The PREVASC study: the clinical effect of a multifaceted educational intervention to prevent childhood asthma

Transcription

1 Eur Respir J 2005; 25: DOI: / CopyrightßERS Jourals Ltd 2005 The PREVASC study: the cliical effect of a multifaceted educatioal itervetio to prevet childhood asthma H.J.A.M. Schöberger*, E. Dompelig #, J.A. Kotterus*, T. Maas*, J.W.M. Muris*, C. va Weel " ad C.P. va Schayck* ABSTRACT: As asthma is the most commo chroic disease i childhood, much attetio is directed towards primary prevetio. Here, the cliical effectiveess of a multifaceted educatioal prevetio was studied. A total of 476 high-risk childre were recruited durig the preatal period by geeral practitioers ad radomised to either: 1) a cotrol group, receivig usual care; or 2) a itervetio group i which families received istructio from urses o how to reduce exposure of ewbors to mite, pet ad food allerges, ad passive smokig. A total of 443 ifats were followed-up for 2 yrs. At 2 yrs of age, the itervetio group (5222) had less asthma-like symptoms, icludig wheezig, shortess of breath ad ight-time cough, tha the cotrol group (5221). No sigificat differeces i total ad specific immuoglobuli E were foud betwee the groups. Durig the first 2 yrs of life, the icidece of asthma-like symptoms was similar i both groups; however, subaalysis revealed a sigificat reductio i the female, but ot i the male, itervetio group. I coclusio, the itervetio used i this study was ot effective i reducig asthma-like symptoms i high-risk childre durig the first 2 yrs of life, although it was modestly effective at 2 yrs. Follow-up is ecessary to cofirm whether the itervetio ca actually prevet the developmet of asthma. KEYWORDS: Childhood asthma, house dust mites, passive smokig, pets, prevetio, primary care AFFILIATIONS Depts of *Geeral Practice, ad # Paediatric Pulmoology, Research Istitute CAPHRI, Uiversity Hospital Maastricht, Maastricht, ad " Dept of Geeral Practice, Uiversity Medical Cetre, Radboud Uiversity Nijmege, Nijmege, The Netherlads. CORRESPONDENCE H.J.A.M. Schöberger Dept of Geeral Practice Research Istitute CAPHRI Uiversity Maastricht Caerweg BE Maastricht The Netherlads Fax: Huub.Schoberger@ hag.uimaas.l Received: Jue Accepted after revisio: December Asthma is the most commo chroic disease i childhood ad it is resposible for a large burde of disease, with huge socio-ecoomic cosequeces [1 3]. As the prevalece of asthma is still icreasig [4 8], much attetio is beig directed towards the possibilities for primary prevetio. It is geerally agreed that asthma is a multifactorial disease, which develops i very early life or eve i the uterus [9 12]. Evirometal exposure to allerges ad tobacco smoke durig pregacy or i very early life may ehace sesitisatio ad allergic morbidity, especially i childre with a geetic predispositio [13, 14]. Several primary prevetio trials are curretly i progress or will be fiished soo, ad have recetly bee reviewed [15]. Some trials study the prevetive effect of a reductio i a sigle exposure, such as food allerges [16], or mite ad pet allerges [17, 18], or a dual approach of avoidace of food ad mite allerges [19], combied with a reductio i passive smokig [20]. The study reported here, the Prevetio of Asthma i Childre (PREVASC) study, differs from the previously cited trials, as eligible cases were recruited from a primary care populatio i a routie primary care settig. The study uses a multifaceted approach, by ivestigatig the effect of a reductio i both preatal ad postatal exposure to mite, pet ad food allerges, ad passive tobacco smoke o the developmet of asthma i childre at high risk, those with at least oe first-degree relative with asthma. Through this approach the PREVASC study ackowledges the multifactorial ature of asthma. It brigs together the factors that ca be addressed i daily primary care. I additio, a comprehesive prevetive effect, rather tha the effect of a reductio of a sigle exposure, is assessed. Sice airway morbidity is iflueced by sex [21], ad sex-specific effects of evirometal exposure o asthma have bee reported recetly [22], the cliical effectiveess of the SUPPORT STATEMENT The study was fuded by The Dutch Asthma Foudatio, Prevetio Fud ad Royal Academy of Sciece (KNAW). No competig iterests were declared. Europea Respiratory Joural Prit ISSN Olie ISSN VOLUME 25 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

