- Email: [email protected]
Childhood obesity and asthma: To BMI or not to BMI?
Accepted Manuscript Childhood obesity and asthma –to BMI or not to BMI? Erick Forno, MD MPH PII:
S0091-6749(16)30972-1
DOI:
10.1016/j.jaci.2016.08.020
Reference:
YMAI 12349
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 20 July 2016 Accepted Date: 9 August 2016
Please cite this article as: Forno E, Childhood obesity and asthma –to BMI or not to BMI?, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.08.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Childhood obesity and asthma –to BMI or not to BMI? Erick Forno MD MPH Contact information: Erick Forno, M.D., M.P.H.
6
Assistant Professor of Pediatrics
7
University of Pittsburgh School of Medicine
8
Division of Pulmonary Medicine, Allergy, and Immunology
9
Children’s Hospital of Pittsburgh of UPMC
10
4401 Penn Ave, Pittsburgh, PA 15224
11
Fax +1.412.692.7636, email [email protected]
13
NIH grant number HL125666
14 15
Key words:
M AN U
12
SC
5
RI PT
1 2 3 4
16 17 18 19 20
Over the past several decades there has been a rise in the prevalence of both childhood obesity
21
and childhood asthma, and we have seen a corresponding increase in the epidemiological and
22
scientific evidence that obesity can increase childhood asthma risk and morbidity1,2.
23
Observational and experimental studies have outlined several potential causal mechanisms,3,4
24
and while our understanding of the “obese asthma” phenotype is far from complete, it has
25
become evident that it is likely complex and multifactorial –much like both of the diseases
26
involved.
TE D
EP
AC C
27
Childhood asthma, obese asthma, exhaled nitric oxide.
28
One of the main difficulties in studying obese asthma emerges from our current definition of
29
obesity based on the body mass index (BMI). The formula for BMI was first proposed 180 years
30
ago by Belgian astronomer, statistician and sociologist Adolphe Quételet in an attempt to
31
describe the l’homme moyen –the average man5. After considering weight/height3 for infants,
32
weight/height2 for children, and weight2/height5 for adolescents and adults, he eventually settled
33
for a simplified weight/height2. Several weight and height iterations were subsequently proposed,
ACCEPTED MANUSCRIPT 2 until Ancel Keys coined the term “body mass index” in a 1972 study comparing several indices
35
to a golden standard –the sum of tricipital and subscapular skinfolds– in 7,424 healthy adult
36
men6. Thereafter BMI was quickly adopted as a measure of obesity and in 1985 the National
37
Institutes of Health (NIH) published a consensus statement recommending the use of BMI in the
38
evaluation of obesity7.
RI PT
34
39
Despite its simplicity (or, rather, precisely because of it), BMI has several limitations. Quételet
41
aimed to describe the average man, not dictate the definition of obesity. The study by Keys et al.
42
did not include children or women. BMI is not intended to differentiate between lean and fat
43
mass. It provides no information on the distribution of adipose tissue depots, which may have
44
crucial implications for different diseases. Ironically, the 1985 NIH statement already reported
45
that “recent studies suggest that the distribution of fat deposits may be a better predictor of
46
mortality” than BMI.
M AN U
SC
40
47
In this issue of the Journal, den Dekker et al. address precisely some of these issues by
49
evaluating whether BMI or other measures of adipose tissue distribution are associated with
50
asthma and lung function8. In a cross-sectional analysis of a population-based cohort of 6,178
51
children, the authors measured BMI, body fat mass and its android/gynoid ratio by dual-energy
52
X-ray absorptiometry (deXa), and subcutaneous and pre-peritoneal fat mass by ultrasound. They
53
found BMI to be associated with higher risk of reported wheezing and with higher airway
54
resistance measured by Rint. The body fat mass index was also associated with Rint, but neither
55
general indicator was associated with FeNO, a marker of eosinophilic airway inflammation. In
56
contrast, more localized measures of fat distribution were associated with FeNO: the
57
android/gynoid fat mass ratio was associated with lower FeNO, whereas the amount of pre-
58
peritoneal fat was associated with higher FeNO. Subcutaneous fat mass did not show any
59
significant associations.
