Can early infection explain the sibling effect in adult atopy?

Transcription

1 Eur Respir J 2003; 22: DOI: / Prited i UK all rights reserved Copyright #ERS Jourals Ltd 2003 Europea Respiratory Joural ISSN Ca early ifectio explai the siblig effect i adult atopy? P. Cullia*, J.M. Harris*, A.J. Newma Taylor*, M. Joes*, P. Taylor #, J.R. Dave #, P. Mills*, S.A. Moffat*, C.W. White*, J.K. Figg*, A.M. Moo*, M.C. Bares* Ca early ifectio explai the siblig effect i adult atopy? P. Cullia, J.M. Harris, A.J. Newma Taylor, M. Joes, P. Taylor, J.R. Dave, P. Mills, S.A. Moffat, C.W. White, J.K. Figg, A.M. Moo, M.C. Bares. #ERS Jourals Ltd ABSTRACT: Atopy is strogly ad iversely related to family size, a patter which is plausibly assumed to reflect a protective effect of early ifectio. The curret study tested this hypothesis by case-referet aalysis of a adult cohort i the UK. The study established that atopy, defied by prick tests to commo aeroallerges, was less commo amog those from larger families after adjustmet for potetially cofoudig factors. I particular, a higher umber of brothers appeared to offer protectio. The curret authors attempted to explai this distributio by examiig cotemporary family-doctor records of early childhood ifectios; ad by a umber of other idirect idices of early-life "hygiee". The siblig effect was uexplaied by evidece of ifectio with either hepatitis A or Helicobacter pylori, or by couts of ifectios or atibiotic prescriptios i early life. There was a sigificat ad idepedet egative associatio betwee the umber of gastroitestial ifectios before the age of 5 yrs ad the odds of atopy. Dog owership ad home movig i early life also displayed potetially protective associatios. Although the curret study replicates the fidig that atopy is iversely associated with family size this could ot be explaied by documetary or serological evidece of early ifectio. The fidigs support the suggestio that the "siblig effect" i atopy may ot simply reflect protectio by early ifectio. Eur Respir J 2003; 22: *Depts of Occupatioal ad Evirometal Medicie ad # Microbiology, Imperial College School of Medicie (NHLI), Lodo, UK. Correspodece: P. Cullia, Dept of Occupatioal ad Evirometal Medicie, Imperial College School of Medicie (NHLI), Maresa Road, Lodo, SW3 6LR, UK. Fax: p.cullia@ic.ac.uk Keywords: Atopy early ifectio family size hygiee Received: May Accepted after revisio: July The study was supported by the Colt Foudatio. I a UK birth cohort, atopy ad hay fever were more commo amog childre from small families [1]. The same patters have bee replicated elsewhere, for example amog Germa [2] ad Italia [3] childre. These epidemiological observatios are commoly ascribed to lower rates of ifectio amog first-bor childre or those with few sibligs; it is argued that early ecouters with ifectio ecourage the preferetial developmet of T-helper cell type 1 lymphocytes at the expese of T-helper cell type 2-subtypes associated with allergic resposes to foreig proteis. Direct cofirmatio of this explaatio is lackig although protective roles for measles i West Africa [4], mycobacteria i Japa [5] ad gastroitestially-acquired ifectios, particularly hepatitis A, i souther Italy [6], have bee reported for atopy. The preset study sought a critical test for the hygiee theory amog a populatio of UK adults. The curret authors hypothesised that rates of atopy i this populatio would be iversely related to family size (a idirect marker of early ifectio), ad also that direct markers of ifectio would be more commo i larger families. The ull hypothesis that the patter of atopic risk i relatio to family size would ot be explaied by direct evidece of early ifectio was subsequetly tested. Methods Materials ad methods Over 18 moths, from November 1993, all females presetig for ateatal care at three geeral practices i Ashford, Ket, were ivited to erol i a prospective study of childhood asthma. Six-hudred ad twety-five (93% of those eligible) agreed ad subsequetly gave birth to at least oe live ifat, i ie cases o two occasios. The 625 "first-time" mothers ad their parters form the base populatio for the aalysis described i this report. At recruitmet all but three of the mothers ad 542 (87%) of the fathers uderwet ski-prick tests with Allergopharma (Hamburg, Germay) allerges. Mothers ad fathers are described as atopic if they had oe or more positive (mea weal diameter o3 mm) ski tests to extracts of Dermataphagoides pteroyssius, cat fur or grass polle. By 1998/99, 15 mothers had asked to leave the study ad oe had died. At this poit the remaiig parets were re-iterviewed. 1) A questioaire was admiistered i perso to 583 (97%) mothers ad 480 (90%) of the 534 available parters. It elicited iformatio o medical diagoses of asthma, hayfever or eczema, siblig umbers ad ages, pet owership before the age of five, ad some further domestic details. Participats were described as havig a paretal history of allergy if either paret had a diagosis of asthma, hayfever or eczema. 2) Veous blood was collected from 898 (84%) of the parets (87% of mothers ad 81% of fathers) ad assayed for specific immuoglobuli (Ig)G atibodies to Helicobacter pylori (Sigma Diagostics, Poole, UK), hepatitis A (Biokit Ltd, Logfield, UK) ad Toxocara cais (TCS; Bioscieces Ltd, Botolph Claydo, UK). I each case the cut-off poits suggested by the maufacturers were used. 3) For each adult, cotemporary geeral practice otes were scrutiised for details of ifective illesses ad atibiotic prescriptios up to the age of 5 yrs. Medical records were

