HHS Public Access Author manuscript Author Manuscript
J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01. Published in final edited form as: J Allergy Clin Immunol. 2016 March ; 137(3): 938–40.e1. doi:10.1016/j.jaci.2015.09.012.
Atopic disease and cardiovascular risk factors in US children Jonathan I. Silverberg, MD, PhD, MPH Departments of Preventive Medicine, Medical Social Sciences, and Dermatology, Feinberg School of Medicine at Northwestern University and Northwestern Multidisciplinary Eczema Center, Chicago, Ill. [email protected]
Author Manuscript
To the Editor Atopic diseases, including asthma, hay ssssssfever, and eczema, are common chronic inflammatory disorders of childhood. They are associated with chronic peripheral and organspecific inflammation, including upregulated TH2 inflammation.1 Aside from chronic inflammation, these disorders may be anxiety-provoking and have been found to be associated with chronic sleep disturbances, functional limitations of physical activity, and use of various corticosteroids and other immunosuppressive medications. In turn, each of these sequela was previously found to be associated with increased risk for cardiovascular disease. Indeed, a recent study demonstrated increased cardiovascular risk in 2 studies of US adults with eczema.2 However, few studies have examined the impact of atopic disease on cardiovascular risk in children.
Author Manuscript
I used the 2012 National Health Interview Survey (NHIS), an in-person household survey administered in English and Spanish. One child per household was randomly selected for the child questionnaire. Using data from the US Bureau of the Census, sampling weights were adjusted for age, sex, race, ethnicity, household size, and educational attainment of the most educated household member. The questions used to assess for history of atopic and cardiovascular disease are presented in Table E1 in this article's Online Repository at www.jacionline.org. This study was approved by the institutional review board at Northwestern University.
Author Manuscript
All data processing and statistical analyses were performed with SAS, version 9.4, software (SAS institute, Cary, NC). Bivariable survey logistic regression models were used to determine the associations of asthma, hay fever, and eczema (independent variables) with obesity, hypertension, hyperlipidemia, and diabetes (dependent variables). Multivariate models included age (continuous), sex (male/female), race/ethnicity (white, black, Hispanic, multiracial/other), household income (0-0.9, 1-2.9, 3-3.9, and ≥4.0 poverty index ratio), highest level of household education (high school), birthplace in the United States, and insurance coverage (yes/no). Adjusted odds ratios and 95% CIs were estimated.
Disclosure of potential conflict of interest: J. Silverberg received research support from the Dermatology Foundation and the Agency for Healthcare Research and Quality.
Silverberg
Page 2
Author Manuscript
Two- and 3-way statistical interactions between covariates were tested and included in the above models if P was less than .01, cell frequencies were more than 5 for each level of interaction, and estimates were modified by more than 20%. Complete case analysis was performed; that is, missing values were excluded. A 2-sided P value of less than .05 was taken to indicate statistical significance. However, the multiple dependent tests performed increase the risk of falsely rejecting the null hypothesis. A total of 13,275 children aged 0 to 17 years were included in the 2012 NHIS. The US prevalences (95% CI) of asthma, eczema, and hay fever were estimated to be 14.0% (13.3% to 14.8%), 12.0% (11.3% to 12.7%), and 16.6% (15.7% to 17.4%), respectively.
Author Manuscript
In multivariable models, pediatric asthma and hay fever were associated with higher odds of overweight and obesity, hypertension, and hyperlipidemia, but not diabetes (Table I). However, eczema was associated with higher odds of overweight and obesity, but not hypertension, hyperlipidemia, or diabetes. There were no significant interactions with other covariates in any of the above models. The absolute risk differences for cardiovascular disease risk factors between atopic and nonatopic children were fairly small because of the low prevalence of cardiovascular risk factors. For example, asthma and hay fever were associated with only a 1.28% (0.32% to 2.24%) and 1.14% (0.17% to 2.11%) increased risk of hypertension and 0.91% (0.06% to 1.77%) and 0.88% (0.09% to 1.66%) risk of hypercholesterolemia, respectively.