EP
AC C
60
TE D
48
61
These findings carry two important implications: First, certain adipose tissue distribution patterns
62
may be linked to specific pathways underlying the effect of obesity on asthma. In this case, pre-
63
peritoneal fat may be linked to allergic, eosinophilic-driven airway inflammation. Pre-peritoneal
64
fat represents the circumferential margins of the anterior peritoneum (i.e. the intra-abdominal fat
ACCEPTED MANUSCRIPT 3 that directly underlies the abdominal wall) and is seen as lateral “flank stripes” on abdominal x-
66
ray. The android/gynoid index, on the contrary, encompasses several abdominal and
67
subcutaneous fat depots. Pre-peritoneal fat has been associated with cardiovascular disease in
68
adolescents9, fatty liver10, serum insulin levels11, and other changes associated with the metabolic
69
syndrome12. The finding in the setting of asthma is novel and interesting, and certainly deserves
70
further exploration.
RI PT
65
71
Second, and more generally, the study by den Dekker and colleagues highlights the importance
73
of not limiting our study of obese asthma to the incomplete picture portrayed by BMI. In a recent
74
case-control study of asthma in Puerto Rican children, waist circumference and percent body fat
75
showed associations with exercise-induced asthma symptoms, FEV1/FVC, total IgE, and allergic
76
rhinitis that BMI did not13. Similarly, Chen et al. found central obesity to most accurately predict
77
asthma in a survey of Taiwanese schoolchildren14. Moreover, it may be the metabolic
78
complications of obesity, rather than obesity itself, that affect lung function and asthma risk and
79
morbidity in children15-17.
M AN U
SC
72
80
The study is not without limitations, including attrition bias (mother-child dyads who were lost
82
to follow-up differed from those who remained in the cohort) and the lack of other, more widely
83
utilized measures of lung function such as FEV1 or FEV1/FVC. The proportion of obese children
84
was relatively low at 4.5% (certainly low compared to the prevalence of childhood obesity in the
85
U.S.), which may have resulted in limited statistical power to detect small effects. More
86
importantly, the obesity measures were obtained at the same time as the outcomes, and therefore
87
this cross-sectional analysis cannot determine temporality or causality. Future research should
88
address these limitations by performing prospective studies with more detailed characterization
89
of adipose tissue distribution and more detailed account of asthma-related outcomes.
EP
AC C
90
TE D
81
91
To be clear, not all children with obesity and asthma necessarily have “obese asthma”. In some
92
cases, both diseases may simply coexist without being causally related. In other instances, obese
93
children and adults may exhibit symptoms that resemble asthma or may lead to misdiagnosis18,19.
94
Some children with severe asthma may be at higher risk of obesity. But studies like the one in
95
this issue of JACI recognize the complexity of the phenotype, and take a step in the right
ACCEPTED MANUSCRIPT 4 direction to better understand it. It is not possible to comprehend the effect of obesity on
97
childhood asthma by using BMI alone, just like we cannot understand everything about asthma
98
solely by measuring FEV1.
AC C
EP
TE D
M AN U
SC
RI PT
96
ACCEPTED MANUSCRIPT 5
AC C
EP
TE D
M AN U
SC
RI PT
References 1. Zhang Z, Lai HJ, Roberg KA, Gangnon RE, Evans MD, Anderson EL, et al. Early childhood weight status in relation to asthma development in high-risk children. J Allergy Clin Immunol 2010; 126:1157-62. 2. Bruske I, Flexeder C, Heinrich J. Body mass index and the incidence of asthma in children. Curr Opin Allergy Clin Immunol 2014; 14:155-60. 3. Shore SA. Obesity and asthma: lessons from animal models. Journal of applied physiology (Bethesda, Md.: 1985) 2007; 102:516-28. 4. Celedon JC, Kolls JK. An innate link between obesity and asthma. Nat Med 2014; 20:1920. 5. Quetelet A. A Treatise on Man and the Development of his Faculties. New York: Cambridge University Press; 2013 (original 1842). 6. Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL. Indices of relative weight and obesity. Int J Epidemiol 2014; 43:655-65. 7. NIH. Health Implications of Obesity: NIH Consensus Statement. National Institutes of Health (NIH), 1985:1-7. 8. den Dekker HT, Ros KPI, de Jongste JC, Reiss IK, Jaddoe VWV, Duijts L. Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide and asthma at school-age. Journal of Allergy and Clinical Immunology. 