CORRESPONDENCE inhibitors (e.g., antibodies) against osteopontin or periostin on pulmonary function and pathology would be required, particularly in those with a rapid loss of pulmonary function. In conclusion, albeit these are preliminary insights, the present study suggests that increased expression levels of osteopontin and periostin in asthmatic airways are related to a long-standing decline in FEV1 in asthma. n Author disclosures are available with the text of this letter at www.atsjournals.org. Yoshihiro Kanemitsu, M.D. Isao Ito, M.D., Ph.D. Kyoto University Kyoto, Japan Akio Niimi, M.D., Ph.D. Kyoto University Kyoto, Japan and Nagoya City University School of Medical Sciences Aichi, Japan Kenji Izuhara, M.D., Ph.D. Shoichiro Ohta, M.D., Ph.D. Saga Medical School Saga, Japan

Copyright © 2014 by the American Thoracic Society

Junya Ono, B.S. Shino-Test Corporation Kanagawa, Japan

Insulin Resistance, Puberty, and Nonatopic Asthma in Adolescent Girls

Toshiyuki Iwata, M.D. Hisako Matsumoto, M.D., Ph.D. Michiaki Mishima, M.D., Ph.D. Kyoto University Kyoto, Japan

References 1. Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Silva PA, Poulton R. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349:1414–1422. 2. Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med 1994;150:629–634. 3. Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, Kuwabara K, Tomii K, Otsuka K, Fujimura M, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol 2013;132:305–312.e3. 4. van Rensen EL, Sont JK, Evertse CE, Willems LN, Mauad T, Hiemstra PS, Sterk PJ, Group AS. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med 2005;172: 837–841. 5. Xanthou G, Alissafi T, Semitekolou M, Simoes DC, Economidou E, Gaga M, Lambrecht BN, Lloyd CM, Panoutsakopoulou V. Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets. Nat Med 2007;13:570–578. 6. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, McKenzie AN, Nagai H, Hotokebuchi T, Izuhara K. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol 2006;118:98–104. 7. Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F. Eosinophilic inflammation in cough variant asthma. Eur Respir J 1998; 11:1064–1069. 8. Niimi A, Matsumoto H, Minakuchi M, Kitaichi M, Amitani R. Airway remodelling in cough-variant asthma. Lancet 2000;356:564–565. 9. Kohan M, Breuer R, Berkman N. Osteopontin induces airway remodeling and lung fibroblast activation in a murine model of asthma. Am J Respir Cell Mol Biol 2009;41:290–296.

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10. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, Muller SJ, Fahy JV. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci USA 2010;107:14170–14175. 11. Delimpoura V, Bakakos P, Tseliou E, Bessa V, Hillas G, Simoes DC, Papiris S, Loukides S. Increased levels of osteopontin in sputum supernatant in severe refractory asthma. Thorax 2010;65: 782–786. 12. Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, Dakhama A, Ott VL, Gelfand EW. Effector CD81 T cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004;10: 865–869. 13. Cho SH, Stanciu LA, Holgate ST, Johnston SL. Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD41 and CD81 T cells in atopic asthma. Am J Respir Crit Care Med 2005;171: 224–230. 14. Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest 2007;132:1871–1875. 15. Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, Shelley M, Abbas AR, Austin CD, Jackman J, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol 2012;129: 104–111.e1–9.

To the Editor: The rise and fall of insulin resistance (IR) during puberty is a physiologic phenomenon, regarded as necessary for puberty to proceed and for optimal reproductive competency (1–3). Increasingly, puberty is being recognized as a period of plasticity for many organs, including the lungs, which grow during puberty and are sensitive to IR (4–6). The transition to higher asthma prevalence in adolescent girls from predominance among boys has been attributed to hormonal changes during puberty (6). Although there is some temporal evidence for overweight as a risk factor (7), the association of asthma with puberty hormones has been difficult to confirm (8, 9). Because both adolescent asthma and early puberty rates are increasing in North America (10–12), knowing whether they are interrelated will inform strategies for prevention. This research was funded by the Canadian Institutes of Health Research and AllerGen NCE Inc. N.S.-A. was funded by the Canadian Institutes of Health Research National Training Program in Allergy and Asthma and the Western Regional Training Centre for Health Services Research. A.L.K. was supported by the Women and Children’s Health Research Institute/Stollery Children’s Hospital Foundation from 2008 to 2013. Author Contributions: A.L.K. conceived the study and helped obtain funding, designed the analyses, interpreted the results, and drafted the final manuscript. Y.Z. conducted the statistical analysis and created manuscript figures and tables. N.S.-A., E.A.C.S., C.D.R., and A.B.B. advised on the study design and measures, obtained funding for the study, and participated in data collection. All authors revised the manuscript critically for important content and agreed to the final version of the manuscript. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

