Outcome Preschool Asthma
Role of Allergy in Asthma
UPDATE FEBRUARY 2007:
There have been several very significant publications in the last few years examining wheezing in preschool children. There are still major gaps in our knowledge of asthma in this age group but we now know that:
Normally I would put the update at the end of the page but in this case, I will introduce a publication available on line as a full pdf file, by Andrew Bush on the diagnosis and management of asthma in children less than age 5.
In this publication, Dr. Bush, both quotes the literature but also indicates the places where the literature is lacking and what he does in his practice and why.
There is also an extremely useful editorial entitled "Preschool asthma - not so easy to diagnose." by Dr. Soren Pedersen GO TO EDITORIAL
HISTORY OF MANAGEMENT OF WHEEZING IN PRESCHOOL CHILDREN:
In the 1960s, wheezing in preschool children was diagnosed as "wheezy bronchitis" and most pediatricians said that the parents should not worry because the children would outgrow it. It was felt that asthma should not be diagnosed before age 3. Then an epidemiologic study of childhood asthma suggested that preschool wheezing, labeled as wheezy bronchitis, was really part of the same disease group as chronic asthma Williams, McNicol 1969 (full article). This epidemiologic study, known as the Melbourne study, was continued through the 1970s and yielded important data on childhood asthma. That began the move away from the term "wheezy bronchitis" to labelling all wheezing in preschool children as asthma. Moreover when several studies, especially the Tyneside study, suggested that when wheezing was not called asthma, it was not managed with asthma medication despite repeated episodes of wheezing.1983 Speight, Lee and Hey (full article) there was a very strong tide against the term "wheezy bronchitis" with all wheezing being called asthma. A further study of all 7 year olds in Tyneside, concluded that "it was not possible to separate children with frequent wheeze from asymptomatic controls by their response to histamine." It was concluded that all these wheezy children had symptoms of a common basic disorder and that they should all be treated as asthmatic. Lee, Winslow, Speight, Hey 1983 (full article)
THE PENDULUM SWINGS BACK:
More recent studies have convincingly separated wheezing in preschool children into several categories, many of which are outgrown and should not be managed as agressively as asthma unless the child is very symptomatic.(Epidemiologic Studies: Heterogeneity in Preschool wheeze). "Wheezy bronchitis" is now labled "Viral-associated Wheeze" which is the commonest form of wheezing in preschool children and which is outgrown. Those studies allowed the identification of onset of "true" persisting asthma using an algorithm. Since atopic asthma which persists often begins in the preschool years, it was felt that early use of inhaled steroid as maintenance therapy might modify the course of the asthma preventing persistence and permanent changes in the airways. There were several prospective studies testing that hypothesis (UPDATE 2006) and the three studies agree that treatment with inhaled steroid early in the course of preschool asthma failed to modify the course of the asthma. Guilbert, et al 2006; Bisgaard et al 2006; Murray et al 2006. These studies were reviewed by Martinez 2007 who concluded that "Successful strategies for the prevention of asthma will require a better understanding of the genetic, environmental, and developmental factors that predispose toward inappropriate responses to airway injury. Abnormal airway remodeling and persistent dysregulation of airway tone might be the final common pathway for different disease mechanisms, and this might explain the heterogeneity of clinical phenotypic syndromes that go under the common label of "asthma."
These recent studies have led to a re-evaluation of the management of preschool asthma.
Preschool children, especially the very young are unable to perform the objective measures of lung function and therefore it is not possible to objectively demonstrate the cardinal sign of asthma, namely, variable airflow obstruction. The diagnosis in the preschool age group is based on symptoms and physical examination with a trial of therapy. In the majority of children the physical examination is entirely normal and is used to exclude other rarer and more serious lung diseases. These rarer lung conditions are likely to be seen no more than once per year in a community practice and with such a low frequency, that Dr. Bush argues that the vast majority of preschool children do not even need a chest xray.
Dr. Pedersen suggests that the diagnosis of asthma is more likely when there is a history of several symptoms rather than one or two symptoms including:
In the review by Andrew Bush, the first table is a summary of the important points in the history that would point to an underlying serious diagnosis.
The second table in the review by Bush, outlines a physical examination directed towards detecting uncommon signs that would point to a serious underlying lung disorder. As noted in the editorial by Dr. Pedersen, the serious lung disorders will be rare in a community practice and while they must be eliminated by a thorough history and physical examination, the vast majority of preschool "chesty" children will fall into an asthma-like category.
Dr. Bush presents a table that divides the different "asthma syndromes" in the preschool child into 6 categories which is more than previously described by Martinez et al.
Dr. Pedersen prefers a more dynamic approach of differentiating a preschool child with asthma from either a healthy child or a child with a more serious disorder. "The differentiation between groups increases with an increasing number of positive factors":
TRIAL OF THERAPY:
It seems likely that in the majority of instances of the "chesty" preschool child, there will be a trial of therapy even even in those where a work-up is being done to exclude other disorders. Dr. Pedersen suggests "an eight-week diagnostic treatment trial with a moderate dose of inhaled corticosteroid. Marked improvement of symptoms and recurrence when the treatment is stopped is highly supportive of an asthma diagnosis." Dr. Bush suggests that if the main symptoms are cough and wheeze with viral illnesses, a trial of treatment with intermittent bronchodilator therapy either as a beta-2 agonist or anticholinergic could be tried. If this is ineffective and the possibility of an "asthma syndrome" is still being considered then intermittent, very high dose inhaled steroid may be tried. Alternatively intermittent montelukast given for one week at the time of the viral illness could be tried Robertson 2007.
