THE AUTHORS REPLY

THE AUTHORS REPLY We thank Griffin et al. (1) and Yew et al. (2) for their interest in our article (3). Griffin et al. (1) commented on some factors that could potentially confound the results of our study, one of which is the inadequacy of using level of education as a proxy for socioeconomic status. They suggested that information on housing conditions or overcrowding should have been utilized because these conditions increase the likelihood of exposure to and spread of tuberculosis (TB). Unlike some countries in which public housing was established to provide housing for low-income families, in Singapore a huge majority of residents reside in the public housing flats that they own. Before the 1960s, many people were living in unhygienic slums and crowded squatter settlements because of the shortage of housing; the Singapore Housing & Development Board was set up in 1960 to solve the housing crisis and provide Singaporeans with affordable housing equipped with clean sanitation by building blocks of flats that residents could own. These blocks of flats were clustered in neighborhoods that were then grouped in housing estates designed to be self-sustainable on a satellite town concept, with schools, supermarkets, clinics, hawker centers, and sports and recreational facilities to take care of educational, health-care, and recreational needs. Even today, more than 80% of Singapore’s residents live in such flats in public housing estates (4). Information regarding housing conditions or overcrowding was not collected in our interviews, and we acknowledge that this is a limitation of our study. However, because the recruitment of study participants had been restricted to only those who were residing in public housing estates, there may not be substantial differences between the housing conditions of our study participants and those of the general public that could have affected the likelihood of TB infection. Griffin et al. also commented that it may be worth examining human immunodeficiency virus (HIV) status among our study population (1). The prevalence of HIV in Singapore was approximately 1,364 per 1 million persons in the year 2015, and the highest age-specific rates were in people of 30–59 years of age, who are much younger than the participants in our cohort (5). Hence, although we did not have information on the HIV statuses of our participants, any confounding effect resulting from lack of adjustment for HIV status in this cohort is likely to have a negligible impact on the observed associations because the number of participants in our cohort who are HIV positive is likely to be very small. Griffin et al. also suggested examining drug-resistant TB in our cohort (1). Unfortunately, we did not have information on the drug resistance of the TB cases in our cohort. In Singapore, routine drug susceptibility testing is performed for all patients with culture-positive TB. In 2015, of the incident new, culture-positive pulmonary TB cases among Singapore residents, 5.9% were resistant to 1 drug, 1.0% were resistant to more than 1 drug, and only 0.7% were resistant to multiple drugs (i.e., resistant to at least rifampicin and isoniazid) (5). To date, there has been no case of extensively drug-resistant TB among Singapore-born patients (5). With such a small number of drug-resistant TB cases among the resident population in Singapore, our cohort would not be suitable for an examination of research questions pertaining to drug-resistant TB. Yew et al. made a comprehensive summary of the potential mechanisms by which vitamin A could play a role in TB reactivation and also mentioned controversies in the literature on the pro- or antioxidative effects of vitamin A (2). In the studies that they referenced, the antioxidative effect of vitamin A has been demonstrated in humans and mice (6, 7), whereas studies conducted using rat models showed that vitamin A supplementation enhanced oxidative stress (8, 9). Whether the differential effect in the pro- or antioxidative properties of vitamin A lies in the different metabolic pathways in different organisms, the different dose administered in various studies, or the different tissues examined (e.g., serum, organ, skeletal muscle) remains to be elucidated. The