Wheezing disorders in childhood are common and vary widely in clinical presentation and disease course. Various phenotypes have been proposed and classified either by trigger for the wheeze, for example, “episodic viral wheeze” (triggered only by viral colds) or “multiple trigger wheeze” (triggered also by other factors) [36–38]. Phenotypes have also been classified by historical time course, such as “early transient”, “persistent”, or “late onset” [25, 39]. However, these phenotypes do not elucidate whether they represent distinct or different disease entities with separate aetiologies. The three latter phenotypes “early transient,” “persistent,” and “late onset” can only retrospectively be ascertained and are therefore not of clinical or therapeutic relevance. A panel of 7 experienced clinicians from 4 European countries, working in primary, secondary, and tertiary paediatric care, found that preschool wheezing disorders consist of several phenotypes [40]. During structured discussions disease entities could be narrowed to three entities which were linked to proposed mechanisms: (1) allergic wheeze, (2) nonallergic wheeze due to structural airway narrowing, and (3) nonallergic wheeze due to increased immune response to viral infections. Both smoking during pregnancy and prematurity were considered predisposing factors for airway narrowing and therefore should not define separate disease entities.

In 2008, a task force from the European Respiratory Society defined two phenotypes, “episodic viral wheeze” and “multiple trigger wheeze” (Table 1) [27]. The former is defined as a phenotype where wheezing only occurs during viral colds, while the latter better resembles asthma, with wheezing also occurring without colds and during physical strain, laughing, and so forth. Furthermore, it was advised not to use the term “asthma” in children with preschool wheeze. In addition, up to now there is no prospective validation of the two phenotypes, episodic viral wheeze and multiple trigger wheeze. It may well be that some children with episodic viral wheeze, continue to wheeze and develop asthma, while some children with multiple trigger wheeze stop wheezing by the age of six.

The “allergic wheezing” phenotype, defined by the expert panel, and the “multiple trigger wheezing”, as defined by the ERS task force, are more or less similar. This is also true for the “nonallergic wheezers due to increased immune response to viral infections” and the “episodic viral wheeze.” The most important issue is that the clinical validity of these phenotypes still remains to be prospectively proven. Yet, from a therapeutic perspective, the two phenotypes defined by the ERS task force seem to be the most practical clinical approach at this moment. Other respiratory tract diseases that cause wheezing, such as gastroesophageal reflux, anatomic abnormalities of the airways, aspiration of foreign bodies, immune deficiencies, cardiac abnormalities, and cystic fibrosis, should be excluded.

Periods of viral-induced wheezing, cough, and chest tightness occur in many children and currently it remains difficult, if not impossible, to identify which child is at risk of developing asthma later in life. In order to effectively treat the preschooler with asthma, it is necessary to identify the asthma early in the course of the disease. Yet, in order to avoid overtreatment, including the possible side effects of especially ICS therapy, the child with transient wheezing episodes also needs to be identified early.

Respiratory syncytial virus (RSV) and rhinovirus (RV) have both been linked to initial wheezing episodes and to the risk of recurrent wheezing in early childhood [41]. RSV infections during the autumn and winter are of major importance for clinicians that, due to the many emergency room consultations and clinical admissions, they necessitate. Yet, RV infections during the first three years of life have a significantly stronger association with the development of asthma, by the age of six years, than RSV infections in early life. When considering wheezing during the first three years of life, Jackson et al. [41] showed that wheezing with RSV alone was associated with an increased risk (OR 2.6) of asthma by the age of 6, compared with children who did not wheeze with RV or RSV. Wheezing with RV, regardless of RSV wheezing history, was associated with an even greater increased risk of asthma by the age of six (OR 10.0).

However, children with early-onset allergic sensitisation and recurrent respiratory wheezing seem to be at risk for asthma in adolescence and adulthood. These observations suggest that both respiratory viral infections and allergic sensitisation may injure the airways, resulting in reversible airway narrowing and bronchial hyperresponsiveness to external stimuli, and may lead to continued wheezing.

Various predictive models of clinical indicators of risk have been proposed. Castro-Rodríguez et al. [42] proposed the Asthma Predictive Index (API) in order to assess which child would continue to wheeze at school age (Table 2). They formulated a parental history of asthma and physician diagnosed atopic dermatitis as major criteria, and physician diagnosed allergic rhinitis, wheezing unrelated to colds, and blood eosinophils ≥4% as minor criteria. Using the API, a child with recurrent wheezing and 1 major criterion or 2 of 3 minor criteria had a 4.3 to 9.8 times greater risk of asthma at school age. A few years later the API was modified because allergic rhinitis is difficult to diagnose in young children [20]. Allergic sensitization to ≥1 aeroallergen was added as major criterion, while physician diagnosed allergic rhinitis, allergic sensitization to milk, egg, or peanuts were added as a substitute for the minor criterion.