2 ADULT ATOPY AND EARLY INFECTION 957 obtaied for 1,028 (97%) participats; i 746 (73%) there was iformatio coverig early childhood. Early records were less ofte available for males (71%) tha females (74%) ad for those aged o35 yrs (58%) tha those who were youger (80%). Usig pre-determied criteria, two researchers, uaware of the atopic status of the participats, trascribed records of cosultatios for each ifective illess i the first 5 yrs of life; there were o importat differeces i their trascriptios. Ifectios were categorised by type, ad cosultatios for the same ifectio type v28 days apart were cosidered a sigle episode. Atibiotic prescriptios, by atibiotic class ad idicatio, were couted ad categorised i the same way. Iformatio o vacciatio was ureliably recorded ad this issue is ot discussed further. The mea age of those who took part i the iterviews was 28 yrs (SD 5 yrs), the same as i the base populatio. There were o differeces i blood samplig or the availability of relevat records betwee those who were ad were ot atopic. The ethical committee of the Natioal Heart ad Lug Istitute, Lodo, approved the study. Statistical methods I the mai, the aalyses below cocer potetial determiats of atopic status. Most results are expressed as odds ratios (OR) with 95% cofidece itervals (CI) derived from logistic regressio aalyses. Simple, descriptive aalyses have also bee coducted usig upaired t-tests ad Chi-squared statistics as appropriate. Atopy Results Three hudred ad iety-two (37%) participats were atopic, a frequecy sigificatly higher (p=0.02) amog males ad amog those with a paretal history of allergy (p=0.01; table 1). Atopy was also more commo amog those aged o35 yrs ad those i higher socioecoomic groups although these associatios were ot statistically sigificat. There was a clear ad iverse relatioship betwee rates of atopy ad the umber of sibligs durig early life with a OR of 0.85 (95% CI ) per extra siblig. This relatioship was determied by the umber of brothers (OR 0.76 ( )) rather tha sisters (OR 0.96 ( )); statistically, a model icludig brothers ad sisters separately was a sigificatly better fit tha that icludig sibligs aloe (p=0.02; likelihood-ratio test). The iverse associatio with sibligs was o differet whe older or youger sibligs were examied (OR per older siblig 0.91, per youger siblig 0.86; likelihood ratio test p=0.50) but was strogest whe youger brothers were assessed idepedetly (OR 0.67 ( )). Noe of these associatios was chaged by statistical adjustmet for age, sex, socioecoomic group ad paretal history of allergic disease. Ifectios Positive serology for hepatitis A was ucommo (9%) ad rarer tha a positive test for H. pylori (17%). Each was more commo with icreasig age (adjusted pv0.001 ad p=0.05 respectively); ad amog males ad i those from lower socioecoomic groups although these last differeces were small ad ot statistically sigificat (table 2). A positive test for H. pylori was sigificatly (adjusted pv0.001) more commo amog those with may brothers i early life; although the same was true for also positive hepatitis A serology, the patter was ot statistically sigificat (p=0.23). At least oe ifectio before the age of 5 yrs was recorded i almost all (93%) the examied geeral practice otes. Three or more ifectios were more ofte recorded for youger participats but less commoly amog those from larger families; these patters were statistically sigificat (table 2). Table 1. Sociodemographic associatios with atopy Subjects (%) atopic* OR p-value Adjusted OR # p-value Age f30 yrs (34) 1.02 ( ) ( ) yrs (37) o35 yrs (42) Sex F (34) M (41) 1.35 ( ) 1.40 ( ) Paretal allergy No (34) Yes (43) 1.47 ( ) 1.59 ( ) Social class } I/II (40) III (38) 0.94 ( ) 0.96 ( ) IV/V (35) 0.80 ( ) 0.85 ( ) No. of brothers (44) 0.76 ( ) z v ( ) z v (38) (28) 3z (26) No. of sisters (37) 0.96 ( ) ƒ ( ) ƒ (40) (35) 3z (34) F: female; M: male; OR: odds ratio; CI: cofidece iterval. *: oe or more positive ski tests to extracts of Dermataphagoides pteroyssius, cat fur or grass polle; # : adjusted for the other factors i the table; : per year; z : per brother; ƒ : per sister; } : defied by occupatio: I/II professioal/ itermediate, III skilled omaual/maual, IV/V uskilled.

