Obesity and childhood asthma

Obesity and childhood asthma

S62 Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78 O.23.2 Complication of untreated sleep-disordered breathing Obstructive ...

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Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78

O.23.2 Complication of untreated sleep-disordered breathing

Obstructive Lung Disease

M.S. Urschitz. University of Tuebingen, Children’s Hospital, Tuebingen, Germany

14:30–16:00

Question: Several studies report on an association between sleepdisordered breathing (SDB) and neurocognitive consequences in children. We aimed to review research on this topic including some of the authors’ own studies. Methods: Literature review and results from a population-based cross-sectional study in 1144 third graders in Germany. Results: Findings of > 50 studies suggest strong evidence that childhood SDB is associated with deficits in behaviour and emotion regulation, school performance, sustained attention, selective attention, and alertness. There is also evidence that SDB has minimal association with a child’s typical mood, expressive language skills, visual perception, and working memory. Mechanisms by which SDB might result in neurobehavioral morbidity are explored, but clinical symptoms such as chronic snoring remain the best predictors of morbidity. In the author’s studies, habitual snoring as key symptom of SDB was significantly associated with hyperactive (odds ratio [OR]: 2.4) and inattentive behaviour (4.0), daytime tiredness (7.1), sleepiness (2.6–4.8), bad conduct (2.8), emotional symptoms (5.5), and peer problems (9.7). Habitual snoring was also an independent risk factor for poor academic performance in school subjects like mathematics (2.7), science (2.4), and spelling (2.3). Conclusions: Most recent studies add evidence for a causal relationship between SDB and neurocognitive impairments. Applying commonly used guidelines for causal inference, even in the absence of randomized controlled trials, consistency among studies and specificity of effect have been shown. Clinicians should be alert to the coexistence of SDB symptoms and concerns about a child’s academic progress, attention, behavior, or emotion regulation. O.23.3 BPAP and CPAP use in children C.L. Marcus. University of Pennsylvania, Philadelphia, PA, USA In children, the primary treatment for the obstructive sleep apnea syndrome (OSAS) is adenotonsillectomy. However, children who do not respond to adenotonsillectomy (and the few children who are not candidates for surgery) will require alternative therapies, primarily CPAP or BPAP. CPAP use in the pediatric population has increased, due to the increase in pediatric obesity. CPAP is highly effective in treating OSAS in children, with only minimal side-effects. However, its utility is limited by poor adherence. Adherence is affected by multiple factors, in particular, maternal education. Effective CPAP use is associated with an improvement in polysomnographic parameters, but also with improvements in measures of behavior, sleepiness and psychological well-being. Behavioral modification programs are often needed to optimize CPAP adherence in children. BPAP is effective in the treatment of many forms of respiratory failure in children. For OSAS, adherence is not better with BPAP than with CPAP. Children present unique issues with triggering and cycling of BPAP. A limiting factor for both CPAP and BPAP use in children is the lack of suitable pediatric equipment and interfaces.

Association of Lifestyle and Asthma Room A

O.24.1 Obesity and childhood asthma J.E. Lang1,2 . 1 Division of Pulmonology, Allergy & Immunology, Nemours Children’s Clinic, Jacksonville, Florida; 2 Center for Pharmacogenomics and Translational Research, Nemours Children’s Clinic, Jacksonville, Florida Correspondence: Jason E. Lang. Division of Pulmonology, Allergy & Immunology, Center for Pharmacogenomics and Translational Research, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, FL 32207, USA. Tel.: 904 697 3676; fax: 904 697 3683. E-mail: [email protected] Keywords: Asthma, obesity, children, adolescents, body mass index, pulmonary function

