Abstract
Wheeze in preschool children (5 years of age and younger) is common. The majority of severe episodes are triggered by viral colds. Unlike atopic asthma in adults and young people, the underlying pathology of this condition is poorly understood, and the label of “preschool wheeze” should therefore not be regarded as a diagnosis but a description of symptoms. It is important to consider other causes of wheeze, but, for the most part, serious conditions such as cystic fibrosis and foreign body aspiration are associated with atypical features on careful history and examination. There remain significant uncertainties about the optimal management of children with this condition. Short-acting bronchodilators are indicated for the acute treatment of wheeze, and current evidence suggests that daily inhaled corticosteroid therapy is an effective preventive therapy, at least in a subgroup of children. Some trials suggest that preemptive therapy with inhaled corticosteroids may be as effective as regular inhaled corticosteroids. Since wheeze is intermittent for the majority of children, preemptive therapy is a logical approach. However, more studies are needed to confirm whether preemptive inhaled corticosteroids are as, or more, effective than regular preventer therapy.
Keywords
preschool wheeze, preschool asthma, inhaled therapy
Epidemiology and Burden
Preschool asthma (i.e., wheeze in children 5 years of age and younger) is a common condition. Indeed, a UK study reported that between 1990 and 1998, there was an increase in the prevalence of parent-reported preschool “wheeze ever” (from 16% to 29%), “current wheeze” (from 12% to 26%), “diagnosis of asthma” (from 11% to 19%), and “admission for wheeze” (from 6% to 10%). This high prevalence of wheeze in preschool children results in a high burden of disease. For example, US National Surveillance of Asthma statistics report the highest average annual asthma physician office visits, hospital outpatient department visits, emergency department visits, and hospitalizations in the preschool period than other age groups ( Fig. 44.1 )—a pattern also found in other countries.
Episodes of preschool wheeze are frequently associated with signs of an upper respiratory tract infection (URTI). A wide range of infectious agents triggers these episodes (exacerbations). In a prospective cohort study done in Copenhagen, both respiratory viruses (e.g., picornaviruses, respiratory syncytial virus [RSV], and coronavirus) and bacteria ( Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis ) were isolated from the hypopharynx in just over half of preschool wheeze episodes. Bacteria alone were isolated in just over a third of wheeze episodes, and respiratory viruses alone were isolated in 10% of episodes. In preschool children with clinically severe wheeze, human rhinovirus species C (HRVC) is often isolated, especially in those admitted to hospital. While an increased virulence of HRVC has been suggested for this association, there is accumulating evidence that gene-environment interaction is important. For some children this may be due to genetic susceptibility. In other children, allergy may be important, potentially because of impaired innate immune response leading to increased viral replication.
Diagnosis
Asthma is considered an inflammatory disease presenting with episodic or persistent respiratory symptoms associated with variable airflow obstruction to endogenous or exogenous stimuli. However, preschool children with wheeze do not always have airway inflammation between wheezing episodes. As in adults and older children, asthma in preschool is based on recurrent (i.e., two or more) episodes of airflow obstruction and reversibility with appropriate inhaled medication. The diagnosis should be considered in children aged 12 months and older with no suspicion of another condition. Wheeze is the most specific sign of airflow obstruction; it refers to the presence of a continuous musical tone or squeaking commonly heard on auscultation in early expiration or at the end of inspiration. Accompanying signs of obstruction include cough, tachypnea, accessory muscle use, hypoxemia, and, in severe cases, alteration of the mental state. Significant clinical improvement with bronchodilators or corticosteroids is required to document reversibility or, alternatively, fluctuation of symptoms spontaneously over time.
In infants, there is some inconsistency about the diagnostic label applied for wheeze heard on auscultation. A frequent condition in this age group is bronchiolitis—a condition that is associated with signs of a respiratory infection, predominantly, but not exclusively, associated with primary RSV infection of the lower respiratory tract. Infants with bronchiolitis typically do not display significant reversibility, either to bronchodilators or other asthma medications, and in this condition a therapeutic trial is not indicated. Although the diagnosis of bronchiolitis is clinical, its varied definition results in diagnostic confusion. In Canada and the United States, a diagnosis of bronchiolitis is a first episode of wheezing in children up to the age of 1 and 2 years, with lower respiratory signs that include wheeze. By contrast, in the United Kingdom and South Africa, the diagnosis of bronchiolitis is mainly limited to infants under 6 months of age, typically with fine crackles but without wheezing. Consequently, wheeze in children, particularly those between 6 months and 2 years, with a first or second episode of respiratory difficulty, and no observed clinical response to asthma medication falls into a clinically unclear area, and is thus frequently labeled as “preschool wheeze” while awaiting a firm diagnosis. However, preschool wheeze is not a diagnosis, but only a symptom underlying an, as yet, poorly defined pathological entity. By careful observation including, when indicated, a therapeutic trial—clinicians should aim to make a definitive, if not at least a presumptive, diagnosis to apply appropriate therapy. In this regard, a therapeutic trial of asthma medication (bronchodilators with oral corticosteroids [OCS], in case of a moderate or severe exacerbation) would be indicated in children aged 12 months and older to document reversibility.