3 958 P. CULLINAN ET AL. Table 2. Sociodemographic associatios with markers of early ifectio Subjects (%) HAV zve (%) H. pylori zve o3 recorded ifectios (%) Age f (5) 1.13 ( ) # 46 (15) 1.04 ( ) # 236 (80) 0.91 ( ) # (9) 49 (17) 162 (65) o (12) 56 (19) 116 (58) Sex F (8) (15) (72) 0.96 ( ) M (10) 0.79 ( ) 73 (19) 1.11 ( ) 213 (66) Social class I/II (11) (15) (68) 1.00 III (8) 0.78 ( ) 73 (15) 1.09 ( ) 289 (69) 0.96 ( ) IV/V (11) 1.07 ( ) 36 (18) 1.24 ( ) 112 (67) 0.91 ( ) No. of brothers (10) 1.15 ( ) } 35 (12) 1.34 ( ) } 180 (75) 0.81 ( ) } (6) 61 (16) 225 (68) (9) 34 (22) 75 (62) 3z (18) 21 (29) 34 (64) F: female; M: male; OR: odds ratio; CI: cofidece iterval;zive: positive; HAV: hepatitis A virus. *: adjusted for all other factors i the table; # : per year; } : per brother. No importat variatios were foud whe differet types of ifectio were examied separately. Upper respiratory ifectios were most commo (at least oe i the first 5 yrs of life was recorded i 65% of all records), followed by lower respiratory (56%), ski (45%), ad ear (33%) ifectios. I 27% of records at least oe gastroitestial ifectio was recorded; ad i 16% there was a record of measles ifectio. For most categories of ifectio the media age of firstrecorded ifectio fell with icreasig umbers of brothers: for example the media ages for first recorded gastro-itestial ifectio were 1.91, 1.77, 1.21 ad 1.22 yrs respectively for adults with o, oe, two ad three or more brothers. Atibiotic prescriptios Sevety-six per cet (=564) of records cotaied oe or more prescriptios for a atibiotic before the age of 5 yrs. The records for those agedv31 yrs (84%) were more likely to cotai a atibiotic prescriptio tha those for participats aged (72%) yrs or older (69%), a tred which was statistically sigificat (pv0.001). There were o importat differeces betwee males ad females, betwee those from differet socioecoomic groups or betwee those from variously sized families. Other factors Pet dogs were kept, durig the first 5 yrs of life, by 42% of the populatio. This figure did ot differ importatly betwee males ad females, those of differet ages or by socioecoomic group. There was, however, a cosistet, positive relatioship (pv0.001) with family size: those with o or a sigle siblig were much less likely to have kept a dog (36%) tha those with two (42%), three (48%) or more (54%) sibligs. The patter was similar whe brothers (ad sisters) were examied separately. Those who had owed a dog were a little less likely (66%) to have a record of three or more ifectios i their medical records tha those without dogs (71%, p=0.03); there were o importat differeces betwee categories of ifectio. Just uder half (462, 44%) of participats had lived i the same home for their first 5 yrs; 92 (9%) had moved home three or more times. The frequecy of house moves was ot related to family size (p=0.67). Atopy ad ifectio Atopy was urelated to a positive test for either hepatitis A or H. pylori (table 3). This lack of associatio was maitaied across all age groups ad was ot modified by family size. Whe all recorded ifective episodes were cosidered, there was also o relatioship with atopic status (table 3). Lower respiratory ifectios, however, were positively associated with atopy (OR 1.08 ( ) per recorded episode) whereas gastroitestial (ad other) ifectios demostrated a statistically sigificat iverse relatioship (OR 0.73 ( ) per recorded gastroitestial episode). These relatioships were maitaied after adjustmet for age, sex, socioecoomic status, paretal allergic disease ad umber of brothers. Importatly the iverse associatio betwee umbers of brothers ad atopy was uaffected by adjustmet for ay of the measures of early ifectio (table 3). The adjusted odds ratios for recorded ifective episodes at each age are plotted i the figure 1. Those for respiratory ifectios icreased each year to age 5 yrs; the opposite patter was foud for gastroitestial ifectios. Atopy was less commo amog those with a recorded measles ifectio (30% versus 38%) but the differece was ot sigificat (p=0.11). Whe this was examied by age of ifectio, atopy was sigificatly (p=0.004) less commo i the 28 adults who had a record of measles by age 3 yrs (11% versus 38%). The prescriptio of atibiotics before 5 yrs was urelated to subsequet atopy (OR 1.01 ( ) per prescriptio). This lack of a associatio was foud for all classes of ad idicatios for atibiotics (data ot show). Risk estimates for atibiotic prescriptios (all types) teded to rise with age of prescriptio but the icreases were small ad oe was statistically sigificat: OR 0.85, 1.01, 1.07, 1.09 ad 1.09 per prescriptio at ages v1 5 yrs respectively (all pw0.05). Atopy ad other factors Owership of a dog before the age of 5 yrs was strogly ad iversely related to atopy (OR 0.72 ( )), a associatio which did ot chage after adjustmet for age,