Abbreviations: Body mass index (BMI); Forced Vital Capacity (FVC); Forced Expiratory Volume (1 sec) (FEV1 ); Forced Expiratory Flow (FEF25–75 ); Peak Expiratory Flow Rate (PEFR); PC20 Introduction: Obesity and asthma are serious public health problems in many parts of the world. The World Health Organization expects by the year 2015 that the number of overweight adults will exceed 2.3 Billion [1]. Obesity is also a problem in children. There are more than 20 million children globally considered overweight below the age of 5. Obesity rates have increased dramatically among adult in past decades, however the acceleration of obesity has been greatest among children [2,3]. These statistics suggest that obesity in coming decades will evolve into a true public health crisis. Asthma has also increased in prevalence in recent decades, raising the question of a possible causal link between obesity and asthma. Over 15 cohort studies have been conducted in adults and children. Obesity clearly increases the risk for new asthma diagnosis in adults [4–11] and children [12–18], though the precise nature of the association remains controversial [19–24]. Obesity also appears to be associated with distinct asthma characteristics, and therefore optimal management of the obese asthmatic child requires a thoughtful, tailored approach. In this brief review, we will discuss what is known about asthma risk among obese children and the possible causes for this link. We will also discuss how obesity impacts pulmonary function, symptom severity, symptom control, exacerbation risk, and the best asthma management in children. Asthma Risk: Cohort Studies: Assessing incident risk requires prospectively following an affected cohort (obese) and an unaffected cohort (non-obese) for the development of the condition in question (asthma), and cannot rely solely on cross-sectional or case-control studies. Several high-quality cohort studies have been conducted among diverse populations assessing the risk of incident asthma among lean and obese children [12–18]. These studies involve children of varying ages, socioeconomic status and race/ethnicity. These studies followed children without asthma and compared the risk of developing new asthma in overweight versus normal weight children. Overweight status appears to increase asthma risk across the complete pediatric age spectrum. Overweight nonasthmatic infants, toddlers, pre-pubescent school-age children, and adolescents have all been shown to display increased risk for incident asthma. Though risk ratios vary by study, obesity appears to roughly double the incident risk for asthma in children [13,15,16]. Though obesity-related asthma risk has been reported to be stronger among adult females, there is not a clear and consistent link with either gender among pediatric studies. Obesity-related asthma risk also does not appear to be related to greater atopy [12–14,17]. Rapid change in adiposity or body habitus, distinct from obesity status itself, may also influence asthma risk in children. Gold found that extremes in body mass index (BMI) change and low baseline BMI were also associated with asthma risk [15].

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Asthma lacks a precise set of diagnostic criteria, and evidence exists for over-diagnosis of asthma [25,26] in some groups. A rationale hypothesis is that obesity alters the perception of perturbations in airway function, leading to a lower threshold to symptom reporting. Greater rates of false diagnosis of asthma could contribute to reported asthma risk among cohort studies using ‘physiciandiagnosis’ as the sole outcome measure. Obesity-related false asthma diagnosis is unlikely to explain the increased asthma risk. Castro-Rodriguez et al reported increased objective markers of true asthma (peak flow variability and responsiveness to bronchodilator) in overweight girls compared with lean girls. We evaluated lean and obese children referred to a pediatric asthma clinic in order to determine whether high BMI-percentile is associated with misdiagnosis of asthma or significantly different objective measures of asthma compared to lean referrals [25]. We found that the prevalence of high BMI-percentile was the same among the referral population and the cases confirmed by a specialist with accompanying objective data. Referring physiciandiagnosed asthmatics did not have higher rates of obesity, and referring physician-diagnosed asthmatics had objective indicators of asthma that were the same as asthmatics diagnosed by a specialist. There was good diagnostic correlation between referring physicians and asthma specialists that was not affected by BMI. Among specialist-diagnosed asthmatics, increased BMI-percentile was associated with significantly reduced forced expiratory volume in 1 second (FEV1), forced expiratory flow during the middle half of the forced vital capacity (FEF25–75), and FEV1/forced vital capacity (FVC). We concluded that referring physicians do not appear to overly or erroneously diagnose children with asthma due to overweight status. Our data confirm that overweight status is extremely high in children with true asthma and likely increases the risk for true asthma. Asthma Risk: Possible Etiologies: The etiology underlying the increased asthma risk among overweight children is unknown. Several theories exist that have been detailed previously [20,27,28]. These include abnormal circulating inflammation and oxidant stress, obesity-related comorbidities, chest restriction with airway closure, and shared genetics. One or more of these mechanisms may play a role in animal models of obesity and lung responses. In murine models, obesity appears to: (1) increase innate airway responsiveness, (2) increase airway responses to common asthma triggers, and (3) increase airway inflammatory responses. These same obesity-related responses have not been conclusively demonstrated in children. Assessing lung inflammation and responses among obese children remains challenging and limited by current technologies. Therefore, discussion about the link between obesity and asthma risk among children remains speculative. One hypothesis for the obesity-asthma link is that obesity-related circulating inflammation primes the lung for exaggerated responses to environmental triggers, leading to asthma-like symptoms. This notion is plausible since chronic inflammation and oxidative stress are hallmarks of both obesity and asthma. Asthmatic and obesity-related inflammation involves similar mediators, including TNFa [29,30] and leukotrienes [31–33]. Adipose releases proinflammatory ‘adipokines’ that impact multiple organ systems, including the lung [29,34]. These molecules (e.g. adiponectin, IL-6, TNFa, leptin) impact inflammation and can alter lung responses [34–37]. Therefore, obesity-related inflammation may play a role in the development and severity of asthma [38] that may be a distinct phenotype from the common atopic childhood phenotype. Despite the excess in circulating markers of inflammation, obesity does not appear to be independently related to increased airway inflammation in children. Another hypothesis proposes that obesity-related co-morbidities may increase the risk for asthma diagnosis. Gastro-esophageal reflux is increased among obese children and adults, and has been proposed as a trigger for cough and wheezing. However, evidence