2 itervetio programme was evaluated separately i males ad females. METHODS The Ethical Committee of the Uiversity Maastricht (Maastricht, The Netherlads) approved the study. Study populatio The PREVASC study is a radomised itervetio study carried out i the Dutch primary care settig, ivestigatig the effectiveess of a primary prevetio programme of asthma directed towards high-risk families expectig a child. The ratioale ad desig of the PREVASC study have bee described previously [14, 23]. I summary, pregat mothers were recruited by geeral practitioers (GPs) ad midwives durig the first two trimesters of their pregacy whe they visited their GP or midwife. I the Dutch healthcare system, all patiets are registered with a GP over a log period of time ad cosult their GP for all their healthcare eeds, icludig pregacy [24]. Mothers were asked for writte iformed coset whe the GP had established that their ubor babies were at high risk from familial occurrece of asthma (asthma i at least the mother, father or siblig(s)). This allowed ateatal idetificatio of those who would subsequetly be at icreased risk of developig asthma. Itervetio The itervetio group received stadardised istructio from (specially traied) urses i three home visits: at the start at 4 6 moths of pregacy, at 8 moths of pregacy, ad 1 3 weeks after birth. The istructio cosisted of recommedatios to reduce four mai evirometal exposures, as follows. 1) Mite allerges by saitatio measures, icludig daily cleaig of floors i the house, washig bed clothes o a hot cycle (o60 C), removig textile floor coverigs, reducig air humidity by vetilatig/airig ad heatig, usig miteimpermeable beddig (mattress, quilt ad pillow, ad/or sleepig bag) for both parets ad ifat (Mitecare H ; Saalife BV, Lelystad, The Netherlads). These measures have bee show to be effective i reducig mite allerge levels [14]. Parets were iformed of these ati-mite measures durig the secod visit ad they were ecouraged to apply them before the ifat was bor ad durig the first 2 yrs of life. Ati-mite ecasigs were provided 1 moth before birth. 2) Pet allerges by disposig of pets or keepig them outside the house ad washig them at least oce a moth. Istructio o these measures was give durig the first visit ad repeated i the secod ad third visits. Parets were asked to start by applyig the measure at least 3 moths before birth ad to cotiue this durig the first 2 yrs of life. The timig of the istructio to apply these two measures was chose so that a low level of these allerges could be achieved by the time the child was bor. 3) Food allerges by breastfeedig the ifat durig at least the first 6 moths of life. If breastfeedig was stopped before a child was 6 moths old or if supplemetatio was ecessary, a extesive hydrolysed formula milk (Nutrilo Pepti H ; Numico, Zoetermeer, The Netherlads) was prescribed. I additio, it was recommeded that the itroductio of the first solid food itake was postpoed util after 6 moths of age. Istructio o these measures was give durig the secod visit ad repeated durig the third visit. 4) Passive smokig durig pregacy by materal abstetio from smokig ad postatally by paretal abstetio from smokig i the first 2 yrs of life. Istructio o these measures was give durig the first visit ad repeated durig the secod ad third visits. The cotrol group received usual care provided by the GP. I the guidelies of the Dutch College of Geeral Practitioers o asthma i childre [25], prevetive measures are recommeded oly whe childre are already asthmatic (secodary prevetio). Measures to prevet asthma i high-risk ifats are curretly ot part of the guidelies. Outcome variables The primary cliical outcome variables were symptoms that might poit at a possible developmet of asthma (referred to as asthma-like symptoms) at ay time i the first 2 yrs of life ad durig the last moth of the 2d year of life (referred to as curret symptoms). Symptoms were derived from paretal ad GP reports. For measurig the occurrece of asthma-like symptoms i the first 2 yrs of life, questioaires from the Iteratioal Study of Asthma ad Allergies i Childhood (ISAAC) were used [26], admiistered at the followig ages: 6 moths, 1 ad 2 yrs. I order to eable comparisos of the results, ISAAC outcomes were brought ito lie with those used i other primary prevetio studies [18]. The items studied icluded: ighttime cough without cold, wheezig at least oce, wheezig with awakeig ad recurret wheezig (more tha 4 times) at ay time i the first 2 yrs of life. Curret asthma-like symptoms icluded wheeze, shortess of breath ad ight-time coughig, ad were derived from paretal reports o these symptoms i the 4 weeks prior to the child s 2d birthday. GP reports cosisted of prospectively recorded asthma-like symptoms ( wheezig without fever, shortess of breath ad coughig ) observed whe the parets cosulted the GP whe their child was ill durig the first 2 yrs of life. I additio, stadardised diagoses (atopic dermatitis, brochi(oli)tis ad peumoia) were recorded, based o defiitios of the Iteratioal Classificatio of Health Problems i Primary Care (ICHPPC) [27]. As a gold stadard for asthma at 0 4 yrs is lackig, asthma diagosis was