Author Manuscript Author Manuscript
Previous studies demonstrated associations between obesity, hypertension, hyperlipidemia, and/or metabolic syndrome in clinical cohorts of children with asthma.3-5 The present study builds on these studies and demonstrates an indirect public health burden of allergic disease from increased cardiovascular risk in US children. Recently, we demonstrated increased obesity, hypertension, hyperlipidemia, and adult-onset diabetes in US adults with eczema, due in part to increased smoking, alcohol consumption, and sedentary lifestyle.2 In the present study, I could not examine these health behaviors because they were not asked in the NHIS child questionnaire. Smoking and alcohol are less likely to be major contributing factors in younger children/pread-olescents, though decreased physical activity might be a contributing factor. Children often avoid intense physical activities, which may aggravate their airway disease and/or cutaneous itch. Moreover, chronic inflammation occurring in eczema and other allergic diseases may directly contribute toward the increased cardiovascular risk. Future studies are needed to determine the mechanism(s) of association between pediatric allergic and cardiovascular disease. Moreover, clinical studies are needed to determine whether early and aggressive treatment of allergic disease is able to mitigate increased cardiovascular risk. The lack of association between eczema and hypertension is in contrast to a recent multicenter pediatric dermatology case-control study of 132 children with moderate-severe atopic dermatitis and 143 age-matched healthy controls, which found higher overall systolic and diastolic blood pressures and increased odds of systolic blood pressure (>90%) in moderate-severe atopic disease.6 In the present study, however, I was unable to assess the severity of eczema or allergic disease. The lack of association between atopic disease and
J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01.
Silverberg
Page 3
Author Manuscript
diabetes may be related to reduced power owing to the relative rarity of childhood diabetes and/or heterogeneity from type 1 and 2 diabetes. Previous studies found inverse associations between childhood eczema and type 1 diabetes.7 In future, even larger studies are needed to determine whether childhood eczema is associated with type 2 diabetes.
Author Manuscript
The strengths of this study include prospective data collection, US population–based, largescale diverse sample, complex sample weighting that allows for generalization of results to the entire US population, and controlling for multiple confounding variables in multivariable models. However, this study has limitations. All exposures and outcomes in the study were assessed by caregiver report and not verified by physical examination and may be subject to misclassification. However, a recent multicenter validation study of the eczema question used in the NHIS found good sensitivity, specificity, and positive and negative predictive values.8 Moreover, self-report of asthma has been previously validated.9 Thus, I believe that the case definitions for allergic disease are sufficiently valid for epidemiological study. Nevertheless, confirmation of these findings using objective measures is warranted. In conclusion, pediatric allergic disease was found to be associated with increased odds of obesity, hypertension, and hyperlipidemia. Future studies using clinical examination and objective measures of adiposity and metabolic syndrome are needed to confirm these associations.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments Author Manuscript
This publication was made possible with support from the Agency for Healthcare Research and Quality (grant no. K12HS023011) and the Dermatology Foundation.
References
Author Manuscript
1. Broide DH. Molecular and cellular mechanisms of allergic disease. J Allergy Clin Immunol. 2001; 108:S65–71. [PubMed: 11498675] 2. Silverberg JI, Greenland P. Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol. 2015; 135:721–8.e6. [PubMed: 25579484] 3. Granell R, Henderson AJ, Evans DM, Smith GD, Ness AR, Lewis S, et al. Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study. PLoS Med. 2014; 11:e1001669. [PubMed: 24983943] 4. Ross KR, Hart MA, Storfer-Isser A, Kibler AM, Johnson NL, Rosen CL, et al. Obesity and obesity related co-morbidities in a referral population of children with asthma. Pediatr Pulmonol. 2009; 44:877–84. [PubMed: 19639627] 5. Bibi H, Shoseyov D, Feigenbaum D, Genis M, Friger M, Peled R, et al. The relationship between asthma and obesity in children: is it real or a case of over diagnosis? J Asthma. 2004; 41:403–10. [PubMed: 15281326] 6. Silverberg JI, Becker L, Kwasny M, Menter A, Cordoro KM, Paller AS. Central obesity and high blood pressure in pediatric patients with atopic dermatitis. JAMA Dermatol. 2015; 151:144–52. [PubMed: 25536049] 7. Thomsen SF, Duffy DL, Kyvik KO, Skytthe A, Backer V. Relationship between type 1 diabetes and atopic diseases in a twin population. Allergy. 2011; 66:645–7. [PubMed: 21121932]
J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01.