Several other predictive models have subsequently been proposed [31, 43–46], yet few (the API, the modified API, and the PIAMA risk score) [20, 42, 45] have been externally validated. In a recent evaluation of the predictive performance of the API and the modified API in the Tucson group, Leonardi et al. [47] also validated both forms of the API in the 1998 Leicester cohort [48]. Using the API and simpler prediction rules, based only on wheeze frequency and a random rule, to elucidate the predictive performance of chance, they attempted to predict asthma at school age. The predictive performance of the API in the Leicester cohort was, although comparable to the original study, modest and similar to the prediction based only on the frequency of preschool wheeze [47]. Savenije et al. recently published a review of this subject [49]. Similar to the results of Leonardi et al., they concluded that the currently available prediction rules, aiming to identify preschool children having asthma at school age, are of modest clinical relevance. The authors suggested that the prediction rules used may be enhanced by a more precise definition of risk factors, by the addition of exposures and interaction with exposures with other risk factors, by more precise phenotyping with objective measures, by the combination of noninvasive techniques with developed prediction rules, and by the addition of a personal genomic risk profile. Although the conclusions drawn are valid, the use of this combination is currently not feasible or relevant in daily clinical practice.

Childhood asthma is common in the Western world and underdiagnosed in minority populations in Europe and the United states. Minority populations are significantly burdened by asthma morbidity [55, 56] and suffer higher rates of emergency department visits, hospitalization, and even death [55]. Quality of life (QoL) in childhood asthma is affected by asthma control. The better the asthma control, the better the QoL is. Uncontrolled asthma is associated with a reduced lung function, impaired performance in physical exercise, and impaired QoL [57].

Most asthma symptoms occur at night. Almost half of asthmatic children presenting at a university hospital outpatient clinic suffered from nocturnal symptoms [58]. Nocturnal symptoms cause loss of sleep [59]. Even in children with stable asthma, quality of sleep is diminished [60]. Sleep disruption influences daily activities, such as school attendance and performance. Nocturnal awakening may also cause parental work absenteeism, and may disrupt family life [61]. More severe asthma leads to more frequent school absenteeism which may negatively affect an individual's level of education and, possibly, choice of career. Furthermore, frequent nocturnal awakenings may cause depression, aggressive behaviour, and attention problems in adulthood [62].

Exercise, induced airway obstruction (EIAO) is yet another burden for children with asthma. Together with the frequent nocturnal awakenings due to dyspnea, EIAO may hamper social contacts. Exercise is a common trigger of bronchial hyperresponsiveness and may cause cough, wheezing, and chest tightness [63, 64]. EIAO is indicative of insufficiently controlled asthma [65].EIAO occurs in up to 23% of school children and has serious repercussions on the quality of life of these children [66, 67]. EIAO limits participation in sports and play, and 79% of children experience EIAO as the most burdensome of their asthma [68, 69]. EIAO is highly specific for childhood asthma, as it is indicative of airway inflammation [66, 70]. Sports and play are of great importance for a child, stimulating the development of both social and motor skills. Unfortunately, symptomatic history is neither a sensitive nor a specific tool for diagnosing EIAO.[71–73] EIAO may induce reluctance to exercise and a sedentary lifestyle, which in turn may lead to a low cardiovascular fitness and an increased body mass index (BMI). Lower cardiovascular fitness results in higher breathing rate at a relatively low work load, which is the trigger for EIAO. Furthermore, an increased breathing rate results in a feeling of dyspnea, which may be misinterpreted by children and their parents as EIAO. An increased BMI has been associated with bronchial hyperresponsiveness for both exercise and methacholine [71, 74–76]. In conclusion, asthmatic children with a low cardiovascular fitness and/or a high BMI, compared to peers, will have a relatively higher breathing rate during play and sports. This, in turn, increases the trigger for EIAO, further compromising athletic performance and QoL.

Childhood socioeconomic status in the United States seems to be strongly associated with the onset of chronic diseases such as asthma. In a longitudinal population based study in the USA, paternal education was negatively associated with the risk of developing asthma. Maternal education was correlated to high school dropout [77]. Hatzmann et al. studied the QoL consequences in parents of Dutch children with various chronic diseases. The largest subgroup was parents of children with asthma. Parents of all groups had a significantly lower health-related quality of life. Subgroup analysis showed lower health-related quality of life with respect to sleep, social functioning, daily activities, vitality, positive emotions, and depressive emotions in disease-specific groups [78].