based o the Dutch Guidelie Asthma i Childre (further referred to as GP-based diagosis asthma) [25]. Measuremet of IgE Atopic status was determied at 2 yrs of age by the measuremet of total ad specific immuoglobuli (Ig)E agaist mite (Der p1), cat (Fel d1) ad dog (Ca f1) allerges. Total ad specific IgE were determied i heel-prick blood, sampled o filter paper at 2 yrs. Absorbed material was eluted by icubatio with phosphate buffered salie (PBS)-T (PBS/Twee-20 (0.1% v/v)) for 16 h uder costat rotatio. Elutats were separated from filter paper by cetrifugatio. Determiatio of total IgE i eluted blood spots was performed as previously described [28] usig sepharoseimmobilised reagets ad 125 I-labelled ati-ige raised i sheep. c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 4 661

3 Test results were expressed i IU per ml (1 IU represetig,2.4 g of IgE). Specific IgE agaist mite, cat ad dog were assessed with a radio-allergosorbet fluorescet immuoassay (RAST). Measuremet of evirometal exposures to mite, pet ad food allerges, ad passive smokig The effect of the itervetio, with respect to mite ad pet allerges, was measured by comparig mite, cat ad dog allerge levels i three settled dust reservoirs (the livig room floor, paretal ad ifat mattresses) at baselie, directly after erolmet (3 5 moths before birth) ad exactly 1 yr later (7 9 moths after birth), i order to avoid seasoal iflueces i allerge levels [29]. At the same time, dust samples were take i the cotrol group. Dust collectig was performed by research assistats i a stadardised maer, by vacuumig (1300-W-vacuum H ; Bosch, Rotterdam, The Netherlads) the livig room floor (two areas of 1 m 2, for 2 mi) ad the paretal ad crib mattresses (1 m 2, for 2 mi) with covers but without sheets. The preparatio of dust samples for measuremet, ad the measuremet of Der p1, Fel d1 ad Ca f1 have bee described previously [30]. Oe IU Ca f1 correspods to 1 g Ca f1, whereas 1 mu Fel d1 correspods to 4 g Fel d1. The detectio limit was 2 g?g -1 of dust for Der p1, ad 1g?g -1 of dust for Fel d1 ad Ca f1. Allerge cocetratios were calculated as g per metre squared vacuumed surface [31]. Data o exposure to food allerges (breastfeedig ad/or type of formula feedig) were derived from weekly diary recordig ad, i the case of the itroductio of solid foods, a questioaire whe the child was 6 moths old. Preatal ad postatal passive smokig were assessed o the basis of a paretally recorded questioaire whe the child was 1 yr old. Radomisatio As blidig for the itervetio measures was ot possible, families were allocated to the itervetio ad cotrol groups by pre-radomisatio (radomised coset desig, i which both groups were iformed about their ow trial arm but ot about the other [32]). To prevet cotamiatio betwee the itervetio group ad the cotrol group, the preradomisatio was performed i clusters, takig ito accout the post (zip) code of the domicile of the recruited family i combiatio with the locatio of the geeral practice the family atteded. Oce a geeral practice was allocated, every family subsequetly recruited i that practice was allocated automatically to the same group. I this way, 242 families, recruited i 106 geeral practices with, (SD) patiets per practice, were allocated to the itervetio group; ad 234 families, recruited by 146 geeral practices with, (SD) patiets per practice, were allocated to the cotrol group. Aalysis Differeces i baselie characteristics ad exposures betwee the itervetio ad cotrol groups were tested usig the Chi-squared test for proportios ad the upaired t-test for ormally distributed cotiuous variables. The depedet variables reported ad observed at age 2 yrs icluded asthma-like morbidity, atopic dermatitis, ad total ad specific IgE. Some data o the frequecy of smokig (23 (10%) ad 17 (8%), i the itervetio ad cotrol groups, respectively) ad of breastfeedig (14 (6.3%) ad 2 (1%), i the itervetio ad cotrol groups, respectively) were missig. Therefore, aalyses were performed: 1) cosiderig missig data as such (adherersoly aalysis); ad 2) cosiderig cases with icomplete smokig data as passive smokers ad those without breastfeedig data as ot beig breastfed. Differeces i morbidity outcome betwee the groups were expressed as odds ratios (OR) with 95% cofidece itervals (95% CI). Total IgE data were ormally distributed after logarithmic trasformatio. I a post hoc aalysis, the comparisos betwee the itervetio ad cotrol groups were repeated separately for males ad females. As bed-sharig of ifats ad parets is very commo [33], ad as childre are also exposed to allerges i the livig room, the mea of the specific allerge cocetratios measured i the paretal ad crib mattress dust ad i the livig room dust was calculated for each case, to obtai a overall measure of ifat allerge