In my practice, I did not use bronchodilator therapy for viral induced wheeze, either non-atopic or atopic, since we had a long experience with the use of bronchodilators with viral illnesses in preschool children when it was not possible to administer inhaled steroid because the mask-spacer devices had not been developed and nebulized budesonide was not available. When I was the director of the division of Allergy at the Hospital For Sick Children, Toronto, we described a group of very atopic preschool children who had chronic asthma requiring maintenance inhaled steroid as opposed to a group of non-atopic and minimally atopic children who had intermittent wheeze with viral illnesses and did not require maintenance inhaled steroid.Zimmerman et al 1988. When I went into a community-based practice, I quickly found that the majority of wheezing preschool children were not atopic and had much milder symptoms compared to the group who had been referred to the clinic at the tertiary hospital. Subsequently when these preschool "asthmatic" children were studied, it was found that the atopic asthmatic infants had higher levels of circulating eosinophils and serum ECP compared to the non-atopic wheezers.Zimmerman et al 1994. From then onwards, I reverted to diagnosing the non-atopic, viral-induced wheezing as "wheezy bronchitis" and the atopic wheezing infants as asthmatic. I was less aggressive in the management of the non-atopic "wheezy bronchitis", using intermittent inhaled steroid initiated at the first sign of a cold. It has since been shown that those children are very likely to outgrow the viral-induced wheeze as predicted by the old-time pediatricians based on their clinical experience. Although the data is fragmentary, I found that a moderate dose of inhaled steroid initiated at the first sign of a cold, in preschool children known to wheeze with each viral illness, would suppress the "chestiness" to a far greater degree than intermittent bronchodilator and over-time the degree of "chestiness" with colds would ameliorate so that the entire syndrome would become milder. Once the evidence began to appear that the use of inhaled steroid early in the course of persisting, atopic asthma did not modify the course of the illness, I also began to consider the use of montelukast although I still feel (without a lot of evidence) that the atopic, wheezy preschool children did better using inhaled steroid than montelukast.
Dr. Bush is also impressed with the studies that have failed to show prevention of progression of atopic asthma from intermittent to chronic with inhaled corticosteroid treatment. He states that "if intermittent therapy is unsuccessful, and the symptoms are of sufficient severity, then a trial with a continuous anti-inflammatory medication (inhaled corticosteroid or leukotriene receptor antagonist) should be considered."
|AN INTERACTIVE CASE OF INFANT WHEEZING - IS IT ASTHMA?|
|Should an investigation be done?|
It is common for preschool children to be "chesty" with colds. Some years ago, we found that about 10% of children age 0 - 5 in the Toronto area had wheezed in the previous year and another 8 - 10% had persisting cough.Abstract  Recurrent viral induced wheezing is not associated with allergy in the majority of infants and toddlers, as will be discussed later and if the child remains non-atopic, there is a good chance of outgrowing the "chestiness". Recurrent wheezing or persisting cough with each viral illness, occurs commonly in infants following an episode of RSV induced bronchiolitis. Abstract As will be discussed, there is good evidence that recurrent wheezing associated with viral infection in children is a separate entity from atopic asthma. The pattern of such wheezing is of discrete episodes of viral infection of the upper respiratory tract leading to lower respiratory tract symptoms and decreased lung function.Abstract,Abstract.
RECURRENT COUGH AND WHEEZE
QUESTIONS FOR HISTORY OF PRESENTING COMPLAINT
After: Strunk R. Defining asthma in the preschool child.
Laboratory Investigation in Preschool Children with Wheeze.
INVESTIGATE:If there are positive answers to the differential diagnosis screen or physical findings apart from Eczema, investigate. Treatment for asthma can be initiated while awaiting the results of the investigation.
Unless trivial, recurrent episodes may warrant a screening chest X-Ray.
TREAT:If there are no positive answers to the differential diagnosis screen and the physical is negative apart from Eczema, begin treatment.
Wheezing in preschool children is common and estimated to occur in 20 - 30% of children (von Mutius 2001). Viral illnesses are associated with the majority of acute wheezing episodes with RSV predominating in children less than age 2 and rhinovirus in older preschool children (Duff 1993). (Kotaniemi-Syrjanen 2003) .
Asthma is defined as a disorder of airway inflammation producing paroxysmal or persistent symptoms associated with variable airflow limitation and airway hyperresponsiveness.(Boulet 1999). The very definition of the disease implies that one should be able to document or at least suspect the 3 elements before making a diagnosis of asthma that is: airway inflammation, reversible airway obstruction and airway hyperreactivity. However objective measures of the 3 elements are not routinely available in preschool children and this contributes to the difficulty in making a diagnosis of asthma in this age group. The diagnosis is primarily based on the history of recurring cough and wheeze that last a few weeks with each cold.
Martinez et al. (1995) suggested that there was heterogeneity in preschool wheezing. These authors described a six-year follow-up of a birth cohort of 1246 children of whom 826 were available for study at age 6. They characterized 3 groups of wheezing preschool children:
Modified from: Martinez FD et al. Asthma and wheezing in the first 6 years of life.
60% of wheezing infants "outgrow" the phenomenon by age 6
Rusconi et al. (1999) cohort of 16,333 children; 2810 wheezed or 17.2%
Sherriff et al (2001)enrolled a birth cohort of children at 4 - 8 months of age and at age 3.5 years, 8,594 subjects were followed from the original 10, 409.
2342 children or 27.3% had wheezed.
Martinezhas since suggested that preschool wheezing can be divided into 3 types. (1998)
Group 1: Low Lung function:
Group 2: Non-Atopic, viral-induced Asthma:
Group 3: Atopic Asthma:
Supporting Evidence: The data are supported by studies by the Perth group (1991) (1994) (1995a) (1995b) (2000a) (2000b) (2002) They described 23 infants in a birth cohort of 243 infants who had reduced lung function at 4 weeks and 6 months of age and increased airway reactivity at 12 months of age. These infants made up 10% of this randomly selected cohort and were asymptomatic at 4 weeks of age, but by 2 years of age they had a 7-fold higher incidence of physician-diagnosed asthma. Turner et al. followed a group of these "flow-limited" infants to age 11 and found that they had stopped wheezing by age 4. At age 11, they still had increased airway reactivity but were not associated with atopy or parental asthma Turner et al. 2002 . They had minor abnormalities in lung function that persisted at age 11. Atopy and parental asthma were not increased in the flow-limited group.
A number of studies have shown that maternal smoking during pregnancy is associated with the birth of infants with low lung volumes. This association was made in the large epidemiologic study by Martinez and co-workers and is amply supported by other studies
Hanrahan 1992 Hanrahan 1993 Hanrahan 1995 Hanrahan 1995 Stick 1996 Perth 2000 Dezateux 1999 Dezateux 2001 Murray 2002 Sheikh 1999 Tager 1993 .
