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Childhood asthma is not a singular disease, but rather a uniquely diverse disorder with variable presentation throughout childhood. Asthma affects 8.3% of children in the United States and is the most common chronic disease of childhood (1, 2). Childhood asthma is responsible for 50 billion dollars in annual healthcare expenditures and is a major cause of emergency room visits, hospital admissions, school absences, and loss of parental workdays (1–3).

Asthma is characterized by inflammation leading to bronchoconstriction, edema, and increased mucous production in the airways. Interestingly, the disorder is more prevalent in boys in the first decade of life. However, after puberty and in the second decade of life, it appears that asthma is more prevalent in young women (4). Asthma disproportionately affects minority and low-income children with African American and Hispanic children having the highest prevalence rates, morbidity and mortality due to asthma (5, 6).

Asthma is considered a chronic disease of childhood however there are periods of time during which disease can go into remission or resolve altogether. Important risk factors for the development of childhood asthma have been identified. The phenotypes of childhood asthma and varied presentations are best defined through the periods of the pediatric life course and are described herein.

The perinatal period has been implicated in the development of childhood asthma. Several cohort studies have unveiled risk factors for the development of asthma in offspring, with factors that span from genetic and environmental risk factors to features such as child's sex and presence of atopy.

Studies of asthma's natural history have shown that almost 80% of cases begin during the first 6 years of life (31). The symptoms of pediatric asthma in this age group are varied and not specific to asthma making the diagnosis challenging. The primary symptoms of asthma in infancy and early childhood include cough, both dry and productive (albeit young children rarely expectorate), wheeze, shortness of breath, and work of breathing. Asthma symptoms are a result of airway inflammation, bronchospasm, airway edema, and airway mucous gland hypertrophy. Interestingly, these symptoms can also present with a multitude of other pediatric diseases including respiratory tract infections and congenital airway anomalies posing a diagnostic challenge. It is well-established that asthma in this age group is frequently under-diagnosed and undertreated (32, 33).

Often, clinicians including pediatric asthma specialists (pulmonologists and allergists) define asthma in this age group as symptoms of airway inflammation that reverse with bronchodilator therapy. However, given the diagnostic challenge in this age group, the Asthma Predictive Index (API) was developed to guide the diagnosis of childhood asthma in children under age 3 years (34). The API has limited sensitivity but reasonable specificity. The API major criteria were defined as physician-diagnosed eczema or parental asthma. The minor criteria were defined as physician-diagnosed allergic rhinitis, wheezing apart from colds, and serum eosinophilia >4%. Positive loose index were defined as parental report of wheezing on surveys at age 2 or 3 years and either 1 major or 2 minor criteria. Positive stringent index was defined as frequent wheezing on surveys at age 2 or 3 years and either 1 major or 2 minor criteria. Children with a positive loose index were found to be four times more likely to have active asthma on surveys at age 6, 8, 11, and 13 years (sensitivity 42%, specificity 85%). Children with a positive stringent index were seven times more likely to have asthma on a school-age survey (sensitivity 16%, specificity 97%). The API is most useful for its negative predictive value and thus, when negative, is an essential tool for determining who is not likely to go on to having later asthma. While not a perfect tool, a slightly modified API, with criteria of a higher score of frequent wheezing and replacing “physician-diagnosed allergic rhinitis” with skin prick testing, is endorsed by the US National Asthma Education and Prevention Program Expert Panel Report 3 for use in diagnosing asthma in this young age group (35).

Often in this age group, particularly over 0–3 years, symptoms are virally triggered rather than allergically triggered. Infants will often have very few symptoms until they experience an upper respiratory infection, which can trigger a significant and severe inflammatory cascade.

In children, the initial few years following asthma diagnosis are critical. For both physician visits and hospitalizations, the number of children having had a second asthma encounter peaked at 3 years after diagnosis and then stabilized (36). Overall, 75% of children had a second asthma episode within 3 years of diagnosis, suggesting that it takes ~3 years to control and stabilize asthma episodes (36). The frequency of asthma episodes soon after diagnosis points to the need for attentive follow-up and aggressive management and education strategies in the early years (36). The mainstays of therapy in this age group are based on recurrence of wheezing symptoms or in severity. For those children with recurrent wheezing or significant morbidity with multiple emergent visits, oral steroid courses or hospital admissions, inhaled corticosteroids are the main therapy. There are a limited number of pathophysiological asthma studies in children under 5 years of age, which presents a challenge in the evidence base for the management of childhood asthma.