Silverberg
Page 4
Author Manuscript
8. Silverberg, JI.; Patel, N.; Immaneni, S.; Rusniak, B.; Silverberg, NB.; Debashis, R., et al. Assessment of atopic dermatitis using self- and caregiver-report: a multicenter validation study. Br J Dermatol. Jul 17. 2015 [published online ahead of print]http://dx.doi.org/10.1111/bjd.14031 9. Senthilselvan A, Dosman JA, Chen Y. Relationship between pulmonary test variables and asthma and wheezing: a validation of self-report of asthma. J Asthma. 1993; 30:185–93. [PubMed: 8325827]
Author Manuscript Author Manuscript Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01.
Author Manuscript
0.2 (0.1-0.3)
Diabetes†
0.3 (0.0-0.7)
1.7 (0.9-2.6)
2.1 (1.2-3.0)
18.8 (17.3-20.4)
17.7 (16.1-19.2)
59.0 (57.1-61.0)
4.4 (3.5-5.4)
% Prev (95% CI)
2.06 (0.59-7.16)
2.02 (1.09-3.74)
1.93 (1.04-3.58)
1.50 (1.33-1.69)
1.19 (1.05-1.35)
1.00 [ref]
0.99 (0.77-1.27)
aOR (95% CI)
Yes (n = 1,923)
.26
.03
.04
J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01. Published in final edited form as: J Allergy Clin Immunol. 2016 March ; 137(3): 938–40.e1. doi:10.1016/j.jaci.2015.09.012.
Atopic disease and cardiovascular risk factors in US children Jonathan I. Silverberg, MD, PhD, MPH Departments of Preventive Medicine, Medical Social Sciences, and Dermatology, Feinberg School of Medicine at Northwestern University and Northwestern Multidisciplinary Eczema Center, Chicago, Ill. [email protected]
Author Manuscript
To the Editor Atopic diseases, including asthma, hay ssssssfever, and eczema, are common chronic inflammatory disorders of childhood. They are associated with chronic peripheral and organspecific inflammation, including upregulated TH2 inflammation.1 Aside from chronic inflammation, these disorders may be anxiety-provoking and have been found to be associated with chronic sleep disturbances, functional limitations of physical activity, and use of various corticosteroids and other immunosuppressive medications. In turn, each of these sequela was previously found to be associated with increased risk for cardiovascular disease. Indeed, a recent study demonstrated increased cardiovascular risk in 2 studies of US adults with eczema.2 However, few studies have examined the impact of atopic disease on cardiovascular risk in children.
Author Manuscript
I used the 2012 National Health Interview Survey (NHIS), an in-person household survey administered in English and Spanish. One child per household was randomly selected for the child questionnaire. Using data from the US Bureau of the Census, sampling weights were adjusted for age, sex, race, ethnicity, household size, and educational attainment of the most educated household member. The questions used to assess for history of atopic and cardiovascular disease are presented in Table E1 in this article's Online Repository at www.jacionline.org. This study was approved by the institutional review board at Northwestern University.
