Bernsen, RMD (Roos)

Jongste, Johan

Wouden, Hans

English

EUR Research Repository

Lower risk of atopic disorders in whole cell pertussis-vaccinatedchildrenR.M.D. Bernsen*, J.C. de Jongste#, J.C. van der Wouden*Lower risk of atopic disorders in whole cell pertussis-vaccinated children. R.M.D.Bernsen, J.C. de Jongste, J.C. van der Wouden. #ERS Journals Ltd 2003.ABSTRACT: This study addressed whether whole cell pertussis-vaccinated childrenhave a different risk of atopic disorders compared with children who did not receive thisvaccination.Data on vaccination status, atopic disorders and child and family characteristics ofthe children of 700 families were collected in this retrospective study. A minority ofthese 700 families refused vaccinations for religious reasons. The relation betweenpertussis-vaccination status and atopic disorders was analysed by means of adjustedlogistic regression for repeated measurements in order to account for the correlationbetween sibship members.The 700 families included 1,961 children. Data on vaccination status and atopicdisorders were available for 1,724 children. Vaccinated children had a reduced risk ofatopic disorders.Whole cell pertussis vaccination is associated with a lower risk of atopic disorders,though other vaccine components (diphtheria, tetanus, poliomyelitis) or other vaccina-tions may also be involved.Eur Respir J 2003; 22: 962–964.*Dept of General Practice and #Dept ofPediatrics, subdivision of Pediatric RespiratoryMedicine, Erasmus MC University MedicalCenter Rotterdam, the Netherlands.Correspondence: R.M.D. Bernsen, Dept ofGeneral Practice, Room Ff324, Erasmus MC -University Medical Center Rotterdam, PO Box1738, 3000 DR Rotterdam, the Netherlands.Fax: 31 104632127E-mail: r.bernsen@erasmusmc.nlKeywords: Allergyasthmaatopyeczemawhole cell pertussis vaccinationReceived: April 9 2003Accepted after revision: July 15 2003An increased risk of atopic disorders in pertussis ordiphtheria tetanus pertussis (DTP) vaccinated children hasbeen reported [1–4], but this was not confirmed by morerecent observational studies [5–7], a randomised placebo-controlled trial [8], and an ecological study [9]. Reports ofadverse effects of vaccinations usually cause controversy anddebate between advocates and opponents of vaccinationprogrammes. The current study evaluated the role of thepertussis vaccination as a risk factor for atopic disorderswithin a study of family size and birth order as risk factors forasthma, allergy and eczema in a population of 700 families inthe Netherlands.Material and methodsStudy subjectsIn a study in the Netherlands designed to determine the roleof sibship size and birth order as risk factors for asthma,allergy and eczema 700 families with index children born in1988, 1989 or 1990 were sampled from files administered bythe Municipal Health Service covering the municipality ofZwijndrecht, a town withw40,000 inhabitants. A subgroup ofthese families adhere to the orthodox reformed religion andtheir children mostly attend orthodox reformed schools.Some of the parents of this group refrain from vaccinationsfor religious reasons. According to an official schedule in theNetherlands, children receive four vaccinations of DTP(whole cell), Poliomyelitis and Haemophilus influenzae typeB at aged v1 yr (before 1998 at aged 3, 4, 5 and 11 months),mumps-measles-rubella (MMR) at aged 14 months, a boosterof DT-Poliomyelitis at aged 4 and 9 yrs and a booster ofMMR at aged 9 yrs. Since 2002 a booster of acellularpertussis is administered at aged 4 yrs.Study designThis was a retrospective study using datafiles from routinehealth checkups from birth till adolescence.MethodsData on preventive health checkups of index children aged6 yrs performed by the Municipal Health Service werecollected from the files. Data from files of their siblingswere also extracted. The following data were used: presenceand type of allergy, asthma, eczema, current medication, birthorder, sibship size, date of birth, sex, date of checkup, year ofbirth of the mother, postal code, country of birth of theparents, occupation of the breadwinner, atopic disorders ofthe parents, vaccination status, and duration of breastfeeding.A child was considered having asthma, allergy or eczema ifthis was mentioned in the file by the physician who did thecheckup, in the questionnaire filled out by the parents or in aletter from a paediatrician/pulmonologist.AnalysisThe independent relation of pertussis-vaccination statuswith allergy, eczema, asthma and any atopic disorder (allergy,eczema or asthma) was evaluated within families by means oflogistic regression for repeated