By this age, children can more reliably perform spirometry, and reversible airway obstruction on spirometry can be a helpful diagnostic tool. However, it is important to note that in children with asthma, spirometry values can be normal despite significant disease and morbidity (37). Therefore, in children, spirometry is often used as a monitoring tool for asthma symptoms after the diagnosis has been established through other assessments (38).

Symptoms in this age group transition more from discrete episodes of wheezing in response to viral infections to allergic triggered exacerbations. In this age group, exercise-induced symptoms manifest more clearly which may be due to a true change in the clinical presentation of asthma in this age group or also due to sports and exercise becoming a more discreet activity for children of this age wherein caretakers are able to appreciate the symptoms of dyspnea or cough with exertion. In children who avoid or develop a loss of interest in exercise or physical activities, it is important to consider that asthma may be underlying.

Some children in this age group will have few day-to-day symptoms, but have severe asthma attacks in response to specific triggers such as cold weather, cigarette smoke, or seasonal allergies. Virally triggered asthma exacerbations occur in this age group but less often than in the 0–6 year age range and may contribute to the lower rates of healthcare utilization in this age group as compared with younger years of 0–4 years (2).

Puberty has an interesting impact on childhood asthma, specifically relating to sex. Prior to puberty, asthma risk is higher among male children. At the time of puberty, the risk of asthma is approximately equal between males and females, and after puberty, girls have a higher risk of asthma (39). Some of these differences could be explained by the differences in airway development between the sexes. The fetal lung is less developed in boys from 16 to 26 weeks, measured by mouth movements that reflect fetal breathing, a critical determinant of lung development. In the last 4 weeks of gestation, airway resistance is higher in males (21). Boys up to 10 years old appear to have smaller airways in relation to lung size as compared with girls of the same age, height, and weight (21). After puberty, smaller airway caliber is then observed in the female sex (39). The known sex differences in asthma may also be due to other factors such as hormonal effects, genetic susceptibility, immunologic response, and differences in consultation practices and health-seeking behaviors by sex (4, 40).

Asthma symptoms in this age group are most predominantly shortness of breath with exertion, wheezing in response to triggers, chest pain, chest tightness, and cough. In this age group, asthma symptoms can significantly impact sleep, school, sports, and social engagements. Children are more aware of symptoms in this age range and often feel more embarrassment or stigma around using an inhaler and in particular a spacer, often leading to under treatment of asthma symptoms (40).

Remission is common in adolescence, with remission rates reported at 16–60% (41). Factors that have been implicated in an increased probability of asthma remission include mild disease and minor airway inflammation before adolescence, male sex, and the absence of allergic sensitization (42, 43).

Childhood wheezing phenotypes have been explored given that nearly 50% of children experience wheezing before age 1, yet only 20% of those children progress to have continued wheezing later in childhood (44). While there are several longitudinal birth cohorts that have described wheezing phenotypes, we will describe the classifications according to the earliest of these studies: the Tucson Children's Respiratory Study and the most recent systematic comparison of the clinical and epidemiologic classifications (45).

This Describes Children who do not Experience any Wheezing.

This describes children who have their first wheeze before the age of 3 years with resolved wheezing by age 6 years. Transient wheeze is not strongly related to atopy and genetic risk; there are only mild impairments in lung function in this phenotype, and medication use is very uncommon (45).

This describes children who experience first wheezing before age 3 year, however go on to have continued wheezing at age 6 years. Persistent wheeze was strongly related to the asthma risk locus on chromosome 17, however this phenotype appears to be unrelated to environmental determinants. Interestingly, bronchodilator administration dramatically improved any compromises in lung function for children with this phenotype (45).

This describes children who experience rare (or no) wheezing before 18 months of age, but persistent wheeze thereafter. Intermediate-onset wheeze has associations with atopy, but only to pollen sensitization (45).

These children develop wheezing between age 3 and 6 years. Late-onset wheeze is strongly associated with fractional exhaled nitric oxide levels and sensitization to inhaled allergens at 6 years and at 4 years. There appears to be severe and irreversible reduction in lung function in this phenotype and asthma medication use is common (45).