The diagnosis of preschool asthma (defined previously) is best made on the observation of a trained health care professional (or alternatively a convincing parental history) of two or more episodes with signs of airflow obstruction and reversibility. A thorough history and examination is essential to make a presumptive or conclusive diagnosis of asthma and to exclude alternative diagnoses that may cause respiratory symptoms in infancy and early childhood. There are two important caveats to parent-reported wheeze: the accuracy of the vocabulary and the lower sensitivity of ears compared with a stethoscope. When taking a history, wheeze should be separated from other respiratory sounds by asking about “a high-pitched whistling or squeaking sound from the chest, not the throat.” Parental reporting of wheeze cannot be regarded as the gold standard. For example, in a large population-based study, 17% of families did not define wheeze as a whistling noise, despite being given a description of wheeze in a questionnaire. Showing parents a video of common respiratory signs and then asking them to identify the closest match help distinguish wheeze from other sounds such as stridor and upper airway rattles. However, direct observation of signs of airflow obstruction and reversibility during an exacerbation by a trained health care professional remains the preferred approach. In a child with a prior documented exacerbation or a convincing history of an exacerbation, who does not present with clinical signs of airflow obstruction, an alternative approach is to document reversibility with a 12-week trial of maintenance inhaled corticosteroids (ICS), with parent-reported change in the frequency and severity of chronic and acute symptoms. This treatment should be discontinued if there is no benefit; many would want to exclude the possibility that the child had in fact recovered spontaneously by having a trial period of stopping treatment.
Parents should be asked about the nature and duration of symptoms, exacerbating factors, family history, and presence of atopy, rhinitis, and smoking in the home or car. History and examination should focus on eliminating the other important diagnoses that may cause respiratory symptoms in infancy and early childhood. Alternative diagnoses include structural abnormalities, gastroesophageal reflux, congenital heart disease, foreign body, chronic aspiration, chronic airway infection, and the consequences of extreme prematurity. Red flags for alternative diagnoses include prominent upper airway symptoms, symptoms from the first day of life, sudden onset of symptoms, chronic moist cough, symptoms worse after meals, and weight loss ( Table 44.1 ). Examination should pay attention to clubbing, wasting, severe tonsillar hypertrophy, severe chest deformity, fixed monophonic or asymmetrical wheeze, and cardiac murmurs. A 2016 review of the diagnostic evaluation of infants with recurrent or persistent wheezing (despite adequate inhaled asthma therapy) by the American Thoracic Society recommends flexible bronchoscopy, pH monitoring, and a swallowing study; however, the evidence to support these recommendations was found to be of low quality ( Table 44.2 ).
| Diagnosis | Clinical Features |
|---|---|
| Aspiration syndromes (e.g., gastroesophageal reflux, H-type fistula) | Vomiting, poor weight gain, coughing during feeding, and abdominal distension with H type fistula |
| Inhaled foreign body | Prior episode of coughing or choking (this may be absent), chronic cough |
| Immune deficiency | Wheeze with infections that are severe, persistent, unusual, or recurrent |
| Cystic fibrosis | Cough in first weeks of life, poor weight gain |
| Primary ciliary dyskinesia | Rhinorrhea in first weeks of life, term respiratory distress, with or without situs invertus |
| Bronchomalacia | Harsh, monophonic expiratory sound |
| Bronchopulmonary dysplasia/chronic lung disease of prematurity | Premature birth, home oxygen |
| Cardiac abnormality | Tachycardia, hepatomegaly, pulmonary crackles |
| Post infectious obliterative bronchiolitis | History of previous viral infection (especially adenovirus), tachypnea |
| Investigation | Recommendation | Quality of Evidence |
|---|---|---|
| Fiberoptic bronchoscopy | Should be done | Very low |
| Bronchoalveolar lavage | Should be done | Very low |
| 24-hour esophageal pH monitoring | Should be done | Very low |
| Gastroesophageal scintigraphy instead of pH monitoring | Not preferred to pH monitoring | Very low |
| Swallowing function study | Should be done | Very low |
Investigations should be tailored to the medical history, physical examination, and suspected diagnosis. For the majority of wheezy preschool children, no investigations are needed. For the minority of children with clinically very severe wheeze (and no red flags on history and examination), it is reasonable to perform a chest radiograph and assess the possibility of sensitization to outdoor and indoor allergens as contributing factors. Exposure to cigarette smoke should be ascertained for all children, with a firm recommendation for a smoke-free environment.
