OH)D3] at the time of registration using 20 21 electrochemiluminescence in a COBASE 601 Roche analyser by chemiluminescence 22 23 immunoassay. Data analysis was performed using the chi square test and multivariate 24 25 logistic regression. 26 27 RESULTS: There were 306 eligible TB patients, including 96 with smear positive 28 29 30 pulmonary TB, 187 with smear negative pulmonary TB and 23 with extra pulmonary 31 32 TB (EPTB). Of these, 95 (31%) had normal blood glucose, 83 (27%) had pre-DM and http://bmjopen.bmj.com/ 33 34 128 (42%) had DM. Median serum vitamin D levels were 16.1 ng/ml in TB patients 35 36 with normal FBG, 12.6 ng/ml in TB patients with pre-DM and 12.1 ng/ml in TB 37 38 39 patients with DM (P< 0.001). In TB patients with normal FBG, the odds of vitamin D 40 on September 30, 2021 by guest. Protected copyright. 41 deficiency (25-(OH)D3 <20 ng/ml) were significantly higher in patients with smear 42 43 negative TB (P=0.003), cigarette smokers (P=0.001) and the cold season (P<0.001). 44 45 Severe vitamin D deficiency (25-(OH)D3 < 10 ng/ml) was strongly associated with 46 47 living in a rural area for TB patients with pre-DM (P=0.043) and with being aged 60 48 49 50 years and over for DM-TB patients (P=0.031). 51 52 CONCLUSION: Vitamin D levels are lower in TB patients with pre-DM and DM and 53 54 are also affected by certain baseline characteristics including older age and rural 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017. Downloaded from BMJ Open Page 4 of 29 4 1 2 3 residence. TB programmes need to pay more attention to vitamin D status in their 4 5 patients, especially if there is co-existing pre-DM or DM. 6 7 8 9 10 STRENGTHS AND LIMITATIONS OF THIS STUDY 11 12 • In contrast to many previous studies on this subject in China, the current study 13 14 enrolled a large number of patients with tuberculosis who were consecutively 15 For peer review only 16 registered in the routine programme setting in urban and rural settings 17 18 19 • Rural settings were further divided into non-poverty and poverty areas to 20 21 assess the influence of this factor on 25-(OH)D3 levels 22 23 • Blood samples for measurement of 25-(OH)D3 were taken without collecting 24 25 detailed information about the patient’s history, and there is therefore no data 26 27 28 on duration of symptoms or signs which might have impacted on vitamin D 29 30 levels. 31 32 • The presence or absence of co-morbidities that affect vitamin D status http://bmjopen.bmj.com/ 33 34 depended on medical documentation or patient self-reports and these may 35 36 37 have been missed 38 39 • 25-(OH)D3 levels were only measured at one time before anti-TB treatment 40 on September 30, 2021 by guest. Protected copyright. 41 and therefore there is no information about whether these changed during the 42 43 six months course of anti-TB treatment 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-017557 on 25 September 2017.
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