Question 3: Can we diagnose asthma in children under the age of 5 years?

Abstract

The diagnosis of asthma in children under five years has been controversial due to changing concepts of what true asthma is in this age group. Previous diagnostic algorithms that used clinical indices to predict the persistence of asthma symptoms or phenotypes based on asthma triggers do not predict which children will benefit from asthma medication. A pragmatic approach to asthma diagnosis in this age group is based on identifying signs and symptoms of reversible airflow obstruction and documenting their response to asthma medication. Hopefully, this approach will provide clearer guidance to clinicians and improve asthma morbidity in these young children.

INTRODUCTION

Asthma is the most common chronic disease of childhood [1] and is characterized by the presence of reversible airflow obstruction and airways inflammation in the setting of compatible clinical symptoms [2–4]. In older children and adults, diagnosis centers around identifying asthma symptoms and confirming variable airflow obstruction. The ability to diagnose asthma in preschool children, typically defined as those under age 5 [3,5,6] or 6 [2,4] years is controversial. Several issues contribute to the debate including difficulty in differentiating bronchiolitis from asthma [7], reticence in assigning a chronic disease label at an early age [8], belief that asthma medications do not work in this age group [9], and the impression among some physicians that pulmonary function testing [PFT] is required to make a diagnosis of asthma given the inaccuracy of a clinical diagnosis in older children and adults [10,11]. Moreover, a larger debate is whether symptoms or a common pathophysiology defines asthma. This was highlighted in a recent Lancet Commission which suggested that the term asthma be used to describe a constellation of symptoms with no assumptions of underlying pathophysiology and that treatable traits such as inflammation or airflow limitation be identified and treated [12]. This review will discuss the controversies, frameworks, and current state of testing for the diagnosis of asthma in children under 5 years of age.

BURDEN OF ASTHMA IN PRESCHOOLERS

The prevalence of asthma among children ranges from 8.3% to 12.3% in westernized countries [13–16] with 80% of pediatric asthma patients manifesting symptoms before the age of 6 years [17]. Preschool aged children experience the highest rate of morbidity with a 4-fold higher prevalence of emergency room visits [18], and up to a 10-fold higher rate of hospitalizations [19] than older age groups.

Long term cohort studies have found that lung function trajectory is established in childhood [20,21] and that children with asthma are at risk for irreversible airways obstruction in adulthood with pathologic findings of airways remodeling developing between 12 months and 3 years of age [22,23]. Therefore, the pre-school years are a critical time for intervention [24]. While there is some degree of over-diagnosis of asthma [25,26], much of the morbidity associated with preschool asthma relates to underdiagnosis [1] and concomitant lack of initiation or adherence to preventative therapies. As such, recognition and accurate diagnosis of asthma in preschool aged children may help the child and caregivers understand symptoms, improve treatment adherence [8], and adjust life-style to minimize exposure to potential triggers.

PARADIGMS FOR THE DIAGNOSIS OF ASTHMA IN PRESCHOOL CHILDREN

Symptoms that persist into childhood = true asthma

The Tucson Children’s Respiratory Study allowed the separation of 3 groups of wheezing children: (i) transient early wheezers, (ii) persistent wheezers and (iii) late onset wheezers, based on whether wheeze was present at 3 and 6 years of age [27]. Markers of atopy were significantly but weakly associated with persistent wheezing and it was this group that was classified as having ‘‘true asthma”. Using these data, the Asthma Predictive Index (API) [28] and later the Modified Asthma Predictive Index were developed [29]. The API has a sensitivity of 57% and specificity of 81% for predicting asthma at age 6; with a population prevalence of 10% this equates to a positive predictive value of 26% and negative predictive value of 94% [28]. In the last two decades, a variety of asthma predictive algorithms have been developed and include factors such as age at wheeze onset [30], frequency and timing of wheeze episodes, presence of personal or family history of atopy, skin prick tests [31] and markers of allergic inflammation in blood [32], exhaled breath [33,34] and sputum [35–38] to forecast persistence of asthma symptoms. Unfortunately, the low predictive power of these indices makes them unreliable for individual patients and as they were derived from population based samples, they do not reflect the patients that are seen in the clinical setting.

Although this approach was adopted by asthma guidelines in the past [3], the limitation of retrograde extrapolation to diagnose asthma in preschool aged children is the lack of sensitivity of existing asthma predictive indices at the individual patient level [38,39]. Relying on such predictive indices would result in the underdiagnosis of asthma in non-atopic wheezers. As non-atopic children comprise 60–75% of children with asthma in this age group [40,41], this would result in significant untreated morbidity. This paradigm also assumes that individuals who eventually outgrow their symptoms do not have a response to asthma medications in their preschool years, which has not been shown in clinical trials [40].

Multi-trigger wheeze = true asthma

A second paradigm differentiates multi-trigger wheeze from episodic viral wheeze. A 2008 ERS Task Report [5] recommended that those with multi-trigger wheeze be treated with inhaled steroids and that those with episodic viral wheeze be treated with leukotriene receptor antagonists. Although not stated, it was popularized that episodic viral wheeze was a benign condition that did not respond to inhaled steroids and that it was synonymous with transient wheezing. A 2014 update of this statement downplayed the distinction between multi-trigger and episodic viral wheeze [42] however this terminology continues to be popular [43].

