mm BRIEF BCG Vaccination and Risk of Atopy Tyra G. Krause, MD) Anders Hviid, MSe Anders Koch, MD, PRD MD Thomas Hjuler, MD Jan Wohlfah, MSe Jeppe Fribor Bjarne Kristensen Mads Melbye, MD, DMSe T HAS BEEN PROPOSED THAT CHILD- hood exposure (o certain infec- ions and vaccinations that in- duce Tyl-type immune responses may protect against atopic diseases, which are characterized by a T,2-type cytokine expression." In particular, BCG vaccination has been suggested 16 have such an effect based on its ability to elicit a strong Tal-type immune re- sponse in humans.” In support of this theory, routine BCG vaccination has been stopped in most western coun- tries where an increase in allergy has been observed.* Results [rom the few epidemiologic studies that have ad- dressed the hypothesized association between BCG vaccination and allergic diseases are conflicting®” and possibly distorted by selection bias, as they have been carried out in countries where BCG vaccination is either a part of the rouline vaccination program or given only to high-risk subjects, In Greenland, BCG vaccination was siven routinely toall infants until 1990, ‘when it was abruptedly stopped." This provided a unique opportunity to com- pare the risk of atopy in unselected. ‘groups of children who were either all vaccinated with BCG or all unwacci- nated. Furthermore, we obtained infor A012 JAMA Februty 26, 2005 29, No, Downloaded From: http:/jamanetwork.com/ on 10/23/2016 Context It has been suggested that 8CG vaccination may protect against develop- ‘ment of allergic diseases, particularly when given just after birth. BCG vaccination was given routinely to all infants in Greenland until 1990, when it was withdrawn from the vaccination program. Whether ths resulted in an increased prevalence of atopy in children bor after the stop of BCG vaccination is unknown, Objective To determine whether BCG vaccination and age at BCG vaccination are associated with development of atopy. Design, Setting, and Participants Cross-sectional study among schoolchildren aged & to 16 years in 4 towns on the northwest coast of Greenland. Participants had a blood sample drawn and information on BCG vaccination was obtained during 2 periods, November 1998 and November 2001..A total of 1686 children (79% of avali- able children) participated, 1575 of whom had complete information on vaccination, status. Atopy was defined as a positive test result in an assay that tess for IgE specific against the most common inhalant allergens in serum. ‘Main Outcome Measures Odds ratio (OR) of atopy in BCG-vaccinated com- pared with unvaccinated children and OR according to age at vaccination. Results The rsk of atopy was the same in BCG-vaccinated compared with unvac~ inated children after adjustment for confounders (OR, 1.03; 95% confidence inter- val, 0.72-1.48). The tsk of atopy in BCG-vaccinated children was not associated with age at vaccination (P=.17). Conclusions BCG vaccination administered to infants is not associated with re- duced risk of development of atopy. JAMA, 2003288:1012-1015, wer jama com ‘mation on exact date of BCG vaccina- garding sociodemographic variablesand, lion, enabling estimation ofthe risk of hada venous blood sample drawn, Pa- atopy according (o age al vaccination, rental place of birth was used as an in- nT dicator of ethnicity. Thus, if both the METHODS. child and his or her parents were born The study was conducted in the towns in Greenland, 96% of grandparents were of Sisimiut, Hulissat, Aasiaat, and Ma- also born in Greenland, making it nlitsoq, located on the northwest coast highly likely that the child was of Inuit, of Greenland. These towns are similar origin." Children living in Sisimiut who in the number of inhabitants (3500- were examined twice were only in 5200), climate, infrastructure, and li ing conditions. In November 1998, all_jaramabong Deprinentolfplemioow fe children aged 8 through 16 years in Si-_seuch, DanthEpdemoogy