exposure. As the cocetratios of mite, cat ad dog allerges i samples of house dust ad mattresses were ot ormally distributed eve after logarithmic trasformatio, their media levels were used for the estimatio of the effect of allerge-reducig measures. I additio, to assess the idepedet effects of the exposure to mite, pets ad food allerges, ad of passive smokig o the outcome measures, multiple logistic regressio aalysis was performed. Differeces betwee the groups were tested usig the Ma-Whitey U-test ad withi the groups usig the Wilcoxo siged-rak test. A two-sided p-value,0.05 was cosidered to be sigificat. RESULTS Study populatio From , 476 families were recruited, of whom 93% (5443) completed the 2-yr study period. Figure 1 shows the trial profile. After 2-yrs follow-up, 9% (520) i the itervetio group ad 6% (513) i the cotrol group dropped out, resultig i the participatio of 222 families i the itervetio group ad 221 i the cotrol group. No differeces i baselie socio-demographic characteristics were foud betwee the itervetio ad cotrol groups, either as a whole or withi the subgroups of males ad females, with the exceptio of lower mite allerge levels i the cotrol group (table 1). Sigificatly more itervetio families tha cotrol families erolled i the autum/witer: 182 (82%) versus 152 (69%), p Baselie mite allerge levels were foud to be lower i the cotrol group tha i the itervetio group, ad this was also the case whe aalysed withi the male ad female groups (table 1). After 2-yrs follow-up, some data o applied itervetio measures were missig. However, they were equally divided betwee the itervetio ad cotrol groups. There were o idicatios for a selective item orespose (data ot show). 662 VOLUME 25 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

4 Pregat females who met iclusio criteria ad gave iformed cotet =476 Cluster radomisatio o postcode ad geeral practice Allocated to the itervetio group =242 patiets recruited i 106 geeral practices Allocated to the cotrol group =234 patiets recruited i 140 geeral practices Families dropped out =20 (abortio =11; still birth =2; moved =4; withdrawal =3) Families dropped out =13 (abortio =6; log-lastig hospitalisatio =2; still birth =1; moved =3; withdrawal =1) Childre completed the study =222 Childre completed the study =221 FIGURE 1. Trial profile of the Prevetio of Asthma i Childre (PREVASC) study after recruitmet. The effect of the itervetio programme o exposure The effect of the itervetio programme o exposure to food allerges ad passive smokig is show i figure 2, ad to mite ad pet allerges i figure 3. Ifats i the itervetio group, whe compared to the cotrol group, were cosiderably more exclusively breastfed ad/or received more hypoallergeic bottle feeds. The itervetio group received their first solid food less frequetly before they were 6 moths old whe compared with the cotrol group. Preatal ad postatal exposure to smokig were equal for the itervetio ad the cotrol groups. Oe year after baselie measuremets, mite, cat ad dog allerge cocetratios were sigificatly lower i the TABLE 1 Demographic ad other baselie characteristics of the cotrol ad itervetio groups stratified for sex Total s s Itervetio Cotrol Itervetio Cotrol Itervetio Cotrol Subjects Age yrs mother Low educatio # mother 2 (14.5) 20 (9.0) 17 (14.4) 12 (10.8) 15 (14.6) 8 (7.3) Family history of asthma Father 84 (38.0) 80 (36.5) 48 (41.0) 36 (32.7) 36 (34.6) 44 (40.4) Mother 118 (53.4) 111 (50.7) 60 (51.3) 59 (53.6) 58 (55.8) 52 (47.7) Sibligs 83 (60.1) 95 (68.3) 43 (59.7) 46 (65.7) 40 (60.6) 49 (71.0) Birth weight 3387 (528) 3475 (583) 3438 (569) 3492 (624) 3329 (474) 3465 (538) Pregacy duratio weeks 39.7 (1.7) 39.7 (1.6) 39.6 (1.8) 39.7 (1.8) 39.7 (1.4) 39.7 (1.6) Delivery at home 71 (32.0) 81 (36.7) 34 (28.8) 46 (41.8) 37 (35.6) 35 (31.8) Ucomplicated delivery 172 (77.8) 168 (76.0) 85 (72.6) 81 (73.6) 87 (83.7) 86 (78.2) Age house f20 yrs 101 (47.4) 120 (54.8) 52 (45.6) 59 (53.6) 49 (49.5) 61 (56.0) First-bor 87 (39.2) 85 (38.3) 46 (39.0) 43 (38.7) 41 (39.4) 41 (37.3) Day-care attedace 78 (38.2) 70 (36.6) 41 (36.9) 34 (36.2) 37 (39.8) 36 (37.1) Bor i sprig/summer 108 (49.5) 112 (50.5) 54 (45.8) 55 (49.5) 53 (51.0) 59 (53.6) Exposure at baselie Der p1 g?m -2 (IQR) " 148 (1421) + 79 (474)*** 136 (1670) + 88 (484)** 193 (1617) + 65 (380)** Fel d1 g?m -2 (IQR) " 94 (244) 73 (288) 96 (285) 83 (362) 96 (288) 69 (278) Ca f1 g?m -2 (IQR) " 34 (274) 39 (258) 26 (356) 40 (533) 42 (255) 42 (184) Smokig mother 28 (14.1) 32 (15.7) 16 (15.1) 22 (22.0) 12 (12.9) 10 (9.6) Smokig father 46 (24.1) 46 (23.5) 24 (24.0) 28 (29.2) 22 (24.2) 18 (18.0) Presece of cat or dog 62 (31.5) 71 (34.9) 35 (32.7) 39 (39) 27 (29.3) 32 (31.7) Data are preseted as (%) or mea SD, uless otherwise stated. # : oly primary school; " : calculated as the mea level of the media amout of the specific allerge levels i dust from paretal ad ifat mattresses ad livig room floor. **: p,0.01; ***: p,0.001; + : statistically sigificat, itervetio versus cotrol group. c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 4 663

