Asthma is one of the most frequent chronic diseases.1–3 In Spain, its prevalence ranges between 7.1% and 12.9% in children aged 6–7 years, and between 7.1% and 15.3% in those aged 13–14 years.3 Studies conducted outside of Spain have estimated a prevalence of paediatric asthma of 2.5%.4,5 Despite advances in treatment, severe asthma continues to be associated to high rates of morbidity6 and to a mortality rate that, despite a decrease in recent years, continues to be significant.7 Furthermore, asthma generates high direct and indirect costs,8 with severe asthmatic patients consuming most of the resources allocated to this disease.1,8

Severity is an intrinsic characteristic of asthma that reflects the intensity of the pathophysiological abnormalities, encompassing both the intensity of the disease process and the response to treatment.9 We ought to differentiate between the concepts of severity and control. Control is the degree to which therapeutic interventions minimise or lead to the absence of asthma symptoms and the goals of therapy are met while reducing the risk of exacerbations and medication side effects.1,9,10 The correct identification of patients with severe asthma is essential to the appropriate management of the disease, mainly because the treatment and followup of patients depend on it.9,11 Similarly, a correct assessment of control is needed to adjust the treatment.9 However, the recommendations for the definition of severe asthma and for assessing control are inconsistent across guidelines.1,9–12

In response to the disparate criteria that affect the assessment of asthma severity and control, we developed a project in order to learn the perspective on these aspects from paediatric pulmonologists and paediatric allergists with expertise in the management of severe asthma. Our goal was not to create new definitions of severity and control, but to unify the criteria used in the diagnosis of severe asthma in clinical practice and specify the measures required for the correct followup of these patients. Furthermore, we developed consensus recommendations for the appropriate referral of children with severe asthma to specialised or tertiary care, and for the management of patients according to disease severity, including the use of novel therapies, particularly of recently introduced biological agents.13

Eleven paediatric pulmonologists and allergists with expertise in paediatric asthma from seven autonomous communities in Spain responded to the survey. The questionnaire consisted of 65 items divided into four sections (Tables 1–4).

The first section addressed the definition of severe paediatric asthma. Consensus in agreement was reached for 22 out of the 26 proposed items (84.6%). The second section addressed the monitoring of control in severe paediatric asthma, with consensus reached for 12 of the 18 items (66.6%): 11 in agreement and one in disagreement. Sections III and IV dealt with the referral of and therapeutic approach to children with severe asthma. A consensus was reached for 5 of the 9 items in section III (55.5%, 4 in agreement and 1 in disagreement), and for 11 of the 12 items in section IV (91.6%).

After the two evaluation rounds, a consensus had been reached for 50 out of the 60 items in the questionnaire (76.92%): 48 in agreement and 2 in disagreement (Fig. 1 and Tables 1–4). We summarised the most relevant items for which a consensus was reached into 10 recommendations (Table 5).

Figure 1.

Proportions of consensus reached in agreement and in disagreement and of lack of consensus for the total of items under analysis.

(0.06MB).

This document attempts to provide a practical and consensus-based perspective on severe paediatric asthma with emphasis on its definition and level of control, as well as patient referral and optimal management. The first three items of the questionnaire showed that the definition of severe paediatric asthma is not sufficiently clear in various guidelines, such as the Guía Española de Manejo del Asma (Spanish Guideline for the Management of Asthma [GEMA]),9 the Global Strategy for Asthma Management and Prevention (GINA) guidelines,1 or the International Consensus on Pediatric Asthma (ICON) guidelines for the paediatric population.10 Indeed, the definitions for asthma and for severity and control are not only inconsistent across these three guidelines, but also in relation to the European Respiratory Society/American Thoracic Society (ERS/ATS)12 and the World Health Organization guidelines.11 Most guidelines agree that severity of disease ought to be determined mainly on the basis of the step of treatment the patient requires to maintain control. However, their definitions of severity and control and the steps of treatment are not uniform. This inconsistency is probably the reason why the panel of experts agreed on considering that there is no clear definition of severe asthma and that the term is applied according to the judgement of each individual physician, as indicated by item 4 in the questionnaire.

In this regard, we must take into account that the assessment of severe asthma is different in infants, on one hand, and preschoolers, schoolchildren and adolescents, on the other. Thus, the asthma diagnosis must be reevaluated and confirmed before diagnosing severe asthma, ruling out other diseases with similar manifestations and keeping in mind that the classification of a patient with asthma is dynamic and can change over time.