Evidence for Atopic Asthma vs transient wheeze and non-atopic wheeze
Epidemiology: As cited previously, in a prospective study, Martinez and co-workers in Arizona (Martinez 1995) investigated the factors affecting wheezing before the age of three years and their relation to wheezing at six years of age. They studied 1246 newborns in the Tucson, Arizona area and had follow-up data at both three and six years of age for 826. They found that at the age of six years, 425 children (51.5 percent) had never wheezed; 164 (19.9 percent) had had at least one lower respiratory illness with wheezing during the first three years of life but had no wheezing at six years of age; 124 (15.0 percent) had no wheezing before the age of three years but had wheezing at the age of six years, and 113 (13.7 percent) had wheezing both before three years of age and at six years of age. The children who had wheezing before three years of age but not at the age of six had diminished airway function, were more likely than the other children to have mothers who smoked but not mothers with asthma, and did not have elevated serum IgE levels or skin-test reactivity. Children who started wheezing in early life and continued to wheeze at the age of six were more likely than the children who never wheezed to have mothers with a history of asthma (p < 0.001), to have elevated serum IgE levels (p < 0.01) and normal lung function in the first year of life and to have elevated serum IgE levels (p < 0.001) at age 6. At age 6, 60% of them were skin test positive to at least one local aeroallergen. They concluded that the majority of infants with wheezing had a transient condition associated with diminished airway function at birth and did not have increased risks of asthma or allergies later in life. In a substantial minority of infants, however, wheezing episodes was probably related to a predisposition to asthma.
The Tucson group continued with a study that determined if measures of airway lability and of allergy could identify distinct wheezing phenotypes during childhood. They concluded that Methacholine responsiveness and peak flow variability assessed at age 11, together with markers of allergy (IgE and skin test reactivity to allergens) identify three different wheezing phenotypes in childhood: "transient early wheezing" limited to the first three years of life and unrelated to increased airway lability; "non-atopic wheezing" of the toddler and early school years associated with positive peak flow variability but not with methacholine hyperresponsiveness; and "IgE-associated wheeze/asthma" associated with persistent wheezing at any age and with methacholine hyperresponsiveness, peak flow variability, and markers of atopy (Stein 1997).
They next went on to determine if their observations could be used to create a clinical index to predict the risk of asthma (vs transient wheezing) in young children with recurrent wheezing (Castro-Rodriguez 2000). They developed two indices for the prediction of asthma. A stringent index included frequent wheezing during the first 3 yrs of life and either one major risk factor (parental history of asthma or eczema) or two of three minor risk factors (eosinophilia, wheezing without colds, and allergic rhinitis). A loose index required any wheezing during the first 3 yrs of life plus the same combination of minor risk factors described previously. Children with a positive loose index were 2.6 to 5.5 times more likely to have active asthma between ages 6 and 13 than children with a negative loose index. Risk of having subsequent asthma increased to 4.3 to 9.8 times when a stringent index was used. They found that 59% of children with a positive loose index and 76% of those with a positive stringent index had active asthma in at least one survey during the school years. Over 95% of children with a negative stringent index never had active asthma between ages 6 and 13. They concluded that the subsequent development of asthma could be predicted with reasonable accuracy using simple, clinically based parameters. However the sensitivity of the stringent index was often low while the specificity was consistently high.
Rusconi et al (1999) enrolled 16,333 children, 6 to 7 yrs old, in a population-based study to examine the risk factors associated with the wheezing groups proposed by Martinez. Having siblings and attending a day care center were both risk factors for transient early wheezing (OR: 1.41 [95% CI: 1.21 to 1.64] and 1.70 [95% CI: 1.48 to 1.96], respectively) and protective factors against wheezing of late onset (OR: 0.83 [95% CI: 0.70 to 0.97] and 0.72 [95% CI: 0.59 to 0.88]). There was a stronger (p<0.0001) positive association between personal history of eczema or allergic rhinitis and persistent and late-onset wheezing than transient early wheezing.
Sporik R, Holgate ST, Cogswell JJ. (1991) studied a group of 67 babies at risk of developing allergic disorders. The group was followed prospectively for 11 years. At 11 years the group was restudied, symptoms were assessed by questionnaire, and bronchial hyperreactivity (BHR) to histamine was measured. On the basis of skin testing, 35 children were allergic and 32 were not. Allergy increased with age. Hay fever increased with age; eczema declined, while wheeze showed a bimodal distribution with a peak before the age of 2 years and a gradual increase thereafter. Of the 21 children who wheezed before their second birthday, most never wheezed again and did not show bronchial hyperreactivity (BHR) at 11 years. Of the 21 children whose first wheezing was after 2 years of age, 17 were still wheezing at 11 years and 12 showed BHR. Of the children who wheezed before 2 years of age, 10 were or became allergic, compared with 20 of the 23 children who wheezed at 11 years. These findings suggest that childhood asthma is a heterogeneous condition with allergy being strongly associated with the persistence of wheeze.
The same group of patients was followed to age 22 and in 2002 the findings were published (Rhodes 2002). Sixty-three of 100 subjects recruited remained on follow-up at 22 yr. The annual prevalence of both wheeze and atopy increased with age. Twenty-five percent of adults showed both wheeze and BHR (asthma). Remission of wheeze was common in subjects younger than 5 yr of age and likely if wheezing occurred on less than two occasions, but wheeze at 11 yr was likely to persist. Sixty percent (60%) of the adult subjects with asthma developed sensitivity to common allergens by the age of 2 yr and were showing BHR by mid-childhood. Sensitization to dietary allergens occurred in infancy and waned after early childhood but predicted the early sensitization to inhalant allergens. In conclusion, adults with asthma can begin wheezing at any age but tend to sensitize early and have abnormal airway characteristics by the age of 11 yr.
