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Infections in Child Day Care Centers and Later Development of Asthma, Allergic Rhinitis, and Atopic Dermatitis: Prospective Follow-up Survey 12 Years After Controlled Randomized Hygiene Intervention

Infections in Child Day Care Centers and Later Development of Asthma, Allergic Rhinitis, and... Abstract Objective To evaluate the effect of successful prevention of common infections in child day care centers on the later development of allergic diseases. Design Prospective follow-up survey with a questionnaire administered 12 years after a controlled randomized hygiene intervention. Setting Twenty municipal child day care centers in Oulu, Finland. Participants A questionnaire was sent to 1354 prior participants (98%) in the intervention trial. The response rate was 68% (928 of 1354 participants). Main Intervention Hygiene intervention from March 1, 1991, to May 31, 1992. Main Outcome Measures The number of respondents who had a diagnosis of asthma, allergic rhinitis, and/or atopic dermatitis made by a physician, and the number of those who reported symptoms of atopic diseases. Results Asthma was diagnosed by a physician in 48 of the 481 respondents (10%) from the intervention child day care centers, with markedly fewer infections, and in 46 of the 447 controls (10%) (relative risk, 1.0; 95% confidence interval, 0.7-1.4). Similarly, no differences were found in the numbers of children who had a diagnosis of other atopic diseases or who had reported such symptoms. Conclusion The prevention of common respiratory tract and enteric infections during early childhood does not change later allergic morbidity. In 1989 Strachan1 introduced the hygiene hypothesis, which postulates that the inverse association between the number of siblings in the family and hay fever at ages 11 and 23 years noted in a British cohort was due to the protective effect of specific environmental factors such as infections in infancy. Since then, numerous observational surveys have been published, only some of them supporting this inverse association between infections and allergic disorders.2-8 Even though the association has not been found in all surveys, reports with a positive finding have gained almost universal acceptance.9 At the same time these clinical observations were made, it was found that a dominance of helper T type 2 (TH2) subsets of CD4 T lymphocytes promotes allergic disorders10 and that infections can shift this TH2 dominance to TH1 dominance.11 In experimental models, microbial compounds were found to modify allergic inflammation and it was concluded that the shift toward TH1 dominance could prevent the development of allergic disorders.12 Along with these developments in the theoretical immunological background, interest in the hygiene hypothesis increased markedly. Our immunological knowledge has widened rapidly in recent years, however. It has been learned, for example, that CD8 T lymphocytes have subpopulations (cytotoxic T type 1 cells [TC1] and cytotoxic T type 2 cells [TC2]) that inhibit either TH1 (by TC2) or TH2 (by TC1) cells, making the immunological explanation behind the hygiene hypothesis much more complex.13,14 Furthermore, it has been learned that the specific TH1 and TH2 polarization caused by infection is a diverse phenomenon regulated by the signaling Toll-like receptors and varies with the type of microbe.15,16 Observational surveys serve as a source of hypotheses that should then be tested in controlled randomized intervention trials to properly control for confounding factors.9 Nevertheless, there are many hypotheses in clinical medicine that cannot be tested in this way, such as effects of smoking and breastfeeding. Similarly, it is not feasible to induce infections in a randomized manner to evaluate the development of allergic disorders. It is possible, however, to evaluate the prevention of infections in a randomized controlled trial. We conducted a randomized hygiene intervention trial lasting 15 months from March 1, 1991, to May 31, 1992, at child day care centers (CDCCs), where we succeeded in reducing infections.17 The number of days with rhinitis was reduced by 17%, cough by 11%, and diarrhea by 18%. Still more importantly, there were 27% fewer episodes of acute otitis media and the number of days receiving antimicrobials was 24% fewer among those who attended the intervention CDCCs. We hypothesized that if the hygiene hypothesis applies to either common viral or bacterial respiratory tract and enteric infections in childhood, there should be more atopic diseases among those who had attended the intervention CDCCs in our earlier trial than among those who had attended the control CDCCs. Thus, we conducted a follow-up survey 12 years after the randomized hygiene intervention