Asthma is an inflammatory disease of the airways characterized by typical patterns of symptoms, such as recurrent episodes of wheezing, coughing, shortness of breath, and chest tightness. These features are associated with hyperresponsiveness of the asthmatic airways to inhaled irritants or endogenous stimuli that cause airway obstruction [1].

Asthma is one of the most common chronic disease affecting children, and it often starts in infancy and preschool years. Previous studies demonstrated that frequent wheezing in early life is associated with the development of asthma in later childhood and reduced lung function persisting into adulthood [2-4]. Early diagnosis of asthma is, therefore, important to avoid treatment delay and reduce morbidity. However, it is difficult to clearly define “asthma” in preschoolers because the underlying pathophysiology in this age group is poorly understood yet and there are no definitive biomarkers, and also because objective pulmonary function tests are unavailable [5].

Wheezing, a sign of airway obstruction, is very common in young children, who have much smaller airways than older children and adults. Their airways are so small that even a small amount of inflammation caused by viral infection can induce flow limitation and wheezing. In some children, wheezing is the first episode of asthma and often triggered by viral respiratory infection. Half of preschool children experience at least one episode of wheezing, and a third of them will have persistent wheezing and develop asthma at school age [6]. Thus, the classification of phenotypes of early wheezing is needed to identify the children at high risk of developing asthma later who might benefit from early intervention.

This article aimed to reach a consensus regarding the diagnosis and management of asthma in young children through a review of recent studies and current asthma guidelines.

Bronchiolitis, a lower respiratory tract infection (LRTI), is the most common cause of hospitalization in infancy, and severe bronchiolitis is known to be associated with the later development of childhood asthma.

Bronchiolitis is generally considered a single disease entity, but many studies have reported that it is a heterogeneous condition [16,17]. There are increasing and convincing evidences showing that not all viral bronchiolitis corresponds to the same clinical condition, and that affected patients have high heterogeneity in clinical presentation, immune responses, and response to bronchodilators, and progression to recurrent wheezing or asthma [17]. The upper age limit for the diagnosis of bronchiolitis varies among countries; that is, bronchiolitis is defined in infants aged up to 24 months in North America and the United Kingdom, 12 months in some European countries, and 18 months in Australia [16]. The causative virus and the inclusion or exclusion of patients with a previous history of wheezing are additional sources of variability [16,17].

Most children with asthma that starts before 6 years of age initially present with bronchiolitis during infancy (the first episode), and asthma in infancy and preschoolers overlaps with virtually all traditional definitions of bronchiolitis [18]. Moreover, most exacerbations of preschool asthma are triggered by the same viruses implicated in bronchiolitis. Thus, we asked whether the wheezing infant has “bronchiolitis” (i.e., should receive supportive care) or “preschool asthma” (i.e., should receive early intervention with appropriate treatment) [18]. In fact, these 2 groups cannot readily be distinguished on a clinical basis and require clarification in further studies [17,18].

The relationship between respiratory syncytial virus (RSV) and asthma or atopy is known to be relatively low [19,20], but a recent study showed that certain RSV genotypes (ON1 and BA) preferentially cause bronchiolitis in infants with a possible genetic predisposition toward asthma and atopy [21]. Rhinovirus (RV) bronchiolitis is associated with a high risk of subsequent asthma at school age, especially in children with early sensitization to multiple allergens, higher immunoglobulin E (IgE) levels, higher eosinophil counts, and a history of wheezing [22,23].

A recent prospective cohort study of infants hospitalized for bronchiolitis identified 5 distinct clinically meaningful metabotypes by profiling the nasopharyngeal metabolome, and those with the metabotype characterized by high inflammatory amino acids and low polyunsaturated fatty acids were at the highest risk of developing asthma by 5 years of age [24].

Most current bronchiolitis guidelines define viral bronchiolitis as a single respiratory syndrome and recommend no active treatment options other than supportive care irrespective of viral etiology, host responses, or risk factors. However, recent studies suggest that it is reasonable to consider pharmacological treatment, that is, bronchodilators or corticosteroids, in infants with moderate to severe respiratory distress, particularly in those with risk factors for asthma [17]. Two separate randomized trials of systemic corticosteroid use in children with first-time RV bronchiolitis reported long-term efficacy in reducing the risk of asthma development [19].

In summary, although previous data indicated that bronchiolitis should be treated on a more personalized basis and that children with first wheezing episodes and risk factors for asthma may require early intervention, evidence remains insufficient. Further studies to define the phenotypes of viral bronchiolitis based on clinical and molecular levels and larger trials to support phenotype-based treatments are needed.

Many birth cohort studies demonstrated that various wheezing phenotypes coexist during preschool years and approximately 30% of infants and preschoolers with recurrent wheezing develop asthma at school age [6]. Early identification of and intervention for children at risk of developing asthma may be crucial to improve the prognosis of the disease. Thus, during the last 2 decades, many asthma prediction models have been developed based on the risk factors associated with persistent wheezing identified in previous cohort studies.