American Journal of Respiratory and Critical Care Medicine Volume 190 Number 4 | August 15 2014

CORRESPONDENCE A

B 4

4

3

3

HOMA-IR

HOMA-IR

n=1 2

2

1

1

0

0

Age 10.5

Age 12.5 New–onset nonatopic asthma Existing nonatopic asthma

Age 10.5

Age 12.5

Atopic asthma Remitted/No asthma

Figure 1. Median Homeostasis Model Assessment of Insulin Resistance levels at age 10.5 and 12.5 years for children in puberty according to sex (A, girls; B, boys) and asthma phenotype.

IR predicts new-onset asthma in adults (13). An association with childhood asthma has been reported, albeit in cross-sectional studies that did not adjust for pubertal status (14–16). Independent of any causal role in asthma, persistent IR in childhood has long-term harmful effects for the development of cardiovascular disease and diabetes (17). In a prospective study of 395 Canadian schoolchildren, here we report a greater risk for nonatopic asthma (NAA) in nonobese adolescent girls with IR at age 10.5 years, but not at age 12.5 years. This risk was highest among girls with persistent IR at both ages, independent of puberty stage or

progression. IR was defined by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and NAA was diagnosed during the study by physician specialists and a negative skin test to allergens. A description of the methods and Study of Asthma, Genes, and the Environment (SAGE) population (Table E1) can be found in the online supplement. Results

Median HOMA-IR values at age 10.5 years were higher in girls, overweight children, children with central obesity, and urban

Table 1. Likelihood of Nonatopic Asthma in Adolesent Girls without Central Obesity, according to IR and Puberty Crude Association for HOMA-IR and Puberty IR at age 10.5 years Puberty status Asthma, age 9 years IR at age 12.5 years Puberty status Asthma, age 9 years Large delta HOMA-IR Puberty status Asthma, age 9 years Persistent IR (both ages) Puberty status Asthma, age 9 years

7.01 (1.89–26.0) 6.85 (1.45–32.4)* 1.90 (0.28–12.9) 3.86 (0.48–31.3)† 1.07 (0.22–5.31) 8.01 (1.70–37.8)‡ 15.0 (3.50–64.4) 8.01 (1.70–37.8)‡

Adjusted for Current Puberty Stage, Age, and Asthma 6.88 3.71 6.60 2.76 6.87 8.15 3.94 3.24 5.85 14.4 2.81 6.77

(1.47–32.1) (0.93–14.9)* (1.96–22.2) (0.45–17.0) (0.77–61.7)† (2.35–28.3) (1.02–15.2) (0.79–13.3)* (1.77–19.4) (2.66–78.3) (0.68–11.7)* (1.88–24.4)

Adjusted for Transition to Stage 3, Age, and Asthma 6.19 4.87 6.72 1.82 2.91 7.53 3.39 4.31 6.44 13.0 3.68 6.90

(1.28–29.9) (1.22–19.5)‡ (1.98–22.8) (0.32–10.4) (0.84–10.1)‡ (2.20–25.8) (0.86–13.3)x (1.05–17.7)‡ (1.91–21.7) (2.33–72.7) (0.89–15.2)‡ (1.91–25.0)

Definition of abbreviations: HOMA-IR = Homeostasis Model Assessment of Insulin Resistance; IR = insulin resistance. Data are given as odds ratio (95% confidence interval). *Puberty stage at age 10.5 years (Tanner 21). † Puberty stage at 12.5 years (Tanner 31). ‡ Puberty transition to Tanner 31. x P = 0.08.