measurements (GeneralizedEstimating Equations) [10], families being the units ofEur Respir J 2003; 22: 962–964DOI: 10.1183/09031936.03.00039803Printed in UK – all rights reservedCopyright #ERS Journals Ltd 2003European Respiratory JournalISSN 0903-1936analysis, which takes correlation between family membersinto account. Analyses were performed both in univariate andmultivariate models with adjustments for the subset of thefollowing variables, which changed the univariate pointestimate by at least 10% [11]: sibship size, birth order, yearof birth, season of birth, sex, breast feeding forw1 month (yes/no), age at the time of checkup, allergy or asthma of theparents, level of occupation of the bread-winner (five levels),age of the mother at the time of delivery, level of urbanisation(two levels) and country of origin (both parents born in theNetherlands yes/no). A two-sided p-value of 0.05 was con-sidered significant.ResultsThe 700 families comprised 1,961 children. Both vaccina-tion status and atopic status was available for 1,724 children;of these 44 (2.6%) were not vaccinated for pertussis, mostlyfor religious reasons. Of these, 39 had received no vaccina-tions at all, four received only the polio-vaccination, and onereceived DT-polio (without pertussis). The 1,724 children hadtheir health checkup at a mean age of 5.9 yrs (SD: 0.6 yrs).The types of allergy mentioned were house-dust mite, pollen,furry pets, food allergy, hay fever and allergic rhinitis. Theprevalence of atopic disorders in both groups is shown intable 1. Crude odds ratios (OR)s for atopic disorders(vaccinated/unvaccinated) varied between 0.33–0.69. AdjustedORs ranged 0.23–0.40, consistent with a substantially reducedrisk of atopy in pertussis-vaccinated children. The sameanalysis in the subgroup of children attending orthodoxreformed schools (39 unvaccinated and 128 vaccinated child-ren) yielded similar point estimates. For "any atopic disorder"the adjusted OR (vaccinated/unvaccinated) in this subgroupwas 0.16 (95% confidence interval 0.04–0.67, data not shownin table).DiscussionIn the present study, pertussis-vaccinated children were at aconsiderably lower risk of atopic disorders than unvaccinatedchildren. Most vaccinated children received the combinedDTP-polio vaccine. Hence, the comparison of children withand without pertussis vaccination was almost equivalent tothe comparison of DTP-polio vaccination and no vaccinationat all. Data used for this study were not collected to answerthe present research question, and consequently no samplesizes for vaccinated and unvaccinated groups were computed.A total of 44 unvaccinated children were found and therelations studied were significant. Adjustment for confoun-ders could have been a problem with so few children at risk,with resulting empty cells and huge confidence intervals.However, this was not the case and the results of the adjustedanalyses showed similar relations. All data were collectedretrospectively from files and possibly misreporting, mostlikely underreporting, of atopic diseases may have occurred.It could be that this misclassification is differential, i.e. relatedto the risk factor under study. This may mean that parents ofvaccinated children report less atopy than unvaccinatedchildren. However, the relations found persisted and evenbecame somewhat stronger when the analyses were restrictedto the more homogenous group of children attending orthodoxreformed schools. Even if within this more homogenousgroup underreporting would be differential, it would be morelikely that parents of unvaccinated children (more orthodoxreligious families) would report less than parents of vacci-nated children. However, this bias would lead to an attenua-tion of the OR and the unbiased OR would even be moreextreme.In the Netherlands pertussis is endemic in childhood andshows 4-yearly peaks [12]. The highest incidence is reportedin infants aged v1 yr (35 per 100,000 per year during1989–1993). Pertussis cases are reported both in vaccinatedand unvaccinated children, the incidence in the latter groupbeing roughly 10-fold the incidence in the vaccinated group.The relatively low incidence in the unvaccinated group(compared to completely unvaccinated groups in Germany)can be explained by herd immunity.As only 0.7% of the study population was born after 1997,the role of acellular pertussis vaccine is negligible in this study.Given the hygiene hypothesis, it would be expected that theimmune system of the unvaccinated children would haveshifted more towards the T-helper cell 1-side, inconsistentwith a raised risk of atopy. On the other hand, the immunesystem of