4 ADULT ATOPY AND EARLY INFECTION 959 Table 3. Relatioships betwee atopy ad markers of early ifectio 0 ifectios (or egative for serology sectio) o1 ifectio (or positive for serology sectio) (%) atopic (%) atopic (per episode for ifectios) p-value Adjusted OR # for associatio betwee atopy ad umber of brothers p-value Serology Hepatitis A serology (37) (36) 0.96 ( ) ( ) 0.01 Helicobacter serology (37) (35) 0.87 ( ) ( ) 0.01 Ifectios All ifectios (39) (36) 1.01 ( ) ( ) All respiratory ifectios (37) (36) 1.03 ( ) ( ) All orespiratory ifectios (38) (36) 0.99 ( ) ( ) Lower respiratory ifectios (36) (37) 1.08 ( ) ( ) Upper respiratory ifectios (35) (37) 1.00 ( ) ( ) Ear ifectios (37) (36) 1.00 ( ) ( ) Ski ifectios (37) (36) 1.05 ( ) ( ) Eye ifectios (36) (39) 1.21 ( ) ( ) Uriary tract ifectios (37) (32) 0.95 ( ) ( ) Gastroitestial ifectios (39) (29) 0.75 ( ) ( ) Other ifectios (38) (33) 0.83 ( ) ( ) OR: odds ratio; CI: cofidece iterval. *: adjusted for age, sex, social class, paretal allergic disease ad umber of brothers; # : adjusted for age, sex, social class, paretal allergic disease ad relevat ifectio cout. sex, socioecoomic status, paretal allergic disease ad umber of brothers (table 4). Owership of a cat (admitted to by 30% of the populatio) did ot show ay sigificat relatioship with atopic status. Oly two subjects (0.2%, both dog owers) had clear serological evidece of prior ifectio with T. cais. Atopy was more commo amog those who did ot move house before the age of 5 yrs tha those who moved oce, twice or three times. This relatioship was statistically sigificat (p=0.02) ad remaied so after adjustmet for the factors above icludig owership of a dog. After statistical adjustmet for all potetially cofoudig factors (documetary or serological evidece of early ifectio, dog owership or house movig) there was little chage to the poit estimate odds ratio for the associatio betwee atopy ad umber of brothers (OR 0.78 ( )). The same was true whe all sibligs were cosidered. Odds ratio All ifectios GI ifectios Respiratory ifectios Age (yrs) at first ifectio ad type of ifectio Fig. 1. Atopy odds ratios (adjusted for age, sex, social class, paretal allergy ad umber of sibligs) associated with ifectious episodes before the age of 5 yrs ad for 1 5 yrs separately. Discussio This aalysis cofirms a clear iverse associatio betwee adult atopy ad family size i early childhood, a patter largely drive by the umber of brothers. However, this could ot be accouted for by several differet idices of childhood ifectio. Coversely, apparetly protective effects associated with early gastroitestial ifectios with dog owership ad with movig home i the first 5 yrs of life were foud. Although the curret study9s populatio is relatively small, it has the distictio of beig highly represetative of adults from South East Eglad; both the participatio ad followup rates were high, ad higher tha those i other, similar studies. I additio the curret authors used ot oly a objective outcome but were careful also to esure blided assessmets of serological results ad cotemporary geeral practice records. The relatioships foud were uchaged by adjustmet for several potetial cofouders suggestig that other importat factors had ot bee eglected. Geeral practice records are ievitably a icomplete ad potetially biased source of iformatio about early ifectio. May extraeous factors, icludig birth order, but also socioecoomic status, sex ad era determie whether a paret will take her child to the doctor. I the preset study9s populatio, the existece of early, cotemporary records was i part determied by age ad was less commo for males. The records examied were more likely to cotai a metio of three or more ifectios before the age of 5 yrs amog those adults who were brought up i small families. However a systematic