Scenes Cer, Salers Simiut alone were invited to partici. Sumlstul, Copenhagen, Denna (rs Kase, pate In November 2001 all uldren Seay Sut St Ge ged through 13 yeaa towne Oe an Puce Cpeagin Sc tree vied: The sample was nied tg ce, Uden bom in Green Theehl- 30g fe Res Sa dren answered a self-administered ques- grieve; 5, DK 2300 Copenhagen S, Denmark tionnaire together with their parents re- (emai tgvOs. dt 1 Reprinted) (©2003 American Medical Association. AI rights reservedcluded at the time of their first blood sample. Ethics committee approval was ‘obtained from the Commission for Se centific Research in Greenland. Writ- ten informed consent was obtained fromall participating children and their parents. Venous blood samples were ana- lyzed for total IgE with the Unieap total IgE test (Pharmacia, Copenhagen, Den- mark) and for specific Ig with the Pha- diatop test (Pharmacia), which is a qualitative (yesino) assay testing for the 8 most common inhalant allergens (grass, birch, mugwort, dog, cat, horse, Cladosporium herbarum, house dust mite) in 1 pool. Children with a post- live specific IgE test result were con- sidered atopic Information on child's place of birth, parents place of birth, mother's age at Tirst birth, and birth order was ob- tained for all children from the Danish Civil Registration System. All inhabit- ants of Greenland are registered in the system with a unique identification number. Information on birth weight ‘was obtained from birth records, BCG Vaccination Until 1990, infants in Greenland re- ceived the BCG vaccination once intra- cutaneously in the deltoid region; all in- fans received thesame dose within a few days after birth. The BCG vaccine ad- ministered from 1980 to 1990 (Copen- Jhagen strain No. 1331) has been widely used in many countries around the ‘world. Due toa reduction in incidence ‘of tuberculous meningitis and pulmo- nary tuberculosis, BCG vaccination was ‘withdrawn from the vaccination pro- ‘gram at the beginning of 1990" and stopped completely at all hospitals in Greenland during the following year. Due to local outbreaks of tuberculosis, [BCG vaccination was introduced again in 1997 to newborns in the routine vac- ination program. Asan exception, Ma- niitsoq children who were born from 1990 to 1097 but not vaccinated wer all offered vaccination in 1997, In most towns in Greenland, exact date of BCG vaccination is registered both in vaccination protocols kept at the (©2003 American Medical Association, All rights reserved, Downloaded From: http:/jamanetwork.com/ on 10/23/2016 CG VACCINATION AND RISK OF ATOPY health center where the child is born and in hospital records kept at the health center in the town where the child is living, Information on BCG vac- cination was primarily obtained from vaccination protocols (77%) available in isimiut, Aasiaat, and Maniitsog. The remaining information was obtained from hospital records (23%). Statistical Analyses The odds ratio (OR) for the prevalence of atopy in vaccinated compared with unvaccinated children and the OR for prevalence according to age at vaccina- tion were estimated using logistic re- gression. To identify variables confound- ing the association between BCG and atopy, we used the change-in-estimate method,"* including the background variables presented in TABLE 1 with the calegoriess presented ifa change in the BCG OR of more than 10% was pres: ent. Adjustment for age was made us- ing quadratic splines with knots at ages 8, 12, and 16 years. Analyses were car- ried out using SAS v8.2 (SAS Institute Inc, Cary, NC); P=.05 was used to de- ermine statistical significance. RESULTS In November 1998, 820 children aged 8 to 16 years (85% of available children) were enrolled and had a blood sample drawn, of whom 789 were born in Greenland. In November 2001, 1139 children aged 8 o 13 years (74% of avail- able children) were enrolled and had a blood sample drawn, of whom 1102 were born in Greenland. A total of 