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in children remains lacking that gastric reflux alone triggers greater asthma diagnosis. Obesity increases the risk for sleep-disordered breathing including obstructive sleep apnea. It is rationale to hypothesize that altered sleep leading to episodic hypoxemia or other mechanisms may predispose to asthma. When controlling for both obesity-related esophageal reflux and obesity-related sleep apnea, the relationship between obesity and asthma among adults remains unchanged [39,40]. These co-morbidities require further research in the pediatric age group. In various models, obesity-related chest restriction has been shown to alter healthy airway physiology in two ways. Compression of the lungs and chest wall reduces tethering of the airways by the surrounding lung parenchyma, leading to reduced airway caliber. Obesity-related chest wall restriction also has been associated with reduced total lung capacity and a breathing pattern characterized by reduced functional residual capacity and tidal volumes. Normal tidal breathing with periodic deep “sigh” breaths serves to stretch airway smooth muscle, detach actin-myosin cross-bridges and maintain normal cyclic bronchodilation and airway caliber. Restricted respiration seen in the obese involves reduced airway dilation [41], likely due to unloading of airway smooth muscle and greater smooth muscle tone. Over time these changes could lead to fixed reductions in airway caliber and enhanced airway responsiveness [42]. These physiologic characteristics seen in obese adults may be more subtle and variable in children [43–48] and may play a reduced role in obesity-related pediatric asthma symptoms. Lifestyle factors related to obesity may also play a role in asthma risk. The typical “Western” high-fat diet contains up to 25-fold more omega-6 (n-6) polyunsaturated fatty acids (PUFA) than n-3 PUFAs. This 25:1 ratio is much higher than the 1–2:1 ratio typical for humans during the majority of evolution [49– 51]. A “Mediterranean” diet higher in antioxidants from fruits and omega-3 fatty acids appears to protect from recurrent wheezing in young children [52]. A diet with elevated n-6 PUFA appears to increase production of inflammatory mediators from the 5-lipoxygenase pathway, and increases free radical generation and oxidative stress [53–56]. Also, increases in dietary and inflammatory cell n-3/n-6 fatty acid ratio have been associated with improvements in asthma outcomes [57–61]. Importantly, obese individuals have been shown to consume more n-6 dietary PUFAs, and have a reduced n-3/n-6 ratio in their diet compared to leans [62]. Obese adolescents do appear to have lower n-3 PUFA (especially DHA) and lower n-3/n-6 PUFA serum levels compared to lean adolescents [63]. The pattern of essential fatty acids among obese adolescents appears to differ significantly from leans, suggesting there may exist abnormal essential n-3 PUFA metabolism in the obese. A typical high-fat ‘Western’ diet maintains a low leukocyte phosholipid membrane n-3/n-6 PUFA ratio, leading to greater cellular expression of 5-lipoxygenase pathway products, (such as leukotrienes), TNFa, and other molecules important in asthma pathogenesis [64–67]. A second lifestyle factor that is an important consideration in the obesity-asthma link is physical activity. Children who are overweight or obese sustain less routine physical exertion than lean counterparts. Some reports suggest that physical activity may be important in reducing asthma-risk [68] and reducing asthma symptoms [69–71], though other reports have not corroborated these findings [14, 52]. Lucas et al has raised the concern that past cohort studies have not adequately controlled for reduced physical activity, raising the question of whether reduced activity in combination with other obesity-related factors may be the cause of increased asthma incidence [21]. Within repeated exercise comes hyperventilation, cyclic ASM stretch, and bronchodilation. In-vitro studies suggest that exercise-related cyclic respiratory epithelial compression may improve airway clearance and caliber [72]. It would also be rationale to hypothesize that the obesity-asthma link stems from common genetic origins [28,73]. It is likely that genes contributing to one multi-factorial complex disease