differece i seekig medical advice betwee parets with small ad larger umbers of childre [7] may have hidde a truly higher rate of ifectio amog those from larger families. This is suggested by the higher rates of Helicobacter ad hepatitis A ifectio i those with several sibligs. As it happes, amog cotemporary UK families there is remarkably little evidece of a true relatioship betwee ifectio ad family size or birth order, although i Swede [8] hospitalisatio for respiratory ifectio ad i the Netherlads [9] meigococcal carriage are both higher i large families. Eve if ot associated with a reduced risk of early ifectio, growig up i a small family may however icrease the media age of first, relevat ifectio(s) [10], a patter suggested by the records i this study.

5 960 P. CULLINAN ET AL. Table 4. Other associatios with atopy Subjects (%) atopic p-value Dog owership age v5 yrs No (40) Yes (33) 0.72 ( ) Cat owership age v5 yrs No (38) Yes (37) 0.94 ( ) No. of house moves age v5 yrs (43) 0.88 ( ) per move (32) (40) (30) OR: odds ratio; CI: cofidece iterval. *: adjusted for age, sex, social class, paretal allergic disease ad umber of brothers. Positive serology for hepatitis A, a postulated marker for a uhygieic early childhood, was iversely associated with atopy amog souther Italia military recruits [11]. The curret study could ot replicate this fidig i a populatio where atopy was more commo (37% versus 28% i Italy) ad evidece of hepatitis ifectio less frequet (9% versus 27%). Similarly, i a small case-referet aalysis from Aberdee [12], where positive hepatitis A serology was much commoer (61%), atopy was more ofte associated with a positive test although the differece was ot statistically sigificat. The curret study9s rates of positivity to H. pylori were lower tha those i Italy ad Aberdee (each 50%) although the differeces were less marked; i Italy this was also related, iversely, to atopic status a fidig which agai could ot be replicated i the preset study. These variatios probably reflect differet epidemiologies of early hepatitis A ad Helicobacter ifectio i the UK ad Italy. Early lower-respiratory ifectios were more commoly recorded for atopic adults, a patter which icreased with the age of ifectio ad which the curret authors suggest reflects the emergece of accompayig asthma over the first 5 yrs of life. Ideed the difficulty i separatig cause from effect probably reders the epidemiological study of respiratory ifectios ad allergic disease impossible, eve whe specific markers of ifectio are available. Coversely, recorded gastroitestial ifectios were less commo amog atopic adults, a patter which also stregtheed with age of ifectio, which was see despite the probable behavioural bias above ad which remaied after adjustmet for possible cofoudig factors. A protective effect of such ifectios i early life is broadly cosistet with the fidigs of a large survey i the USA [13]; ad there is evidece that the gut coloisatio i early life may affect the subsequet differetiatio of T-cell populatios [14]. Coversely, amog a very large cohort of cotemporary British childre [15] o protective effect of early gastroitestial ifectios o cliical diagoses of asthma, hayfever or eczema was foud; IgE atibody productio was ot examied, however, ad the average period of follow-up was short (3 yrs). The iformatio collected was isufficietly detailed to allow aalysis of particular gastroitestial ifectios although, at this age, most were probably viral. The curret study9s fidig of a apparetly protective effect of measles ifectio at age 3 yrs should be iterpreted with care sice it is based o small umbers; ad the ifrequecy with which this disease was recorded suggests a degree of uderascertaimet. It does however accord with fidigs of a study of asthma i Aberdee [16]. I several respects the curret fidigs are at variace with those of a earlier UK study of allergy ad ifectios recorded i geeral practice records up to the age of 12 yrs [17]. There, o relatioship betwee sibship ad recorded atopic disease (asthma, eczema or hayfever as described i the medical records) was foud. Gastroitestial ifectios were ot reported as a separate category; but treatmets with atibiotics for respiratory (particularly lower respiratory), uriary ad ski ifectios i the first year of life were associated with markedly