The key limitations to this approach are that phenotypes are not stable in individuals over time and those with episodic viral wheezing do not necessarily outgrow their symptoms [44,45]. Additionally, the frequency and severity of viral-triggered episodes was not a factor when deciding on a therapeutic plan and these factors have been shown to predict response to inhaled corticosteroids [46].

Asthma symptoms that respond to asthma medication = asthma

To address the morbidity burden in preschoolers, current asthma consensus statements advocate for a pragmatic approach and a trial of asthma therapy (bronchodilators and daily inhaled corticosteroids or a short burst of systemic corticosteroids) in all children with clinical evidence of significant persistent or recurrent episodic reversible airflow obstruction [2,4,6] (Fig. 1). For those children who improve, a diagnosis of asthma can be made. Given that 50–60% of patients with wheezing outgrow their symptoms by school age [27], the diagnosis and treatment must be reassessed periodically [2].

Fig. 1.

From the diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Pediatric Society position paper.

The reason to diagnose asthma in younger children is to initiate treatment that will decrease short term asthma-related morbidity given that inhaled steroids do not have a disease modifying effect in this age group [47–49]. Although there are fewer clinical trials of asthma medications in this age group, there is growing evidence that supports the benefit of asthma medication in young children. Systematic reviews of inhaled steroids show that compared to placebo they decrease the symptoms of wheezing and asthma exacerbations with a relative risk of 0.59 and a number needed to treat of 7 [50]. Leukotriene receptor antagonists have been largely studied in children with episodic viral wheeze, without evidence of benefit in a recent systematic review [51] although further studies showing benefit have been published since that review [40]. There have been contradicting studies examining the usefulness of systemic steroids in this age group for acute exacerbations in the emergency room setting, which may be related to the severity of presentation in these studies [52,53]. Improvement with oral steroids in patients with bronchiolitis and a personal or family history of atopy suggests overlap between these two disease or syndromes and points to the need for identification of treatable traits in all airways diseases [54].

This pragmatic approach is limited by the subjective nature of treatment effectiveness and the fact that symptoms such as cough may spontaneously resolve without treatment, leading to an over diagnosis of asthma. These limitations are balanced by a decrease in short-term morbidity.

SUMMARIZING BOX: HOW TO MAKE A DIAGNOSIS OF ASTHMA IN A CHILD UNDER 5 YEARS [2,4,6]

In a child presenting with acute symptoms of airflow obstruction (wheeze, signs of increased work of breathing), a trial of short acting beta agonists ± oral steroids should be given to assess response. If there is clear improvement and the child has had similar episodes previously, a diagnosis of asthma can be made.

In a child that has a history of recurrent asthma symptoms (wheeze, work of breathing, cough) but is not acutely symptomatic the frequency and severity of the reported symptoms should be considered. If the child has a history of severe exacerbations (requiring oral steroids, emergency room visits, hospitalization) or frequent symptoms, a trial of daily inhaled corticosteroids should be undertaken to determine response. If the frequency and/or severity of symptoms improves, a diagnosis of asthma can be made. If the symptoms are infrequent and mild, the child can be assessed when symptomatic to better determine the nature of the symptoms and their acute response to treatment (Fig. 1).

ASTHMA PHENOTYPES

A variety of different pathophysiologic processes may result in airways inflammation and reversible airway obstruction. ‘‘Lumping” all of these pathways under the diagnosis of asthma is likely to be an oversimplification [12]. Nonetheless, numerous attempts to ‘‘split” asthma into different phenotypes based on age of onset (early, persistent or late onset wheeze [27]) and types of triggers (multi-trigger vs episodic viral wheeze [5]), have so far failed to demonstrate clinical usefulness in this age group [55].

Theoretically, phenotyping provides an opportunity for predicting treatment response and prognosis, but this is limited in preschoolers due to the narrow range of available asthma medications in this age group and instability of phenotypic classification over time [44]. Studies in this age group have found characteristics or biomarkers that predict improvement with inhaled or systemic corticosteroids including markers of Th2 inflammation such as serum eosinophils over 300 cells/ul, aeroallergen sensitization or elevated serum eosinophilic cationic protein [40], demographic characteristics such as being male or Caucasian and having more severe disease identified by an Emergency Room [ER] visit or hospitalization for asthma in the past year, and being more symptomatic at baseline [46].

Research to identify genetic or metabolomic biomarkers that classify children into asthma phenotypes is ongoing. Such research is critical for promoting our understanding of the causal pathways in asthma and to allow development and use of targeted therapies in this age group in future. However, the importance of such research should not overshadow the current need to diagnose, treat and thereby reduce morbidity in children under 5 years with asthma.