At 22 yr, 43 (72%) (CI 59, 83%) of the 60 subjects were atopic. Fifty-two subjects underwent skin prick tests at every time point during the study. The age of first sensitization was in infancy to ingestants (only one occurred when older than 2 yrs) and throughout childhood for aeroallergens (p< 0.001 using Cochran's Q test). The number of children with aeroallergen sensitization increased throughout childhood. The positive skin reactions to egg and milk tended to be transient, whereas those for airborne allergens tended to be permanent. For example, of 13 participants with a positive reaction to egg or milk at 2 yr or younger none had positive tests at every subsequent follow-up compared with 6 of 16 for airborne allergens (p 0.02). Those children who showed sensitivity to ingestants (egg or milk) when younger than 2 yrs were more likely to develop aeroallergen sensitivity, and this occurred at an earlier age than those who had not shown ingestant sensitivity. The lifetime prevalence of sensitization to the allergens tested was house dust mite 54% (CI 39, 69%), grass pollen 54% (CI 39, 68%), cat 50% (CI 36, 64%), dog 33% (CI 20, 47%), egg 25% (CI 14, 39%), and milk 8% (CI 2, 19%).
Van Asperen and Mukhi (1994) in Australia studied the role of allergy in the natural history of wheeze and bronchial hyperreactivity in childhood.
They prospectively followed a birth cohort of children of allergic parents to document the development of allergic disease in the children. They wished to study the natural history of bronchial hyperreactivity (BHR) and wheeze at 10 years of age and to relate this to allergy. Thirty-three (70%) of the children wheezed at some time during their 10 years of life, with 13 starting in infancy. Twenty-two children (47%) were wheezing at 10 years of age. Wheeze in infancy was a poor predictor of wheeze at age 10 while wheeze starting after infancy was a good predictor. In contrast both allergy in infancy and current allergy were strong predictors of current wheeze. Analysis of BHR confirmed the importance of allergy in predicting its occurrence and severity. These observations confirmed the importance of allergy in predicting outcome in children with asthma and suggest that wheezing in infancy and wheezing in later childhood may have different pathogenetic mechanisms.
Those authors also showed that Allergy in infancy predicted the severity of bronchial hyperresponsiveness (BHR ) in later childhood (Van Asperen 1990). They prospectively followed 52 children of atopic parents from birth to age 7 years, documenting clinical allergic disease and allergen skin test reactions. They concluded that subjects most likely to develop the more severe degrees of BHR (bronchial hyperreactivity) during later childhood were children who manifested allergy in infancy.
Duff et al., (1993) found that in children under age 2 wheezing is viral, with no allergy vs. over age 2 wheezing was predicted by virus plus IgE antibody to aeroallergen.
Lau et al (2002) in a cohort studied from birth to age 7 (German Multicentre Allergy Study) showed that children sensitised to any allergen early in life and sensitised to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at age 7 (odds ratio (OR) = 10.12; 95% confidence interval (CI) = 3.81-26.88).
Sherriff et al (2001) examined factors leading to asthma in cohort from birth to age 3. Atopy was associated with onset after 6 months of age.
Gustafsson et al (2000) documented the association of asthma with atopic dermatitis. 94 children with atopic dermatitis were followed to age 3 and 43% of them developed asthma.
Linna (1992) had published similar results for generalized eczema in which, despite improvement in the eczema, 50% had developed asthma.
Kotaniemi-Syrjanen and co-workers(2000,2002,2003) followed 82 children who had been hospitalized for wheezing at less than age 2. In this highly selected group of patients atopy was a significant predictor of asthma after hospitalization for wheeze in infancy. The children hospitalized for wheezing at age < 2 years, were re-examined at the median age of 7.2 years. Asthma was present in 33 (40%) of the children. The significant asthma-predictive factors, present on entry to the study, were blood eosinophilia (p = 0.0008), atopic dermatitis (p = 0.0089), elevated total serum immunoglobulin E (IgE) (p = 0.0452), and a history of earlier episodes of wheezing in infancy (p = 0.0468). Skin prick test positivity in early childhood was also associated with school-age asthma (p = 0.002). When present in wheezing infants, specific IgE of >/= 0.35 kU/L to wheat, egg white, or inhalant allergens was predictive of later childhood asthma. They suggested that detection of those specific IgE antibodies in wheezing infants might facilitate the early diagnosis of asthma, especially in cases with no clinically evident atopic manifestations.
From: Castro-Rodriguez JA et al. (2000) A Clinical Index to define the risk of asthma in young children with recurrent wheezing
Am J Respir Crit Care Med 2000;162:1403-6
Unfortunately the algorithm is not very useful for clinically defining atopic and nonatopic preschool asthma. Determining the presence of an atopic immune system is most easily done by prick skin-testing even in infants and toddlers. It must be recognized, however, that the skin test results, when properly done, are specific for only that point in time and do not predict the risk for the future development of allergy. The risk for developing allergy in future can best be predicted by the family history. A history of allergy in the immediate family, especially the mother, suggests that there is a significant risk for the preschool patient developing aeroallergen sensitivity that would create eosinophilic inflammation in the lower airways and the development of persisting asthma.
THE IMPORTANCE OF DISTINGUISHING SUBTYPES OF PRESCHOOL ASTHMA
Diagnosis of Preschool Asthma: Conclusions based on Evidence from the Literature Review:
In young children, documentation of airway inflammation rests on invasive procedure that the clinical management cannot in most circumstances ethically justify. Our understanding of the cellular and molecular events that trigger and maintain asthma has been based in part on studies of biological specimens obtained from asthmatic airways. Few such studies have been published from bronchial biopsies in young children and all have been reported either in abstract form only or in non-English literature ( Bush 2000). While bronchoscopy, bronchial biopsies and bronchoalveolar lavage are routinely performed in asthma research involving adults volunteers, their use in children is still regarded as invasive and can only be justified if it will contribute to the management of the patient himself ( Payne 2001) despite a rather low risk ( < 2%)of major complications after bronchoalveolar lavage in large series (DeBlic 2002). Furthermore, firm recommendations on the methodology of pediatric bronchoalveolar lavage outside of the immunocompromised host preclude its use in asthmatic research.( DeBlic 2000)
Bronchoalveolar lavage obtained from children with atopic asthma and viral-associated wheeze showed that there might be different patterns of inflammation in these populations with overall increased total cell counts but elevated levels of eosinophils and mast cells in atopics and neutrophils dominating the pattern of others (Stevenson 1997, Marguet 1999 ). The same neutrophilic pattern was also demonstrated in children < 3 year old with recurrent wheezing who failed to respond to steroids ( Le Bourgeois 2002). In a younger age group (< 18 months old) unresponsive to bronchodilators, neutrophilic dominance was associated with infections or aspirations. (Schellhase 1998). Finally, in a group of mostly atopic persistent wheezers ( mean age 14.9 month) with clinical benefits from bronchodilators and steroids suggesting "asthma", no difference in the percent cell types was found in comparison with controls (Krawiec 2001). Overall, studies in young children support the view that we cannot extrapolate data from adult studies if we want to learn about the factors that trigger, sustain or even treat the basic mechanisms of asthma in children.