The goal of asthma therapy in children is to achieve asthma control by optimizing lung function, reducing day and night time symptoms, reducing limitations in daytime activities and the need for reliever treatment, and by reducing asthma exacerbations [79]. However, especially in children, it is important to achieve control with a minimum of medication side effects.

Asthma control is assessed by the presence of daytime symptoms, limitation in activities, nocturnal symptoms and awakenings, need for reliever medication, and lung function assessment in children from the age of 6 (Table 4). Total control is possible, but optimal effect of medication is often hampered by poor adherence and poor inhalation technique. Apart from these factors, additional conditions such as dysfunctional breathing, allergic rhinitis, obesity, and mental condition may hinder optimal control. Clinical practice shows that many children are not well controlled [80, 81]. In the latter (Swiss) study, asthma control was excellent in only 18% of children [81], satisfactory in 33%, and unsatisfactory with disrupted sleep, restricted activities, and school absence in 49%. In addition, the authors found a mismatch between poor asthma control and perception of control by the parents. Eighty-nine percent of the parents of children with poor asthma control were actually satisfied with the results of treatment. The same misconception applies for physicians. Van den Berg et al. [82] interviewed 118 Dutch paediatricians and 152 general practitioners, in order to assess the view of the physician with respect to the patient's asthma management. A questionnaire was used with similar questions to those of the AIRE study [83]. Dutch physicians believed that the asthma in the majority of their patients is well controlled and underestimate the prevalence of daytime symptoms. They believe that their patients are aware of the differences between reliever medication and maintenance medication and overestimate the number of patients in possession of a written action plan.

Asthma control in the GINA guidelines aims at improving control by assigning each patient to one of five treatment steps [1]. If a patient is not well controlled, depending on the medication step he or she started with, controller medication should be started, or the dose should be increased. In adult patients, the Goal study investigated this strategy [84]. A 1-year, randomized, stratified, double-blind, and parallel-group study of 3421 patients with uncontrolled asthma compared fluticasone and salmeterol/fluticasone in achieving totally and well-controlled asthma. Treatment was stepped up until total control was achieved (or maximum 500 μg corticosteroid twice a day).Only 19% of the adult patients on fluticasone and 41% of on salmeterol/fluticasone achieved total control.

This study emphasizes that other, previously mentioned, factors such as poor adherence to medication, poor inhalation technique, and unrecognised comorbidity play an important role. Physicians and nurses should recognise and try to improve these behavioural aspects. Seeking partnership with parents and children and setting individual chosen goals of therapy may be helpful in improving disease control. A written self-management plan and asthma education aimed at better perception by parents and children may enhance success [85–87].

The majority of children with asthma are easy to manage with occasional bronchodilator use or a low or moderate dose of ICS. Children who are referred to specialist care, but do not respond to standard therapy, are defined as having problematic severe asthma. The burden for this group is severe. Children with uncontrolled asthma despite high dose ICS and controller therapy have a decreased QoL, consume a disproportionate amount of resources, and may die prematurely [88]. The exact prevalence of this group is hard to estimate but is probably approximately 5% of all children with asthma or 0.5% of the pediatric population [89]. The key question to pose is whether these children have been sufficiently evaluated over a period of time by a specialist [90]. A number of studies have shown that the majority of these children ultimately receive a different diagnosis have poor adherence to their medication or have a poor inhaler technique [91, 92].

Problematic severe asthma needs careful evaluation. The patients form a heterogeneous group requiring a specific workup. The group consists of (1) children with an incorrect diagnosis of asthma; (2) children with asthma in addition to another disease; (3) children with difficult asthma (which can be improved after optimizing basic management) (4) children with therapy resistant asthma (severe symptoms despite the implementation of all the basic management steps).

Asthma may be mimicked by other diseases such as dysfunctional breathing (hyperventilation or vocal cord dysfunction, VCD), malformations of the airway anatomy such as a tracheal malacia, or vascular anomalies such as a vascular ring. Other diseases that should be excluded are cardiac anomalies, immune deficiencies, primary cilliairy dyskinesia, cystic fibrosis, bronchiectasis, obliterative bronchiolitis, inhaled foreign body, allergic rhinitis and gastroesophageal reflux.

Asthma itself may be mild or moderate, but comorbidities such as those mentioned above may also be present. VCD is often seen in conjunction with asthma and is a respiratory condition characterized by adduction of the vocal cords, resulting in airflow limitation at laryngeal level. Newman et al. [93] found that 53% of laryngoscopically confirmed adult VCD patients also had asthma. Most of the patients were young woman and with an average of 4.8 years of misdiagnosed asthma. Typically, the abnormal breathing sounds disappear when the child with VCD is asleep, and in contrast to asthma, a child with VCD does not suffer from nocturnal awakenings. Other conditions, as mentioned under Incorrect Diagnosis of Asthma, as well as psychosocial factors, should be considered as co-morbidities.