5 a) % b) 100 % Ever breastfed Materal preatal smokig Exclusively breastfed *** *** Exclusively breastfed ad/or hypoallergeic bottle fed Materal postatal smokig Receivig first weaig solids Smokig parter FIGURE 2. Effectiveess of the Prevetio of Asthma i Childre (PREVASC) itervetio programme o a) feedig practice i the first 6 moths of life ad b) tobacco smokig. &: itervetio group (5222); &: cotrol group (5221). Ever: at least 1 week. ***: p,0.001, usig Pearso s Chi-squared test. itervetio group tha i the cotrol group (fig. 3). The same results were foud withi the male ad female groups (data ot show). Cliical effectiveess Paretally reported ad GP-based symptoms ad diagoses Table 2 shows the frequecies of the asthma-like symptoms i the itervetio ad cotrol groups, ad their risk estimates with 95% CI. No differeces were foud betwee the groups for paretally reported ad GP-observed asthma-like symptoms durig the first 2 yrs. The same held for the GP-based diagosis of asthma. Paretally reported curret asthma-like symptoms occurred sigificatly less i the itervetio group compared with the cotrol group (table 2). Whe aalysed for females ad males separately, both asthmalike symptoms i the first 2 yrs of life, as well as curret symptoms, occurred sigificatly less amog females i the itervetio group tha i the female cotrol group, whereas there was o differece amogst males. This was the case for paretally reported symptoms durig the first 2 yrs of life or curret symptoms (fig. 4), as well as for GP-observed symptoms (fig. 5). I the female itervetio group, GP diagosis of asthma teded to be less frequetly preset (p50.08) compared with the female cotrol group, whereas amog males this was ot the case. Serum IgE levels The mea serum cocetratio of total IgE was similar for the itervetio ad cotrol groups (table 3). I additio, mite-, cat- ad dog-specific IgE were similar i both groups. Separate subaalysis of the outcomes for males ad females revealed that females i the itervetio group teded to be less sesitised agaist mites, whereas the opposite was observed i the male group, although the differeces did ot reach statistical sigificace (p50.09; table 3). Whe the aalyses o the associatio betwee asthma-like ad atopic morbidity were repeated, assumig that the childre with missig data o smokig ad breastfeedig behaviour were exposed to passive smoke ad were ot breastfed, respectively, the results did ot chage essetially (data ot show). a) 180 b) c) 160 Cocetratio g m *** *** *** 0 t0 Mite allerge t1 t0 Cat allerge t1 t0 Dog allerge t1 FIGURE 3. Effectiveess of the Prevetio of Asthma i Childre (PREVASC) programme o exposure to mite ad pet allerges. Media overall cocetratios of a) mite, b) cat ad c) dog allerges i dust samples of livig room, paretal ad ifat mattresses at baselie (t0) ad 1 yr later (t1) for the itervetio group (&) ad the cotrol group (&). ***: p50.001, itervetio versus cotrol group after the itervetio (t1), usig Ma-Whitey U-test. 664 VOLUME 25 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

6 TABLE 2 Occurrece of asthma-like symptoms ad allergic morbidity at 0 2 yrs ad at 2 yrs i the itervetio ad cotrol groups Itervetio Cotrol OR (95% CI) Paretally reported symptoms at 0 2 yrs Wheezig at least oce 64 (127/200) 57 (113/200) 1.4 ( ) Wheezig with awakeig at least oce 14 (26 /188) 17 (30/182) 0.88 ( ) Recurret wheezig o4 times 26 (49/189) 26 (47/184) 1.1 ( ) Night-time cough without a cold at least oce 48 (95/197) 53 (101/190) 0.78 ( ) Paretally reported curret # symptoms at 2 yrs Wheezig 8 (15/187) 15 (25/171) 0.73 ( ) " Shortess of breath 16 (30/187) 25 (43/171) 0.76 ( ) " Night-time cough 44 (57/184) 56 (72/168) 0.72 ( ) " GP-recorded morbidity at 0 2 yrs Wheezig without fever at least oce 34 (72/212) 40 (80/200) 0.87 ( ) Shortess of breath at least oce 27 (57/212) 31 (62/200) 0.90 ( ) Coughig at least oce 68 (144/212) 70 (139/200) 0.96 ( ) Diagosis asthma 26 (54/212) 31 (61/200) 0.88 ( ) Diagosis atopic eczema 27 (58/212) 23 (46/200) 1.1 ( ) Data are preseted as % (/N), uless otherwise stated. GP: geeral practitioer; OR: odds ratio; CI: cofidece iterval. # : at least oe diary-reported episode i the last 4 weeks before the 2d birthday; " : sigificat effects. Relatioship betwee exposure ad asthma-like morbidity Table 4 shows the ORs for asthma-like symptoms for the group as a whole (the itervetio ad cotrol group together) i relatio to exposure to mite, cat, dog ad food allerges, ad passive smokig, adjusted for each other