205 chil- dren living in Sisimiut had been exain- {ned twice and were only included in the study with their frst blood sample, re- sulting in a study group of 1686 chil- dren aged 8 to 16 years. Information on BCG vaccination was obtained for 1575 children (03%). Of these 1065 (68%) had been vaccinated, but 3 children had miss- ing information on exact dates of BCG vaccination. A total of 81 children were vaccinated when they were older than 1 year. Of these, 62 (76.5%) lived in Ma- nlitsoq and had been vaccinated as part of the vaccination campaign performed fn that own in 1997, The BCG vaccina- (Reptnee) JAMA, February 28,2003 lion coverage before age 1 year was 94% among children born before January 1, 1990, 53% among children born in 1990, and only 2% among children born after January 1, 1991 Children receiving the BCG vaccine ‘were older than unvaccinated children (Table 1). Furthermore, a higher pro- portion of the BCG-vaceinated chil- dren were examined in 1998 compared ‘with 2001. The number of persons per room in the home differed heween [BCG-vaceinated and unvaccinated chil- dren in univariate analysis but was sini- laralier adjusting for age (P=-46). Oth- cerwise, the distribution of background variables was similar in BCG-vacci- nated and unvaccinated children, The adjusted OR for prevalence of atopy according to BCG vaecination and age at BCG vaccination was examined in 2 logistic regression analyses (TABLE 2). In the first, only age Was a confounder, whereas in the second, age, year at examination, and birth weight ‘were confounders, The adjusted risk of atopy was the same in BCG-vace nated compared with unvaceinated chil- dren (OR, 1.03; 05% confidence inte val [CI], 0.72-1.48). There was no effect modification by geographical site (P2.23) or by source of BCG vaceina- tion information (vaccination proto- cols vs hospital records) (P=.39). Pur- thermore, if children with repeated measurements of atopy (n=205) and. children living in Maniitsog (n=176) were excluded, the overall risk of atopy remained unchanged (OR, 0.94; 05% C1, 0.61-1.47 and OR, 1.00; 95% 1 0.68-1.47, respectively). There was no cllect of age at BCG vaccination on risk of atopy (P=.17 for heterogeneity). The data could not be described by a trend. The OR for atopy in children with, missing information on BCG vaceina- lion compared with BCG-vaccinated children was 0.89 (05% C1, 0.51-1.77), Ina subanalysis we classified children ‘with missing information on BCG vac- ination as either BCG-vaccinated or unvaccinated according to year of birth (children born before 1990 and the first, © months of 1990 as vaccinated and children born later as unvaccinated). soe 018BEG VACCINATION AND RISK OF ATOPY qr ‘Aged 8-16 Years and Born in Greenland (N = 1575) We. ’aet Variable (i= 005) geal oaminaton.y @ 64) a 12 (TO w Ta TE a 706. @ 20 7935) = Tare a TOT ® 526 (10.4) eae) ‘Smut 1008) 654 61 ‘esa 709 0: Rasaal 2008 105 (8) Sa ao antooa, FETE arena ple of rth (Grea Gresrland 904 4.9 Greanendlotier Taher Greandunnan Materatage attest y 110 020 0 Eahoraer 1 ‘Tater ecueaon Tahal \Grasee 8-12 Tradavocabona ‘reergraduate, graduate 11a 0.7) Theron tra) Tip ot parsons par oom home 1 195 (126) Toe Boe 67-4) Tiaomn ‘ieoerce Ph - 1014 JAMA Febnuny No.8 Reprinted) Downloaded From: http:/jamanetwork.com/ on 10/23/2016 jaccinated Not BCG-Vaccinated| er 796 (258) TT eSB) 27-6 ZED, Teo Tra Oo) Or 254 189.8) 255 6021 7514.27 55,20) 106 208), 15a 0) DE 221 649) SET oa ea 229 (88.9) 272683} Bra 180 25.) 