reduced risk of active TB with increased vitamin A intake in our cohort was similar among never and current smokers, and this suggests that the protective association is likely contributed by antimycobacterial effects besides the modulation of oxidative stress. Vitamin A has been shown to mediate antimicrobial mechanism against Mycobacterium tuberculosis via the regulation of Niemann-Pick disease type C2 gene (NPC2) expression to reduce cellular cholesterol (10), an important molecule for phagocytic entry and intracellular survival of mycobacteria (11). Consistent with this finding, we have also reported higher dietary intake of cholesterol to be associated with a higher risk of developing active TB in our cohort (12). Although vitamin A can also enhance immune responses (13), Yew et al. noted that immune modulation with vitamin A may differ in the steady and inflammatory states. With the huge complexity in the role of vitamin A in modulating oxidative, antimycobacterial, and immune pathways, this warrants further research, both experimental and clinical, to have a deeper understanding of the underlying mechanisms by which vitamin A administration can potentially reduce the incidence of active TB. Acknowledgments Conflict of interest: none declared. References 1 Griffin I , Algarin A , White S , et al. . Re: “Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort study” [letter]. Am J Epidemiol . 2018 ; 187 ( 7 ): 1571 – 1572 2 Yew WW , Chan DP , Leung CC , et al. . Re: “Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort study” [letter]. Am J Epidemiol . 2018 ; 187 ( 7 ): 1570 – 1571 . 3 Soh AZ , Chee CBE , Wang YT , et al. . Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort study . Am J Epidemiol . 2017 ; 186 ( 4 ): 491 – 500 . Google Scholar CrossRef Search ADS PubMed 4 Housing & Development Board . Public Housing – A Singapore Icon. Singapore, Republic of Singapore : Housing & Development Board ; 2015 . http://www.hdb.gov.sg/cs/infoweb/about-us/our-role/public-housing--a-singapore-icon. Updated October 26, 2015. Accessed November 22, 2017. 5 Singapore Ministry of Health . Communicable Diseases Surveillance in Singapore 2015. https://www.moh.gov.sg/content/moh_web/home/Publications/Reports/2016/communicable-diseases-surveillance-in-singapore-2015.html. Singapore, Republic of Singapore : Singapore Ministry of Health ; 2015 . Accessed November 22, 2017. 6 Meerza D , Iqbal S , Zaheer S , et al. . Retinoids have therapeutic action in type 2 diabetes . Nutrition . 2016 ; 32 ( 7–8 ): 898 – 903 . Google Scholar CrossRef Search ADS PubMed 7 Schwarz KB , Cox JM , Sharma S , et al. . Possible antioxidant effect of vitamin A supplementation in premature infants . J Pediatr Gastroenterol Nutr . 1997 ; 25 ( 4 ): 408 – 414 . Google Scholar CrossRef Search ADS PubMed 8 Gasparotto J , Petiz LL , Girardi CS , et al. . Supplementation with vitamin A enhances oxidative stress in the lungs of rats submitted to aerobic exercise . Appl Physiol Nutr Metab . 2015 ; 40 ( 12 ): 1253 – 1261 . Google Scholar CrossRef Search ADS PubMed 9 Petiz LL , Girardi CS , Bortolin RC , et al. . Vitamin A oral supplementation induces oxidative stress and suppresses IL-10 and HSP70 in skeletal muscle of trained rats . Nutrients . 2017 ; 9 ( 4 ): E353 . Google Scholar CrossRef Search ADS PubMed 10 Wheelwright M , Kim EW , Inkeles MS , et al. . All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2 . J Immunol . 2014 ; 192 ( 5 ): 2280 – 2290 . Google Scholar CrossRef Search ADS PubMed 11 de Chastellier C , Thilo L . Cholesterol depletion in Mycobacterium avium-infected macrophages overcomes the block in phagosome maturation and leads to the reversible sequestration of viable mycobacteria in phagolysosome-derived autophagic vacuoles . Cell Microbiol . 2006 ; 8 ( 2 ): 242 – 256 . Google Scholar CrossRef Search ADS PubMed 12 Soh AZ , Chee CB , Wang YT , et al. . Dietary cholesterol increases the risk whereas PUFAs reduce the risk of active tuberculosis in Singapore Chinese . J Nutr . 2016 ; 146 ( 5 ): 1093 – 1100 . Google Scholar CrossRef Search ADS PubMed 13 Stephensen CB . Vitamin A, infection, and immune function . Annu Rev Nutr . 2001 ; 21 : 167 – 192 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Epidemiology Oxford University Press