Physician's diagnosis of asthma at least once per lifetime or recurrent diagnoses of spastic, obstructive, or asthmatic bronchitis as reported by the parents at age 6 years.

Wheeze on a monthly basis for at least 1 year between age 1 and 6 years.

Having symptoms between wheezing episodes or having wheeze without a cold at least once between age 1 and 6 years.

Having symptoms between wheezing episodes or wheeze without a cold for 2 or more years between age 1 and 6 years.

Having at least 2 common asthma triggers leading to wheeze between ages 3–6 years.

Wheezing episodes associated only with viral upper respiratory infection between age 1 and 6 years.

Children that do not seem to respond to standard treatment are referred to as severe or difficult to control asthma, and these children experience substantial morbidity from asthma symptoms. To classify a child into this phenotype, the first step is to exclude an incorrect diagnosis, poor adherence to treatment, or incorrect technique with an inhaler and spacer (46, 47). Supervised asthma therapy programs can be extremely useful in managing asthma symptoms and reducing healthcare utilization for children with poor medication adherence and inhaler and spacer technique (48, 49). It is important to differentiate between severe therapy-resistant asthma and difficult-to-treat asthma due to comorbidities Difficult to treat asthma is a much more common reason for persistent symptoms and exacerbations and can be managed if comorbidities, such as allergic rhinitis and chronic exposure to asthma triggers, are directly targeted. Home visiting programs and assessment of the school environment are important features of the evaluation for children with concern for chronic exposure to asthma triggers (50–52). Children with persistent symptoms and exacerbations despite correct inhaler technique and good medical adherence to standard asthma therapy (steroid-resistant or therapy resistant asthma) should be referred to an asthma specialist to consider more potent biologic therapies such as anti-IgE, anti-IL-5, or anti-IL-13 therapies and further evaluation (47).

Eosinophilic inflammation is considered to be the main feature of allergic asthma in children (53). Sputum eosinophils and serum periostin are biomarkers that have been proposed for defining which children with asthma will respond to anti-IgE, anti-IL-5, or anti-IL-13 asthma treatment (54). However bronchoscopy is not routinely done in children with asthma, therefore serum eosinophils are often the least invasive and most common biomarker utilized to indicate the presence of eosinophilic predominant asthma and help predict responsiveness to inhaled corticosteroid therapy (55).

While initially most childhood asthma was thought to be eosinophilic in nature, a neutrophilic predominance has emerged as an important phenotype. In this phenotype, children generally have low IgE levels, low serum and sputum eosinophil counts with very little allergic symptoms. Neutrophil-predominant asthma is the most severe asthma phenotype with poor corticosteroid response (54) and may explain some of the children who have not respond well to standard asthma therapy.

Croup, inflammation of the upper airway, which presents as barky cough and stridor, is a common isolated entity in infancy and early childhood. However, the presence of recurrent croup may indicate the presentation of underlying asthma in childhood. Recurrent croup has been shown to be a risk factor for childhood asthma and airway hyperreactivity (56) as well as strongly associated with bronchial asthma in children (57).

Asthma in children is associated with significant atelectasis and specifically with middle lobe and lingula collapse, (58) and often infants and children who ultimately develop asthma, present as recurrent atelectasis, or mucous plugging in the right middle lobe and lingula. In contrast to adults, children are thought to have higher resistance to collateral airflow, possibly due to increasing number and size of collateral alveolar ventilation, through pores of Kohn and bronchoalveolar Lambert's channels, that develop from birth to adulthood (59). This theory is supported by the finding that pores of Kohn are absent in newborns, and develop around 4 years of age, with the greatest numbers of pores of Kohn found in the apical portions of upper and lower lobes, as well as in peribronchial, perivascular, and subpleural areas, (60, 61), leaving the right middle lobe and lingual vulnerable to atelectasis and mucous plugging, particularly in children with asthma.

In a child with recurrent multi-lobar pneumonia, with a normal immune function evaluation, asthma should be considered as an underlying cause of the recurrent chest infections. Many children referred to specialty care with recurrent chest infections will be found to have undiagnosed or undertreated asthma. Often the history reveals that most have recurrent episodes of cough, wheeze and breathlessness, with trigger factors of upper respiratory tract infections, exercise, cold air, emotional upset, or exposure to pets and other aero-allergens suggestive of asthma (62). In several studies, asthma was the main underlying cause for recurrent pneumonia in children (63).