9 21a) 9 220 (05.9 2203.1) Te} @ 750187 BIO 25) 22102) GHZ) 5108) 264518) wai fe 1. Dutibution of Background Varebies mW BCGrVacchaled and Unvaccinated ChIGren Vale for Heterogeneity 001 28 001 19 a 25 98 cost The overall estimate was unchanged (OR, 1.02; 95% Cl, 0.70-1.48). Total IgE levels did not differ be- tween BCG-vaceinated and unvacei- nated children (mean [SD] total IgE level among BCG-vaccinated and un- vvaceinated children: 253 [681] and 2 [590] KU/L, respectively, P=.65) ‘COMMENT Based on a large cross-sectional study, ‘we found BCG-vaccinated children to ik of atopy as wavac- inated children, Furthermore, no sig- nificant dilferences inthe risk of atopy were found according to age at BCG vaccination. Overall, these results do not support the hypothesis that BCG vaccination has a protective effect on the development of atopy Five previous studies have ad- dressed the hypothesis that BCG vacel- nation protects against allergic dis ceases by comparing the prevalence of atopy or allergic diseases in BCG- vaceinated and unvaccinated children. Strannegird et al? found no protective ellect of BCG vaccination onallergic dis- ceases in Swedish 4 to 9-year-old chil- dren, while a nonsignificant effect was observed among foreigners. Similarly, ‘Alm et al? found no association with BCG vaccination and atopy or allergic diseasesin 2-0 7-year-old children with atopic heredity. However, a potential protective elfect of BCG vaccination may have been masked by the strong g¢ netic predisposition to atopy in the chil- dren. Purthermore, in Sweden BCG vac- ination isonly given to children at high risk of tuberculosis resulting in a BCG vaccination rate of 4%," a likely source of selection bias. In a study conducted in Africa, Aaby et aP reported that BCG- vaceinated children had a lower preva- lence of atopy compared with unvacci- nated children, particularly when the vaccine had been administered in the first week after birth, Gruber etal found no effect of BCG vaccination given be- fore age © months on development of atopy of allergic manifestations at age 7 years in a cohort study; in this study 13% of the children at high risk of tuberculosis were BCG-vaceinated, and have the same (©2003 American Medical Association, All rights reserved.children born outside of Germany were overrepresented in the BCG- vaccinated group. In another cross- sectional German study among pre- school children a weak protective elfect ‘of BCG vaccination against asthma was observed in German children, whereas 4 stronger protective effect on atopic manifestations was observed in chil- dren of non-German ethnicity.” The strength of our study was ts abil- lty to minimize selection bias, as prac Lically all children within a bith co- hort were either vaccinated oF not vaccinated. By examining children of the same age in 1998 and 2001 we were able to compare the prevalence of atopy in vaceinated and unvaccinated children ‘within the same age group. The 2 ex- laminations were performed in exactly the same manner at the same time of year, and we obtained high participa- lion rates in both years. It could be speculated that an inerease in the preva- lence of atopy from 1998 to 2001 would bias our results. However, we found the prevalence of atopy according to age to he the same in 1098 and 2001, and we adjusted for year of examination in the analyses. Furthermor prevalence of atopy in the last 3 years would have tended to bias our esti- mates in favor of a protective effeet of [BCG vaccination. Our study was fur- ther strengthened by measuring atopy objectively in all children, and by ob- laining information on BCG vaceina- lion status and exact date of vaceina- tion independently of the outcome for 193% of the children. The fact that the majority of the children were vacei- nated just after birth, when the protec liveellect of BCG on atopy has been stg gested to be strongest, reduced the risk fof missing a potential protective effect of BCG vaccination, as did the fact that cour study was not restricted to ehil- dren who were genetically predisposed to atopy. Although our study does not sup- port the hypothests that vaccination with, [BCG is capable of preventing the devel- ‘opment of atopy, we cannot rule out that the effect of BCG vaceination may be dil- ferent in populations with other ge- ‘an inerease inthe (©2003 American Medical Association, All rights reserved, Downloaded From: http:/jamanetwork.com/ on 10/23/2016 CG VACCINATION AND RISK OF ATOPY ‘Table 2. Prevalence of Atopy Accoring to BCG Vaccination and Age st Vaccnaion ™ Chiron Aged 8-16 Years Bom in Greenland (N = 1575) No. of Chiron Variable” __Totalt With Atopy Prevalence, 6 OR 95% Cl) __Heterogenelty oS accratedt Yee Nec Value for 162 108(0.72-1.48) 722 aternce 117 076 (098-182) Be) Zoi 1S2 (080216) Teo TT (ORET) av 152105 (057-151) 7 OSH O01 18) 3e__a7rwaster) ‘tomers nan not marian ciatee# an low et found net tet een 085173, ‘Fae at vacaaton, ‘a ma zr 2 me Tae ie ee CE netic constitutions."