Editorial

Nosing out the future asthmatic?

A. BushImperial School of Medicine at National Heart and

Lung Institute, and Royal Brompton Hospital, London,

UK

Dr Andrew Bush

Department of Paediatric Respiratory Medicine

Royal Brompton Hospital

Sydney Street

London SW3 6NP

UK

Accepted for publication 14 March 2000

``Is it asthma, doctor?'' must be among the commonestquestions asked by anxious parents of a wheezy child,and the paediatrician dealing with this problem mustsigh for a simple answer to a super®cially simple quest-ion. According to the simple (and excellent) de®nition ofthe Paediatric Consensus Group (1), asthma is ``wheezeand/or cough in a setting where asthma is likely, andother, rarer, conditions have been excluded''. Therefore,if the child truly is wheezing (and this may be dif®cult todetermine even in English, but much more so inlanguages with no word for ``wheeze'' [2]), then, byde®nition, the child has asthma ± of a sort. However, it isabundantly clear that the word ``asthma'' covers anumber of phenotypes (Crimi et al. [3], Table 1), andthat re®ning my opening question would lead to thesupplementary question, ``Does my child have the sortof asthma that means his airways are in¯amed, and thatif he is not treated aggressively, his airways will undergostructural remodelling and later develop ®xed air¯owobstruction?'' The dif®culty is that we simply do notknow how to answer that question.

At one end of the spectrum of the wheezing pheno-types (4) are the virus-associated wheezers; they haveneither a personal nor a signi®cant family history ofatopic disease, and wheeze only with viral colds. Thereis compelling evidence that the basis of their symptomslies in prenatal events affecting baseline airway calibre.This evidence includes the detection of airway obstruc-tion soon after birth in infants of mothers who smokedin pregnancy, or were atopic, or, interestingly butinexplicably, had hypertension of pregnancy (5±7); thedetection of air¯ow obstruction prior to the ®rst wheezy

episode (8±10); the absence of an association betweenbronchial hyperreactivity and wheeze (11, 12); the poorresponse of viral associated symptoms to inhaledcorticosteroids (13); the lack of airway eosinophiliaon blind lavage studies (14); and the excellent prognosisfor long-term lung function, whatever treatment isgiven (15). At the other extreme is the infant who hasatopic dermatitis and perhaps multiple food allergies,with wheezing with viral colds, but also wheezingtriggered by dust, furry pets, and other triggers. Even inthis group, half will remit by the early school years (16).The vast majority of wheezers fall neatly between theseextremes, and this makes advising parents and planningtreatment sensibly very dif®cult.

De®ning the wheezing phenotype is of greatpractical therapeutic importance. Up to 50% ofchildren wheeze before the age of 6 years. Evidencefrom a randomized controlled trial in adults (17) andobservational data in children (18) suggest that delayin initiating inhaled corticosteroids may prejudiceultimate lung function. On the other hand, over-treatment with even low-dose inhaled steroids maycause growth failure (19), and, according to animalstudies, possible reduction in alveolarization in thedeveloping lung (20).

The obvious way to resolve these dif®culties is to ®nda way of measuring airway in¯ammation in these smallinfants. Studies using serum levels of markers such aseosinophil cationic protein have either been unpromis-ing or lacked follow-up for a suf®cient length of time toallow a balanced judgement of their importance (21,22). Unfortunately, sputum induction is not feasible in

Allergy 2000: 55: 685±687Printed in UK. All rights reserved

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ALLERGYISSN 0105-4538

685

infants, and there are only limited data on the use ofnitric oxide in this age group (23). Since it is notunreasonable to assume that there is no sudden changeat the level of the vocal cords, and the nose is contigu-ous with the bronchial tree, changes in the nose mayre¯ect the lower airway and increase diagnostic pre-cision. A number of groups have used nasal lavage,biopsy, aspirates, brushing, and swabs (24±32), and inthis issue of Allergy Frischer et al. (33) report a nasallavage study which attempted prospectively to identifyinfants at risk of developing respiratory symptoms inthe ®rst year of life. They are to be congratulated on thelarge number of infants studied, and their prospectivedesign. However, their study, although admirable,needs to be interpreted with caution at this time.

Firstly, the nose is not the bronchus; it is designedto ®lter out especially particulate materials that areundesirable in the lower airway, and ensure that thevariable atmospheric air is warmed and humidi®edbefore it reaches the bronchial tree. Although nasaland bronchial biopsy may be similar, at least onestudy showed important quantitative differencesbetween the two sites in normal and asthmaticadults (34). During exercise, the responses of lowerairway and nose are different, at least physiologically(35). Thus, caution is always warranted beforeassuming that the bronchus is but the nose in

miniature. However, in one respect, nasal studiesare easier to interpret than bronchoalveolar lavage, inthat indicators such as inulin can be added to nasallavage ¯uid to correct for the effects of dilution (25,26); in this context, it is a pity that Frischer et al. (33)did not do this. It is also surprising that they did notlook at lavage eosinophil counts, as well as eosinophilproducts. Secondly, it is not clear that suf®cient carehad been taken to distinguish the different patterns ofwheeze described above. One would expect aneosinophilic lavage possibly to predict atopicwheeze, but not virus-associated, noneosinophilicwheeze, and failure to separate the two is likely toreduce the power of any study. Finally, the results ofthis study will become relevant only in several years'time, when it is clear whether or not there is acorrelation between early eosinophilic lavage andatopic asthma in mid-childhood. It is not possible atan early stage to determine the prognosis of evenatopic wheezers, half of whom may outgrow theirsymptoms by the early school years (16). For theirdata to be useful, Frischer et al. will have to show

1) that their test predicts the onset of wheeze thatpersists

2) that early treatment is bene®cial in preventingwheeze or secondary consequences such as airwayremodelling.

This will take time.Nevertheless, it is clear that Frischer et al. have

commenced a study which must be continued longterm, and has the potential to give us very interestingand important information. At follow-up, it will beparticularly important to de®ne carefully the variouswheezing phenotypes by clinical descriptions, andmeasurements of bronchial hyperreactivity and, ifpossible, noninvasive markers of airway in¯ammationsuch as induced sputum and exhaled nitric oxide (36).It is obvious that questions about long-term prog-nosis (the most important ones, and the most dif®cultto answer) can be answered only by a long-termstudy, which, by de®nition, takes a long time; and thelack of the passage of time is what weakens thisreport. Nonetheless, this preliminary report shouldwhet our appetite for more.

References

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Table 1. Components of asthma phenotype (modi®ed from Crimi et al. [3])

1) Intermittent and reversible N Change with time and

air¯ow obstruction bronchodilator therapy

2) Bronchial hyperreactivity N e.g., histamine, methacholine

challenge

3) Cellular airway in¯ammation N Release of chemical

mediators in

microenvironment

N Release of chemokines

and cytokines to

recruit other

in¯ammatory cells

N Modi®cation of resident

cell behaviour, e.g.,

airway nerves

4) Changes in baseline airway calibre N Developmental reduction

in airway calibre

N Airway remodelling

in association

with in¯ammation

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