Children with asthma have an increased risk of developing chronic obstructive pulmonary disease (COPD) in adulthood. Specifically, it has been shown that children who smoke tobacco and also have asthma are at increased risk for developing low lung function and COPD as adults, when compared to smokers who did not have asthma in childhood (64).

Asthma remission occurs most commonly between the ages of 14–21 years (65). However, large longitudinal studies have also shown that, among children who wheezed before age 3 years, more than 50% had stopped wheezing either by 6 years of age (44) or by 12 years of age, (36, 66) depending on the study. Remission rates of childhood asthma have been reported between 16 and 60% by early adulthood, according to prior longitudinal studies (41, 65, 67). The wide variation in reported remission rates is likely due to diverse study designs, varying follow-up periods, and different study populations. In longitudinal studies, children with the following characteristics had higher remission rates: episodic asthma (rather than persistent asthma), milder initial asthma severity, less allergic sensitization, less allergic rhinitis, less atopic dermatitis, and male sex (36, 65).

While the morbidity of childhood asthma is significant, fortunately, mortality from childhood asthma is rare with an estimated 28 deaths per million children with asthma (2). As with childhood asthma morbidity, there are grave racial disparities in childhood asthma mortality, and black, and Hispanic children suffer disproportionately from the highest mortality rates (2).

Asthma is increasingly recognized as an umbrella term for a heterogenous group of conditions that has been likened to the term “arthritis” in Rheumatology—not a specific diagnosis but a term that describes a diverse group of conditions clinically and biologically (68). Some have suggested discarding the term asthma altogether (69).

Asthma is a common condition amongst adults, estimated to affect 235 million people worldwide, and is estimated to cause more than 350,000 deaths per year (70). It carries a huge economic, morbidity and mortality burden in both developing and developed nations (70). The mortality in developed countries from asthma has remained static for more than a decade and it is clear that a better understanding and management of this diverse group of conditions is required (71).

Asthma is considered a childhood disease by many but this is erroneous as longitudinal studies have shown that approximately half of middle aged patients with asthma have had onset in adulthood rather than childhood (72–74). This proportion of adult onset asthma increases with age (73). The annual incidence of asthma amongst adults is estimated to be 0.5%, similar to the incidence in childhood and it remains unclear as to whether adult-onset asthma is a different disease to that occurring in childhood (75).

The area of asthma phenotyping amongst adults has been developing at a rapid rate. Initially clinical phenotypes were identified that help to categorize asthma in adults by clinical traits including that of early and late onset, obese vs. non-obese, and atopic vs. non-atopic (76, 77). More recently biologic phenotyping has been increasingly recognized and performed clinically, particularly with the availability of targeted biologic agents, and this phenotyping is currently based on presence of allergic or eosinophilic inflammation although this is a rapidly evolving field (68). This has led on to more complex molecular phenotyping which may well-inform future precision medicine in asthma (78).

The natural history of asthma occurring in adulthood is complex because it is such a heterogenous disease. Despite the complexities adult-onset asthma appears to run a different course to that of childhood-onset disease where the majority of the disease is mild and remission is common (79) (Table 1). In adults with asthma remission is uncommon and disease is often more severe and progressive (80).

Although there has been significant development and research into asthma phenotypes in the past two decades the concept has developed slowly and to some remains controversial (68). In this context phenotype refers to subtypes of the disease that have recognizable properties produced by interactions of the genotype and the environment (81). From this concept has emerged the concept of asthma endotypes where a biologic pathway is identified that leads to the clinical phenotype (82). Phenotypes and endotypes are an attractive concept but unfortunately patients rarely fit into these classifications perfectly with many factors that muddy the waters including presence of comorbidities and confounders. For this reason a more pragmatic concept of treatable traits has gained momentum (83). Rather than attempting to categorize people with asthma, this approach seeks to describe traits associated with an individual's asthma including clinical aspects, biological characteristics, and comorbidities (83).

Phenotypes of asthma can be broadly categorized into clinical, biological, and molecular although there is considerable overlap between these and, ultimately, it is the combination of the three that is likely to form the asthma phenotypes of the future.