Correspondence

475

CORRESPONDENCE children. In girls (Table E2), HOMA-IR was also higher at Tanner 21 puberty stage and with NAA. After mutual adjustment, independent associations were found for puberty status, overweight, and central obesity in girls, but statistical significance was lost for persistent NAA (Table E3). HOMA-IR in boys at age 10.5 years was associated with overweight and central obesity, but not with puberty stage or NAA. No associations with HOMA-IR at age 10.5 years were found for atopic asthma in boys or girls (Table E3). At age 12.5 years, median HOMA-IR was higher in girls, overweight children, and boys and girls with Tanner 31 puberty but was not related to asthma phenotype. HOMA-IR values rose in most girls to a median value of 2 or more at age 12.5 years but fell in girls with new-onset NAA (Figure 1). As expected, HOMA-IR was associated with overweight and pubertal stage at age 12.5 years. HOMA-IR values declined only in girls with incident NAA. IR in girls at age 10.5 years was associated with NAA at age 12.5 years, in interaction with central obesity (P for interaction , 0.06). IR was not a risk factor for NAA in girls with central obesity (unadjusted odds ratio [OR] = 0.85 [95% confidence interval (CI), 0.13–5.75]; puberty-adjusted OR = 0.89 [95% CI, 0.12–6.44]) and was not associated with NAA in boys (pubertyadjusted OR, 1.01; 95% CI, 0.27–3.79). Subsequently, results are reported in full for girls without central obesity (waist circumference in the three lowest quartiles). In girls without central obesity (Table 1), crude analyses revealed that both IR and puberty at age 10.5 years were associated with an approximately sevenfold increased risk for NAA at age 12.5 years. The IR association persisted after adjustment for puberty stage and diagnosed asthma at age 9 years. The OR for NAA fell slightly to a 6.2-fold risk (95% CI, 1.28–29.9) when adjusted for puberty progression, which also retained its statistical significance. Hence, IR at age 10.5 years was observed in nonobese girls who developed NAA; this association was only partially explained by puberty stage or progression. Both puberty progression and large delta (drop in) HOMA-IR values between age 10.5 and 12.5 years were associated with NAA in girls without central obesity (Table 1). Delta HOMA-IR’s association diminished to nonsignificance when adjusted for puberty progression. At a 15-fold increased risk, the strongest predictor of NAA in these girls was persistent IR. It minimally changed after adjustment for puberty at 10.5 years, or for puberty progression, and for existing asthma (OR = 13.0; 95% CI, 2.33–72.7). In these models, puberty stage or progression lost statistical significance. In sum, an association between NAA in girls and a large drop in HOMA-IR was attributed to puberty progression. However, persistent IR remained a strong risk factor for NAA, independent of puberty stage or progression. IR was unrelated to atopic asthma at age 12.5 years in girls (puberty-adjusted OR = 1.10; 95% CI, 0.43–2.82) or boys (pubertyadjusted OR = 1.21; 95% CI, 0.55–2.65). No associations were found for IR and new-onset bronchial hyperresponsiveness at age 12.5 years in girls (puberty-adjusted OR = 0.90; 95% CI, 0.25–3.21) or boys (puberty-adjusted OR = 1.09; 95% CI, 0.52–2.30). Statistical significance was not attained in cross-sectional analyses at age 12.5 years between IR and NAA in all girls (puberty-adjusted OR = 1.71; 95% CI, 0.54–5.36) or boys (puberty-adjusted OR = 0.28; 95% CI, 0.03–2.21). Finally, NAA was not related to measured perinatal factors, nor did they modify its association with IR. 476

