Severe asthma features in children: a case–control online survey

The vast majority of asthmatic children exhibit a mild or moderate form of the disease, and only a small proportion requires aggressive maintenance therapy for several months or remains difficult-to-treat [1]. Nevertheless, these children account for a relatively large amount of resource expenditure among asthmatic patients [1, 2]. In the last few years, guidelines and consensus documents have been implemented to address the problem of poorly controlled asthma and to provide a uniform definition of severe asthma (SA) in children [3–5]. A Global Allergy and Asthma European Network (GA2LEN) task force suggested a reasoned approach to children with problematic SA and proposed recommendations for its assessment and treatment [5]. Recently, a joint Task Force supported by the European Respiratory Society (ERS) and the American Thoracic Society (ATS) reviewed the terminology and provided evidence-based recommendations for defining and treating SA in children and adults [2].

So far, very few studies have explored the distinguishing features of SA in childhood [6–10], and due to the lack of a recognized international definition of SA, inclusion criteria and study design were heterogeneous. Two studies were carried out in the United States [6, 7]. The first was a large study on patients with either severe or difficult-to-treat asthma enrolled in the TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) study [6]. The other study recruited children across five large academic centers participating in the Severe Asthma Research Program supported by the National Heart, Lung and Blood Institute [7]. Only three studies were performed in Europe, specifically in France [8], Sweden [9], and Norway [10], and enrolled smaller sample sizes than those from the United States. Furthermore, while studies from Northern Europe recruited children in several hospitals and university clinics [9, 10], the French study enrolled patients from a single specialized center [8]. Therefore, data on pediatric SA in Europe, and particularly in Southern Europe, are still scarce. Identifying the distinctive characteristics of children with SA may be useful not only for improving scientific knowledge of SA-related risk factors and phenotypes, but also as the basis for developing tailored approaches to asthma-patient management.

The aim of this study was to provide a detailed characterization of children treated in specialized pediatric asthma centers across Italy who complied with the recent ERS/ATS definition of SA [2], and to compare these children with age-matched peers with non-severe persistent asthma (NSPA).

At recruitment, additional controllers to inhaled corticosteroids used by the study subjects were long-acting inhaled bronchodilators (95 % of children with SA versus 47 % of patients with NSPA, p < 0.001), oral Montelukast (68 % versus 36 %, p < 0.001), maintenance oral steroids (2 % versus 0 %, p = 0.3), oral sustained release methylxanthines (7 % versus 0 %, p = 0.04), or subcutaneous Omalizumab (32 % versus 0 %, p < 0.001). Twelve percent of patients with SA and 6 % of children with NSPA had missed at least one dose of controller medications more than once a week during the previous six months (p = 0.3). The inhaler technique was good for both groups, with a median score of 9 (range, 6–10) for SA and 9 (range, 5–10) for NSPA subjects (p = 0.6).

The careful characterization of children with SA is considered an important step towards improving the knowledge of this small but very challenging group of patients [2, 5]. This is one of the few studies describing the distinguishing features of SA in children and adolescents in Europe. Hospital admissions for asthma, emergency-department visits during the past year, symptoms triggered by physical activity, lower spirometric values, and worse HR-QoL, but not well-being index, were differentiating features of SA versus NSPA. Current signs and symptoms possibly associated with atopy (i.e. rhinoconjunctivitis and eczema), eosinophil count, total IgE levels, and FE_NO values were similar in children with SA and NSPA, while lifetime sensitization to food allergens was an independent factor associated with SA. Home environment was similar in both groups, even though children with SA had a borderline higher prevalence of smoking parents.

SA in children is a challenging disorder with significant public health implications [1, 2, 19]. Unsurprisingly, in this study the occurrence of hospital admissions and emergency-department visits for asthma was a discriminating feature of SA versus NSPA. Nevertheless, 20 % of patients with SA had never been hospitalized, 71 % and 54 % were not hospitalized or admitted to the emergency department during the year preceding the study, and none had been admitted to intensive care units during the previous year. These findings are consistent with an earlier report from Sweden [9], where criteria for patient inclusion were similar to ours, while children enrolled in 5 specialized USA centers participating in the Severe Asthma Research Program [7] and those recruited in 12 specialized French centers at the beginning of Omalizumab treatment [20] had more severe exacerbations or at least required a larger utilization of health care services. Furthermore, most of our patients with SA regularly play a sport and are as physically active as their peers with NSPA.