Author Manuscript
All data processing and statistical analyses were performed with SAS, version 9.4, software (SAS institute, Cary, NC). Bivariable survey logistic regression models were used to determine the associations of asthma, hay fever, and eczema (independent variables) with obesity, hypertension, hyperlipidemia, and diabetes (dependent variables). Multivariate models included age (continuous), sex (male/female), race/ethnicity (white, black, Hispanic, multiracial/other), household income (0-0.9, 1-2.9, 3-3.9, and ≥4.0 poverty index ratio), highest level of household education (high school), birthplace in the United States, and insurance coverage (yes/no). Adjusted odds ratios and 95% CIs were estimated.
Disclosure of potential conflict of interest: J. Silverberg received research support from the Dermatology Foundation and the Agency for Healthcare Research and Quality.
Silverberg
Page 2
Author Manuscript
Two- and 3-way statistical interactions between covariates were tested and included in the above models if P was less than .01, cell frequencies were more than 5 for each level of interaction, and estimates were modified by more than 20%. Complete case analysis was performed; that is, missing values were excluded. A 2-sided P value of less than .05 was taken to indicate statistical significance. However, the multiple dependent tests performed increase the risk of falsely rejecting the null hypothesis. A total of 13,275 children aged 0 to 17 years were included in the 2012 NHIS. The US prevalences (95% CI) of asthma, eczema, and hay fever were estimated to be 14.0% (13.3% to 14.8%), 12.0% (11.3% to 12.7%), and 16.6% (15.7% to 17.4%), respectively.
Author Manuscript
In multivariable models, pediatric asthma and hay fever were associated with higher odds of overweight and obesity, hypertension, and hyperlipidemia, but not diabetes (Table I). However, eczema was associated with higher odds of overweight and obesity, but not hypertension, hyperlipidemia, or diabetes. There were no significant interactions with other covariates in any of the above models. The absolute risk differences for cardiovascular disease risk factors between atopic and nonatopic children were fairly small because of the low prevalence of cardiovascular risk factors. For example, asthma and hay fever were associated with only a 1.28% (0.32% to 2.24%) and 1.14% (0.17% to 2.11%) increased risk of hypertension and 0.91% (0.06% to 1.77%) and 0.88% (0.09% to 1.66%) risk of hypercholesterolemia, respectively.
Author Manuscript Author Manuscript
Previous studies demonstrated associations between obesity, hypertension, hyperlipidemia, and/or metabolic syndrome in clinical cohorts of children with asthma.3-5 The present study builds on these studies and demonstrates an indirect public health burden of allergic disease from increased cardiovascular risk in US children. Recently, we demonstrated increased obesity, hypertension, hyperlipidemia, and adult-onset diabetes in US adults with eczema, due in part to increased smoking, alcohol consumption, and sedentary lifestyle.2 In the present study, I could not examine these health behaviors because they were not asked in the NHIS child questionnaire. Smoking and alcohol are less likely to be major contributing factors in younger children/pread-olescents, though decreased physical activity might be a contributing factor. Children often avoid intense physical activities, which may aggravate their airway disease and/or cutaneous itch. Moreover, chronic inflammation occurring in eczema and other allergic diseases may directly contribute toward the increased cardiovascular risk. Future studies are needed to determine the mechanism(s) of association between pediatric allergic and cardiovascular disease. Moreover, clinical studies are needed to determine whether early and aggressive treatment of allergic disease is able to mitigate increased cardiovascular risk. The lack of association between eczema and hypertension is in contrast to a recent multicenter pediatric dermatology case-control study of 132 children with moderate-severe atopic dermatitis and 143 age-matched healthy controls, which found higher overall systolic and diastolic blood pressures and increased odds of systolic blood pressure (>90%) in moderate-severe atopic disease.6 In the present study, however, I was unable to assess the severity of eczema or allergic disease. The lack of association between atopic disease and
J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01.
Silverberg
Page 3
Author Manuscript
diabetes may be related to reduced power owing to the relative rarity of childhood diabetes and/or heterogeneity from type 1 and 2 diabetes. Previous studies found inverse associations between childhood eczema and type 1 diabetes.7 In future, even larger studies are needed to determine whether childhood eczema is associated with type 2 diabetes.