Natural History
The first complete picture of the natural history of preschool wheeze originated from the Tucson Children’s Respiratory Study. Retrospective analysis of this longitudinal dataset from 1246 newborns assessed at both 3 years and 6 years revealed distinct temporal patterns of wheeze that were associated with different factors. First, there are “transient infant wheezers” (the majority of wheezers in this cohort) who wheezed occasionally during the first 3 years of life and then did not wheeze after the age of 3 years. This pattern was not significantly associated with markers of atopy, such as blood eosinophilia or high levels of serum immunoglobulin E (IgE), but was associated with lower lung function (measured in infants prior to their first episode of wheezing) and maternal smoking during pregnancy. Although many of these preschoolers probably met the definition of preschool asthma (obstruction and reversibility with asthma therapy), this pattern was not significantly associated with parent-reported ongoing asthma symptoms at and beyond 6 years of age, suggesting a transient asthma phenomenon. Second, there were “nonatopic wheezers” who begin wheezing at 3 years, but whose wheeze resolved by 6 years. Third, there are “atopic wheezers,” whose preschool wheeze continued as allergic asthma after 6 years of age. Similar trajectories of preschool wheeze have subsequently been reported in other longitudinal cohorts, albeit with subtle differences. For example, an analysis of longitudinal data from the Leicestershire and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts found patterns consistent between the two cohorts. Those children with persistent wheeze and chronic cough, associated with atopy, have reduced lung function and a poorer prognosis, whereas those with early-onset nonpersistent wheeze have a more favorable prognosis. To date, however, these important epidemiological studies have not produced a clinically useful method for predicting which preschool children will develop asthma symptoms at school age. Indeed, a systematic review of 12 asthma prediction models, including the asthma predictive index (API), found that although some models were better at predicting ongoing asthma at 6 years, and other models were better at ruling it out, no single model could accurately do both. Thus the prediction of whether preschoolers with asthmalike symptoms will continue to have asthma at 6 years, from contemporaneously obtained information, cannot be achieved with sufficient precision in a large proportion of preschool children with wheeze. One main reason is that most children have symptoms only in preschool years and “outgrow” symptoms before the age of 6 years, although, unfortunately, some still have residual lung function impairment. Another reason is the different prevalence of disease in various settings, such as the general population, a family physician practice, or a specialist clinic. When discussing outcomes with parents, clinicians therefore should make it clear that (1) wheezing is very common in the first few years of life, (2) there is a good chance that wheeze will resolve by school age and only a minority of affected children will become lifelong asthmatics, and (3) there is an increased chance of exhibiting ongoing asthma symptoms at school age if wheeze continues beyond 3 years of age, and particularly if it is associated with allergies, although accurate prediction of outcome is not possible. As the pattern of wheeze changes over time, the subgroup of children who become persistent or recurrent wheezers needs careful follow-up and treatment (or at least a therapeutic trial) to improve symptoms and reduce the frequency and severity of exacerbations. Importantly, as a group, preschoolers with wheezing (confirmed or suspected asthma) are at an increased risk of attenuated lung function growth, and those with more frequent or severe exacerbations appear to be most affected.
Environmental Factors
Exposure to air pollution is associated with an increased risk of developing preschool wheeze. A longitudinal study of US children found that increased exposure to traffic-derived pollution at birth was associated with both preschool wheeze that subsequently resolved by 7 years (transient) and with wheeze that continued to 7 years (persistent). In this study, exposure to traffic-derived air pollution from birth to 1 year of age and from 1 to 2 years of age were both associated with persistent wheeze. There is emerging evidence that prenatal exposure to chemicals, especially bisphenol A and phthalates, increases risk of preschool asthma. For example, a recent study reported that metabolites of these compounds in the urine of pregnant Spanish women are associated with increased risk of wheeze in their offspring during the first 4 years of life.