Discussion

Our prospective follow-up of almost 400 Canadian schoolchildren in a community-based sample contributes novel and confirmatory findings for IR in adolescence. HOMA-IR values increased with Tanner stage in girls at age 10.5 years and among all children at age 12.5 years, typical of the physiologic IR of puberty (2, 18). Similar to other European populations, HOMA-IR was elevated in boys and girls with total and central obesity (19, 20). Independent of puberty stage and progression, NAA was sixfold higher (95% CI, 1.28–29.9) in girls who had IR but no central obesity 2 years earlier. Nonatopic asthma was 13 times more likely among girls with persistently high HOMA-IR. IR was unrelated to NAA in boys. Although our findings align with Thuesen and colleague’s observations of IR as an independent risk factor for new-onset asthma in adults (13), we present new evidence for a role for IR in the development of NAA in adolescent girls. The sex shift in asthma prevalence during preadolescence is speculated to be the outcome of pubertal changes in sex and endocrine hormones (6). Reductions to insulin sensitivity at puberty onset (2) increase to luteinizing hormone pulsatility after insulin administration, and delays in menarche after metformin treatment all implicate a role for IR in controlling puberty onset and progression (3, 21). Further, the elevation in HOMA-IR is of a greater magnitude in girls with early-onset menarche or pubarche (22, 23). In our study, at least half of the girls with NAA had HOMA-IR values within the IR range at age 10.5 years (24). IR at this age may reflect early-onset puberty, but as we did not have pubertal status at age 8 years, the lower limit of normal pubertal onset in girls (12, 23, 25), we were unable to confirm this. Sørensen and colleagues (23) speculated that early-onset puberty is also characterized by a steeper fall in IR in later puberty. Indeed, girls with new-onset NAA in our study were the only ones to exhibit declining HOMA-IR values by age 12.5 years. At this age, they were all in Tanner stage 3 or 4, when estrogen levels are known to rise (26). We observed that progression to Tanner 3 breast development, signaling transition to menstruation and rising sex hormones (12, 25), negated the association between HOMA-IR decline and female NAA. Put together, our findings point to a role for exaggerated IR and/or early puberty in the onset of the female NAA during adolescence. Not unlike children with premature pubarche or early menarche who are insulinresistant throughout puberty and adulthood (22, 27), we found persistently high HOMA-IR values to be the strongest determinant of NAA in girls. n Author disclosures are available with the text of this letter at www.atsjournals.org. Anita L. Kozyrskyj, Ph.D. University of Alberta Edmonton, Alberta, Canada and University of Manitoba Winnipeg, Manitoba, Canada Yiye Zeng, M.Sc. University of Alberta Edmonton, Alberta, Canada Natalija Saurek-Aleksandrovska, M.Sc. Elizabeth A. C. Sellers, M.D.

American Journal of Respiratory and Critical Care Medicine Volume 190 Number 4 | August 15 2014

CORRESPONDENCE Clare D. Ramsey, M.D. Allan B. Becker, M.D. University of Alberta Edmonton, Alberta, Canada

References 1. Jasik CB, Lustig RH. Adolescent obesity and puberty: the “perfect storm”. Ann N Y Acad Sci 2008;1135:265–279. 2. Hannon TS, Janosky J, Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Pediatr Res 2006;60:759–763. 3. Pralong FP. Insulin and NPY pathways and the control of GnRH function and puberty onset. Mol Cell Endocrinol 2010;324: 82–86. 4. Wright RJ. Perinatal stress and early life programming of lung structure and function. Biol Psychol 2010;84:46–56. 5. Becklake MR, Kauffmann F. Gender differences in airway behaviour over the human life span. Thorax 1999;54:1119–1138. 6. Postma DS. Gender differences in asthma development and progression. Gend Med 2007;4 (Suppl B):S133–S146. 7. Noal RB, Menezes AM, Macedo SE, Dumith SC. Childhood body mass index and risk of asthma in adolescence: a systematic review. Obes Rev 2011;12:93–104. 8. Al-Sahab B, Hamadeh MJ, Ardern CI, Tamim H. Early menarche predicts incidence of asthma in early adulthood. Am J Epidemiol 2011;173: 64–70. 9. Vink NM, Postma DS, Schouten JP, Rosmalen JG, Boezen HM. Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents’ Individual Lives Survey (TRAILS) study. J Allergy Clin Immunol 2010;126:498–504, e1–e6. 10. Akinbami L; Centers for Disease Control and Prevention National Center for Health Statistics. The state of childhood asthma, United States, 1980-2005. Adv Data 2006;(381):1–24. 11. Garner R, Kohen D. Changes in the prevalence of asthma among Canadian children. Health Rep 2008;19:45–50. 12. Euling SY, Herman-Giddens ME, Lee PA, Selevan SG, Juul A, Sørensen TI, Dunkel L, Himes JH, Teilmann G, Swan SH. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics 2008;121:S172–S191. 13. Thuesen BH, Husemoen LL, Hersoug LG, Pisinger C, Linneberg A. Insulin resistance as a predictor of incident asthma-like symptoms in adults. Clin Exp Allergy 2009;39:700–707. 14. Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med 2011;183:441–448. 15. Arshi M, Cardinal J, Hill RJ, Davies PS, Wainwright C. Asthma and insulin resistance in children. Respirology 2010;15:779–784. 16. Al-Shawwa BA, Al-Huniti NH, DeMattia L, Gershan W. Asthma and insulin resistance in morbidly obese children and adolescents. J Asthma 2007;44:469–473. 17. Melnik BC. Permanent impairment of insulin resistance from pregnancy to adulthood: the primary basic risk factor of chronic Western diseases. Med Hypotheses 2009;73:670–681. 18. Ball GD, Huang TT, Gower BA, Cruz ML, Shaibi GQ, Weigensberg MJ, Goran MI. Longitudinal changes in insulin sensitivity, insulin secretion, and beta-cell function during puberty. J Pediatr 2006; 148:16–22. 19. Labayen I, Ruiz JR, Ortega FB, Harro J, Merenakk ¨ L, Oja L, Veidebaum T, Sjostrom M. Insulin sensitivity at childhood predicts changes in total and central adiposity over a 6-year period. Int J Obes (Lond) 2011;35:1284–1288. 20. Manios Y, Moschonis G, Kourlaba G, Bouloubasi Z, Grammatikaki E, Spyridaki A, Hatzis C, Kafatos A, Fragiadakis GA. Prevalence and independent predictors of insulin resistance in children from Crete, Greece: the Children Study. Diabet Med 2008;25: 65–72. 21. Ibañez ´ L, Lopez-Bermejo A, Diaz M, Marcos MV, de Zegher F. Early metformin therapy to delay menarche and augment height in girls with precocious pubarche. Fertil Steril 2011;95:727–730.