THE AUTHORS REPLY

American Journal of Epidemiology , Volume Advance Article (7) – Jan 12, 2018

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Abstract

We thank Griffin et al. (1) and Yew et al. (2) for their interest in our article (3). Griffin et al. (1) commented on some factors that could potentially confound the results of our study, one of which is the inadequacy of using level of education as a proxy for socioeconomic status. They suggested that information on housing conditions or overcrowding should have been utilized because these conditions increase the likelihood of exposure to and spread of tuberculosis (TB). Unlike some countries in which public housing was established to provide housing for low-income families, in Singapore a huge majority of residents reside in the public housing flats that they own. Before the 1960s, many people were living in unhygienic slums and crowded squatter settlements because of the shortage of housing; the Singapore Housing & Development Board was set up in 1960 to solve the housing crisis and provide Singaporeans with affordable housing equipped with clean sanitation by building blocks of flats that residents could own. These blocks of flats were clustered in neighborhoods that were then grouped in housing estates designed to be self-sustainable on a satellite town concept, with schools, supermarkets, clinics, hawker centers, and sports and recreational facilities to take care of educational, health-care, and recreational needs. Even today, more than 80% of Singapore’s residents live in such flats in public housing estates (4). Information regarding housing conditions or overcrowding was not collected in our interviews, and we acknowledge that this is a limitation of our study. However, because the recruitment of study participants had been restricted to only those who were residing in public housing estates, there may not be substantial differences between the housing conditions of our study participants and those of the general public that could have affected the likelihood of TB infection. Griffin et al. also commented that it may be worth examining human immunodeficiency virus (HIV) status among our study population (1). The prevalence of HIV in Singapore was approximately 1,364 per 1 million persons in the year 2015, and the highest age-specific rates were in people of 30–59 years of age, who are much younger than the participants in our cohort (5). Hence, although we did not have information on the HIV statuses of our participants, any confounding effect resulting from lack of adjustment for HIV status in this cohort is likely to have a negligible impact on the observed associations because the number of participants in our cohort who are HIV positive is likely to be very small. Griffin et al. also suggested examining drug-resistant TB in our cohort (1). Unfortunately, we did not have information on the drug resistance of the TB cases in our cohort. In Singapore, routine drug susceptibility testing is performed for all patients with culture-positive TB. In 2015, of the incident new, culture-positive pulmonary TB cases among Singapore residents, 5.9% were resistant to 1 drug, 1.0% were resistant to more than 1 drug, and only 0.7% were resistant to multiple drugs (i.e., resistant to at least rifampicin and isoniazid) (5). To date, there has been no case of extensively drug-resistant TB among Singapore-born patients (5). With such a small number of drug-resistant TB cases among the resident population in Singapore, our cohort would not be suitable for an examination of research questions pertaining to drug-resistant TB. Yew et al. made a comprehensive summary of the potential mechanisms by which vitamin A could play a role in TB reactivation and also mentioned controversies in the literature on the pro- or antioxidative effects of vitamin A (2). In the studies that they referenced, the antioxidative effect of vitamin A has been demonstrated in humans and mice (6, 7), whereas studies conducted using rat models showed that vitamin A supplementation enhanced oxidative stress (8, 9). Whether the differential effect in the pro- or antioxidative properties of vitamin A lies in the different metabolic pathways in different organisms, the different dose administered in various studies, or the different tissues examined (e.g., serum, organ, skeletal muscle) remains to be elucidated. The reduced risk of active TB with