nutrients Review Children with Obesity and Asthma: Which Are the Best Options for Their Management? Lorenza Di Genova, Laura Penta, Anna Biscarini, Giuseppe Di Cara and Susanna Esposito * Pediatric Clinic, Department of Medical and Surgical Sciences, Università degli Studi di Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy; [email protected] (L.D.G.); [email protected] (L.P.); [email protected] (A.B.); [email protected] (G.D.C.) * Correspondence: [email protected]; Tel.: +39-075-578-4417; Fax: +39-075-578-4415 Received: 15 August 2018; Accepted: 31 October 2018; Published: 2 November 2018 Abstract: Obesity and asthma are complex disorders related to gene-environment interactions and various lifestyle factors. At present, they represent two of the most significant paediatric health problems worldwide, particularly in industrialized nations. The aim of this narrative review is to evaluate possible therapeutic strategies to manage asthma in children with overweight/obesity. PubMed was used to search for all of the studies published from January 2008 to June 2018 using the following key words: “asthma” and “overweight” or “obesity” or “obese” and “children” or “paediatric”. The literature review showed that growing evidence underlines the existence of an “obese asthma” phenotype characterised by difficult-to-control asthma with additional symptoms, worse control, more frequent and severe exacerbations, reduced response to inhaled corticosteroids, and lower quality of life than other phenotypes. Currently, therapeutic strategies centred on prevention are suggested and the development of resources to assist families with weight loss strategies seems useful for effective weight control and optimal asthma management. Studies on vitamin D supplementation and further knowledge are needed to better define the best therapeutic options to manage asthma in children with overweight/obesity and to reduce the onset and severity of this chronic respiratory disease through the design of a multifactorial intervention. Keywords: asthma; obesity; overweight; vitamin D; weight loss 1. Introduction Obesity and asthma are two of the most significant paediatric health problems worldwide, particularly in industrialized nations, and in recent decades their prevalence has increased dramatically [1–3]. Since 2015, the Centers for Disease Control and Prevention (CDC) has listed obesity as a major risk factor for asthma in children [4,5]. The mechanisms that lead to these disorders may start at a paediatric age and include changes in lung mechanics, comorbidities, dietary intake and low physical activity, alterations in insulin and/or glucose metabolism, and systemic inflammation. Moreover, among children with asthma, overweight is associated with a decreased response to drugs and poorer quality of life [6]. This narrative review has the aim to evaluate possible therapeutic strategies to manage asthma in children with overweight/obesity. 2. Methods PubMed was used to search for all of the studies published from January 2008 to June 2018 using the following key words: “asthma” and “overweight” or “obesity” or “obese” and “children” or “paediatric”. As experts in the field, we considered the last ten years as an appropriate time-span for the aim of this narrative review because the problem of asthma in children with overweight/obesity has been particularly considered in this time-frame. More than 100 articles were found, but only those Nutrients 2018, 10, 1634; doi:10.3390/nu10111634 www.mdpi.com/journal/nutrients Nutrients 2018, 10, 1634 2 of 14 published in English and providing evidence-based data on nutritional approach were included in the evaluation. 3. Epidemiology of Obesity and Asthma In the past four decades, mean BMI and obesity in the paediatric population have significantly increased worldwide. Whilst the trend in children’s and adolescents’ mean BMI has plateaued, albeit at high levels, in many high-income countries since 2000, an increase in mean BMI has been observed in low-income countries [7]. In particular, the global age-standardised prevalence of obesity in childhood and adolescence increased from 0.7% in 1975 to 5.6% in 2016 in girls and from 0.9% in 1975 to 7.8% in 2016 in boys [7]. About 334,000,000 people worldwide have asthma, and it is the most common chronic disease in paediatric age [8]. Asthma is among the top 20 chronic diseases in disability-adjusted life years at paediatric age; at midchildhood ages (5–14 years), it is among the top 10 causes [8]. Asthma has become more common in childhood from the mid-1990s to the mid-2000s. A time trends analysis from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three showed increases in global prevalence from 11.1% to 11.6% in children aged 6–7 