i a multiple logistic regressio aalysis. Beig breastfed (o1 week) from birth decreased the risk of curret asthma-like symptoms at 2 yrs. Abstiece from materal smokig reduced the risk of recurret wheeze ad of curret wheeze at 2 yrs. Low mite levels sigificatly decreased the risk of curret wheezig ad shortess of breath. DISCUSSION The PREVASC study is the first study i a primary care eviromet to ivestigate the cliical effectiveess of a multifaceted approach aimed to prevet the developmet of asthma i high-risk childre. The results of this study idicate that the itervetio was able to reduce exposure to mite, pet ad food allerges, but ot to passive smokig. Despite this reductio, there was o effect o either paretally reported or GP-observed symptoms durig first 2 yrs of life, or o total ad specific IgE at 2 yrs. However, asthma-like symptoms at the ed of the 2d yr were less frequetly reported i the itervetio group. Moreover, the decrease appeared to be more proouced i ad maily cofied to the females i the itervetio group. The itervetio might have caused the differeces i symptoms at the ed of the 2d yr, but other explaatios a) 100 b) c) d) e) % # # # 10 0 FIGURE 4. Occurrece of paretally reported asthma-like symptoms i ISAAC questioaire ad weekly diary for male ad female childre i the itervetio (&) ad cotrol (&) groups: a) recurret (o1 episode withi 4 weeks prior to 2d birthday) wheeze 0 2 yr; b) o1 wheeze with awakeig 0 2 yrs; c) curret wheeze; d) curret shortess of breath; ad e) curret ightly coughig. # :p50.04; " :p c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 4 665

7 a) b) c) d) % # ** FIGURE 5. Occurrece of asthma-like symptoms i the first 2 yrs of life as diagosed by the geeral practitioers for male ad female childre i the itervetio(&) ad cotrol (&) groups: a) wheezig without fever; b) shortess of breath; c) coughig; ad d) diagosis of asthma. **: p50.01; # :p50.02; " :p for the reported decrease i curret asthmatic symptoms also have to be cosidered. A major limitatio is the fact that most of the evirometal exposure-reducig measures, icludig breastfeedig, weaig practices, procurig pets ad smokig, caot be blidly executed. All birth cohort itervetio studies experiece this problem [17, 20]. Therefore, reportig bias caot be excluded as a explaatio for the decrease i asthma-like symptoms i the itervetio group at age 2 yrs. Parets i the itervetio group are aware of the applied itervetio ad might expect their childre to have a reduced asthma-like morbidity, whereas i the cotrol group o such placebo effect is to be expected. GPs i the itervetio group were also ot blided for the itervetio, ad this could have iflueced their iterpretatio of the observed symptoms ad their diagostic labellig. However, it was foud that both the parets ad GPs allocated to the itervetio group reported ad classified asthma-like symptoms less frequetly i the female childre tha i the male childre, ad it is ulikely that a reportig bias is iflueced by sex. Several radomised itervetio studies have reported results o various cliical symptoms at age 1 [17, 20, 34], 2 [18, 35], 3 [36], 4 [37] ad 8 yrs [19]. Whe the results of itervetio studies are compared, it has to be kept i mid that compariso is hampered, as the studies differ i defiig high-risk cases, the applied itervetio(s) ad the defiitio of outcomes. I the Machester Allergy ad Asthma Study ( ac MAAS) study [36, 38], striget ati-mite measures were provided i the homes of expectig atopic parets, where the mothers had to be at least sesitised for mite, cat or dog allerges, as show by ski testig, but who had o cats or dogs. A sigificat reductio of (reported) severe wheeze with breathlessess ad with exertio at age 1 yr was foud [38], as well as a better specific airway resistace i the itervetio group at 3 yrs [36]. The Prevetio ad Icidece of Asthma ad Mite Allergy (PIAMA study) [18] recruited pregat females at high risk o the basis of a reported persoal history of asthma, hay fever or reported allergy for house dust, mite or pet allerges. Ati-mite covers for crib ad paretal mattresses ad pillows were provided. At 2 yrs, oly a slight but sigificat reductio i reported ight-time cough without a cold was reported, whereas the other (ISAAC) outcomes were ot sigificatly differet. The small improvemet i the PIAMA study was attributed by the authors to pre-existet low mite levels. However, i the PREVASC study, low mite levels at baselie were also foud. I cotrast to the PIAMA study, the data preseted here show a more proouced effect of the TABLE 3 Serum total ad specific immuoglobuli (Ig)E for mite, cat ad dog at age 2 yrs i the itervetio ad cotrol groups stratified for sex Total s s Itervetio Cotrol Itervetio Cotrol Itervetio Cotrol Total IgE IU?mL Presece of specific # IgE agaist Mite 6.6 (13/197) 5.3 (11/208) 9.3 (10/107) 3.9 (4/103) 3.3 (3/90) 6.7 (7/105) Cat 6.9 (7/192) 5.7 (12/209) 6.7 (7/105) 7.8 (8/103) 0.0 (0/87) 3.8 (4/106) Dog 4.9 (9/185) 4.8 (10/208) 6.9 (7/102) 5.8 6/ (2/83) 3.8 (4/105) Data are preseted as % (/N) or geometric mea SD. # : positive RAST o0.35 IU?mL -1. No sigificat differeces were foud betwee the itervetio ad cotrol groups for total IgE (t-test) or for specific IgE (Chi-squared test). 666 VOLUME 25 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