Difficult asthma is defined as that which is poorly controlled despite a daily dose of at least 800 µg budesonide or equivalent for a minimum of six months [94]. Symptoms may be worsened by continuing environmental factors, such as smoking by the parents or the child, or allergens [95]. Environmental causes of secondary steroid resistance, such as continuing allergen exposure or environmental tobacco smoke exposure, should be identified [96–98].

It is therefore necessary to evaluate the home situation, and to contact the general practitioner and school. In a multidisciplinary consultation with physicians and asthma nurses, all results of the history, adherence to therapy, inhalation technique, allergy testing, lung function measurements (spirometry and bronchial hyperresponsiveness challenges), the results of the home visit for the evaluation of environmental triggers, and psychosocial issues need to be addressed [90].

It is worthwhile attempting the reduction in symptom levels in difficult asthma. Not only because of current symptoms, but also to reduce future risks [90], such as failure of normal lung growth [99], risk of loss of future asthma control, risk of future exacerbations, risk of long-term chronic obstructive pulmonary disease (COPD) [100], and risk of medication side effects.

Once all has been checked, what remains is classified as severe therapy resistant asthma. Bush and Saglani proposed a stringent workup of these patients [101]. The child should be assessed prior to, and after, a steroid trial with injection of triamcinolon. Assessment should include airway symptoms (asthma control test), use of rescue medication, lung function (spirometry, reversibility after administration of a short-acting β ₂ mimetic), airway inflammation (exhaled nitric oxide, induced sputum, and fibreoptic bronchoscopy with bronchoalveolar lavage and endobronchial biopsy).

With this protocol Bush and Saglani attempt to answer the following questions: (1) what is the pattern of airway inflammation, (2) is there concordance between symptoms and inflammation, (3) does the child have steroid responsive asthma, and (4) does the child have persistent airflow limitation? This protocol may enable physicians to better phenotype this small group of children and may help to better future therapies.

A number of nonpharmacological measures to improve symptoms and disease outcome should be discussed with the parents. As previously mentioned, partnership with parents is important in order to set individually chosen goals of therapy and may be of help in improving control of the disease. Furthermore, possible fear of side effects of drugs should be discussed. Inhalation technique should be trained, and a written self-management plan should repeatedly be discussed on several occasions. Nonpharmacological measures are similar in preschool children and children above the age of 6. However, there are also nuances with respect to children in puberty. The asthma team should be aware that children may start to smoke before the age of 15, mostly because of peer group pressure [102]. Another point of concern is (lack of) adherence to medication.

Environmental tobacco smoke induces wheezing in the preschool child. Exposure to environmental tobacco smoke in utero is strongly associated with preschool wheezing [4, 103]. After birth it may also induce wheezing and lead to exacerbations [104]. Moreover, children exposed to smoke are more likely to smoke later in life and are prone to develop COPD [105, 106].

There is no evidence that avoidance of allergens improves symptoms in children with viral wheeze. In the case of clinical evidence of allergy and allergic sensitisation, symptoms may be aggravated by exposure. Various population studies have demonstrated that children growing up with pets are less likely to develop sensitisation to pets [107, 108]. This may be due to selection bias since families with allergic individuals tend to avoid having pets.

House dust mite (HDM) reduction measures have been shown to reduce HDM levels in households [109] but have not been shown to improve asthma symptoms in children [110].

The pathogenesis of recurrent wheezing, coughing, chest tightness, and breathlessness at preschool age is heterogeneous. This is an explanation for the variation in effectiveness of the different drug therapies in the younger age group. Low drug deposition in the lungs despite optimal inhalation, anatomy of the upper airways, and difficulty in inhaling medications in a correct manner may explain the moderate effectiveness of the different medications in preschool children [111]. Lung deposition may be improved by using a pressurized metered dose inhaler (pMDI) with extra-fine particles. However, even if the most optimal device is chosen, correct administration remains the single most important determinant for efficient drug delivery. A small facemask leak may dramatically reduce the delivered dose, making a good seal essential. The dosage reaching the lungs is minimal during crying [112, 113].

Worldwide, different guidelines for the management of asthma in childhood are in use. Many countries have a unique guideline. The GINA guideline and the British Guideline on the Management of Asthma are leading and available for many physicians around the world [1, 114]. Table 5 shows pharmacological management in preschool wheezers of 5 years and younger as suggested in the GINA guidelines [79].