ASSESSING AIRWAY FUNCTION

The objective assessment of reversible airflow obstruction or hyperresponsiveness to bronchoprovocation challenge is a key supporting element in the diagnosis of asthma [3]. The American Thoracic Society (ATS) Report on lung function testing in young children found several assessments to be safe and feasible, including infant raised-volume rapid thoracic compression and plethysmography (i.e. infant PFTs), preschool spirometry, specific airway resistance, the interrupter technique, the forced oscillation technique, and multiple breath washout [56]. However, aside from infant PFTs, few data exist in children under 5 years. While infant PFTs may have some value in monitoring drug response in infants with recurrent wheeze [57,58] it does not reliably differentiate infants who ultimately develop persistent asthma [59] even with the use of bronchoprovocation challenge [60]. The reliance on specialized equipment, staffing, and sedation, as well as, lack of normative data and demonstrable value in diagnosing asthma limits its clinical applicability. Spirometry, the gold standard for diagnosing obstructive lung disease in children and adults, may be achievable with loosened testing criteria for preschool-aged children [61], however successful production of a forced expiratory flow manoeuver is age dependent [62].

Effort-independent tests in infants and toddlers show promise [63], with forced oscillation technique (FOT) seeming closest to clinical utility. FOT [64] detects airways resistance and reactance from oscillatory waveforms of energy at distinct frequencies. Several studies in older children have demonstrated FOT to have clinical utility in diagnosis [65] and management of asthma [66–68]. Some studies suggest that young children may have more success with oscillometry than with spirometry [69], particularly when ill [70], however this also diminishes with younger children [71]. Recently, FOT techniques have proven feasible without sedation in newborns [72] and infants, with adaptation of standard equipment [73,74]. The optimal parameters for diagnostic utility, response to therapy, and device-specific normative values [56], need to be determined in the youngest age [75].

Multiple breath washout has been studied across age ranges as young as infants [76], however reliable data collection in the toddler age has required the use of sedatives in some studies [77]. Despite success in detecting early CF lung disease, the differences between preschool wheezers and control children has been less pronounced, even after administration of bronchodilators [78].

ASSESSING INFLAMMATION

Airway inflammation is considered a key feature in asthma although its assessment is not part of current diagnostic criteria in any age group. There are various ways to measure airway inflammation ranging from endobronchial biopsy, alveolar lavage or induced sputum cell counts to indirect measures of airway inflammation such as serum eosinophil counts and fractional exhaled nitric oxide (FeNO). All of these tests measure inflammation in different lung compartments and it is not known which measurement best predicts response to treatment or prognosis. Induced sputum samples for cellular analysis are difficult in this age group with only 32% of samples being of adequate quality to be assessed in one study [79]. On the other hand, exhaled nitric oxide using a tidal breathing method has been successful even in young children [80].

There are very few studies comparing different tests of inflammation in this age group. When comparing induced sputum and alveolar lavage samples, sputum was found to be more neutrophilic and less eosinophilic than alveolar lavage samples [79]. Serum eosinophilia, and not sputum eosinophilia, was found to correlate better with alveolar lavage eosinophils [79].

Although eosinophilic airway inflammation is well described in older children and adults with asthma, airway neutrophilia and mixed inflammation has also been described in adults during exacerbations and older children with severe asthma [81–83]. Induced sputum samples in wheezy preschool children did not show eosinophilia, although paired alveolar lavage samples did show an increased eosinophil percentage compared to non-wheezers [79]. In comparison to older children with asthma, infants with recurrent viral wheezing were less likely to have alveolar eosinophils (27% of infants compared to 64% of older asthmatics) and more likely to have alveolar neutrophilia over 10% (1/2 of infants compared to 1/3 of asthmatics) and this was particularly the case in infants with positive bacterial cultures [84].

These studies of airway inflammatory markers highlight the heterogeneity of inflammation in the wheezy young child and the difficulty in obtaining these samples precludes their widespread use in diagnostic algorithms.

DIRECTIONS FOR FUTURE RESEARCH

If asthma is considered a constellation of signs and symptoms with no assumptions on underlying pathophysiology [12], the diagnosis of asthma in children under 5 years is less controversial. The challenge then becomes identifying the different components of airway disease in this age group. The focus can then shift to assessing how patterns of symptoms, airway inflammation and obstruction can be treated to prevent exacerbations and long term airway remodeling.

Future needs for diagnostic testing in the wheezy infant and toddler will add greatest value by providing objective measures of airway structure and function and patterns of inflammation. These tests can then be used to find associations with the risk for repeat exacerbations of airways disease, chronic respiratory impairment, or irreversible airway obstruction. Ultimately, the lessons learned from preschool children about the pathobiology of viral induced exacerbations and mechanisms of airway remodeling will have applications and implications into adulthood.

Until we have improved diagnostic methods in this age group, the diagnosis of asthma in preschool children will continue to be based on a history of the frequency and severity of symptoms and the response of these symptoms to asthma medications.

Educational aims.

The reader will appreciate that children under 5 years of age:

• Can be diagnosed with asthma on the basis of having symptoms of reversible airway obstruction that respond to asthma medication.

• Have the highest rates of emergency room visits and hospitalizations for asthma compared to older children.

• Have improved symptom control and fewer asthma exacerbations with use of inhaled corticosteroids.