years and from 13.2% to 13.7% in children aged 13–14 years [9]. There were variations around the world. While asthma has become more common in high-income countries, in many cases, its prevalence was the same or even decreased [9]. Overall, epidemiological data have highlighted the link between obesity and asthma [5,10]. Obesity is a risk factor for incident asthma and it may impact on asthma management [11–13]. One meta-analysis of prospective epidemiologic studies in children discovered that asthma incidence increases by 20% in children with overweight and that there is a two-fold higher risk in children with obesity with a dose–response relationship between body weight and incident asthma [14]. Even though overweight/obesity and asthma may simply co-exist in some children, growing evidence underlines the existence of an “obese asthma” phenotype in which high body weight affects and modifies asthma characteristics [15,16]. The “obese asthma” phenotype is complex and multifactorial (Table1). Nevertheless, several observational analyses have tried to describe its particular molecular and developmental mechanisms [17–21]. Some studies have defined the “obese asthma” phenotype as characterised by additional symptoms, worse control, more frequent and severe acute episodes, reduced response to inhaled corticosteroids, and lower quality of life than other phenotypes [22–26]. Diaz and colleagues described two different “obese asthma” phenotypes categorised by age of onset of asthma symptoms and Th2 inflammation: early-onset and late-onset obese asthma [27]. Table 1. “Obese asthma” phenotypes. Obese Asthma Phenotypes Early-Onset Asthma Late-Onset Asthma Age at onset <12 years >12 years Gender Female = Male Female > Male Airway function (FEV1, FVC) Severe decrease in airway function Minimal airway obstruction Nature Atopic Non-atopic Severe airway Airway hyperreactivity Less airway Hyperresponsiveness Hyperresponsiveness Symptom score High symptom score Low symptom score Airway inflammation Eosinophilic airway infiltration Neutrophilic infiltration Th1-Th2 profile High Th2 biomarkers Low Th2 biomarkers Children with the early-onset phenotype present asthma symptoms at an age <12 years with an important atopic component, which is characterised by eosinophilic infiltration of the airway and Nutrients 2018, 10, 1634 3 of 14 subsequent high exhaled nitric oxide levels [28]. Increased IgE levels, decreased airway function, airway hyperresponsiveness, and poor asthma control also characterize this phenotype. In the early-onset group, obesity may play a complicating role; male and female patients are affected equally. In contrast to early-onset obese asthma, Diaz and colleagues defined patients with late-onset asthma, with characteristics such as females presenting at age >12 years and lacking atopic characteristics. Pulmonary function testing demonstrates that late-onset asthmatic patients have minimal airway obstruction and less airway hyperresponsiveness with better asthma control and lower symptom scores than early-onset asthmatic patients [27]. This late-onset phenotype has a Th2 low profile with predominant neutrophil infiltration as well as low IgE and low eosinophilic infiltration [29]. The authors underlined that both obese asthma phenotypes are characterised by a severe asthma with more exacerbations and poorer symptom control than lean asthmatic patients [27]. These findings were confirmed by other analyses [5]. In particular, through a nationwide study of school children, Chen and colleagues examined the influence of long-term adiposity status/short-term adiposity changes on asthma with high or low eosinophilic inflammation after measuring exhaled nitric oxide (FeNO) and atopy, airway inflammation, and lung function. They enrolled 2450 fourth-grade children; new-onset asthma was stratified by airway inflammation status using FeNO. The authors found that long-term adiposity status increased the risk of asthma among children with low FeNO, whereas short-term adiposity changes predicted risks of asthma with high FeNO. Moreover, this cohort study showed that long-term adiposity status reduced pulmonary function, whereas rapid adiposity growth was linked with airway inflammation and atopic diseases [30]. However, the mechanisms involved in both obese asthma phenotypes need to be better defined, as their clinical characteristics may simply overlap. Therefore, several analyses have highlighted the need to consider “obese asthma” characterised by difficult-to-control asthma [5]. In a hospital database record study of 74 children aged between 10 and 17 years with asthma, obese patients with early-onset persistent asthma reported clinically worse symptoms than those reported by lean participants. The authors