icreased risk estimates for subsequet atopic disease. A survey of childre aged 5 10 yrs attedig Rudolph Steier schools i New Zealad reported remarkably strog associatios betwee atibiotic use ad a history of asthma; particularly whe symptoms of the latter started after the age of oe ad the drugs had first bee prescribed durig ifacy [18]. Similar fidigs have bee reported amog Germa schoolchildre [19]. I oe of these studies ca recall or protopathic biases be excluded. Coversely, the preset authors, usig a objective defiitio of atopy derived separately from geeral practice records, were uable to cofirm ay sigificat icrease i risk with ay class of (or idicatio for) documeted atibiotic use i the first 5 yrs. This is a importat egative fidig; ad probably corroborates the recet fidigs for British childre cocerig early atibiotic use ad cliical allergies [15]. I some other aspects the curret fidigs are similar to those of a comparable, albeit larger, survey of adult atopy carried across Europe [20] although this did ot iclude ay direct markers of early ifectio. I that study idividuals from large families, particularly those with may brothers, ad, idepedetly those who kept dogs, were less likely to be atopic. Ideed, the evidece idicatig a protective effect of dog owership is icreasigly cosistet [21] although ot etirely so [22]. I the curret study9s populatio, the effect was strog ad could ot be accouted for by statistical adjustmet for cofoudig factors, i particular family size. The specificity of the effect, both here ad i the pa- Europea study, is suggested by the absece of ay such relatioship with pet cats. A bias, whereby allergic families ted ot to keep pets, is a improbable explaatio for these fidigs. The relatioship was ot affected by adjustmet for paretal allergy, ad a earlier report of this cohort showed that the keepig of a pet cat is urelated to geeral or specific allergies withi the family [23]. Bacterial, viral ad parasitic ifectios may each be trasmitted from dogs to humas [24] although with ucertai frequecy, ad the curret authors suggest that the preset fidigs support a protective role for early (uidetified) ifectio(s) i the developmet of atopy; alteratively levels of edotoxi, itself postulated to be protective, may be higher i homes where pets are kept [25]. The fidig of reduced rates of atopy amog those who had moved home i early life was uexpected; ideed a earlier study of childhood asthma suggested the opposite effect [26]. It is possible that movig home is associated with a

6 ADULT ATOPY AND EARLY INFECTION 961 icreased rate of childhood ifectio (viral mixig) although the curret authors are ot aware of ay direct evidece for this. The curret study was plaed as a critical test of the plausible explaatio for the iverse associatio betwee family size ad atopic status: that higher rates of early ifectio amog larger families are protective. The preset study could ot accout for the relatioship with sibship by several markers of early ifectio icludig evidece of ifectio with hepatitis A ad Helicobacter pylori as observed i other populatios. Withi the Ashford birth cohort the curret authors have recetly reported [27] that mothers of small families are more likely to be atopic, a patter that could ot be accouted for by materal age. This observatio is as yet uexplaied but together with the results reported here ad elsewhere [28] suggests that the well-established iverse associatio betwee atopy ad family size may be a maifestatio of materal or itra-uterie evets rather tha solely a reflectio of early-life ifectio. Ackowledgemets. The authors are very grateful to the geeral practitioers who have made this study possible, to W. Atkiso for his laboratory assistace, ad to the Colt Foudatio for their cotiuig fiacial support. Refereces 1. Stracha DP, Harkis LS, Johsto ID, Aderso HR. Childhood atecedets of allergic sesitisatio i youg British adults. J Allergy Cli Immuol 1997; 99: Vo Mutius E, Martiez FD, Fritzsch C, Nicolai T, Reitmeir P, Thiema H-H. Ski test reactivity ad umber of sibligs. BMJ 1994; 308: Forastiere F, Agabitit N, Corbo GM, et al. Socioecoomic status, umber of sibligs ad respiratory ifectios i early life as determiats of atopy i childre. Epidemiology 1997; 8: Shahee SO, Aaby P, Hall AJ, et al. 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