Non-invasive methods of airway inflammation evaluation such as induced sputum, exhaled gas analysis or exhaled breath condensates have been described in adults. They would ethically be most attractive in children. In preschool children, we lack tissue samples to act as validated gold standards and young children are unable to produce or spit out sputum. Furthermore, although international recommendations over standardisation of fractional concentration of Nitric Oxide (FeNO) measurement in exhaled breath have been published (ATS 1999) there is still controversy over the validity of the various measurements in infants or the comparison of the various techniques used ( Godfrey 2002). Breath condensate analysis represents an attractive alternative to the methodological difficulties of FeNO measurement in the sense that breath condensate measurements are flow-independent and can be obtained with a simple technology. They can also allow the detection of inflammatory markers such as cytokines. Yet, further work is required to establish standards in children and again to compare them with gold standards such as bronchoalveolar lavage.
There are a few publications that indicate that young non-allergic children who wheeze with viral illnesses do not have eosinophilic inflammation. They differ from allergic childhood asthma which has eosinophilic inflammation.
Azevedo and co-workers (2001) documented increased cells especially neutrophils and ECP in BALF of wheezy infants compared to non-wheezing infants. This result suggested that inflammation and activated cells play a role in infant wheezing. The BALF ECP correlated with the number of neutrophils and not eosinophils in the BALF. It has recently been found that ECP is not specific for eosinophils in the airways and identifies both neutrophils and eosinophils (2002).
In a further study they documented the presence of neutrophils and not eosinophils in the airways of severely wheezy infants (2002)
Schellhase and co-workers (1998) performed flexible bronchoscopy on infants with recurrent wheeze and found increased neutrophil inflammatory cells.
Nagayama and co-workers (45, 46) described increasing levels of eosinophils in stained samples of sputum of infants as they aged.
Stevenson and colleagues, (1997) examined fluid rinsed through the lungs of children undergoing anesthesia for operation and compared the cells in the lungs of children with allergic asthma and non-allergic asthma. This study investigated the cellular constituents of BAL fluid in children with a history of atopic asthma (AA) non-asthmatic atopic children (NAA) or viral associated wheeze (VAW). A total of 95 children was studied: 52 with atopic asthma (8.0 years, range 1.1-15.3, 36 male), 23 with non-asthmatic atopy (median age 8.3 years, range 1.7-13.6, 11 male) and 20 with VAW (3.1 years, range 1.0-8.2, 13 male). Total lavage fluid recovered was similar in all groups and the total cell numbers were higher in the VAW group. Eosinophil (p < or = 0.005) and mast cell (p < or = 0.05) numbers were significantly elevated in the group with atopic asthma. During relatively asymptomatic periods there is on-going airways inflammation, as demonstrated by eosinophil and mast cell recruitment, in children with asthma and atopy but not in children with viral associated wheeze or atopy alone. This strongly suggests that there are different underlying pathophysiological mechanisms in these two groups of children who wheeze. The VAW children were significantly younger than the atopic asthmatics and normal controls.
These same workers examined the inflammatory mediators (proteins) in bronchoalveolar lavage samples from children with and without asthma (1999). They found histamine concentrations were elevated in both the allergic asthmatic and viral-associated wheeze groups compared with controls and additionally higher concentrations were obtained in allergics with asthma compared with allergics without asthma, whereas ECP was only elevated in those asthmatics with allergy. The results suggested that even in relatively quiescent periods, there is some ongoing activation of airway eosinophils in children with allergic asthma.
Serum ECP and Peripheral Blood Eosinophils
Zimmerman et al. (1994) examined preschool children (median age, 18 months) and showed that non-atopic preschool children who wheezed had lower levels of eosinophils and eosinophilic cationic protein (a measure of activated eosinophils) in their peripheral blood than allergic asthmatics.
Koller et al. (1997) found that serum ECP was useful in predicting the onset of asthma in infants.
Villa et al. (1998) also found that serum ECP and eosinophils predicted which children (age 2 -4 years) would continue to wheeze over a 2 year follow-up.
Shields et al. (1999) found that serum ECP and Peripheral Blood Eosinophils were useful in predicting which asthmatic children would have eosinophils in their airways.
Rakes et al (1999)found that wheezing with virus (usually RSV) in infants was associated with elevated nasal ECP.
Only a few studies have been performed with bronchoalveolar lavage in preschool children and generally only in infants with wheezing unresponsive to treatment for asthma. Although these are a very selected group, the studies suggest that those children have elevated inflammatory cells in their airways but more commonly neutrophils rather than eosinophils. It seems likely that those infants are drawn from the non-atopic wheezing preschool children described by Martinez. Eosinophilic inflammation becomes more common in slightly older children when atopic asthma begins to predominate. Serum ECP which seems to be a measure of eosinophilic inflammation and peripheral eosinophil counts seem to be elevated in children with persisting, recurrent asthma. Serum ECP and eosinophils seem to distinguish atopic from non-atopic preschool asthmatics. However the data at present is not consistent and further research needs to be done to establish the nature of any inflammation in the airways of wheezing preschool children and non-invasive techniques that might lend themselves to the routine clinical assessment of wheezing preschool children need to be developed.