8 TABLE 4 Associatios of exposure to mite, cat, dog ad food allerges, ad passive smokig with paretally reported symptoms without group allocatio Recurret wheezig 0 2 yrs Ever wheezig with awakeig 0 2 yrs Curret # wheezig Curret # shortess of breath Breastfeedig " 0.32 ( ) ( ) ( ) ( ) Hypo-allergeic formula feedig " 1.3 ( ) 0.72 ( ) 0.66 ( ) 0.95 ( ) Itroductio of first solid foods,6 moths 1.1 ( ) 1.3 ( ) 1.4 ( ) 0.77 ( ) No materal smokig 0.49 ( ) ( ) 0.38 ( ) ( ) No pateral/parter smokig 0.91 ( ) 0.65 ( ) 0.67 ( ) 0.65 ( ) Mite allerges below media 0.78 ( ) 0.63 ( ) 0.30 ( ) ( ) + Cat allerge below media 0.87 ( ) 0.66 ( ) 1.2 ( ) 0.75 ( ) Dog allerge below media 1.4 ( ) 1.6 ( ) 1.2 ( ) 0.78 ( ) Data are the results of the multiple logistic regressio aalysis ad are preseted as odds ratio (OR) (95% cofidece iterval). ORs are adjusted for the other listed exposures. # : at least oe episode i the 4 weeks before the 2d birthday; " : ever breastfed or hypo-allergeic bottle fed; + : sigificat effect. itervetio at 2 yrs, ot oly o ight-time cough but also o other asthma-like symptoms, which might be explaied by the multifaceted approach used i the PREVASC study. The Isle of Wight study [19] defied high-risk cases whe allergy i at least two first-degree relatives or i oe first-degree relative with a elevated cord blood IgE was preset. A dual prevetive approach was used, i.e. ecasemet of the crib mattress (ot the paretal mattress) ad materal avoidace of food allerges durig lactatio. At age 8 yrs, the itervetio group was foud to be at a sigificatly reduced risk for wheeze i the past year, octural cough ad mite sesitisatio; however, the umbers were small because of the relatively high drop-out rate [19]. A Caadia itervetio study [39, 40] had a uiversity hospital-based settig, used comparable iclusio criteria ad also carried out a multifaceted itervetio like the PREVASC study. I their study, the cliical outcome (probable or possible asthma diagosed by paediatric allergists) at age 2 yrs was sigificatly (sigificace oe-sided tested) less preset i the itervetio group (16%) tha i the cotrol group (23%) [40]. A comparable differece was foud i GP-diagosed asthma i the PREVASC study, although this differece, tested twosided, did ot reach statistical sigificace. The Childhood Asthma Prevetio (CAPS) study [41] focused o mite allerge avoidace ad/or supplemetatio with omega-3 fatty acids. The mite itervetio was associated with lower use of oral steroids but ot with wheeze, serum IgE, atopy or doctor-diagosed asthma. However, the diet itervetio resulted i a lower paretally reported prevalece of wheeze durig the first 18 moths. I this study, o sigificat effect of the itervetio was foud o the icidece of specific IgE agaist mite, cat ad dog allerge at age 2 yrs. I additio, the Caadia study [40], the PIAMA [18], the CAPS study [41] ad the Study of Prevetio of Allergy i Childre i Europe (SPACE) [35] all foud o effect of the itervetio o mite sesitisatio at age 2 yrs, while the ac MAAS study reported that the striget mite avoidace regime was associated with a icreased risk [36]. Oe explaatio for this might be that the itervetio was started too late, as sesitisatio might already have occurred i utero [42, 43]. I the preset study, it was show that it is possible to reduce exposure to mite, pet ad food allerges, but ot to passive smokig. The mai reductio i mite levels was attaied i mattress dust by the use of ati-mite ecasigs. I geeral, low pre-itervetio levels of mite ad pet allerges were foud at baselie, probably as a result of (already) successful efforts of asthmatic families to achieve a low-allerge eviromet, as reported previously [44]. I spite of the pre-existet low mite level, ifats with mite allerge levels below the media had a reduced risk of curret asthma-like symptoms whe compared to ifats exposed to levels above the media. Multiple logistic regressio aalyses of the relatioship betwee exposure ad asthma-like (wheezig) symptoms revealed that exposure to mite ad food allerges, ad passive smokig cotributed, idepedetly of each other, to asthmalike symptoms, cofirmig that asthma is a multifactorial disease. A reductio of a sigle exposure seems to be less effective, as is supported by recet reports. A large