LETTERS Reply From the Author: I am grateful to Baker and colleagues for their kind remarks concerning my recent editorial (1, 2) Here, Baker and colleagues distance themselves from the editorial’s primary conclusion, that foreign-born individuals should be targeted for latent tuberculosis infection (LTBI) testing and treatment regardless of time of residence in the United States. They instead focus on a statement from the editorial that is incompletely quoted: “reluctance to change this recommendation [LTBI treatment based on residency duration] is due to concern about drug toxicity in older individuals.” The verbatim quote is, “If the reluctance to change this recommendation is due to concern about drug toxicity in older individuals, it would be instructive to analyze U.S. immigrants from Mexico stratified by age and time since entry into the U.S. It may well be that the majority of these individuals are relatively young” (1). The statement in its entirety was intended as a hypothetical example of just one of perhaps many scenarios that might assuage concerns over broadening LTBI treatment for foreign-born persons in the United States. It was also clearly conditional and not intended as an unqualified endorsement for any specific policy. The abbreviated statement suggests an advocacy that was not the original intent of the full comment but is used to drive subsequent comments by Baker and colleagues. They do, in fact, provide the requested information about the numbers of Mexico-born persons younger than 35 years living in the United States for more than 5 years. Although not making up the majority of the group, there are still 3.9 million of these individuals, accounting for 38% of all Mexico-born persons who have lived in the United States for more than 5 years. The subsequent discussion begins with a persuasive argument against limiting testing on an age-specific basis because of treatment safety concerns, which specifically addresses their objections to the hypothetical scenario I proposed and could be seen as supportive of the editorial’s primary conclusion. However, Baker and colleagues then address their real objections to the editorial’s conclusions and argue that if residency duration restrictions were discontinued, the U.S. healthcare infrastructure would be inadequate for screening and treating all newly eligible

Seasonality and Total 25-Hydroxyvitamin D Levels as Sources of Potential Misclassification of Vitamin D Deficiency To the Editor: The Western Australian Pregnancy (Raine) cohort that measured serum 25-hydroxyvitamin D levels from a subset of mothers from a longitudinal community-based study (n = 929) has provided Zosky and colleagues with a unique opportunity to examine relationships among prenatal vitamin D deficiency, asthma, and reductions in lung function for offspring when they are 6 and 14 years old (1). The main findings included a modest reduction in FVC in a combined analysis of 6-year-old boys and girls in


persons. Further, they argue that eliminating the residency duration criterion for LTBI testing and treatment in foreign-born individuals would leave a “prioritization vacuum” for providers. Perhaps inadvertently, Baker and colleagues provide a possible solution to these latter concerns, harking back to the quoted statement. I concede that safety of LTBI treatment in foreign-born individuals is not a justification for age-specific targeted testing. However, if an age cutoff of 35 years were used for Mexico-born persons residing in the United States for more than 5 years, fully 3.9 million persons, or 38% of the potentially eligible pool, would become candidates for targeted testing. If the Mexico-born figures can be extrapolated to the foreign-born population in the United States as a whole, that same 38% would become a significantly larger number of persons eligible for LTBI testing and treatment, but not so many, hopefully, as to overwhelm U.S. healthcare capacity. Targeting foreign-born persons who have been in the United States more than 5 years and who are younger than 35 years would also provide a well-defined prioritization structure. Baker and colleagues note “an urgent need to identify a practical, prioritized public health approach to [LTBI] among foreign-born persons.” Until better approaches are identified, why not target 38% of all foreign-born persons younger than 35 years who have been in the United States more than 5 years? It may not be the best or final solution, but it will significantly expand LTBI testing and treatment in the most important population contributing to U.S. tuberculosis morbidity. Author disclosures are available with the text of this letter at www.atsjournals.org. David E. Griffith, M.D. University of Texas Health Science Center Tyler, Texas

References 1 Griffith DE. Testing for latent tuberculosis: applying the best of intentions [editorial]. Ann Am Thorac Soc 2014;11:594–595. 2 Baker BJ, Jeffries CD, Moonan PK. Decline in tuberculosis among Mexico-born persons in the United States, 2000-2010. Ann Am Thorac Soc 2014;11:480–488. Copyright © 2014 by the American Thoracic Society

association with an increased asthma association for boys, neither of which were evident at age 14 years. As the authors measured total 25-hydroxyvitamin D levels and did not take seasonal variation into account, residual confounding might have contributed to the earlier findings. Exposure to ultraviolet B radiation provides the main source of vitamin D, so circulating levels can decrease with lesser sun exposure in the absence of supplementation, particularly in regions of maximum latitude. Even for South Florida, which is usually warm and sunny all year round (latitude 25.468 N), compared with levels measured in winter, serum 25-hydroxyvitamin D levels during the summer months were still significantly increased, going up by 14.8% and 13% for participating men and women, respectively (2). As Perth in Western Australia is at a latitude