increased vitamin A intake in our cohort was similar among never and current smokers, and this suggests that the protective association is likely contributed by antimycobacterial effects besides the modulation of oxidative stress. Vitamin A has been shown to mediate antimicrobial mechanism against Mycobacterium tuberculosis via the regulation of Niemann-Pick disease type C2 gene (NPC2) expression to reduce cellular cholesterol (10), an important molecule for phagocytic entry and intracellular survival of mycobacteria (11). Consistent with this finding, we have also reported higher dietary intake of cholesterol to be associated with a higher risk of developing active TB in our cohort (12). Although vitamin A can also enhance immune responses (13), Yew et al. noted that immune modulation with vitamin A may differ in the steady and inflammatory states. With the huge complexity in the role of vitamin A in modulating oxidative, antimycobacterial, and immune pathways, this warrants further research, both experimental and clinical, to have a deeper understanding of the underlying mechanisms by which vitamin A administration can potentially reduce the incidence of active TB. Acknowledgments Conflict of interest: none declared. References 1 Griffin I , Algarin A , White S , et al. . Re: “Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort study” [letter]. Am J Epidemiol . 2018 ; 187 ( 7 ): 1571 – 1572 2 Yew WW , Chan DP , Leung CC , et al. . Re: “Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort study” [letter]. Am J Epidemiol . 2018 ; 187 ( 7 ): 1570 – 1571 . 3 Soh AZ , Chee CBE , Wang YT , et al. . Dietary intake of antioxidant vitamins and carotenoids and risk of developing active tuberculosis in a prospective population-based cohort study . Am J Epidemiol . 2017 ; 186 ( 4 ): 491 – 500 . Google Scholar CrossRef Search ADS PubMed 4 Housing & Development Board . Public Housing – A Singapore Icon. Singapore, Republic of Singapore : Housing & Development Board ; 2015 . http://www.hdb.gov.sg/cs/infoweb/about-us/our-role/public-housing--a-singapore-icon. Updated October 26, 2015. Accessed November 22, 2017. 5 Singapore Ministry of Health . Communicable Diseases Surveillance in Singapore 2015. https://www.moh.gov.sg/content/moh_web/home/Publications/Reports/2016/communicable-diseases-surveillance-in-singapore-2015.html. Singapore, Republic of Singapore : Singapore Ministry of Health ; 2015 . Accessed November 22, 2017. 6 Meerza D , Iqbal S , Zaheer S , et al. . Retinoids have therapeutic action in type 2 diabetes . Nutrition . 2016 ; 32 ( 7–8 ): 898 – 903 . Google Scholar CrossRef Search ADS PubMed 7 Schwarz KB , Cox JM , Sharma S , et al. . Possible antioxidant effect of vitamin A supplementation in premature infants . J Pediatr Gastroenterol Nutr . 1997 ; 25 ( 4 ): 408 – 414 . Google Scholar CrossRef Search ADS PubMed 8 Gasparotto J , Petiz LL , Girardi CS , et al. . Supplementation with vitamin A enhances oxidative stress in the lungs of rats submitted to aerobic exercise . Appl Physiol Nutr Metab . 2015 ; 40 ( 12 ): 1253 – 1261 . Google Scholar CrossRef Search ADS PubMed 9 Petiz LL , Girardi CS , Bortolin RC , et al. . Vitamin A oral supplementation induces oxidative stress and suppresses IL-10 and HSP70 in skeletal muscle of trained rats . Nutrients . 2017 ; 9 ( 4 ): E353 . Google Scholar CrossRef Search ADS PubMed 10 Wheelwright M , Kim EW , Inkeles MS , et al. . All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2 . J Immunol . 2014 ; 192 ( 5 ): 2280 – 2290 . Google Scholar CrossRef Search ADS PubMed 11 de Chastellier C , Thilo L . Cholesterol depletion in Mycobacterium avium-infected macrophages overcomes the block in phagosome maturation and leads to the reversible sequestration of viable mycobacteria in phagolysosome-derived autophagic vacuoles . Cell Microbiol . 2006 ; 8 ( 2 ): 242 – 256 . Google Scholar CrossRef Search ADS PubMed 12 Soh AZ , Chee CB , Wang YT , et al. . Dietary cholesterol increases the risk whereas PUFAs reduce the risk of active tuberculosis in Singapore Chinese . J Nutr . 2016 ; 146 ( 5 ): 1093 – 1100 . Google Scholar CrossRef Search ADS PubMed 13 Stephensen CB . Vitamin A, infection, and immune function . Annu Rev Nutr . 2001 ; 21 : 167 – 192 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

American Journal of EpidemiologyOxford University Press

Published: Jan 12, 2018

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