Author Manuscript
The strengths of this study include prospective data collection, US population–based, largescale diverse sample, complex sample weighting that allows for generalization of results to the entire US population, and controlling for multiple confounding variables in multivariable models. However, this study has limitations. All exposures and outcomes in the study were assessed by caregiver report and not verified by physical examination and may be subject to misclassification. However, a recent multicenter validation study of the eczema question used in the NHIS found good sensitivity, specificity, and positive and negative predictive values.8 Moreover, self-report of asthma has been previously validated.9 Thus, I believe that the case definitions for allergic disease are sufficiently valid for epidemiological study. Nevertheless, confirmation of these findings using objective measures is warranted. In conclusion, pediatric allergic disease was found to be associated with increased odds of obesity, hypertension, and hyperlipidemia. Future studies using clinical examination and objective measures of adiposity and metabolic syndrome are needed to confirm these associations.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments Author Manuscript
This publication was made possible with support from the Agency for Healthcare Research and Quality (grant no. K12HS023011) and the Dermatology Foundation.
References
Author Manuscript
1. Broide DH. Molecular and cellular mechanisms of allergic disease. J Allergy Clin Immunol. 2001; 108:S65–71. [PubMed: 11498675] 2. Silverberg JI, Greenland P. Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol. 2015; 135:721–8.e6. [PubMed: 25579484] 3. Granell R, Henderson AJ, Evans DM, Smith GD, Ness AR, Lewis S, et al. Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study. PLoS Med. 2014; 11:e1001669. [PubMed: 24983943] 4. Ross KR, Hart MA, Storfer-Isser A, Kibler AM, Johnson NL, Rosen CL, et al. Obesity and obesity related co-morbidities in a referral population of children with asthma. Pediatr Pulmonol. 2009; 44:877–84. [PubMed: 19639627] 5. Bibi H, Shoseyov D, Feigenbaum D, Genis M, Friger M, Peled R, et al. The relationship between asthma and obesity in children: is it real or a case of over diagnosis? J Asthma. 2004; 41:403–10. [PubMed: 15281326] 6. Silverberg JI, Becker L, Kwasny M, Menter A, Cordoro KM, Paller AS. Central obesity and high blood pressure in pediatric patients with atopic dermatitis. JAMA Dermatol. 2015; 151:144–52. [PubMed: 25536049] 7. Thomsen SF, Duffy DL, Kyvik KO, Skytthe A, Backer V. Relationship between type 1 diabetes and atopic diseases in a twin population. Allergy. 2011; 66:645–7. [PubMed: 21121932]
J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01.
Silverberg
Page 4
Author Manuscript
8. Silverberg, JI.; Patel, N.; Immaneni, S.; Rusniak, B.; Silverberg, NB.; Debashis, R., et al. Assessment of atopic dermatitis using self- and caregiver-report: a multicenter validation study. Br J Dermatol. Jul 17. 2015 [published online ahead of print]http://dx.doi.org/10.1111/bjd.14031 9. Senthilselvan A, Dosman JA, Chen Y. Relationship between pulmonary test variables and asthma and wheezing: a validation of self-report of asthma. J Asthma. 1993; 30:185–93. [PubMed: 8325827]
Author Manuscript Author Manuscript Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2017 March 01.
Author Manuscript
0.2 (0.1-0.3)
Diabetes†
0.3 (0.0-0.7)
1.7 (0.9-2.6)
2.1 (1.2-3.0)
18.8 (17.3-20.4)
17.7 (16.1-19.2)
59.0 (57.1-61.0)
4.4 (3.5-5.4)
% Prev (95% CI)
2.06 (0.59-7.16)
2.02 (1.09-3.74)
1.93 (1.04-3.58)
1.50 (1.33-1.69)
1.19 (1.05-1.35)
1.00 [ref]
0.99 (0.77-1.27)
aOR (95% CI)
Yes (n = 1,923)
.26
.03
.04