In 2000, the first model, the original asthma predictive index (API), originated from the TCRS and defined 2 prediction rules: loose API and stringent API [25]. The API, developed in the general population, has been the most popular prediction model and is commonly considered the reference to which newly developed models are compared. Children with a positive loose index were reportedly 4 times more likely than those with a negative loose index to have active asthma at school age (sensitivity, 42%; specificity, 85%; positive likelihood ratio [LR+], 2.8). Children with a positive stringent index were reportedly 7 times more likely to have active asthma at school age (sensitivity, 16%; specificity, 97%; LR+, 5.3) [25].

The API has been validated in other cohort studies and new populations, and the stringent API has been the most commonly tested model in different cross-sectional and case-control studies [26,27]. A recent population-based cross-sectional study in Korea of 916 preschool children showed a significant association between questionnaire-based current asthma and API, suggesting that the API can be used as a diagnostic tool for asthma with reasonable accuracy in preschool children [28]. The API was modified by replacing the clinical diagnosis of allergic rhinitis with evidence of allergic sensitization, a more objective criterion (Table 1). The modified API (mAPI) was developed in the high-risk COAST (Childhood Origins of ASThma) cohort of infants with at least 1 atopic parent (a parent with positive aeroallergen sensitization and/or physician-diagnosed asthma) [29]. A positive mAPI increased the probability of an asthma diagnosis later in school age to nearly 90% in preschoolers with atopic parents and frequent wheezing [29].

The API was mentioned in the Global Initiative for Asthma (GINA) guideline [1], and the mAPI was described as useful for identifying children who are more likely to respond to inhaled corticosteroid (ICS) therapy in the Expert Panel Report 3 guideline of the National Asthma Education Prevention Program (NAEPP) [30]. Both API and mAPI have been used as recruitment tools in many randomized clinical trials as well as to identify preschool wheezers with the “type 2 high” endotype [31]. The API, the first and the most frequently used model, had a relatively good positive LR and its major strength is its simplicity, which makes it easy to use. However, its negative LR is insufficient to rule out the development of school-age asthma [31].

Other prediction models that were validated externally are the model from the PIAMA birth cohort and the asthma prediction tool (APT) from the Leicestershire cohort, both of which were developed in high-risk groups [32,33]. The PIAMA model proposed a somewhat complicated asthma prediction score (range, 0–55) using 8 predictor variables in preschool children who presented with wheezing and/or night coughing without a cold in the previous 12 months and showed that children with high scores (≥30) had a 42% risk of developing asthma later in school age [32]. The APT model was developed in preschool children who visited doctors with respiratory symptoms: ≥1 wheezing or chronic cough (cough without a cold or night coughing) in the previous 12 months and used 10 predictor variables. APT classified the children into low risk (score ≤5), medium risk (score 6–9), and high risk (score ≥10) groups and showed 16%, 48%, and 79% risks of developing asthma later, respectively [33].

Recently. existing prediction models were reviewed for their predictive ability for school-age asthma and clinical applicability [29,34]. There are many differences among the models in study design, study size, target population, predictor variables, diagnostic criteria of school-age asthma, and statistical methodology (Table 2).

Most prediction models developed to date have shown moderate predictive performance and modest generalizability when validated externally, but they remain far from perfect in terms of widespread implementation in clinical practice [29,34].

It is particularly difficult to establish a diagnosis of asthma in infants and preschoolers, the reasons of which include difficulties in performing pulmonary function tests at this age, a lack of evidence for underlying airway inflammation, and the fact that the disease may subside during the childhood. The diagnosis of asthma in young children is most often based on symptom patterns, presence of risk factors, and therapeutic responses.

Many international and national asthma guidelines, including 4 major guidelines: the NAEPP, the Practical Allergy (PRACTALL) Consensus Report by the European Academy of Asthma and Allergy, Evidence Based Approach by the European Respiratory Research (ERS) task force, and GINA guidelines, have been developed during the past 2 decades to increase physicians’ awareness of the disease, improve diagnosis and management, and promote international collaboration in asthma research [35,36]. Current asthma guidelines commonly describe that diagnosis of asthma in infants and preschoolers is difficult because they express different patterns of wheezing illnesses, but most guidelines implicitly accept that the diagnosis of asthma can be established without an age limit. However, the ERS guideline denies to use the term “asthma” in preschool children with wheezing episodes since they might disappear over time [12].

Diagnosis of asthma in this age group is based on physician’s interpretation of the following clinical findings: (1) symptoms and signs of airflow obstruction (frequent wheezing, chronic cough, shortness of breath); (2) improvement of these signs and symptoms with asthma therapy; and (3) no clinical suspicion of an alternative diagnosis.

The effective management of early-life wheezing/asthma is very important because irreversible impairment of lung function may occur in infancy and preschool years. This age group tends to have significantly higher exacerbations caused by frequent respiratory infections than older children, and repeated and cumulative lung injuries might affect normal lung growth and asthma persistence [39]. A recent study showed the association between asthma control trajectories in preschoolers and disease remission: the worse the control, the lower the likelihood of remission [40].

Diagnosis of asthma in infants and preschoolers is particularly difficult because objective lung function tests cannot be performed and definitive biomarkers are lacking. Moreover, management of asthma is challenging due to different phenotypic presentation of early asthma. Many recent studies have investigated the application of personalized medicine for early asthma by identifying specific phenotypes. Further researches, including genetic and molecular studies, are needed to establish a clear definition of asthma and develop more targeted therapeutic approaches in this age group.