to compare the development of atopic dermatitis, allergic rhinitis, and asthma between these 2 groups of adolescents. Methods Study design Altogether, 1376 children had participated in the hygiene intervention trial in 1991 and had been in the follow-up for at least 2 months. Details of the infection prevention program and its implementation have been published.17 In brief, the hygiene intervention was conducted in 10 CDCCs, while 10 other randomly allocated centers matched with them for size and geographical location served as controls. The basic background data of the study population were collected in both 1991 and 2003. The intervention included several steps, of which the most important was the improvement of hand hygiene by the use of an alcohol-based hand rub. In 2003, we sent a questionnaire to 1354 adolescents and their families. Altogether, 708 of them had participated in the infection prevention program and 646 had served as controls. Replies were received from 928 participants (68%), including 481 who had attended intervention CDCCs and 447 who had attended control CDCCs (Figure 1). The questionnaire was the same as that used in the International Study of Allergy and Asthma,18 but we added questions on day care, breastfeeding, number of siblings, occurrence of otitis media, food allergy, family histories of atopy and asthma, pets, and smoking at home. The ethical committee of Oulu University Hospital found the protocol ethically acceptable. Figure 1. View LargeDownload Study profile. CDCC indicates child day care center. Statistical analysis The differences between those who responded and those who did not respond to the questionnaire were tested with either χ2 test (number of nonsmoking and smoking mothers and fathers and number of mothers and fathers with basic or higher education) or t test. We used t test for parametric variables (mean age of attendance in CDCC, mean duration of exclusive breastfeeding, mean number of episodes of acute otitis media, and mean number of days receiving antimicrobials). Univariate analysis of variance was used to test interaction in parametric variables of background data (mean age of attendance in CDCC at the beginning of the intervention, mean duration of exclusive breastfeeding, mean number of episodes of acute otitis media, and mean number of days receiving antimicrobials) between subjects assigned to the intervention and control CDCCs and whether they replied to the questionnaire in 2003. In this analysis, the differences between the proportions of nonsmoking and smoking mothers as well as nonsmoking and smoking fathers were tested with the standard normal deviate test.19 The differences between proportions of mothers and fathers with basic or upper secondary degree education and mothers and fathers with higher education were tested likewise (Table 1). Table 1. View LargeDownload Demographic Data on Subjects Assigned to the Intervention and Control Child Day Care Centers in 1991 and 1992 Grouped According to Whether They Replied to the Questionnaire in 2003 The primary outcome measure was the number of respondents who had a diagnosis of asthma, allergic rhinitis, and/or atopic dermatitis made by a physician, backed up by a corresponding analysis of self-reported symptoms. Separate analyses were performed to compare the ages of the children at the time of diagnosis (asthma, allergic rhinitis, and/or atopic dermatitis) between the intervention and control CDCC participants. The possible increases in the risks of developing atopic dermatitis, allergic rhinitis, and asthma were evaluated according to diagnoses made by a physician or to corresponding self-reported symptoms after the hygiene intervention by calculating relative risks with 95% confidence intervals between the hygiene intervention and control groups. Ages at the time of diagnosis of asthma, allergic rhinitis, or atopic dermatitis were compared between the intervention and control participants with cumulative hazard curves and log-rank test. The data were analyzed using SPSS for Windows, version 12.0 (SPSS, Inc, Chicago, Illinois). Those who replied to the questionnaire differed from those who did not reply in having a higher average level of parental education, less parental smoking, more episodes of acute otitis media, and more days receiving antimicrobial agents when they were younger than 2 years. Most importantly, however, the intervention respondents and nonrespondents and control respondents and nonrespondents did not differ in their background demographic data (Table 1). Thus, the subjects who responded were representative of their initial group. Results Asthma was diagnosed by a physician in 48 of the 481 respondents (10%) from the intervention CDCCs, with markedly fewer infections, and 46 of the 447 controls (10%), with