INTRODUCTION:Because it is difficult to perform studies in very young children, the few published trials of therapy are usually done on small numbers of young children using symptom scores as outcomes. Despite that, the data is consistent. Persistent allergic asthma responds to inhaled steroid similar to the findings in older children with allergic asthma. Bisgaard et al. 1990 Ilangovan et al. 1993 DeBlic et al. 1996 Wennergren et al. 1996 Volovitz et al. 1998
However the data is more complicated in viral-induced non-allergic asthma. Studies have suggested that treatment with oral steroid at the onset of symptoms can improve viral-induced asthma. Brunette et al. 1988 The literature suggests that there is no value in using continous inhaled steroid to manage this condition but that there is value in the use of intermittent inhaled steroid started at the very first sign of a cold.
BACKGROUND: Recurrent episodic wheeze in association with viral upper
respiratory tract infection (URTI) is a specific clinical illness distinct from
persistent atopic asthma.
OBJECTIVES: The objective of this review was to identify whether corticosteroid treatment, given episodically or daily, is beneficial to children with viral episodic wheeze.
SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of corticosteroid treatment versus placebo in children under 17 years of age who suffer from 'episodic viral wheeze', which is defined by wheeze in association with symptoms with minimal or no intercurrent lower respiratory tract symptoms. DATA
COLLECTION AND ANALYSIS: Trial quality was assessed independently by two reviewers. Study authors were contacted for missing information. Studies were categorised according to whether treatment was given episodically or daily (maintenance). The primary outcome was episodes requiring oral corticosteroids. Secondary outcomes addressed episode severity, frequency and duration and parental treatment preference.
MAIN RESULTS: Five randomised controlled trials in children with a history of mild episodic viral wheeze were identified. Most of the children had previously required no or infrequent oral corticosteroids and had very infrequent hospital admissions. There were three studies of preschool children given episodic high dose inhaled corticosteroid (1.6 - 2.25 mg per day), two using a crossover and one a parallel design. The two studies of maintenance corticosteroid (400 micrograms per day) were parallel in design, one of pre-school children the other of children aged 7 -9 years. Results from the two cross-over studies of episodic high dose inhaled corticosteroids showed a reduced requirement for oral corticosteroids (Relative risk (RR)=0.53, 95% CI: 0.27, 1.04). In these 2 double blind studies, this treatment was preferred by the children's parents over placebo (RR=0.64, 95% CI: 0.48,0.87). Maintenance low dose inhaled corticosteroids did not show any clear reduction over placebo in the proportion of episodes requiring oral corticosteroids (N=2 trials, RR=0.82, 95%CI: 0.23,2.90) or in those requiring hospital admission (N=1 trial, RR=0.21, 95% CI: 0.01,4.11).
REVIEWER'S CONCLUSIONS: Episodic high dose inhaled corticosteroids provide a partially effective strategy for the treatment of mild episodic viral wheeze of childhood. There is no current evidence to favour maintenance low dose inhaled corticosteroids in the prevention and management of episodic mild viral induced wheeze.
In this study the effect of budesonide (400 micrograms/day) was assessed in a four month double blind parallel trial, in 41 children (0.7-6.0 years) with predominantly episodic viral wheeze. Analysis of the last three months showed no difference between budesonide or placebo in mean daily total symptom score (median values 0.6 and 0.63), episode number (mean values 2.6 and 2.4), or score/episode (mean value 30 and 31).
Conclusion: Four months of treatment with inhaled budesonide had no effect on acute episodes of wheeze in this group of children.
OBJECTIVES: To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children.
DESIGN: Randomised, double blind, placebo controlled trial.
SETTING: Community based study in Southampton.
SUBJECTS: 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months.
INTERVENTIONS: After a run in period of 2-6 weeks children were randomly allocated twice daily inhaled beclomethasone dipropionate 200 micrograms or placebo through a Diskhaler for 6 months with a wash out period of 2 months. Children were assessed monthly.
MAIN OUTCOME MEASURES: Forced expiratory volume in 1 second (FEV1); bronchial responsiveness to methacholine (PD20); percentage of days with symptoms of upper and lower respiratory tract infection with frequency, severity, and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate.
RESULTS: During the treatment period there was a significant increase in mean FEV1 (1.63 v 1.53 1; adjusted difference 0.09 1 (95% confidence interval 0.04 to 0.14); p = 0.001) and methacholine PD20 12.8 v 7.2 mumol/l; adjusted ratio of means 1.7 (1.2 to 2.4); p = 0.007) in children receiving beclomethasone dipropionate compared with placebo. There were, however, no significant differences in the percentage of days with symptoms or in the frequency, severity, or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups.
CONCLUSIONS: Although lung function is improved with regular beclomethasone dipropionate 400 micrograms/day, this treatment offers no clinically significant benefit in school age children with wheezing episodes associated with viral infection.
77 children, aged 11 to 36 months (mean 24) with moderately severe recurrent wheezing, were treated with budesonide pressurised aerosol 400 micrograms twice daily or placebo for 12 weeks in a double-blind, parallel-group trial. Aerosols were inhaled from a spacer with a facemask. Budesonide significantly improved symptom scores of wheezing, sleep disturbance, and patient happiness. The frequency of severe exacerbations that required a course of oral prednisolone was also significantly reduced. The treatment effect appeared to be fully established after 6-8 weeks and no side-effects could be ascribed to the active treatment. The findings indicate that young children below 3 years of age can inhale a pressurised aerosol from a spacer with a facemask. Use of topically active glucocorticosteroids with this simple device may reduce symptoms and distress in young children with moderately severe recurrent wheeze and dyspnoea, and possibly reduce their requirement for oral steroids.The Cochrane review of the literature concluded that daily inhaled steroid was ineffective in viral induced episodic asthma but the article by Doull did show improved spirometric values and the article by Bisgaard (which was not included in the Cochrane review) concluded that there was symptomatic improvement in severe episodic wheezing of young children treated with daily inhaled steroid. However it is felt that in the study by Bisgaard et al., children with chronic asthma were being treated since the patients were chosen from a population of children with more severe asthma. Doull recently reviewed the literature and concluded that while the data clearly show that infants and toddlers with chronic asthma benefit from maintenance inhaled steroid, that is not true for intermittent, viral-induced wheezing. Doull 2003
In a double blind, controlled trial, the effect of high dose beclomethasone dipropionate (750 micrograms three times daily for five days) administered by metered dose inhaler and valved spacer, was compared with placebo, during 70 paired episodes of acute asthma in 24 preschool children. Treatment commenced at home at the first sign of an attack. Parents' blind preference for active treatment was significant. Data from 17 pairs of treatment, however, were affected by interventions such as hospital admission or oral corticosteroid treatment. These events occurred similarly in active and control periods. An intrasubject comparison was made of diary scores from the 18 pairs of episodes in which no intervention occurred in either the active or placebo treatment. Both daytime and night symptoms over the first week of the attack were significantly reduced by active treatment. Intermittent high dose inhaled beclomethasone dipropionate is beneficial in modifying the severity of acute episodic asthma in preschool children able to use a spacer device.