The items that followed (5–22) sought a consensus on the elements that must be included in the definition of severe paediatric asthma. The agreement reached on this subject was that asthma should be considered severe in patients in whom one of the following occurs in the context of asthma control: having required two or more courses of oral corticosteroids in the previous year; requiring daily treatment with medium-dose inhaled corticosteroids combined with other controller medication, or requiring daily treatment with high-dose inhaled corticosteroids with or without additional controller medication, such as long-acting β2-agonists (LABAs) or leukotriene receptor antagonists (LTRAs); or using one short-acting β2-agonist (SABA) inhaler per month. In their comments regarding the questionnaire, some panellists stated that the use of as few as two SABA inhalers per year should be considered severe asthma, in adherence with current guidelines,16,17 as SABA use could be indicative of uncontrolled disease. The inclusion of inhaled corticosteroids at medium doses as monotherapy (consensus reached in the second round) and the consideration of SABA use are not criteria applied to the definition of severe asthma in the ICON, GINA or GEMA guidelines. However, the panellists expressed that in everyday clinical practice, these patients are usually considered to have severe disease.

In addition to determining severity by means of the step of treatment required for control, the panel reached a consensus on other clinical situations that may be considered severe in everyday clinical practice and that mainly pertain to the intrinsic severity of the disease. In this sense, a patient is considered to have severe asthma in the following cases: if the disease is life-threatening or significantly impairs quality of life; if exacerbations are occasional but severe, leading to hospitalisation and threatening the life of the patient; or if the patient has been hospitalised twice or more due to asthma in the previous year. A recently published document12 even considered a single admission to the ICU or to the hospital sufficient to categorise asthma as severe. Along the same lines, the panel also defined severe asthma as the patient not responding to optimised conventional treatment despite its correct implementation; the patient achieving adequate asthma control, but with a treatment that causes too many adverse effects in the opinion of the paediatrician; or the patient experiencing frequent symptoms despite good adherence to maintenance treatment. Furthermore, to complete the spectrum of clinical situations indicative of severe asthma, the panel reached a consensus in the second round regarding factors extrinsic to the disease, including factors pertaining to the patient or to the patient's social environment. Thus, the panel considered that the definition of severe asthma may also include patients that justifiably use health care resources frequently and regularly, or whose asthma worsens due to psychosocial or environmental factors that impede its control (for instance, non-adherence to treatment, improper inhaler use, poor understanding of the symptoms or the disease, exposure to smoke in the household, insalubrity, or unavoidable exposure to allergens), that is, with severe asthma that is difficult to control. All these clinical scenarios may guide the paediatrician in identifying patients with severe asthma in order to adjust their management accordingly. The panel also considered that it would be useful to have a validated composite index (one assessing symptoms, exacerbations, lung function and treatment needed for control) allowing the identification of children and adolescents with severe asthma and the assessment of disease severity. This recommendation is consistent with the high number of clinical situations that have been considered definitions of severe asthma in this section.

When it comes to the items in Section I for which a consensus was not reached, we want to highlight the exclusion from the definition of severe asthma of cases in which the isolated finding, in the absence of any other objective evidence of severity, is a decline in lung function with a forced expiratory volume in 1 second (FEV1) of less than 80%, despite it being a parameter included in many guidelines. Furthermore, we consider that a FEV1 of more than 80% does not rule out the presence of severe asthma.

Section II dealt with the monitoring of severe paediatric asthma. We ought to note that, consistent with the recommendations of the GEMA and GINA guidelines, the panel agreed that in addition to pursuing current control, monitoring should include the assessment and reduction of future asthma-related risk (worsening, exacerbations, decline in pulmonary function and adverse effects of treatment). To monitor these aspects, we recommend the use of questionnaires specifically designed for the paediatric population, and believe that clinical questions asked during the history taking do not suffice to assess control in paediatric patients with severe asthma. However, no consensus was reached as to which questionnaire ought to be used. When panellists were asked specifically which tool is best for assessing the level of control in paediatric patients with severe asthma, there was no consensus in choosing between the paediatric Asthma Therapy Assessment Questionnaire (ACQ), the paediatric Asthma Control Test (ACT) or the Control del Asma en Niños (Asthma Control in Children [CAN]), although a consensus was almost reached in favour of the latter.

