Asthma is defined as a disease of variable airflow obstruction associated with inflammation in the airways and the symptoms of cough, wheeze and dyspnea (1). However the diagnosis of asthma in children often relies heavily on history since many children are too young to do the tests that objectively measure airflow obstruction. Several studies have called attention to significant underdiagnosis and undertreatment of childhood asthma (2-5). Yet there are very few studies documenting airway inflammation in childhood asthma, especially very young children (6,7). Children less than 3 years of age who wheeze present a special challenge because of the lack of objective measures of airflow obstruction.
Physicians have felt that young children often "outgrow" intermittent and mild wheezing illnesses and were reluctant to label the child asthmatic resorting to terms such as wheezy bronchitis and asthmatic bronchitis. This reluctance often led to treatment with cough suppressants and antibiotics even when the child had had several episodes of wheezing (2,3,5). In fact recent studies in infants and toddlers suggest that many but not all of them, do seem to "outgrow" the wheezing suggesting that the older concept of wheezy bronchitis was not totally misguided. Nevertheless, if "persisting asthma" in childhood commonly begins before age 5 (8-11), and if early management of the inflammation in the airways can result in diminution of the disease and better lung function (12), then it becomes important to identify the "persisting asthmatics" early and treat them aggressively. On the other hand, the larger group of infantile wheezers who have a self-limiting condition that is "outgrown", may not need as aggressive therapy. These children may be at more risk from the medication than the disease.
There is now strong evidence that the majority of children who wheeze in the first few years of life will no longer be wheezing by school age (13-18). It seems likely that there are a group of young infants, more commonly male who are at risk of wheezing with viral illness based on abnormal lung anatomy (16, 17) but who are not atopic. In these infants, eosinophils and perhaps other cellular components of inflammation are not mobilized to the same degree as in "true" asthma. Thus children with asthma symptoms under age 3 seem heterogeneous (13 -23). In one study about 30% of children age three or younger had had wheezing but almost 60% of them had stopped wheezing by age 6 (17). It is not clear whether such children are at risk for recurrence of the asthma as adults. Stein et al. (23) have suggested that very young children with cough and wheeze can be divided into three groups: 1. Infants, usually boys who have none of the characteristics of asthma such as personal history of atopy or family history of atopy, but who are born with small airways and develop wheezing as a result but "outgrow" this problem as they get older. A second group of young children present slightly later with symptoms of cough and wheeze during viral illnesses. These children also have no personal or family history of allergy and also tend to outgrow the symptoms. A third group of young children does have a personal history of atopy and are more likely to have persisting asthma. These atopic asthmatics seem to present slightly later in infancy (10, 17) but unfortunately there is significant overlap in the clinical presentations of the different types of "asthma" in these very young children.
The majority of children with onset of wheeze under age 3 are non-atopic and the episodes are viral induced (15,17). By contrast after age 4, wheezing subjects are more likely to be atopic in the majority of instances (15). These studies are consistent with observations in older children showing that airway reactivity as defined by a positive methacholine challenge is related positively to atopy (24-26). Passive cigarette smoke is also positively related to wheezing in the absence of atopy and this wheezing can persist (15,17). Maternal smoking has been found to be significantly associated with both transient and persistent wheezing in infants (17).
The pathophysiology of wheezing in non-atopic viral-induced, episodic asthma is unknown. Bronchial lavage of young children with non-atopic viral induced wheezing suggested that they have non-eosinophilic inflammation in the airways while atopic asthma is associated with eosinophils in the airways (7). Other studies using peripheral blood eosinophils and serum ECP as indirect markers for eosinophilic inflammation in childhood asthma suggest that eosinophils and ECP are higher in atopic than non-atopic asthma (27,28).
A number of studies have documented that following Respiratory Syncytial Virus-induced bronchiolitis, a percentage of the children continue to have recurrent wheeze with subsequent respiratory tract infections (29-35). It has been suggeted that RSV infection induces a TH2 cytokine response that is similar to atopy (36). Welliver found that wheezing with RSV infection was associated with IgE antibody to the RS virus (37). Garofolo et al (38) demonstrated activation of eosinophils during RSV infection. This would suggest that RSV induced wheezing resembles asthma in the nature of the inflammation in the airways yet afterwards most of them have only mild symptoms occurring primarily with viral infections for a period of a few years after the original RSV infection (34). The data suggest that the difference in outcome between post-infectious wheezing and asthma has to do with the presence or absence of atopy (39) and therefore eosinophilic inflammation. An atopic immune system in childhood can lead to greater eosinophilic inflammation resulting in airway reactivity and the possibility of a more persisting chronic asthma.