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contribute directly or indirectly to other multi-factorial complex diseases. To date, our limited understanding has stemmed from discovering associations between obesity and asthma phenotypes and candidate gene variants. For example, several promising genomic areas that contain genes connected with both obesity and asthma (5q23–32, 6p21–23, 11q13, and 12q13–24) have been identified [19,27,28,73–76]. Only 5 genes have polymorphisms that have been associated with both obesity and asthma [77,78]. These are: b2-adrenergic receptor gene (ADRB2), the TNFa gene, the lymphotoxin-a (LTA) gene, vitamin D receptor (VDR) gene and PRKCA. Further interrogation of these and other genetic loci is needed among cohorts with and without obesity and with and without asthma in order to better understand the nature of the obesity-asthma link. It is possible that more than one of the above mechanisms (or mechanisms not yet considered) may act together in increasing asthma risk. We must consider that asthma is a heterogeneous condition with patients varying widely in terms of severity, airflow obstruction, exacerbation triggers, symptom frequency, risk for exacerbation, lung function decline, airflow obstruction, and treatment response. It is possible that the impact of obesity on asthma-risk varies among individuals, depending on an individual’s genetic factors (gene-environment or gene-gene interactions) or concomitant environmental triggers, such as exposure to environmental tobacco smoke or other pollutants. The Obese Asthma Phenotype in Children: Obese children with asthma pose a hefty pediatric management challenge. Several studies have evaluated asthma characteristics among lean and obese children. Several reports suggest that asthma symptoms are more severe among obese children [38,79–83] while others have found no difference in lung function or asthma severity [84–87]. Data suggest that obese asthmatics are at least as hard to control as their lean counterparts, and in some reports are less responsive to conventional therapies [81,82,88–93]. Much of the data describing obese asthma comes from adults. Overall, obese adult asthmatics generally have similar lung function (or modest reductions in lung volumes) and airway responsiveness compared to lean asthmatics. Obese adult asthmatics generally achieve reduced asthma symptom control and are less apt to have severe atopy and eosinophil-driven inflammation. There is evidence that leukotrienes may play a more prominent role in the obese asthma phenotype [94]. Leukotriene production is up-regulated in patients with obesity [95] and is important in asthma pathogenesis [31,32]. We previously determined the allele frequencies of the addition/deletion promoter polymorphism in the ALOX5 gene among a population of asthmatics undergoing a clinical trial [96,97]. The ALOX5 gene encodes for 5-lipoxygenase which catalyzed the oxidation of membrane arachidonic acids to create LTA4 . Recently we have analyzed the allele frequencies of this ALOX5 polymorphism among lean and obese participants of this study and a second population of obese and non-obese, otherwise healthy (non-asthmatic) volunteers (Table). Among the non-asthmatics, 57% of obese individuals carried the variant allele compared to 40% for non-obese individuals. The relative risk of obesity in individuals carrying the variant allele is 2.04 compared to carriers of the wild type (p = 0.0165). It is not clear if or how this promoter polymorphism contributes to obesity. Nevertheless, it is rationale therefore to hypothesize that obese, non-asthmatic persons may be at greater risk for developing asthma due in part to the mutant ALOX5 variant and to greater upregulation of the leukotriene pathway compared to the those with the wildtype genotype [96,98]. Furthermore, due to the higher prevalence of the ALOX5 variant in obese asthmatics, leukotriene levels may be elevated in a larger fraction of obese patients, thus making them prime candidates to benefit from therapies acting on the leukotriene pathway. The obese asthmatic child: Management considerations: Studies in adults have evaluated asthma outcomes following weight-