vaccinated children is triggered with the (albeitkilled) microorganisms at a very young age and from thispoint of view the findings of the current study fit in thehygiene hypothesis and are biologically plausible.The findings of the current study are consistent with arecent study in Germany by GRÜBER et al. [7]. Several studiesfound an increased risk of asthma and allergy in DTP orpertussis-vaccinated children [1–4], but this may be due toresidual confounding or confounding by indication as thereasons for not vaccinating are not described and may berelated to the outcome. A number of studies found no relationbetween the DTP or the pertussis-vaccination and atopy [5–9].One of these is a randomised controlled trial [8], whichcompared three groups that received different cocktails ofDTP with a control group that received DT only. Howeverthe age of evaluation at 2.5 yrs was rather young and this mayaccount for the lack of an effect. HENDERSON et al. [5] foundno difference, but in this study the outcome was wheezing atthe age of not more than 42 months. All (but one) studiesmentioned above are observational and residual confoundingcannot be excluded, especially when the reason for refrainingfrom vaccination is not known. It is important for futurestudies to include groups that are as homogenous as possibleand adequately describe the differences between vaccinatedand unvaccinated groups.ConclusionThe results from this study suggest that whole cell pertussis-vaccinated children have a lower risk of atopic disorders.Table 1. – Prevalence of atopic disorders among unvaccinatedand vaccinated children and crude and adjusted odds ratios(OR)s for atopic disorders (vaccinated/unvaccinated) with95% confidence intervals (95% CI) for adjusted ORs.Allergy Eczema Asthma Any atopicdisorderUnvaccinated % 11.4 13.6 11.4 22.7Vaccinated % 5.2 4.9 8.7 13.8Crude OR 0.40 0.33 0.69 0.51Adjusted OR# 0.23 0.26 0.40 0.3795% CI 0.07–0.79 0.11–0.63 0.10–1.70 0.16–0.87#: Variables included in the multivariate model were for allergy (birthorder, family size, year of birth, atopy of the father, age of mother atbirth), eczema (birth order, atopy of the father, age of mother at birth),asthma (birth order, family size, year of birth, atopy of the father, age ofmother at birth) and any atopy (birth order, family size, atopy of thefather, age of mother at birth). n=44 (unvaccinated) and 1,680(vaccinated).963ATOPY IN PERTUSSIS-VACCINATED CHILDRENHowever, other vaccine components (diphtheria, tetanus,poliomyelitis) or other vaccinations may also play a role.References1. Odent MR, Culpin EE, Kimmel T. Pertussis vaccination andasthma: is there a link? JAMA 1994; 272: 592–593.2. Kemp T, Pearce N, Fitzharris P, et al. Is infant immuniza-tion a risk factor for childhood asthma or allergy?Epidemiology 1997; 8: 678–680.3. Farooqi IS, Hopkin JM. Early childhood infection andatopic disorder. Thorax 1998; 53: 927–932.4. Hurwitz EL, Morgenstern H. Effects of diphtheria-tetanus-pertussis or tetanus vaccination on allergies andallergy-related respiratory symptoms among children andadolescents in the United States. J Manipulative Physiol Ther2000; 23: 81–90.5. Henderson J, North K, Griffiths M, Harvey I, Golding J.Pertussis vaccination and wheezing illnesses in youngchildren: prospective cohort study. BMJ 1999; 318: 1173–1176.6. DeStefano F, Gu D, Kramarz P, et al. Childhood vaccina-tions and risk of asthma. Pediatr Infect Dis J 2002; 21: 498–504.7. Grüber C, Illi S, Lau S, Nickel R, et al. Transientsuppression of atopy in early childhood is associated withhigh vaccination coverage. Pediatrics 2003; 111: 282–288.8. Nilsson L, Kjellman M, Bjorksten B. A randomizedcontrolled trial of the effect of pertussis vaccines on atopicdisease. Arch Pediatr Adolesc 1998; 152: 734–738.9. Anderson HR, Poloniecki JD, Strachan DP, et al. Immuni-zation and symptoms of atopic disease in children: resultsfrom the International Study of Asthma and Allergies inChildhood. Am J Public Health 2001; 91: 1126–1129.10. Diggle PJ, Liang KY, Zeger SL. Analysis of LongitudinalData. Oxford, Clarendon Press, 1994.11. Rothman K. Modern Epidemiology. Philadelphia, Lippincott-Raven, 1998: pp. 256–257.12. de Melker HE, Conyn-van Spaendonck MA, Rumke HC,Sprenger MJ, Schellekens JF. Whooping cough in TheNetherlands, 1989–1994. Ned Tijdschr Geneeskd 1995; 139:1280–1286.964 R.M.D. BERNSEN ET AL.

Lower risk of atopic disorders in whole cell pertussis-vaccinated children.

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Lower risk of atopic disorders in whole cell pertussis-vaccinated children.

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