* Furthermore, our primary focus was on the effect of early BCG vaccination. Thus, we had lim- ited data regarding children vaccinated at ages outside the general recommen- dations. ‘Author Contibutions: Study concep and desi: Krause, Koen, Wohi Olsen, Kestensen, Melye ‘eguiton of data: Kruse, Koen, For, Hide, ten, Metye. ‘naiys and interpretation of dt: Kaus, Hi ‘Wefan en Melye Drang othe minus: Krause, ital ein of te manus for important in felectual content: Hui, Koch, Poors, Hil, ‘eit, Olsen, rstensen, Mebye ‘Sati expert: Hv, Wont (btained funding: Krause Koch, Malye ‘dminstatve tcl ermateal spot Kr, och, Frborg Huler Oven Kstensen Malye ‘Study supervision: Rech, Welln. Mey Funding/Support Ths study was sported by the Dansh Medial Reseach Coune he Research Ce tetorEavrormertl Hea the CarnstetorNert ‘Aan Research the Greenland Homer, the J ‘nb and Olga Madsens Foundation, he Rosa Pe. fersen Foundation, the Dagmar Marshal Founds ton and the Lay Serine Foundation. Role of the Sponsor: Mleral othe i tests were proved Pramad, Copenhagen, Dear The Banish Epidemiology scence Cee supprted by the Danish National Research Foundation, anda therhadaole the design an conduct te suc, inthe data colechon, ana, and interpretation of the data. the preparation, ree, or approval ofthe manu TaN 4. Peshagen G. Can immunization affect the deve ‘pment of alergy? Pasa Alergy Immune. 200 eupa 13) 2638 2 Marne FD, Rol of via nfcone ia the ney fon ofastina and ales durg choad: coud they be potectine? Thorax, 1941 189-1198, 3. Marchant A, Goetghebuer T, Ota MO, al. New- iors develop 2 Tht -ype immune response toMy ‘abate bovis actus Camete- Guerin acon fon] immuno. 1999 16332259-2095, 4 Grobe Cisse L Bosten 8. Do ery chi hood immusiaatonsinduence the development of topy and do ey case alge reac? Pell A ley Immunol 2001:12296311 5 annagual, Larsson, Wennergren Stan egitd Prevalence of alergy in chuen in labon {2 peor BCC vaccination and infection with typical Imyeobacteta Aley 1998:53248-254 "Aims Lia G, PerhagenG,Shenis. Ea AC \aconaton and development of atopy Lancet 1387 $So00a03 7. aby P, Shaheen SO, Heyes CB eta Ely BCG ‘action and veducton in slogy in ules Bs, lin Exp lee 2000 30.688-60, 8 Graber C:Kug Mt, Bergmann R. Guggenmoos- olan ann U- Delayed typeset toe Beran fia mmunogtbuln peat sensi fon, and atop manesatenmongtudnsly flowed a bool Calmette-Guerin vacated ard ram: ‘inte cdren Paditnce 2001107236 5" Graber C, Mentha, Bergmann R. Wabn Stare Te early BCC vacation asodated ith less atopic dseae? an epidemiologiesl study in German preschool caren wit ferent ethnic backgrounds Peta Aly na 2002-13177 im 40. The State of Heath in Greolan: Report fom the Chet Medea! Other for 1990, Nuk Green land tuner 1991 {Ts kiause To, Roch. Pouben LX Kristensen 8, O- Sen OR, Mele M. Aloe senizon among ci tenn an dec emstonment Ci Exp Alergy. 2002; Spear. 42, Rothman 1, Greenang, nvoduction ta sta ‘ed arly Wines O'comer ds Moder Edemilegy- Pilani a: UppeatRaven Pub ers 1998253279 413. Romanus V,Serson A, Halander HO. Tein pact changing ACG coverage on tuberaaes in {lence n Swedh-bom chiren between 1969 aed 1368, Tuber Lng Dis. 195273-10-16h 44, Amis Saja CB Mer EN, etal lop inchi- Areninralaton to Cc vacation and genet poy. morphisms at SLCTTAT Clomerly NRAMP!) and (BaST471 Gener Immun, 20023777 (Reprines JAMA, February 26, 200% Vol 209, No.8 1095