Since there was no specific answer, in the second round the panellists agreed to accept that the level of control in paediatric patients with severe asthma should be assessed following the recommendations of the GEMA guidelines (CAN questionnaire, spirometry in older children, and possibly FeNO in other patients).9 The panel also considered that it would be best to exhaust all diagnostic and evaluation possibilities for the diagnosis and control of severe asthma (clinical assessment, lung function testing, allergy testing, FeNO, cytological analysis of sputum or even bronchoalveolar lavage). However, no consensus was reached when the survey asked specifically about the use of cytological analysis of sputum samples in the assessment of control in paediatric patients with severe asthma that have multiple exacerbations, which would be consistent with other guidelines, such as the ERS/ATS,12 that also do not recommend its generalised use. For the purposes of clinical practise and in summary, the panellists considered that the assessment of control in paediatric patients with severe asthma should take into account the medication needed to achieve control, the adverse effects associated with the medication, the reduction in the rate of exacerbations and the quality of life of the patient. Finally, it is worth noting that the panel considered that the training of the specialist is key in the detection of uncontrolled disease, as monitoring is essentially conducted on the basis of clinical parameters that are often influenced by how the patient or the family perceive the disease.

The referral of patients with severe asthma was addressed in Section III of the questionnaires. There are recommendations for the referral of asthma patients from primary care (PC) to emergency services7 and to specialised care in various guidelines.1,18,19 In response to items that explored whether patients with severe asthma are referred correctly, the panellists considered that it is not infrequent for patients with severe asthma followed up by the PC paediatrician to be referred late to the specialist. Consistent with this, it was agreed that the referral of patients with severe asthma to specialised care should be based on clear criteria agreed upon by PC paediatricians and paediatric asthma specialists, as opposed to the judgement of individual paediatricians. Furthermore, the panel agreed that PC paediatricians ought to refer patients with severe asthma to specialised care with high-priority status, even if the disease is controlled at the moment. On the other hand, no consensus was reached on whether all children with asthma receiving care from a PC paediatrician should be seen by the specialist at least once for evaluation.

The last section in the questionnaire attempted to clarify some concepts regarding the therapeutic approach to children with severe asthma. Most of the items in this section focused on the use of omalizumab, a monoclonal antibody that blocks circulating free immunoglobulin E, which plays a role in the clinical manifestations of allergic asthma.20 Clinical trials on patients aged more than 6 years have demonstrated the efficacy of omalizumab for the treatment of severe asthma.20–25 In the paediatric population in particular, there is evidence of statistically significant improvement in diurnal and nocturnal symptoms, a reduction in the use of medication,26 number of days with asthma symptoms,24 inflammatory markers, exacerbations, emergency room visits, hospital admissions and doctor's visits, an improvement in the quality of life, and the elimination of seasonal spikes in exacerbations associated with viral infections.20–25 The authors agree that the outcomes in everyday clinical practice are probably better than the outcomes achieved in clinical trials.27 The most recent guidelines1,10 place omalizumab in the step prior to treatment with oral corticosteroids. This recommendation is supported by level-A evidence.1

Finally, the panel also agreed that specific units for the diagnosis, control and treatment of children with severe asthma should be set up, as has already been done for adults.28

This study has the limitations inherent in the Delphi method. Chief among them are the difficulty in obtaining nuanced opinions from experts, and the potential for biases due to the influence of the sponsor. However, we tried to minimise the effects of these limitations, as the sponsors did not participate in the analysis and interpretations of the results or in the drafting and editing of the document.

In short, severe asthma is a relevant health problem in the paediatric associated with a high use of health care resources.1,8 While our knowledge of asthma has grown in recent years, there are still many uncertainties and controversial aspects when it comes to severe paediatric asthma.29,30 These uncertainties may be due, in part, to the heterogeneity of the disease and the lack of detailed knowledge of the mechanisms underlying its various phenotypes.31 There is also a wide variability in the definitions of severe asthma and in the followup, referral, and treatment recommendations. This document offers a few practical guidelines that may clarify some concepts and help the paediatrician optimise the management of this disease.

This project was funded and sponsored without restrictions by Novartis Farmacéutica S.A.

C.S.-S. and A.N. have participated in presentations and workshops for Novartis Pharmaceuticals Corporation.