Correspondence

22. Frontini MG, Srinivasan SR, Berenson GS. Longitudinal changes in risk variables underlying metabolic Syndrome X from childhood to young adulthood in female subjects with a history of early menarche: the Bogalusa Heart Study. Int J Obes Relat Metab Disord 2003; 27:1398–1404. 23. Sørensen K, Mouritsen A, Mogensen SS, Aksglaede L, Juul A. Insulin sensitivity and lipid profiles in girls with central precocious puberty before and during gonadal suppression. J Clin Endocrinol Metab 2010;95:3736–3744. 24. Burrows RA, Leiva LB, Weisstaub G, Lera LM, Albala CB, Blanco E, Gahagan S. High HOMA-IR, adjusted for puberty, relates to the metabolic syndrome in overweight and obese Chilean youths. Pediatr Diabetes 2011;12:212–218. 25. Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC. Weight status in young girls and the onset of puberty. Pediatrics 2007;119:e624–e630. 26. Aksglaede L, Sørensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 2009;123:e932–e939. 27. Ibañez ´ L, Ong K, de Zegher F, Marcos MV, del Rio L, Dunger DB. Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche. Clin Endocrinol (Oxf) 2003;58: 372–379.

Copyright © 2014 by the American Thoracic Society

Asthmatic and Normal Respiratory Epithelial Cells Respond Differently to Mechanical Apical Stress To the Editor: Mechanotransduction is increasingly appreciated as being relevant to cell activation. This is pertinent to asthma, in which airway smooth muscle contraction, leading to bronchoconstriction, compresses airway epithelial cells. Several studies have shown that compressive force comparable with that arising in vivo, with bronchoconstriction, promotes bronchial epithelial cell activation in vitro, with generation and release of growth factors and cytokines (1, 2). We have demonstrated the relevance of mechanotransduction to asthma in vivo, with repeated bronchoconstriction inducing epithelial activation and promoting airway remodeling changes (3). These findings are supported by ex vivo work demonstrating up-regulation of contractile proteins and the activation of transforming growth factor b (TGF-b) after airway narrowing (4). It is, however, unclear whether epithelial responses to bronchoconstriction reflect a normal airway response to mechanotransductive stimuli or whether there is an altered response in asthmatic bronchial epithelial cells.

The study was funded by the Medical Research Council UK (G0900453) and National Institute for Health Research Biomedical Research Centre Funding Scheme. Author Contributions: C.G. designed the study, performed the experiments, analyzed the data, and wrote the manuscript. P.D. and L.L. performed the experiments and analyzed the data. D.D. and P.H. designed the study and wrote the manuscript. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

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Insulin resistance, puberty, and nonatopic asthma in adolescent girls.

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