no reduction in the infections (relative risk, 1.0; 95% confidence interval, 0.7-1.4). Similarly, there were no differences in the numbers who had developed allergic rhinitis or atopic dermatitis as diagnosed by a physician or who had reported asthma, allergic rhinitis, or atopic dermatitis symptoms (Table 2). There were no significant differences in the background data between the respondents who had been randomly assigned to the intervention and control CDCCs with regard to their family history of atopic diseases, duration of breastfeeding, or numbers of siblings (Table 3). Table 2. View LargeDownload Occurrence of Atopic Diseases in the Populationa Table 3. View LargeDownload Background Characteristics of Respondents to the Follow-up Questionnaire in 2003a The mean (SD) ages at the time of diagnosis of asthma were 7.2 (4.0) years in the intervention group and 7.5 (4.3) years in the control group (Figure 2), those for the onset of atopic dermatitis were 1.8 (0.8) years in the intervention group and 1.8 (0.9) years in the control group, and those for the onset of seasonal allergic rhinitis were 8.2 (3.8) years in the intervention group and 8.4 (3.7) years in the control group. Figure 2. View LargeDownload Survival analysis of age at diagnosis of asthma in the intervention and control child day care centers. Comment These results indicate that the successful prevention of respiratory tract and enteric infections during early childhood does not increase later allergic morbidity. No differences were found here in the development or clinical course of asthma, allergic rhinitis, or atopic dermatitis in adolescence between those who had fewer infections and those who had experienced markedly more infections. The magnitude of the reduction in infections and the duration of the intervention in our randomized hygiene intervention trial should have led to an increase in asthma rates if the hygiene hypothesis were to apply to common childhood infections. The mean annual number of acute respiratory tract illnesses in children aged 0 to 4 years has been found to be 4.9 in an 11-year community survey.20 Child day care increases the risk of common colds as compared with children cared for at home by approximately 70% in the 1-year age group and by 10% in the 3-year age group.21 Overall, the risk of acute otitis media in day care is 2.5 relative to home care.22 Our infection prevention program succeeded in reducing infectious morbidity significantly, even though it was not reduced to the home care level. For the intervention group as compared with the control group, the number of days spent with any infection symptom was 16% fewer, the diagnoses of otitis media were 27% fewer, and prescriptions for antimicrobials were 24% fewer.17 As our intervention lasted 15 months, we believe that this duration would have been long enough to show at least some effect on the occurrence of asthma, but this was not seen. The response rate for the follow-up questionnaire was 68%, ie, about two-thirds of the former participants responded. We were able to evaluate possible differences between the respondents and nonrespondents using the background data collected 12 years earlier showing that the respondents had higher levels of parental education and more days receiving antimicrobial agents when they were younger than 2 years than the nonrespondents. Most importantly, however, the intervention and control respondents and nonrespondents did not differ in their background characteristics. Thus, it is unlikely that data from those not responding would have changed our results. The association between asthma and respiratory tract infections is difficult to analyze because asthma itself may cause symptoms such as cough and rattly chest that resemble viral respiratory tract infections.23 On the other hand, the symptoms of rhinoviral infections, the most common cause of respiratory tract infection, are often markedly different among individuals with normal airway reactivity and those with hyperreactive airways.20,24-26 Therefore, the viral respiratory tract disease of an individual with asthma is more likely to be prolonged or to be classified as a lower respiratory tract infection than an upper respiratory tract infection. This kind of misclassification bias is well demonstrated by Illi et al,4 who reported that the number of upper respiratory tract infections in infancy was associated with a decreased risk of asthma at age 7 years, whereas the number of lower respiratory tract infections was associated with an increased risk of asthma. Thus, when infections of the upper and lower respiratory tract are added together, the association with asthma disappears.4 A similar misclassification bias is a possible explanation for the finding of an association between antibiotic