9. Hacihamdioglu B, Ocal G, Berberoglu M, Siklar Z, Fitoz S, Tutar E, et al. Preperitoneal fat tissue may be associated with arterial stiffness in obese adolescents. Ultrasound Med Biol 2014; 40:871-6. 10. Onitsuka Y, Takeshima F, Ichikawa T, Kohno S, Nakao K. Estimation of visceral fat and fatty liver disease using ultrasound in patients with diabetes. Intern Med 2014; 53:545-53. 11. Tamura A, Mori T, Hara Y, Komiyama A. Preperitoneal fat thickness in childhood obesity: association with serum insulin concentration. Pediatr Int 2000; 42:155-9. 12. Tadokoro N, Shinomiya M, Yoshinaga M, Takahashi H, Matsuoka K, Miyashita Y, et al. Visceral fat accumulation in Japanese high school students and related atherosclerotic risk factors. J Atheroscler Thromb 2010; 17:546-57. 13. Forno E, Acosta-Perez E, Brehm JM, Han YY, Alvarez M, Colon-Semidey A, et al. Obesity and adiposity indicators, asthma, and atopy in Puerto Rican children. J Allergy Clin Immunol 2014; 133:1308-14, 14 e1-5. 14. Chen YC, Tu YK, Huang KC, Chen PC, Chu DC, Lee YL. Pathway from central obesity to childhood asthma. Physical fitness and sedentary time are leading factors. Am J Respir Crit Care Med 2014; 189:1194-203. 15. Forno E, Han YY, Muzumdar RH, Celedon JC. Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. J Allergy Clin Immunol 2015; 136:304-11 e8. 16. Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med 2011; 183:441-8.
ACCEPTED MANUSCRIPT 6
RI PT
SC M AN U TE D
19.
EP
18.
Vijayakanthi N, Greally JM, Rastogi D. Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation. Pediatrics 2016; 137. Lang JE, Hossain MJ, Lima JJ. Overweight children report qualitatively distinct asthma symptoms: analysis of validated symptom measures. J Allergy Clin Immunol 2015; 135:886-93 e3. Carpio C, Villasante C, Galera R, Romero D, de Cos A, Hernanz A, et al. Systemic inflammation and higher perception of dyspnea mimicking asthma in obese subjects. J Allergy Clin Immunol 2016; 137:718-26 e4.
AC C
17.
S0091-6749(16)30972-1
DOI:
10.1016/j.jaci.2016.08.020
Reference:
YMAI 12349
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 20 July 2016 Accepted Date: 9 August 2016
Please cite this article as: Forno E, Childhood obesity and asthma –to BMI or not to BMI?, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.08.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Childhood obesity and asthma –to BMI or not to BMI? Erick Forno MD MPH Contact information: Erick Forno, M.D., M.P.H.
6
Assistant Professor of Pediatrics
7
University of Pittsburgh School of Medicine
8
Division of Pulmonary Medicine, Allergy, and Immunology
9
Children’s Hospital of Pittsburgh of UPMC
10
4401 Penn Ave, Pittsburgh, PA 15224
11
Fax +1.412.692.7636, email [email protected]
13
NIH grant number HL125666
14 15
Key words:
M AN U
12
SC
5
RI PT
1 2 3 4
16 17 18 19 20
Over the past several decades there has been a rise in the prevalence of both childhood obesity
21
and childhood asthma, and we have seen a corresponding increase in the epidemiological and
22
scientific evidence that obesity can increase childhood asthma risk and morbidity1,2.
23
Observational and experimental studies have outlined several potential causal mechanisms,3,4
24
and while our understanding of the “obese asthma” phenotype is far from complete, it has
25
become evident that it is likely complex and multifactorial –much like both of the diseases
26
involved.
TE D
EP
AC C
27
Childhood asthma, obese asthma, exhaled nitric oxide.
28
One of the main difficulties in studying obese asthma emerges from our current definition of
29
obesity based on the body mass index (BMI). The formula for BMI was first proposed 180 years
30
ago by Belgian astronomer, statistician and sociologist Adolphe Quételet in an attempt to
31
describe the l’homme moyen –the average man5. After considering weight/height3 for infants,
32
weight/height2 for children, and weight2/height5 for adolescents and adults, he eventually settled
33
for a simplified weight/height2. Several weight and height iterations were subsequently proposed,
ACCEPTED MANUSCRIPT 2 until Ancel Keys coined the term “body mass index” in a 1972 study comparing several indices
35
to a golden standard –the sum of tricipital and subscapular skinfolds– in 7,424 healthy adult
36
men6. Thereafter BMI was quickly adopted as a measure of obesity and in 1985 the National
37
Institutes of Health (NIH) published a consensus statement recommending the use of BMI in the
38
evaluation of obesity7.