Similar considerations apply to the diagnosis of asthma presenting with recurrent or persisting cough in the absence of wheeze. Cough can be the sole manifestation of asthma (40), an observation that has been confirmed in children (41-43). Yet persistent cough in childhood is less frequently associated with a positive methacholine or histamine challenge test in children (44). Similarly cough is associated with less atopy (8) and by inference less eosinophil mobilization and activation (27). This implies that persistent cough may not always represent asthma (44,45) and might represent a post-infectious phenomenon that has a different outcome from asthma as suggested by Wright et al (46). We have studied older children with post-infectious cough using the technique of induced sputum. These children had been coughing an average of 2 months after a bout of paroxysmal coughing. Such children had mean eosinophils of 0.58% in their sputum (normal < 2.0%) compared to untreated asthmatics, mean eosinophils 22.9%, p< 0.001. All of the asthmatic children had a positive methacholine challenge while only 55% of the coughers did (Zimmerman, Silverman, Tarlo, Chapman, Kubay, Urch, J Allergy Clin Immunol 2000 Mar;105(3):495-9).Click for Abstract
The distinction between post-infectious cough and asthma variant cough may prove to be important in the long-term outcome of the illness. Furthermore, if the cough does not clear spontaneously or after institution of treatment with inhaled steroids then other diagnoses should be considered including 1. Cough due to postnasal discharge, 2. Cough due to acid-reflux and more obscure causes of chronic cough such as tracheo-esophageal fistula and reflux or aberrant vessel with compression of a bronchus etc.
The studies cited to this point all indicate that the outcome of childhood wheezing is very different in non-atopic and atopic individuals. Studies in adults have suggested that activated eosinophils associated with T lymphocytes producing cytokines of the Th2 subset are the underlying cause of inflammation in asthmatic airways (47-50). Permanent airway remodelling and airway reactivity may result from this inflammation in the airways. Atopy in childhood, seems to be the major source and perhaps the only source of this eosinophilic inflammation which then results in non-specific airway reactivity (51-53). In older children with asthma, the majority, even those who wheeze primarily with respiratory tract infections, are atopic (15). In contrast infants who wheeze are commonly non-atopic and wheeze only intermittently with viral illnesses (10,13,17). However even within infancy, there are a small group of atopic babies who wheeze and are likely to have persisting asthma. It has been shown that infants can demonstrate positive skin tests to airborne allergens (54) and that predicts the development of asthma. Wahn et al (55) have shown that children from high risk families are sensitized to dust mite and cat in infancy and are sensitized by lower quantities of allergens than those children born to non-atopic parents.
It is generally felt that the youngest wheezy children i.e. infants are the most likely to warrant investigation for diseases other than asthma. Asthma is still by far the commonest cause of these symptoms in infants. Alternative diagnoses are far less common and can usually be excluded by history. A history of failure to thrive, recurrent bacterial infections, significant vomiting or reflux, choking cyanotic episodes, sudden onset of symptoms after possible aspiration with no indication of a viral illness would suggest the need for further investigation. Cystic fibrosis occurs in approximately 1 in 2000 children (56) compared to asthma in 1 in 10 children (5). Other diagnoses such as an immune system problem, gastro-esophageal reflux and recurrent aspiration, aspiration of a foreign body, tracheobronchiomalacia, bronchial stenosis, congenital heart disease are also less common than asthma. Physical examination revealing localized chest or cardiovascular abnormalities would also indicate the need for further investigation. Investigation would begin with a simple chest xray but could go on to sweat test, immune function tests, primarily quantitative immunoglobulins including IgG subsets, reflux studies and other more specific tests.