exposure and an increased risk of developing allergic disease,27 as the prolonged and more severe lower respiratory tract infections are more easily treated with antimicrobials. These differences in the clinical courses of viral respiratory tract infections in individuals with and without asthma can easily lead to different treatments and clinical diagnoses, resulting in misclassification biases in observational surveys aimed at evaluating the association of allergic diseases with infections.9 Reporting bias is another effect that may confound observational surveys of infections and asthma. As children with airway hyperreactivity may have symptoms leading to visits to health care centers more often than healthy children with the same viral infections, their infectious episodes will be recalled and reported more exactly. Accordingly, Nystad et al28 found recurrent infections to be mediators of a risk of asthma in early childhood. One cannot rule out the possibility of reporting bias in their survey, however. In the observational study by Ball et al,5 attendance at day care during the first 6 months of life protected against the development of asthma, as did the presence of 1 or more older siblings at home. Attendance at day care during the first 6 months of life is rare in Finland because of the long maternity and paternity leave, and the youngest children attend day care at 9 to 12 months of age. Children have only a few infections while being cared for at home and start to have numerous infections immediately after beginning to attend a CDCC. In our study population, the mean age of those attending CDCCs was 3.3 years. In this age group, a reduction in the rates of common infections had no effect on atopic diseases 12 years later. We have shown that a reduction in infections in children attending CDCCs can be achieved by simple infection prevention practices.17 This reduction in morbidity has a great impact on the quality of life in families with small children, and at the same time it reduces the economic burden. We can now say that it proved to be safe because it had no effect on later atopic morbidity.29 Our results are comparable to those of 2 recent cohort studies27,30 that show no inverse association between the numbers of infection episodes and the occurrence of atopic diseases later in childhood. Conclusions Our analysis of the association of asthma, allergic rhinitis, and atopic dermatitis with infections in the randomized study design enabled us to avoid both misclassification and reporting biases. In these analyses, changes in the occurrence of respiratory and gastrointestinal tract infections did not affect the development of allergic disorders. Our findings do not support the original hygiene hypothesis. Back to top Article Information Correspondence: Teija Dunder, MD, Department of Pediatrics, University of Oulu, PO Box 5000, FIN-90014 Oulu, Finland (teija.dunder@oulu.fi). Accepted for Publication: April 29, 2007. Author Contributions:Study concept and design: Dunder, Tapiainen, and Uhari. Acquisition of data: Dunder, Tapiainen, and Uhari. Analysis and interpretation of data: Dunder, Tapiainen, Pokka, and Uhari. Drafting of the manuscript: Dunder, Pokka, and Uhari. Critical revision of the manuscript for important intellectual content: Dunder, Tapiainen, and Uhari. Statistical analysis: Dunder, Pokka, and Uhari. Obtained funding: Uhari. Administrative, technical, and material support: Dunder, Tapiainen, and Uhari. Study supervision: Uhari. Financial Disclosure: None reported. Funding/Support: This study was supported in part by a grant from the Päivikki and Sakari Sohlberg Foundation and the Department of Paediatrics and Adolescence, Oulu University Hospital, Oulu, Finland. References 1. Strachan DP Hay fever, hygiene, and household size. BMJ 1989;299 (6710) 1259- 1260PubMedGoogle ScholarCrossref 2. Lewis SABritton JR Measles infection, measles vaccination and the effect of birth order in the aetiology of hay fever. Clin Exp Allergy 1998;28 (12) 1493- 1500PubMedGoogle ScholarCrossref 3. Matricardi PMRosmini FRiondino S et al. Exposure to foodborne and orofecal microbes vs airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 2000;320 (7232) 412- 417PubMedGoogle ScholarCrossref 4. Illi Svon Mutius ELau S et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 2001;322 (7283) 390- 395PubMedGoogle ScholarCrossref 5. Ball TMCastro-Rodriguez JAGriffith KAHolberg CJMartinez FDWright AL Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 2000;343 (8) 538- 543PubMedGoogle ScholarCrossref 6. Celedon JCWright RJLitonjua AA et al. Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am J Respir Crit Care Med 2003;167 (9) 1239- 1243PubMedGoogle ScholarCrossref 7. Krämer UHeinrich JWjst MWichmann HE Age of entry to day nursery and allergy in later childhood. Lancet 1999;353 (9151) 450- 454PubMedGoogle ScholarCrossref 8. Yabuhara AMacaubas CPrescott SL et al. TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood. Clin Exp Allergy 1997;27 (11) 1261- 1269PubMedGoogle ScholarCrossref 9. van Schayck CPKnottnerus JA Can the “hygiene hypothesis” be explained by confounding by behavior? J Clin Epidemiol 2004;57 (5) 435- 437PubMedGoogle ScholarCrossref 10. Prescott SLMacaubas CSmallacombe THolt BJSly PDHolt PG Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999;353 (9148) 196- 200PubMedGoogle ScholarCrossref 11. Fujimura TYamanashi RMasuzawa M et al. Conversion of the CD4+ T cell profile from T(H2)-dominant type to T(H1)-dominant type after varicella-zoster virus infection in atopic dermatitis. J Allergy Clin Immunol 1997;100 (2) 274- 282PubMedGoogle ScholarCrossref 12. Tulić MKWale JLHolt PGSly PD Modification of the inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Biol 2000;22 (5) 604- 612PubMedGoogle ScholarCrossref 13. Ishimitsu RNishimura HYajima TWatase TKawauchi HYoshikai Y Overexpression of IL-15 in vivo enhances Tc1 response, which inhibits allergic inflammation in a murine model of asthma. J Immunol 2001;166 (3) 1991- 2001PubMedGoogle ScholarCrossref 14. Cho SHStanciu LABegishivili TBates PJHolgate STJohnston SL Peripheral blood CD4+ and CD8+ T cell type 1 and type 2 cytokine production in atopic asthmatic and normal subjects. Clin Exp Allergy 2002;32 (3) 427- 433PubMedGoogle ScholarCrossref 15. de Jong ECVieira PLKalinski P et al. Microbial compounds selectively induce Th1 cell-promoting or Th2 cell-promoting dendritic cells in vitro with diverse Th cell-polarizing signals. J Immunol 2002;168 (4) 1704- 1709PubMedGoogle ScholarCrossref 16. Netea MGVan der Meer JWSutmuller RPAdema GJKullberg BJ From the Th1/Th2 paradigm towards a Toll-like receptor/T-helper bias. Antimicrob Agents Chemother 2005;49 (10) 3991- 3996PubMedGoogle ScholarCrossref 17. Uhari MMöttönen M An open randomized controlled trial of infection prevention in child day-care centers. Pediatr Infect Dis J 1999;18 (8) 672- 677PubMedGoogle ScholarCrossref 18. Asher MIKeil UAnderson HR et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8 (3) 483- 491PubMedGoogle ScholarCrossref 19. Armitage PBerry GMatthews JNS Statistical Methods in Medical Research. 4th ed. Malden, MA Blackwell Science2002; 20. Monto ASSullivan KM Acute respiratory illness in the community: frequency of illness and the agents involved. Epidemiol Infect 1993;110 (1) 145- 160PubMedGoogle ScholarCrossref 21. Louhiala PJJaakkola NRuotsalainen RJaakkola JJ Form of day care and respiratory infections among Finnish children. Am J Public Health 1995;85 (8, pt 1) 1109- 1112PubMedGoogle ScholarCrossref 22. Uhari MMäntysaari KNiemelä M A meta-analytic review of the risk factors for acute otitis media. Clin Infect Dis 1996;22 (6) 1079- 1083PubMedGoogle ScholarCrossref 23. Seear MWensley D Chronic cough and wheeze in children: do they all have asthma? Eur Respir J 1997;10 (2) 342- 345PubMedGoogle ScholarCrossref 24. Johnston SLPattemore PKSanderson G et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med 1996;154 (3, pt 1) 654- 660PubMedGoogle ScholarCrossref 25. Skoner DPDoyle WJSeroky JVan Deusen MAFireman P Lower airway responses to rhinovirus 39 in healthy allergic and nonallergic subjects. Eur Respir J 1996;9 (7) 1402- 1406PubMedGoogle ScholarCrossref 26. Kotaniemi-Syrjänen AVainionpää RReijonen TMWaris MKorhonen KKorppi M Rhinovirus-induced wheezing in infancy: the first sign of childhood asthma? J Allergy Clin Immunol 2003;111 (1) 66- 71PubMedGoogle ScholarCrossref 27. McKeever TMLewis SASmith C et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. J Allergy Clin Immunol 2002;109 (1) 43- 50PubMedGoogle ScholarCrossref 28. Nystad WSkrondal AMagnus P Day care attendance, recurrent respiratory tract infections and asthma. Int J Epidemiol 1999;28 (5) 882- 887PubMedGoogle ScholarCrossref 29. Bell DMGleiber DWMercer AA et al. Illness associated with child day care: a study of incidence and cost. Am J Public Health 1989;79 (4) 479- 484PubMedGoogle ScholarCrossref 30. Benn CSMelbye MWohlfahrt JBjörkstén BAaby P Cohort study of sibling effect, infectious diseases, and risk of atopic dermatitis during first 18 months of life. BMJ 2004;328 (7450) 1223PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Pediatrics and Adolescent Medicine American Medical Association

Infections in Child Day Care Centers and Later Development of Asthma, Allergic Rhinitis, and Atopic Dermatitis: Prospective Follow-up Survey 12 Years After Controlled Randomized Hygiene Intervention

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Publisher
American Medical Association
Copyright
Copyright © 2007 American Medical Association. All Rights Reserved.