Previous studies have highlighted an association between increasing asthma severity in children and both reduced HR-QoL and parents’ work attendance [10, 21, 22]. Asthma symptoms not only affect children physically, but also impair them and their families socially and emotionally [10, 21, 22]. In line with previous observations, this study demonstrates that poor HR-QoL strongly discriminates SA from NSPA. Interestingly, in our study girls with SA reported a significantly better HR-QoL than boys. Such gender distinction could reflect different psychological responses to limitations imposed by asthma (e.g. on physical activity) rather than actual differences in the disease itself. Moreover, our patients with SA had similar Wellbeing Indexes to peers with NSPA, with no gender differences. Of note, both groups had a median index very close to the poor wellbeing threshold (set at 13), the cut-off value below which it is recommended to test the patient for depression [14]. This finding has never been reported in children with SA and is consistent with the observation that the prevalence of anxiety and depressive disorders is significant among asthmatic patients, particularly adolescents [19, 23]. A more in-depth analysis of psychological aspects in children and adolescents with SA would be worthy also for identifying specific interventions that could help reduce asthma morbidity.

According to some [8, 10] but not all [4] previous studies, most of our SA patients were sensitized to aeroallergens, with no prevalence difference from the NSPA group. Nevertheless, we highlight the novel finding that lifetime sensitization to food allergens was more frequent in SA than in NSPA. Although children with asthma show a strikingly high prevalence of food sensitization [24, 25], the majority have no clinical food allergies [25], which is consistent with the presence of current food allergies in only a third of our children sensitized to food. It is well known that children with food sensitization have increased asthma morbidity, with a higher hospitalization frequency and greater need for steroid medications [26], and even if they have developed tolerance to food allergens by school-age, previous sensitization still represents a risk factor for later asthma development [27, 28]. Our results confirm and extend these findings by demonstrating that lifetime sensitization to food allergens is an independent risk factor for SA.

Reduction in FEV₁ is often used to define childhood asthma severity in treatment guidelines [1] and clinical studies [7, 9, 29]. Interestingly, while our SA patients showed worse spirometric measures than their NSPA peers, more than half had a normal FEV₁, indicating that a reduction in FEV₁ is an insensitive measure of SA. Indeed, contrary to adults, spirometry may be a poor predictor of asthma severity in children, and previous studies examining the relationship between FEV₁ and the childhood asthma severity level have demonstrated very weak correlations between lung function and asthmatic symptoms [19, 29, 30]. FE_NO levels were similar in both groups, in line with some previous studies showing no significant increase in FE_NO values in SA children [9, 21, 29]. As all our subjects were on regular steroids maintenance therapy, the lack of any difference in FE_NO between SA and NSPA may be explained by the anti-inflammatory effects of the treatment.

Unlike previous studies [8–10], a number of comorbidities (i.e. rhinoconjunctivitis, obesity, and symptoms of sinusitis and of gastroesophageal reflux), family characteristics (namely, parental asthma and education), and environmental exposures (i.e. dampness at home and exposure to heavy traffic) were similar in SA versus NSPA patients. Exposure to smoking at home was indeed more prevalent in patients with SA, although the difference did not reach statistical significance possibly because of the low sample size.

We used a national online web-based system to collect a large number of personal, family and environmental data from children with SA and NSPA enrolled in various Italian centers. The main strengths of this system are that it allows for collecting huge amounts of longitudinal data, and ideally enables inclusion of foreign patients for larger international studies. Another strength of our study is that, unlike previous reports [6–8, 10], we included only children with refractory asthma or in whom treatment of comorbidities has been addressed as per the ERS/ATS Guidelines definition [2].

This study has limitations. Firstly, the study was not designed to assess the prevalence of SA in Italy, which would have been difficult to achieve considering the extension of the country. Secondly, the number of patients recruited was small and this prevented us from drawing definite conclusions on the lack of difference in a few variables between patients with SA and NSPA. However, our sample size is similar to that of previous European studies [8–10]. Finally, exposure to smoke and adherence to prescribed medication were assessed via self-reporting. Nonetheless, the lack of any adherence differences between SA and NSPA suggests that this shortcoming did not have much impact on our findings.

This study shows that, compared to children and adolescents with NSPA, discriminating features of SA include lifetime sensitization to food allergens, worse airway obstruction, and increased use of health-care resources. Apart from a greater exposure to parental smoking, environmental, family and personal characteristics as well as comorbidities of our SA patients are not different from those of their peers with NSPA. Finally, SA patients have worse HR-QoL than NSPA peers, and the perception of wellbeing is borderline in both groups, suggesting that the psychological aspects in these patients deserve further investigation.