RI PT
34
39
Despite its simplicity (or, rather, precisely because of it), BMI has several limitations. Quételet
41
aimed to describe the average man, not dictate the definition of obesity. The study by Keys et al.
42
did not include children or women. BMI is not intended to differentiate between lean and fat
43
mass. It provides no information on the distribution of adipose tissue depots, which may have
44
crucial implications for different diseases. Ironically, the 1985 NIH statement already reported
45
that “recent studies suggest that the distribution of fat deposits may be a better predictor of
46
mortality” than BMI.
M AN U
SC
40
47
In this issue of the Journal, den Dekker et al. address precisely some of these issues by
49
evaluating whether BMI or other measures of adipose tissue distribution are associated with
50
asthma and lung function8. In a cross-sectional analysis of a population-based cohort of 6,178
51
children, the authors measured BMI, body fat mass and its android/gynoid ratio by dual-energy
52
X-ray absorptiometry (deXa), and subcutaneous and pre-peritoneal fat mass by ultrasound. They
53
found BMI to be associated with higher risk of reported wheezing and with higher airway
54
resistance measured by Rint. The body fat mass index was also associated with Rint, but neither
55
general indicator was associated with FeNO, a marker of eosinophilic airway inflammation. In
56
contrast, more localized measures of fat distribution were associated with FeNO: the
57
android/gynoid fat mass ratio was associated with lower FeNO, whereas the amount of pre-
58
peritoneal fat was associated with higher FeNO. Subcutaneous fat mass did not show any
59
significant associations.
EP
AC C
60
TE D
48
61
These findings carry two important implications: First, certain adipose tissue distribution patterns
62
may be linked to specific pathways underlying the effect of obesity on asthma. In this case, pre-
63
peritoneal fat may be linked to allergic, eosinophilic-driven airway inflammation. Pre-peritoneal
64
fat represents the circumferential margins of the anterior peritoneum (i.e. the intra-abdominal fat
ACCEPTED MANUSCRIPT 3 that directly underlies the abdominal wall) and is seen as lateral “flank stripes” on abdominal x-
66
ray. The android/gynoid index, on the contrary, encompasses several abdominal and
67
subcutaneous fat depots. Pre-peritoneal fat has been associated with cardiovascular disease in
68
adolescents9, fatty liver10, serum insulin levels11, and other changes associated with the metabolic
69
syndrome12. The finding in the setting of asthma is novel and interesting, and certainly deserves
70
further exploration.
RI PT
65
71
Second, and more generally, the study by den Dekker and colleagues highlights the importance
73
of not limiting our study of obese asthma to the incomplete picture portrayed by BMI. In a recent
74
case-control study of asthma in Puerto Rican children, waist circumference and percent body fat
75
showed associations with exercise-induced asthma symptoms, FEV1/FVC, total IgE, and allergic
76
rhinitis that BMI did not13. Similarly, Chen et al. found central obesity to most accurately predict
77
asthma in a survey of Taiwanese schoolchildren14. Moreover, it may be the metabolic
78
complications of obesity, rather than obesity itself, that affect lung function and asthma risk and
79
morbidity in children15-17.
M AN U
SC
72
80
The study is not without limitations, including attrition bias (mother-child dyads who were lost
82
to follow-up differed from those who remained in the cohort) and the lack of other, more widely
83
utilized measures of lung function such as FEV1 or FEV1/FVC. The proportion of obese children
84
was relatively low at 4.5% (certainly low compared to the prevalence of childhood obesity in the
85
U.S.), which may have resulted in limited statistical power to detect small effects. More
86
importantly, the obesity measures were obtained at the same time as the outcomes, and therefore
87
this cross-sectional analysis cannot determine temporality or causality. Future research should
88
address these limitations by performing prospective studies with more detailed characterization
89
of adipose tissue distribution and more detailed account of asthma-related outcomes.