AnnalsATS Volume 11 Number 8 | October 2014

LETTERS of 31.958 S, even greater variations in seasonal levels might be expected with the potential to misclassify cases of maternal vitamin D deficiency. The Avon Longitudinal Study of Parents and Children, which prospectively measured 25-hydroxyvitamin D levels from a subset of at least 7,700 pregnant women in the southwest of England, found seasonal effects with regard to lung function outcomes for offspring with a mean age of 8.7 years (3). Reductions in the minimally adjusted mean difference for FEV1 and FVC were observed for the lowest compared with the highest quintile of 25-hydroxyvitamin D; however, no differences remained after adjusting for seasonality. The adjustment did not change the null result for asthma. In addition, it is now appreciated that estimated levels of bioavailable 25-hydroxyvitamin D may be more appropriate than the total level, at least with regard to bone homeostasis. Between 85% and 90% of the total 25-hydroxyvitamin D is bound to vitamin D-binding protein, in contrast to the lesser but more functional non–vitamin D–binding protein fraction (4). Compared with white Americans, black Americans were estimated to have similar concentrations of this bioavailable fraction, as well as greater bone mineral density, in spite of the lower total and the correspondingly lower vitamin D–binding protein levels, which might be largely explained by two genetic polymorphisms. Although ethnicity-related data for native-born and migrant Australians are not yet available, a description of the ethnic mix of the Raine study participants might have been informative. This bioavailable form, which is likely to have a genetic basis and is unlikely to be proportionally related to total levels (4), raises the possibility of measurement error and a further source of misclassification of exposure categories. Bioavailable 25hydroxyvitamin D is distinct from the biologically active form, 1,25-dihydroxyvitamin D, and the influence of the latter with regard to the bioavailable form and mineral metabolism has not yet been established (4). A possible benefit of using the active metabolite over total 25-hydroxyvitamin D levels was acknowledged by the authors.

Adopting the use of bioavailable 25-hydroxyvitamin D levels with seasonal adjustment for exposure may prove advantageous when examining, for lung health, the effects of prenatal vitamin D deficiency. The inconsistencies of the current literature may relate in part to the variation of definitions for total 25-hydroxyvitamin D deficiency and variable inclusion of seasonality as a confounder (5) through its influence on the estimated strengths of association for asthma and lung function outcomes.


variations in ultraviolet radiation exposure, leading to annual fluctuations in circulating 25(OH)D levels (2). Seasonal fluctuations in population 25(OH)D levels have been used by many groups as a justification for seasonal adjustment of vitamin D levels in population health studies. However, for our study, seasonal adjustment of 25(OH)D is predicated on the assumption that it is a mother’s vitamin D levels relative to the population at a particular point during gestation, rather than the absolute values of vitamin D, that are important. We argue that normal physiological function requires an as-yetundetermined amount of circulating 25(OH)D to ensure the normal growth of the fetus. Our analysis was conducted with the understanding that having circulating levels of 25(OH)D , 25 nmol/L at 16–20 weeks’ gestation has an effect on postnatal lung function and the risk for asthma, irrespective of whether these low levels are experienced during summer, winter, autumn, or spring. This is consistent with international public health guidelines that specify a particular level of 25(OH)D for normal physiological function

From the Authors: We thank Perret and Lodge for considering the results of our study, in which we showed associations among maternal serum levels of 25-hydroxy vitamin D [25(OH)D], postnatal deficits in lung function, and asthma at 6 years of age (1). Perret and Lodge raised the possibility of two potential confounders that may have introduced additional variation and may explain between-study discrepancies in the link between maternal vitamin D levels and postnatal lung outcomes in children: no seasonal adjustment for 25(OH)D levels in our analysis and measurement of total 25(OH)D levels, as opposed to bioavailable levels. As pointed out by Perret and Lodge, our study was conducted in Perth, Australia, which experiences considerable seasonal Supported by National Health and Medical Research Council Project Grant 1042235 (G.R.Z.).


Author disclosures are available with the text of this letter at www.atsjournals.org. Jennifer L. Perret, M.B. B.S. Caroline J. Lodge, M.B. B.S., Ph.D. The University of Melbourne Melbourne, Victoria, Australia

References 1 Zosky GR, Hart PH, Whitehouse AJ, Kusel MM, Ang W, Foong RE, Chen L, Holt PG, Sly PD, Hall GL. Vitamin D deficiency at 16 to 20 weeks’ gestation is associated with impaired lung function and asthma at 6 years of age. Ann Am Thorac Soc 2014;11:571–577. 2 Levis S, Gomez A, Jimenez C, Veras L, Ma F, Lai S, Hollis B, Roos BA. Vitamin D deficiency and seasonal variation in an adult South Florida population. J Clin Endocrinol Metab 2005;90:1557–1562. 3 Wills AK, Shaheen SO, Granell R, Henderson AJ, Fraser WD, Lawlor DA. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43:1180– 1188. 4 Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013;369:1991–2000. 5 Sokol SI, Tsang P, Aggarwal V, Melamed ML, Srinivas VS. Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis. Cardiol Rev 2011;19:192–201. Copyright © 2014 by the American Thoracic Society


Seasonality and total 25-hydroxyvitamin D levels as sources of potential misclassification of vitamin D deficiency.

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