The natural history of asthma in adults is different to that of asthma in children with less remission of adult-onset asthma than that occurring in childhood.

Many adults with asthma have childhood-onset disease that has persisted and there have been many risk factors that predict the persistence of asthma into adulthood including the severity of childhood disease, the presence of bronchial hyperresponsiveness, atopy, exposure to allergens and a parental history of asthma (134–136). In longitudinal studies the amount of wheeze in early adolescence has been shown to predict the severity in later life. In an Australian-based cohort of second graders with wheezing of various severities followed up to age 50 there was remission of asthma in 64% of those with mild wheezy bronchitis or wheezy bronchitis, 47% of those with persistent asthma and only 15% of those with severe asthma (137). In this group risk factors for persistence of asthma at age 50 were severe childhood asthma, childhood allergic rhinitis, and female sex (137). In another longitudinal cohort 73% with few symptoms at 14 years had little or no asthma 14 years later whereas 68% of those with frequent wheeze at 14 years still had asthma 14 years later (138). Most who had frequent wheeze at 21 still had wheeze at 28 years and of those with infrequent wheeze at 21 years 44% had worsened at 28 years (138). These findings have been replicated in more recent studies—three quarters of children with childhood asthma will outgrow the disease by middle age although overall our understanding of the natural history of childhood asthma remains poorly understood (139).

Adult onset asthma has many different forms and the risk factors appear to be different to that of childhood-onset disease. Compared to childhood asthma, major associations with adult-onset disease are female sex, current smoking, and low socio-economic status but not atopy or a family history of asthma (74). Other risk factors include; clinical—historical symptoms of wheeze, rhinitis, chronic cough; physiological—lower lung function, bronchial hyperresponsiveness, lower height; comorbidities—higher BMI, nocturnal gastroesophageal reflux disease, habitual snoring, IgE reactivity to Timothy grass; and lifestyle—low physical activity amongst men (75, 107, 140–144). The evidence for smoking as a risk factor is mixed with two large cohort studies from Australia and Sweden showing that this is a risk factor for adult-onset asthma and other studies showing that it doesn't appear to be (74, 75, 141, 144).

In a large cohort with severe asthma with onset between 14 and 55 who were followed for 10 years 83% had less severe asthma at 10 years (145). Risk factors for the persistent presence of severe asthma was low socioeconomic status, high comorbidity burden and high adherence to medications in the first year after diagnosis (145). In this cohort sex and other risk factors important in childhood asthma were not associated with continued presence of severe asthma (145).

The sex differences in asthma amongst different age groups are interesting. Amongst children males are more commonly affected by asthma than females and male sex is a risk factor for developing asthma (39). Around the time of puberty this risk becomes equal and after puberty the risk in females is greater than that amongst males, an observation partially but not fully explained by women's smaller airway caliber in adults (39). There is emerging evidence of the association between female hormonal changes and asthma that may partially explain the female predominance of asthma after puberty (146, 147).

Some factors that don't appear to be risk factors for adult onset asthma include level of education, atopy (either baseline or newly positive skin prick tests), occupational exposures or maternal asthma (141, 143, 144).

Despite the differences in risk factors for adult-onset asthma compared to childhood onset disease the prevalence of asthma amongst adults was shown to be increasing in the second half of the twentieth century similar to that of childhood asthma (73, 148).

It is difficult to accurately compare and contrast childhood and adult-onset asthma due to existing gaps in the literature and we acknowledge this limitation. Additionally because some findings are reported more in adults, this does not necessarily mean they are more prevalent, but rather a possible manifestation of publication bias. Nevertheless, we have provided a reflection of the similarities and differences based on the currently available literature (Tables 1, 2). Adult onset disease differed from pediatric onset disease in regard to increased prevalence in women, non-atopic individuals, and obese patients (73). Adult onset disease is associated with more respiratory symptoms and asthma medication use despite higher prebronchodilator FEV1/FVC (73). There is less quiescent disease in adult onset asthma and it appears to be less stable than childhood-onset disease with more relapses and less remissions (73).

Severe asthma in children is distinct from severe asthma in adults and approaches to severe asthma in adults should not be extrapolated to children. In children the factors associated with severity have been found to be asthma duration, medication use and lung function rather than Type 2 inflammatory markers such as increased IgE and elevated FENO that are markers of severity in adult-onset disease (93).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.