EP
AC C
90
TE D
81
91
To be clear, not all children with obesity and asthma necessarily have “obese asthma”. In some
92
cases, both diseases may simply coexist without being causally related. In other instances, obese
93
children and adults may exhibit symptoms that resemble asthma or may lead to misdiagnosis18,19.
94
Some children with severe asthma may be at higher risk of obesity. But studies like the one in
95
this issue of JACI recognize the complexity of the phenotype, and take a step in the right
ACCEPTED MANUSCRIPT 4 direction to better understand it. It is not possible to comprehend the effect of obesity on
97
childhood asthma by using BMI alone, just like we cannot understand everything about asthma
98
solely by measuring FEV1.
AC C
EP
TE D
M AN U
SC
RI PT
96
ACCEPTED MANUSCRIPT 5
AC C
EP
TE D
M AN U
SC
RI PT
References 1. Zhang Z, Lai HJ, Roberg KA, Gangnon RE, Evans MD, Anderson EL, et al. Early childhood weight status in relation to asthma development in high-risk children. J Allergy Clin Immunol 2010; 126:1157-62. 2. Bruske I, Flexeder C, Heinrich J. Body mass index and the incidence of asthma in children. Curr Opin Allergy Clin Immunol 2014; 14:155-60. 3. Shore SA. Obesity and asthma: lessons from animal models. Journal of applied physiology (Bethesda, Md.: 1985) 2007; 102:516-28. 4. Celedon JC, Kolls JK. An innate link between obesity and asthma. Nat Med 2014; 20:1920. 5. Quetelet A. A Treatise on Man and the Development of his Faculties. New York: Cambridge University Press; 2013 (original 1842). 6. Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL. Indices of relative weight and obesity. Int J Epidemiol 2014; 43:655-65. 7. NIH. Health Implications of Obesity: NIH Consensus Statement. National Institutes of Health (NIH), 1985:1-7. 8. den Dekker HT, Ros KPI, de Jongste JC, Reiss IK, Jaddoe VWV, Duijts L. Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide and asthma at school-age. Journal of Allergy and Clinical Immunology. 9. Hacihamdioglu B, Ocal G, Berberoglu M, Siklar Z, Fitoz S, Tutar E, et al. Preperitoneal fat tissue may be associated with arterial stiffness in obese adolescents. Ultrasound Med Biol 2014; 40:871-6. 10. Onitsuka Y, Takeshima F, Ichikawa T, Kohno S, Nakao K. Estimation of visceral fat and fatty liver disease using ultrasound in patients with diabetes. Intern Med 2014; 53:545-53. 11. Tamura A, Mori T, Hara Y, Komiyama A. Preperitoneal fat thickness in childhood obesity: association with serum insulin concentration. Pediatr Int 2000; 42:155-9. 12. Tadokoro N, Shinomiya M, Yoshinaga M, Takahashi H, Matsuoka K, Miyashita Y, et al. Visceral fat accumulation in Japanese high school students and related atherosclerotic risk factors. J Atheroscler Thromb 2010; 17:546-57. 13. Forno E, Acosta-Perez E, Brehm JM, Han YY, Alvarez M, Colon-Semidey A, et al. Obesity and adiposity indicators, asthma, and atopy in Puerto Rican children. J Allergy Clin Immunol 2014; 133:1308-14, 14 e1-5. 14. Chen YC, Tu YK, Huang KC, Chen PC, Chu DC, Lee YL. Pathway from central obesity to childhood asthma. Physical fitness and sedentary time are leading factors. Am J Respir Crit Care Med 2014; 189:1194-203. 15. Forno E, Han YY, Muzumdar RH, Celedon JC. Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. J Allergy Clin Immunol 2015; 136:304-11 e8. 16. Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med 2011; 183:441-8.
ACCEPTED MANUSCRIPT 6
RI PT
SC M AN U TE D
19.
EP
18.
Vijayakanthi N, Greally JM, Rastogi D. Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation. Pediatrics 2016; 137. Lang JE, Hossain MJ, Lima JJ. Overweight children report qualitatively distinct asthma symptoms: analysis of validated symptom measures. J Allergy Clin Immunol 2015; 135:886-93 e3. Carpio C, Villasante C, Galera R, Romero D, de Cos A, Hernanz A, et al. Systemic inflammation and higher perception of dyspnea mimicking asthma in obese subjects. J Allergy Clin Immunol 2016; 137:718-26 e4.
AC C
17.