loss interventions [99–102]. The most consistent findings involve the improvement in breathlessness, exercise tolerance, asthma symptoms and lung volumes. It has been difficult to decipher improvements in general cardiorespiratory health and wellness following weight loss, from asthma-specific improvements. Though the impact of weight-loss in obese children with asthma has not been adequately studied, it is rationale to expect similar improvements in symptom control and lung volumes, and striving for a healthy weight should continue to be a primary goal. Exercise and other life-style intervention remains an important area of future research for obese children with asthma. Current research does not support major deviations from current GINA and NHLBI EPR3 guidelines for the care of all asthmatics. However, volume of distribution and the metabolic/hormonal alterations associated with obesity may impact the pharmacokinetics and pharmacodynamics of therapeutic agents. Recent research may provide important guidance to the clinician for individual obese patients. Evidence suggests that obesity may blunt the response to inhaled corticosteroids [88,91,94] and lowdose theophylline [90]. Limited empirical data suggests that obese asthmatics may respond more favorably to montelukast with increasing BMI [94]. Since much of the impairment domain of asthma control involves subjective assessment and quality of life issues, attention to obesityrelated sequelae that may interact with asthma symptoms remains critically important. Though empiric treatment for “silent” gastroesophageal reflux so far does not seem warranted [103], some obese patients with gastro-esophageal reflux and cough may improve with anti-reflux medications. Clinicians should maintain a high-index of suspicion for certain common obesity-related comorbidities such as sleep-disordered breathing (especially those with snoring, sleep disturbance, or daytime behavior changes) and metabolic syndrome (especially among children with central obesity, acanthosis nigricans, cutaneous striae or recurrent need for oral corticosteroids). The most universally effective management plan for obese children with persistent asthma continues to involve inhaled corticosteroids, weight-loss, daily exercise and repeated asthma education regarding inhaler technique and trigger avoidance. Response heterogeneity likely exists among obese asthmatics as it does among lean asthmatics. This means that a significant portion will respond best to ICS-LABA, a portion will respond best to ICS plus montelukast, and the remaining will respond best to a higher dose of ICS [104]. Because of the flat dose-response curve seen among obese asthmatics, initial step-up therapy for obese asthmatics with poor control with ICS + montelukast may be warranted. Regardless of the step-up therapy chosen, close follow-up is critically important to re-iterate proper inhaler techniques, weight-control, low-fat diet, daily exercise and monitoring of asthma symptoms and medication side-effects. The author has no financial relationships or conflicts of interest relevant to this article to disclose. Reference(s) [1] Swaziland., W.H.O. Obesity and Overweight. 2010 [cited 2010 3/25/2010]; Available from: http://www.who.int/mediacentre/factsheets/fs311/en/ index.html. [2] Eaton, D.K., et al., Youth risk behavior surveillance – United States, 2007. MMWR Surveill Summ, 2008. 57(4): p. 1–131. [3] Ogden, C.L., et al., Prevalence of overweight and obesity in the United States, 1999–2004. JAMA, 2006. 295(13): p. 1549–55. [4] Ford, E.S., Asthma, body mass index, and C-reactive protein among US adults. J Asthma, 2003. 40(7): p. 733–9. [5] Nystad, W., et al., Body mass index in relation to adult asthma among 135,000 Norwegian men and women. Am J Epidemiol, 2004. 160(10): p. 969–76. [6] Camargo, C.A., Jr., et al., Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med, 1999. 159(21): p. 2582–8.

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O.24.2 Asthma and the pediatric athlete L.C. Lands. Pediatrics, McGill University; Pediatric Respiratory Medicine, Montreal Children’s Hospital-McGill University Health Centre, Canada As we strive to encourage a healthy lifestyle and participation in physical activity, it is important to recognize that many individuals are respiratory symptoms associated with exertion, with exercise-induce bronchospasm being a fairly common phenomenon. Exercise-induce bronchospasm is any airway narrowing associated with exercise. Exercise-induced asthma is “a syndrome of cough and/or wheezing, or chest symptoms of tightness or pain associated with 6–8 minutes of continuous or strenuous exercise” (Randolph, 2008). While the incidence varies amongst studies, many studies have found that many school-age athletes have exercise-induced bronchospasm, particularly if they have a history of respiratory symptoms and/or abnormal pulmonary function tests (Rupp et al, 1992). When evaluating a pediatric athlete, it is important to evaluate the environmental context in which the exercise occurs. This may explain why certain sports are associated with a higher incidence of subjects manifesting bronchospasm. Cold air, and especially dry air can worsen symptoms. Indoor chlorinated swimming pools can be provocative (Uyan et al 2009). Indoor skating arenas besides being cold and dry can have increased NO2 exposure due to the ice-maintenance equipment. Further ambient air pollution, particularly ozone exposure, can provoke symptoms, especially those who spend a lot of time performing vigorous activities outdoors in such environments (Mc Connell et al, 2002).