ISSN
1072-4710
DOI
10.1001/archpedi.161.10.972
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17909141
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Abstract

Abstract Objective To evaluate the effect of successful prevention of common infections in child day care centers on the later development of allergic diseases. Design Prospective follow-up survey with a questionnaire administered 12 years after a controlled randomized hygiene intervention. Setting Twenty municipal child day care centers in Oulu, Finland. Participants A questionnaire was sent to 1354 prior participants (98%) in the intervention trial. The response rate was 68% (928 of 1354 participants). Main Intervention Hygiene intervention from March 1, 1991, to May 31, 1992. Main Outcome Measures The number of respondents who had a diagnosis of asthma, allergic rhinitis, and/or atopic dermatitis made by a physician, and the number of those who reported symptoms of atopic diseases. Results Asthma was diagnosed by a physician in 48 of the 481 respondents (10%) from the intervention child day care centers, with markedly fewer infections, and in 46 of the 447 controls (10%) (relative risk, 1.0; 95% confidence interval, 0.7-1.4). Similarly, no differences were found in the numbers of children who had a diagnosis of other atopic diseases or who had reported such symptoms. Conclusion The prevention of common respiratory tract and enteric infections during early childhood does not change later allergic morbidity. In 1989 Strachan1 introduced the hygiene hypothesis, which postulates that the inverse association between the number of siblings in the family and hay fever at ages 11 and 23 years noted in a British cohort was due to the protective effect of specific environmental factors such as infections in infancy. Since then, numerous observational surveys have been published, only some of them supporting this inverse association between infections and allergic disorders.2-8 Even though the association has not been found in all surveys, reports with a positive finding have gained almost universal acceptance.9 At the same time these clinical observations were made, it was found that a dominance of helper T type 2 (TH2) subsets of CD4 T lymphocytes promotes allergic disorders10 and that infections can shift this TH2 dominance to TH1 dominance.11 In experimental models, microbial compounds were found to modify allergic inflammation and it was concluded that the shift toward TH1 dominance could prevent the development of allergic disorders.12 Along with these developments in the theoretical immunological background, interest in the hygiene hypothesis increased markedly. Our immunological knowledge has widened rapidly in recent years, however. It has been learned, for example, that CD8 T lymphocytes have subpopulations (cytotoxic T type 1 cells [TC1] and cytotoxic T type 2 cells [TC2]) that inhibit either TH1 (by TC2) or TH2 (by TC1) cells, making the immunological explanation behind the hygiene hypothesis much more complex.13,14 Furthermore, it has been learned that the specific TH1 and TH2 polarization caused by infection is a diverse phenomenon regulated by the signaling Toll-like receptors and varies with the type of microbe.15,16 Observational surveys serve as a source of hypotheses that should then be tested in controlled randomized intervention trials to properly control for confounding factors.9 Nevertheless, there are many hypotheses in clinical medicine that cannot be tested in this way, such as effects of smoking and breastfeeding. Similarly, it is not feasible to induce infections in a randomized manner to evaluate the development of allergic disorders. It is possible, however, to evaluate the prevention of infections in a randomized controlled trial. We conducted a randomized hygiene intervention trial lasting 15 months from March 1, 1991, to May 31, 1992, at child day care centers (CDCCs), where we succeeded in reducing infections.17 The number of days with rhinitis was reduced by 17%, cough by 11%, and diarrhea by 18%. Still more importantly, there were 27% fewer episodes of acute otitis media and the number of days receiving antimicrobials was 24% fewer among those who attended the intervention CDCCs. We hypothesized that if the hygiene hypothesis applies to either common viral or bacterial respiratory tract and enteric infections in childhood, there should be more atopic diseases among those who had attended the intervention CDCCs in our earlier trial than among those who had attended the control CDCCs. Thus, we conducted a follow-up survey 12 years after the randomized hygiene intervention to compare the development of atopic dermatitis, allergic rhinitis, and asthma between these 2 groups of adolescents. Methods Study design Altogether, 1376 children had participated in the hygiene intervention trial in 1991 and had been in the follow-up for at least 2 months. Details of the infection prevention program and its implementation have been published.17 In brief, the hygiene intervention was conducted in 10 CDCCs, while 10 other randomly allocated centers matched with them for size and geographical location served as controls. The basic background data of the study population were collected in both 1991 and 2003. The intervention included several steps, of which the most important was the improvement of hand hygiene by the use of an alcohol-based hand rub. In 2003, we sent a questionnaire to 1354 adolescents and their families. Altogether, 708 of them had participated in the infection prevention program and 646 had served as controls. Replies were received from 928 participants (68%), including 481 who had attended intervention CDCCs and 447 who had attended control CDCCs (Figure 1). The questionnaire was the same as that used in the International Study of Allergy and Asthma,18 but we added questions on day care, breastfeeding, number of siblings, occurrence of otitis media, food allergy, family histories of atopy and