The aim of this study was to investigate whether budesonide, for 10 d, administered at the first sign of an upper respiratory tract infection, could reduce asthma symptoms in 1-3-y-old children with asthma during infections. Fifty-five children with a mean age of 26 months received either budesonide or placebo via a spacer with a facemask. Each child was monitored for 1 y. Budesonide was given 400 microg q.i.d. for the first 3 d and b.i.d. for 7 d. Symptoms (cough, wheeze, noisy breathing and breathlessness) were scored (0-3) daily by the parents. Asthma symptom scores were lower in children treated with budesonide than in those given placebo. The effect was most pronounced for cough and noisy breathing, but it did not affect the need for hospital care. In conclusion, treatment with budesonide, started at the first sign of a respiratory infection, reduced asthma symptoms in toddlers with episodic asthma.
Thirty two preschool children were entered into a double blind, placebo controlled study using intermittent budesonide to treat viral induced wheeze. Active treatment was either 800 micrograms twice a day via a spacer or 1600 micrograms twice a day via a spacer and facemask in those children too young to use a mouthpiece. Treatment was started at the onset of an upper respiratory tract infection and continued for seven days or until symptoms had resolved for 24 hours. Twenty five children completed 28 treatment pairs. All 25 families were asked to express a preference after completing their first treatment pair: 12 preferred budesonide and six preferred placebo; seven had no preference. Symptom scores were compared in 17 treatment pairs that were completed without the need for oral prednisolone. Mean day and night time wheeze in the first week after infection were significantly lower in those receiving budesonide. Intermittent inhalation of budesonide can modify the severity of wheezing in preschool children developing asthma after viral respiratory infections but improvements were modest with the doses used in this study.
Upper respiratory tract infection (URTI) is a common cause of deterioration of asthma in children. We investigated if inhaled steroids (budesonide), started early after URTI, could reduce asthma. Thirty-one children, 3-10 years of age, with deterioration during URTI participated. Treatment was started at the first sign of URTI. Budesonide/placebo was given by Turbuhaler at 0.2 mg qid for 3 days, tid for 3 and bid for the last 3 days. Twenty-two children completed 67 periods. Eleven visited the emergency room, only three during budesonide therapy. Five received oral steroids and two were admitted to hospital, all receiving placebo. Symptom scores were not significantly lower during budesonide treatment. PEF, both morning and evening, was significantly higher during budesonide than placebo (p = 0.015 and p = 0.022). Inhaled budesonide can attenuate exacerbation of URTI-induced asthma.
Forty children aged 1-3 y completed a placebo-controlled study on the effects of 10 d of inhaled budesonide for asthma caused by respiratory tract infection. The effects on symptoms were significantly better in the active than in the placebo group. In 20 of these children the systemic effects of high-dose inhaled budesonide for 10 d and the effect of a 3-d course of oral betamethasone on asthma exacerbation were evaluated. Short courses of oral betamethasone have pronounced systemic effects, whereas 10 d of high doses of budesonide do not produce significant systemic effects.
BACKGROUND: To investigate if high dose inhaled beclomethasone dipropionate started early after upper respiratory tract infection (URTI) could reduce recurrent wheezing in infants.
METHODS: Twenty-six ambulatory infants, 7-12 months of age, with recurrent wheezing during upper respiratory tract infection participated. All experienced at least three wheezing attacks. Those with underlying lung or systemic disease were excluded. Infants were divided into two groups in an open unblinded manner, until 13 patients had been recruited for each group. The groups were similar in risk factors for recurrent wheezing. Four treatment periods of 5 days were planned for group 1. The dose regimen was nebulized beclomethasone 400 mg by mask tid for 5 days. Treatment was started at the very first sign of URTI prior to any sign of wheezing. Group 2 did not receive any preventive treatment and constituted the control group. Symptom scores were recorded. The number of emergency room visits, hospital admissions and short courses with oral steroids was also noted.
RESULTS: Twelve infants completed 48 treatment periods. Five visited the emergency room, only one during beclomethasone therapy. Six received oral steroids, two receiving beclomethasone. No patient was admitted to the hospital. Symptom scores were significantly lower during beclomethasone treatment (p<0.05). No apparent adverse events were reported.
CONCLUSIONS: The infant with recurrent wheezing during URTI is a therapeutic challenge. Most of these infants have prodromal symptoms for about 24 hours before wheezing starts. In the present study we observed favorable results: a decrease in the number of days the child wheezed and the number of acute attacks, when high dose inhaled beclomethasone was administered during this critical time.