Atopy in infants: Since atopy seems to predict the likelihood of persisting asthma this history must be carefully sought. Infants usually have not developed many of the symptoms that suggest allergy. A strong family history of atopy or asthma might identify the wheezing toddler more at risk of persisting asthma. A history of an immediate reaction to a food such as egg, and/ or the presence of significant atopic dermatitis will suggest the presence of an atopic immune system and identify children at risk for persisting asthma. Studies on the formation of IgE antibody in infancy suggest that when children are allergic in the first few years of life, they react to a food protein, commonly milk, egg or peanut (57-59). This may be associated with a clinical reaction even at the first introduction of the food (60). Once the child has been identified as allergic, by a reaction to a food for example, it should be assumed that they are becoming sensitized to airborne allergens and dust mite control procedures should be initiated (61, 62). If there is a pet in the home, parents must be actively encouraged to eliminate the animal from the home and undertake procedures to reduce the dander levels.
In an epidemiologic study in the Toronto area we found that 10% of children aged 0 to 5 years had had wheezing in the year prior to the study and a further 8 - 10 % had had significant cough (5). Other investigators have reported similar prevalences and an increase over the last ten years (63). These children have lower respiratory tract symptoms for a week or more with each viral infection. Children of this age can have 6 - 8 viral respiratory tract infections per year (64). They are too young to do spirometry correctly and diagnosis relies heavily on the history.
Clinical history: Pre-school children often have cough with or without wheeze during acute viral illness but then may fail to clear the symptoms completely. They are left with residual coughing especially in the morning when they arise or with exercise or other forms of exertion. These symptoms are especially prominent when the child resides in a household with a smoker or smokers (65 - 69). As discussed previously, many of these young children prove to be non-atopic and will outgrow the problem if there is freedom from passive cigarette smoke (17). As the children get older they tend to develop fewer viral respiratory tract infections and improve. However those children who are atopic now increasingly have an inflammation contributed by this immune response to environmental allergens.
Atopy in pre-school children: At around age three, allergic children move from food sensitivity to airborne allergen sensitivity, the allergic march (70,71) and it is this sensitivity especially to the indoor allergens such as dust mite, animal dander, cockroach and mould that seems to be more important in the development of asthma (62). These children may have a history of infantile atopic dermatitis or an immediate reaction to a common food such as milk, egg, peanut or nuts, some of which (i.e. to milk and egg) will have been outgrown. They may give a history suggestive of allergic rhinitis with chronic rhinorrhea, nasal stuffiness, sneezing in the morning and rubbing at the nose. Sneezing and rubbing of the nose are the hallmarks of allergic rhinitis since nasal obstruction and mouth-breathing can also occur with adenoidal hypertrophy. Very young children, even in infancy are capable of being sensitized to their pet animal. Unfortunately symptoms around the pet are often not noticed by parents but it should be suspected in any asthmatic child who has other symptoms of allergy despite an apparent absence of symptoms around the pet animal.
Differential diagnoses: Children who have recurrent lower respiratory tract symptoms with each viral illness are common in the pre-school age and because of the frequency of viral illnesses, they can be almost continuously ill through the winter months. Asthma is by far the commonest cause of these symptoms. Alternative diagnoses are far less common and can usually be excluded by history and a chest xray. The symptoms raising red flags are the same as described in infancy, including a history of poor growth, recurrent bacterial infections, significant vomiting or reflux, choking cyanotic episodes, sudden onset of symptoms after possible aspiration. Symptoms of these types along with a poor response to treatment of asthma with adequate doses of steroids would suggest the need for further investigation. Physical examination revealing localized chest or cardiovascular abnormalities would also indicate the need for further investigation. The investigations could include a chest xray, tests for cystic fibrosis, immune function tests, primarily quantitative immunoglobulins including IgG subsets, reflux studies and other more specific tests.
Trial of asthma therapy: A trial of therapy is often initiated as part of the diagnostic evaluation. Inhaled steroids can be administered even to the youngest children. Failure to respond to a good dose of inhaled steroid within three to four weeks would suggest the need to re-evaluate the diagnosis. Failure could result from three general possibilities: 1) poor parental compliance with administration of medication either for philosophical or technical reasons; 2) a diagnosis other than asthma; or 3) more significant asthma than first appreciated or an intercurrent respiratory tract infection exacerbating the asthma. In any case, it would not be unreasonable to initiate investigation beginning with a chest xray and a review of the history and physical examination seeking alternative diagnoses.
In summary, there are no tests in the pre-school-age group that are definitive for the diagnosis of asthma. A chest xray should be done in any severe or unusual case to exclude foreign body or congenital anomaly. Allergy testing can help to assess etiology and prognosis.