asthma, pets, and smoking at home. The ethical committee of Oulu University Hospital found the protocol ethically acceptable. Figure 1. View LargeDownload Study profile. CDCC indicates child day care center. Statistical analysis The differences between those who responded and those who did not respond to the questionnaire were tested with either χ2 test (number of nonsmoking and smoking mothers and fathers and number of mothers and fathers with basic or higher education) or t test. We used t test for parametric variables (mean age of attendance in CDCC, mean duration of exclusive breastfeeding, mean number of episodes of acute otitis media, and mean number of days receiving antimicrobials). Univariate analysis of variance was used to test interaction in parametric variables of background data (mean age of attendance in CDCC at the beginning of the intervention, mean duration of exclusive breastfeeding, mean number of episodes of acute otitis media, and mean number of days receiving antimicrobials) between subjects assigned to the intervention and control CDCCs and whether they replied to the questionnaire in 2003. In this analysis, the differences between the proportions of nonsmoking and smoking mothers as well as nonsmoking and smoking fathers were tested with the standard normal deviate test.19 The differences between proportions of mothers and fathers with basic or upper secondary degree education and mothers and fathers with higher education were tested likewise (Table 1). Table 1. View LargeDownload Demographic Data on Subjects Assigned to the Intervention and Control Child Day Care Centers in 1991 and 1992 Grouped According to Whether They Replied to the Questionnaire in 2003 The primary outcome measure was the number of respondents who had a diagnosis of asthma, allergic rhinitis, and/or atopic dermatitis made by a physician, backed up by a corresponding analysis of self-reported symptoms. Separate analyses were performed to compare the ages of the children at the time of diagnosis (asthma, allergic rhinitis, and/or atopic dermatitis) between the intervention and control CDCC participants. The possible increases in the risks of developing atopic dermatitis, allergic rhinitis, and asthma were evaluated according to diagnoses made by a physician or to corresponding self-reported symptoms after the hygiene intervention by calculating relative risks with 95% confidence intervals between the hygiene intervention and control groups. Ages at the time of diagnosis of asthma, allergic rhinitis, or atopic dermatitis were compared between the intervention and control participants with cumulative hazard curves and log-rank test. The data were analyzed using SPSS for Windows, version 12.0 (SPSS, Inc, Chicago, Illinois). Those who replied to the questionnaire differed from those who did not reply in having a higher average level of parental education, less parental smoking, more episodes of acute otitis media, and more days receiving antimicrobial agents when they were younger than 2 years. Most importantly, however, the intervention respondents and nonrespondents and control respondents and nonrespondents did not differ in their background demographic data (Table 1). Thus, the subjects who responded were representative of their initial group. Results Asthma was diagnosed by a physician in 48 of the 481 respondents (10%) from the intervention CDCCs, with markedly fewer infections, and 46 of the 447 controls (10%), with no reduction in the infections (relative risk, 1.0; 95% confidence interval, 0.7-1.4). Similarly, there were no differences in the numbers who had developed allergic rhinitis or atopic dermatitis as diagnosed by a physician or who had reported asthma, allergic rhinitis, or atopic dermatitis symptoms (Table 2). There were no significant differences in the background data between the respondents who had been randomly assigned to the intervention and control CDCCs with regard to their family history of atopic diseases, duration of breastfeeding, or numbers of siblings (Table 3). Table 2. View LargeDownload Occurrence of Atopic Diseases in the Populationa Table 3. View LargeDownload Background Characteristics of Respondents to the Follow-up Questionnaire in 2003a The mean (SD) ages at the time of diagnosis of asthma were 7.2 (4.0) years in the intervention group and 7.5 (4.3) years in the control group (Figure 2), those for the onset of atopic dermatitis were 1.8 (0.8) years in the intervention group and 1.8 (0.9) years in the control group, and those for the onset of seasonal allergic rhinitis were 8.2 (3.8) years in the intervention group and 8.4 (3.7) years in the control group. Figure 2. View LargeDownload Survival analysis of age at diagnosis of asthma in the intervention and control child day care centers. Comment These results indicate that the successful prevention of respiratory tract and enteric infections during early childhood does not increase later allergic morbidity. No differences were found here in the development or clinical course of asthma, allergic rhinitis, or atopic dermatitis in adolescence between those who had fewer infections and those who had experienced markedly more infections. The magnitude of the reduction in infections and the duration of the intervention in our randomized hygiene intervention trial should have led to an increase in asthma rates if the hygiene hypothesis were to apply to common childhood infections. The mean annual number of acute respiratory tract illnesses in children aged 0 to 4 years has been found to be 4.9 in an 11-year community survey.20 Child day care increases the risk of common colds as compared with children cared for at home by approximately 70% in the 1-year age group and by 10% in the 3-year age group.21 Overall, the risk of acute otitis media in day care is 2.5 relative to home care.22 Our infection prevention program succeeded in reducing infectious morbidity significantly, even though it was not reduced to the home care level. For the