Clinical Patterns of Wheeze
There have been several attempts to classify preschool asthma by pattern of symptoms, with a view to better targeting treatment (e.g., intermittent treatment for episodic symptoms). A classification suggested by a European Respiratory Society Task Force is to divide children into those with multiple-trigger wheeze, defined as episodes of wheeze associated with one or more triggers (including but not limited to URTIs and interval symptoms), versus those with episodic wheeze, defined as discrete episodes of wheeze (usually triggered solely by URTI) but without interval symptoms. In cross-sectional surveys, episodic wheeze predominates in children younger than 3 years old. Whether wheeze patterns are clinically useful remains unclear, as these are unstable over time in the same child, and there is a high variation in the categorization of patterns between pediatricians.
Pathology
Increased bronchial airway smooth muscle (ASM), subepithelial eosinophilia, and increased reticular basement membrane thickening (a pattern found in adult atopic asthma) are reported in a highly selected group of preschool children with severe recurrent wheeze. Furthermore, increased ASM, but not the latter two features, was associated with an increased risk of having ongoing asthma at school age. There are no reported data from bronchial biopsies in children with less severe disease. However, transient increases in urinary cysteinyl leukotriene metabolites and urinary eosinophil activation markers are reported during acute wheeze —whether these indirect markers reflect airway inflammation is unclear.
Treatment
Compatible with the management objectives for older children and adults, the goals of children presenting with preschool asthma are to achieve good control of symptoms, maintain normal activity levels, and minimize future risk—that is, the prevention of future exacerbations, impaired lung growth and function, and side effects. A diagnosis, at least a presumptive one, is essential to achieve this goal, as treatment varies according to the condition. In reviewing the treatment of preschool asthma, this chapter focuses on children who wheeze after 1 year of age and those younger than 1 year with recurrent wheeze. Treatment recommendations do not apply to infants less than 1 year presenting with a first episode of wheezing where bronchiolitis is suspected. The management of preschool wheeze and asthma includes both nonpharmacological and pharmacologic approaches.
Treatment—Nonpharmacological
All preschool children with suspected or confirmed asthma should have preschool asthma education, with an explanation of the condition, the role of relief and controller medication, and adequate inhalation technique. They should be provided with a self-management plan with written instructions on how to achieve and maintain asthma control (“green zone”), how to manage deterioration (“yellow zone”), and when to consult the physician in case of an asthma attack (“red zone”). While shown effective in all age groups, the only randomized trial that tested an educational guided self-management approach exclusively in preschoolers did not show a significant difference from usual care. However, the authors recognized substantial contamination between groups, with close to half of control patients recalling that they received the same verbal instructions as those in the intervention; further, they acknowledged the absence of documented effectiveness of their recommended intervention—namely preemptive home administration of oral steroids in viral-induced wheezing. Given these study limitations, asthma self-management education remains indicated in preschoolers.
Avoidance of exposure to cigarette smoke and other irritants, and if sensitized, to aeroallergens, should be recommended. Although respiratory illnesses are the most frequent triggers, there is currently no proven, effective approach to avoid the common cold, other than reduced exposure to infected individuals. This is a difficult task when children are placed in childcare during the first years of life or in the presence of numerous siblings.
Treatment—Pharmacological
Challenge to Personalizing Therapy
Despite the worldwide move toward personalized medicine, most, if not all, preschool trials have failed to show convincing evidence that a particular approach is more beneficial for some children than others. Specifically, there is little evidence that children with positive and negative asthma predictive scores respond differently to therapeutic approaches. This is probably due in part to poor stability of these phenotypes within the same child over time and high between-physician variability. Clearly, significant progress in personalized medicine hinges on the future identification of accurate, precise, and reproducible determinants of response, such as preschool lung function, inflammatory markers, genotype, metabolomics, and other “omics” obtainable in preschool children. Stratification on these determinants must then be proven to be associated with differential treatment response, in randomized clinical trials.
Until then, the therapy shown most effective for the majority of preschoolers with asthma in a rigorously designed trial should dictate the best management. The therapeutic section of this chapter is informed by a literature search that identified systematic reviews of randomized controlled trials and randomized controlled trials of children aged 1–5 years described as having preschool wheeze and/or asthma; trials related to wheeze arising from alternative diagnoses (as discussed previously) were specifically excluded whenever feasible. The pharmacological approach is presented by sections corresponding to the “green zone” (maintaining control) and “yellow zone” (managing deterioration) of a self-management plan and for the initial management of an exacerbation in the acute care setting.
Preventive Management—“Green Zone”
The evidence supporting therapy in preschool children is derived from randomized controlled trials and systematic reviews of trials, which included children with either asthma or preschool wheezing with specific or a variety of wheezing phenotypes ( Fig. 44.2 ).