In this age the children are able to perform simple spirometry and the diagnosis can be supported with more formal evaluation. All children in this age group should do spirometry or peak flow measurements. Moreover the majority of asthmatic children in this age group, especially those with significant asthma are atopic (8) and allergy skin tests should be done.
Clinical History: The diagnosis of asthma will be suggested from a characteristic history of recurrent wheeze, shortness of breath and cough or even recurrent cough by itself. The child often has a history of cough and/or wheeze with each viral illness and a history of similar symptoms on exercise. There may also be symptoms occurring between respiratory tract infections at night or in the morning on arising. Any child with a history of night or morning cough due to asthma would be expected to have symptoms with exercise or in cold air.
Even in this age group a persisting cough may follow an infectious episode particularly if the episode was associated with paroxysmal coughing. This persisting cough is more likely to be asthma if the child had a prior history of symptoms with each viral respiratory tract infection or if the child is allergic. If there is a family history of atopy and/ or asthma there is greater likelihood for expression of asthma with the viral illness. In the presence of these prognostic features, the chances for recurring symptoms increases while in their absence a recurrent asthma becomes less likely.
A positive methacholine or histamine challenge test would increase the possibility that the child has asthma. Similarly the diagnosis would be more likely if variability of FEV1 or peak flows can be documented eg 20% response to inhaled Beta2 agonist. Excessive variability in home peak flow monitoring either a diurnal variation of 20% or more or day to day variation of 20% or more, or a 20% response to bronchodilator would help to confirm the diagnosis of asthma.
Atopic status: The presence of an atopic immune system in a child with recurrent respiratory symptoms suggests the possiblity of asthma. An elevated serum IgE (72) or elevated peripheral eosinophil count ( in asthma the elevation is often in the high normal range) (73) might suggest the possibility of atopic asthma. A history suggestive of allergy can be sought. Significant eczema in infancy or an immediate reaction (eg hives or swelling) to a food, commonly milk, egg, peanut, nut or fish would suggest the presence of atopy. Symptoms around animals, (dog, cat, horse etc) including rhinitis, conjunctivitis, asthma, hives or symptoms of allergic rhinitis especially with a seasonal variation would suggest atopy which in turn heightens the risk of asthma.
Differential diagnoses: In this age group, asthma is by far the commonest diagnostic possibility for cough and wheeze. Alternative diagnoses might be suggested by physical examination. A chest xray, sinus xray and possibly a test for cystic fibrosis could be done. At least a third of sinus xrays will be abnormal in simple uncomplicated asthma and the significance of these abnormalities is a matter of some controversy (74). The abnormal xrays are generally not associated with symptoms of sinusitis and may result from the same inflammation occuring in both the upper and lower respiratory tract (75). Symptomatic sinusitis should be treated and recurring bacterial infections of sinuses and elsewhere would suggest the need for an immunologic work-up, particularly looking for an IgG subset deficiency (76). IgG subset deficiency is uncommon but can present in very young children beginning with recurrent otitis media, sinusitis and cough. Recurrent or persistent symptomatic sinusitis, nasal discharge and cough might also suggest the need for nasal ciliary studies to rule out dysmotile cilia syndrome. A history of heartburn and reflux would suggest the need for more sophisticated studies of reflux with a pH probe. A trial of therapy for reflux would be warranted if the diagnosis can be entertained from the history. Occasionally a Mantoux test might be indicated by the history of contact or potential contact with tuberculosis.
Trial of therapy: Because asthma is by far the commonest diagnosis, a trial of therapy could always be undertaken if a work-up for alternative diagnoses is negative. The therapy should include steroid and home peak flow monitoring along with a symptom diary card. This trial should be undertaken aggressively for a 3 - 4 week period since most childhood asthma would be expected to show some response to inhaled steroid in that time frame.
Conclusion: At any age the diagnosis of asthma includes a wide range of severity from mild intermittent symptoms to continuous severe but atopy clearly plays a significant role in the chronicity. Even in older children there is no one test that will determine the severity of an individual patient's asthma. It is possible that in future tests that reflect airway inflammation e.g. sputum eosinophil measurements (77) might help to distinguish subtypes of asthma, but at the present they must be managed according to their clinical status.