intervention group as compared with the control group, the number of days spent with any infection symptom was 16% fewer, the diagnoses of otitis media were 27% fewer, and prescriptions for antimicrobials were 24% fewer.17 As our intervention lasted 15 months, we believe that this duration would have been long enough to show at least some effect on the occurrence of asthma, but this was not seen. The response rate for the follow-up questionnaire was 68%, ie, about two-thirds of the former participants responded. We were able to evaluate possible differences between the respondents and nonrespondents using the background data collected 12 years earlier showing that the respondents had higher levels of parental education and more days receiving antimicrobial agents when they were younger than 2 years than the nonrespondents. Most importantly, however, the intervention and control respondents and nonrespondents did not differ in their background characteristics. Thus, it is unlikely that data from those not responding would have changed our results. The association between asthma and respiratory tract infections is difficult to analyze because asthma itself may cause symptoms such as cough and rattly chest that resemble viral respiratory tract infections.23 On the other hand, the symptoms of rhinoviral infections, the most common cause of respiratory tract infection, are often markedly different among individuals with normal airway reactivity and those with hyperreactive airways.20,24-26 Therefore, the viral respiratory tract disease of an individual with asthma is more likely to be prolonged or to be classified as a lower respiratory tract infection than an upper respiratory tract infection. This kind of misclassification bias is well demonstrated by Illi et al,4 who reported that the number of upper respiratory tract infections in infancy was associated with a decreased risk of asthma at age 7 years, whereas the number of lower respiratory tract infections was associated with an increased risk of asthma. Thus, when infections of the upper and lower respiratory tract are added together, the association with asthma disappears.4 A similar misclassification bias is a possible explanation for the finding of an association between antibiotic exposure and an increased risk of developing allergic disease,27 as the prolonged and more severe lower respiratory tract infections are more easily treated with antimicrobials. These differences in the clinical courses of viral respiratory tract infections in individuals with and without asthma can easily lead to different treatments and clinical diagnoses, resulting in misclassification biases in observational surveys aimed at evaluating the association of allergic diseases with infections.9 Reporting bias is another effect that may confound observational surveys of infections and asthma. As children with airway hyperreactivity may have symptoms leading to visits to health care centers more often than healthy children with the same viral infections, their infectious episodes will be recalled and reported more exactly. Accordingly, Nystad et al28 found recurrent infections to be mediators of a risk of asthma in early childhood. One cannot rule out the possibility of reporting bias in their survey, however. In the observational study by Ball et al,5 attendance at day care during the first 6 months of life protected against the development of asthma, as did the presence of 1 or more older siblings at home. Attendance at day care during the first 6 months of life is rare in Finland because of the long maternity and paternity leave, and the youngest children attend day care at 9 to 12 months of age. Children have only a few infections while being cared for at home and start to have numerous infections immediately after beginning to attend a CDCC. In our study population, the mean age of those attending CDCCs was 3.3 years. In this age group, a reduction in the rates of common infections had no effect on atopic diseases 12 years later. We have shown that a reduction in infections in children attending CDCCs can be achieved by simple infection prevention practices.17 This reduction in morbidity has a great impact on the quality of life in families with small children, and at the same time it reduces the economic burden. We can now say that it proved to be safe because it had no effect on later atopic morbidity.29 Our results are comparable to those of 2 recent cohort studies27,30 that show no inverse association between the numbers of infection episodes and the occurrence of atopic diseases later in childhood. Conclusions Our analysis of the association of asthma, allergic rhinitis, and atopic dermatitis with infections in the randomized study design enabled us to avoid both misclassification and reporting biases. In these analyses, changes in the occurrence of respiratory and gastrointestinal tract infections did not affect the development of allergic disorders. Our findings do not support the original hygiene hypothesis. Back to top Article Information Correspondence: Teija Dunder, MD, Department of Pediatrics, University of Oulu, PO Box 5000, FIN-90014 Oulu, Finland (teija.dunder@oulu.fi). Accepted for Publication: April 29, 2007. Author Contributions:Study concept and design: Dunder, Tapiainen, and Uhari. Acquisition of data: Dunder, Tapiainen, and Uhari. Analysis and interpretation of data: Dunder, Tapiainen, Pokka, and Uhari. Drafting of the manuscript: Dunder, Pokka, and Uhari. Critical revision of the manuscript for important intellectual content: Dunder, Tapiainen, and Uhari. Statistical analysis: Dunder, Pokka, and Uhari. Obtained funding: Uhari. Administrative, technical, and material support: Dunder, Tapiainen, and Uhari. Study supervision: Uhari. 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Journal

Archives of Pediatrics and Adolescent Medicine – American Medical Association

Published: Oct 1, 2007

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