observatioal birth cohort study [45] i Swede aalysed the effect of livig i agreemet with three prevailig prevetive measures: avoidace of materal smokig, breastfeedig the ifat ad reductio of home dampess. Childre of families who had applied all three measures had less wheeze ad asthma tha childre of families who executed oly two measures. The studies might explai why avoidace of a sigle exposure has oly margial or o effects whe other exposures are still existig, as might have bee the case i other prevetio studies [18, 35]. I tertiary prevetio of asthma itervetio studies [46], focusig o a reductio of multiple evirometal exposures has show promisig results, whereas the results of cliical trials targetig oly oe allerge were disappoitig [47, 48]. These studies ad the curret fidigs are a plea i favour of pursuig a multifaceted approach with respect to the prevetio of asthma. I cotrast to most other itervetio studies, the PREVASC study was desiged to work i primary care, by approximatig c EUROPEAN RESPIRATORY JOURNAL VOLUME 25 NUMBER 4 667

9 regular primary care circumstaces as well as possible. This is importat if ad whe the itervetio, oce prove to be effective to prevet asthma, becomes part of regular primary care. As has bee show i the PREVASC study, GPs ad midwives were able to idetify high-risk cases durig routie cosultatio i early pregacy. The itervetio ca be iitiated i primary care, as was doe i the research settig ad executed with the help of practice urses ad/or wellbaby cliics. I a post hoc aalysis, it was observed that the cliical effect of the itervetio was maily cofied to females i the itervetio group. To the curret authors kowledge, this is the first itervetio study reportig that sex might modify the effect of reductio of evirometal exposure o symptoms. The differece betwee the male ad female groups was strikig, ad very cosistet for almost all outcomes derived from three sources, which makes chace as a explaatio less likely. For specific IgE, a osigificat tred for a sex-specific itervetio effect was also observed. However, post hoc aalyses do ot allow coclusios to be draw, but oly preset the possibility of the modificatio by sex as a suggestive hypothesis. So far, the results permit a speculative explaatio of a possible effect modificatio by sex, although there is support i the literature for this iterestig observatio. Airway physiology ad pathology durig the whole life spa, startig i the itrauterie period, is subjected to the ifluece of sex ad might be uder hormoal cotrol, as reviewed by BECKLAKE ad KAUFFMANN [21]. Airways of male ifats are smaller tha those of female ifats, resultig i a lower lug fuctio of youg males [49]. Studies report that symptoms iduced by evirometal exposure are iflueced by sex. Whe exposed to passive tobacco smokig i utero, lug fuctio of youg males with asthma is lower tha of youg females with asthma [50]. Pet-owig females are more susceptible to asthma whe they also smoke [22]. Lug fuctio i females, if sesitised by cat ad polle allerges, is more affected tha i males [51]. The productio of IgE is also iflueced by sex, as the cocetratio of total serum IgE was higher i the males tha the females. O the basis of these observatios, oe might hypothesise that, give the differet reactios of the male ad female immue systems to evirometal exposure, males ad females might also react differetly to a reductio i relevat exposures. Sex-specific effects of the itervetio should be evaluated i further (prospective) research, ad it would be iterestig if all ogoig cohort studies icluded iformatio specifyig whether a sex differece ca be detected. I coclusio, o effect of a multifaceted itervetio programme was foud o asthma-like symptoms i high-risk childre durig their first 2 yrs of life ad atopic sesitisatio at age 2 yrs. However, a small effect was observed o the symptoms at the ed of their 2d yr of life. Further follow-up is ecessary to determie whether the itervetio measures ca actually prevet the developmet of asthma. ACKNOWLEDGEMENTS The PREVASC study is a joit project of the Depts of Geeral Practice of the Uiversity of Maastricht ad the Radboud Uiversity of Nijmege. The authors would like to thak the GPs allied to these departmets ad the participatig midwives for recruitig eligible families. The authors are grateful to all families who readily participated i the project. The authors would also like to thak: the research assistats, I. va Beeredock ad K. Maders; the data maagers, J. Pisters ad K. Coole; the statistical adviser, J. Sijbradij; the urses, who visited ad istructed the participatig families, C. Brik, K. va der Meer, M. Rovers, T. Jeijsma, I. Schaap, M. Terhaar ad E. de Vree; ad the PREVASC secretary, A. Spaiks. 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