Many clinicians advise their patients to increase the dose of inhaled corticosteroids during acute asthma exacerbations, without strong clinical evidence supporting this treatment. This study investigates the effectiveness of inhaled corticosteroids in controlling acute asthma exacerbations in children at home. The study population consisted of children with mild intermittent, mild and moderate persistent asthma aged 1 to 14 years who were treated in our outpatient clinic with inhaled budesonide for 1 year. After participating in an asthma education session, the parents were instructed to initiate treatment with inhaled budesonide at the first signs of asthma exacerbation, starting with 200 to 400 microg budesonide, in combination with beta-2 agonists 4 times a day and followed by a decrease in the dose in 4 to 8 days. Asthma status and peak expiratory flow rates were measured in the 3 monthly follow-up visits. Only children who complied with the treatment regimen and came for follow-up visits regularly were included in the final analysis. One hundred fifty children used our treatment protocol with inhaled budesonide to control their asthma attacks. Clinical improvement of asthma symptoms was achieved after a mean of 1.8 +/- 0.7 days from the beginning of treatment. The parents were able to control 94% of the 1,061 episodes of asthma exacerbation occurring during a cumulative follow-up period of 239 years. In the 3-month period before enrollment, 101 children (67%) had used oral corticosteroids to control their asthma attacks and 50 (33%) were hospitalized. During the entire follow-up period, only 11 children (7%) used oral corticosteroids, and none of the children was hospitalized. The present study demonstrates that children with asthma can control their exacerbations at home using inhaled corticosteroids (budesonide). Treatment, starting with relatively high doses followed by a rapid reduction in dose over 4-8 days, resulted in a decrease in the use of oral steroids and in hospitalization. To achieve good results, patient compliance is essential.
Comment:Volovitz et al., performed an open trial with retrospective control, to assess the efficacy of an "Action Plan" starting high dose inhaled steroid at the first sign of a cold. They demonstrated that with this treatment plan, inhaled steroid reduced symptoms and emergency room visits as well as the use of oral steroid. The weakness of this study is its unblinded design with retrospective controls. It does however, mimic a true-to-life situation and the results are similar to what I see clinically with this method of therapy. However in this study no attempt was made to distinguish non-atopic vs atopic children. The study enrolled children to age 14 and children over age 7 or 8 who have not outgrown their asthma are almost uniformly atopic so that they are at risk for chronic eosinophilic inflammation in their airways. They are very likely to need maintenance inhaled steroid. In contrast, young preschool children are likely to be non-atopic and likely to outgrow the viral-induced asthma. They only need intermittent therapy during viral illnesses. Alhough Volovitz et al., suggested that high dose inhaled steroid should be used, it is my experience that in a general practice, lower doses of inhaled steroid started at the first sign of a cold, before the child even coughs, are sufficient to blunt the symptoms.
The results of the PEAK study have now been published. Guilbert 2006 The outcome was somewhat disappointing since inhaled steroid treatment of the children identified as being in a group at high risk for developing persisting asthma and lung function changes did not change the outcome in the follow-up year compared to the control group. Certainly the children were symptomatically improved while being treated with inhaled steroid but the results failed to suggest that the course of asthma could be modified by early aggressive treatment with steroid to suppress inflammation. Moreover there was a difference in growth velocity between the children treated with inhaled steroid in the first two years of the study compared to those who did not receive treatment with inhaled steroid (12.6 +/- 1.9 cm. in the steroid-treated patients vs. 13.7 +/- 1.9 cm, p<0.001). The difference in growth velocity seemed to occur primarily in the first year of treatment. There was some catch-up growth in the observational year when both groups of children were off inhaled steroid but there still remained a 0.7 cm difference in height between the steroid-treated and the non-steroid treatment group. It was not known whether further catch-up would occur as the children aged. The authors concluded "that the natural course of asthma in young children at high risk for subsequent asthma is not modified by two years of treatment with inhaled corticosteroids. The treatment, however, did reduce the burden of illness. Our findings demonstrate that inhaled corticosteroids can be used to control active disease but should not be used to prevent asthma in high-risk preschool children".
In fact a second study by Bisgaard et al. (published in the same issue of the New England Journal of Medicine) tried to modify the course of intermittent asthma (in a patient group at high risk for developing persisting asthma) using short courses of intermittent inhaled steroid begun during viral induced wheezing (as opposed to the maintenance inhaled steroid used in the PEAK study). These authors also failed to show modification of the course of infantile asthma. Bisgaard 2006 The two studies were very different in design but in total, the results suggest that the development and course of infant asthma could not be modified by early treatment with inhaled steroid.
This was discussed in an accompanying editorial by Gold and Fuhlbrigge. Gold 2006 In this editorial the authors recall that the Childhood Asthma Management Program study of school-aged children, found that treatment with twice-daily inhaled steroid controlled symptoms better than other medication, slightly reduced growth but did not improve lung growth or affect the natural course of the asthma. That led to the hypothesis tested by the current studies, to whit, that the administration of inhaled corticosteroid might modify the course of the illness if started earlier, before the disease had become chronic. Neither of the two studies cited above showed that early therapy with inhaled steroid was able to influence the course of the disease. In the study by Bisgaard et al., the patients were not as well defined a group as in the PEAK study and the treatement with inhaled steroid was started on the third day of symptoms. These authors failed to find that this treatment even modified the course of the intermittent asthma episodes compared to the control group. In the editorial it was noted that starting the inhaled steroid that late after onset of symptoms might have resulted in the failure to show any modification of the episode. The editorial review of these studies cites the guidelines of the National Asthma Education and Prevention Program for the use of corticosteroid therapy in young children. "In recognition of the fact that the diagnosis of asthma is difficult in very young children, the guidelines suggest that among high-risk children who are five years of age or younger, a diagnostic trial of inhaled bronchodilators and antiinflammatory medications may be helpful, with careful monitoring of the response to therapy." The editorial concludes that "These two clinical studies add to the evidence that although inhaled corticosteroids may control persistent or severe wheezing, such drugs should not be used in the hope of altering the course of asthma in childhood."
While there are at least three separate blind placebo-controlled trials suggesting efficacy of treatment with intermittent inhaled steroid in viral-induced asthma of the preschool child, the strongest data in the recent publication by Bisgaard et al. failed to find
any effect of intermittent inhaled steroid. This likely resulted from the study design in which the inhaled steroid was not
started until day 3 of symptoms. Moreover there is a major difference between simple viral induced wheezing versus atopic asthma even in this age group. Considering that the evidence suggests that the course of asthma
cannot be modified by the early introduction of inhaled steroid even in high risk atopic patients, there is no obvious reason to treat more aggressively than is necessary
to obtain relief of symptoms. That suggests that a step-up approach to management, in which the leukotriene receptor antangonist is tried first could be
quite reasonable. Then inhaled steroid might be reserved for the more difficult patients and the ones who do not respond well to the LTRAs.
PRESCHOOL ASTHMA: Summary of Management