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Early Respiratory Infections, Asthma, and Allergy: 10-Year Follow-up of the Oslo Birth Cohort

Per Nafstad, MD, PhD^*,, Bert Brunekreef, PhD^,, Anders Skrondal, PhD and Wenche Nystad, PhD

^* Department of General Practice and Community Medicine, Medical Faculty, University of Oslo, Oslo, Norway
Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, Netherlands

	ABSTRACT

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Objective. It has been hypothesized that early infections protect against the development of atopic disease, but there have been few long-term follow-up studies. We estimated the associations between early respiratory infections and doctor-diagnosed asthma, allergic rhinitis, and skin-prick sensitization in children at 10 years of age in the Oslo Birth Cohort, established in 1992–1993. We also considered birth order and attendance at a child care center as proxy measures of increased exposure to infections early in life.

Methods. A total of 2540 children were followed from birth to the age of 10 years. Experiences of respiratory infections were recorded in follow-up surveys at 6 and 12 months. At age 10, questions were asked about current symptoms of asthma and allergic rhinitis and about having ever received a doctor diagnosis for these diseases. A subsample (n = 1740) of the cohort was tested for skin-prick test reactivity.

Results. Current asthma was related to lower respiratory tract infection (adjusted odds ratio [OR]: 2.1; 95% confidence interval: 1.3–3.0) and croup (adjusted OR: 2.3; 95% confidence interval: 1.3–4.2) in the first year. ORs for allergic rhinitis and skin-prick sensitization were smaller but mainly positive. Birth order and child care attendance at age 1 year were not significantly associated with any of the studied outcomes.

Conclusions. Early respiratory infections did not protect against the development of asthma, allergic rhinitis, or sensitization to common allergens during the first 10 years of life but increased the risk for asthma symptoms at age 10 in this population.

Key Words: children • epidemiology • asthma • allergy • cohort study

Abbreviations: SPT, skin prick test • ETS, environmental tobacco smoke • OR, odds ratio • CI, confidence interval

Having older siblings has been found to be inversely associated with asthma and other atopy-related disorders.^1–6 Some studies have also shown that these disorders are inversely associated with child care attendance outside the home,^6–10 whereas other studies have not been able to confirm these findings.^11–13 A common interpretation of these results has been that older siblings and child care attendance are indirect measures of early-life infections and that early-life infections have a preventive effect on the development of atopic disorders. A number of studies have also assessed the relation between atopic disorders and direct measures of early-life infections,^11,13–23 but fewer have been able to do this prospectively.^{13–15,18–22} Studies that have used direct measures of infections have shown less consistent results than the studies that have used indirect measures, and the inverse relation has often been restricted to subgroups of diseased individuals, mainly those with atopic predisposition. Furthermore, childhood asthma has been found to be more common in children who experienced at least 1 specific type of early respiratory infection, namely respiratory syncytial virus infection.^24–27 The inverse relation between early-life infections and the development of atopic disorders is supported by a plausible biological mechanism, according to which early-life infections stimulate Th1 lymphocytes that may inhibit the proliferation of allergen-specific Th2 lymphocytes and limit the development of allergic diseases.^28,29 Although childhood asthma is considered predominantly an allergic disease, a substantial proportion of children with asthma are not sensitized to common allergens.^17,30 This indicates that there are other mechanisms that could be involved in the development of asthma.^31,32 We used the Oslo Birth Cohort Study to address prospectively the role of several types of early respiratory infections in the development of asthma and allergic rhinitis during the first 10 years of life. We considered both actual infections and factors that are considered as indicators of infectious exposure. We also assessed these factors' association with skin-prick test (SPT) positivity and whether the association between early-life infections and asthma/allergic rhinitis was dependent on children's SPT positivity.

	METHODS

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Study Population
The source population included children who were born in the 2 main birth clinics in Oslo during a 15-month period in 1992–1993, the Oslo Birth Cohort.³³ At birth, 3754 children were included in the study, and information on the child's health and environmental exposures was collected from parents by questionnaires at birth and when the child was 0.5, 1, 1.5, 2, 4, and 10 years of age. The eligibility criteria and data-collection procedures during the first 2 years of life and at the age of 4 years have been described in detail elsewhere.^13,33,34 During 2001–2002, we conducted a 10-year follow-up. A similar questionnaire to that used in the 4-year follow-up was mailed to the parents of the children for whom we succeeded to get a correct mailing address (n = 3529). A completed questionnaire was received from 2549 children (72% of those successfully reached by mail). The participants who were living in Oslo or in the vicinity of Oslo (Akershus County) in 2001 (n = 2846) were also invited to participate in a clinical examination. A mobile unit of trained research nurses visited all schools in the area and conducted the examination, which included SPTs, spirometry, and collection of buccal cells for DNA extraction. Of all invited children, 1815 (64%) were examined, and 1740 received a SPT. For safety reasons, children who reported any kind of severe allergic reactions (n = 43) did not receive SPT. Furthermore, 32 children refused to be tested because of anxiety. In the present study, we focused on children with complete information on asthma and other atopic diseases at the age of 10 years. This left 2540 children for the analyses. We also performed analyses of the subsample of children who had received SPT.

Health Outcomes
The primary outcomes were ever and current asthma and allergic rhinitis (allergy from the nose or eyes including hay fever). These outcomes were defined on the basis of answers to the 10-year follow-up questionnaire, and the questions were asked in the same manner as in the 4-year follow-up.¹³ The outcomes had to be diagnosed by a physician, and current disease meant that the child had experienced symptoms of the disease during the previous 12 months.

SPT Positivity
The SPTs were performed according the ISAAC phase II protocols.³⁵ The following standardized allergens were included: cat, dog, birch, grass (timothy), house dust mite (Dermatophagoides pteronyssinus and Dermatophagoides farinae), molds (Cladosporium herbarum and Alternaria tenuis), codfish, and horse (Soluprick SQ; ALK Laboratories, Hørsholm, Denmark). All of the allergens were Soluprick 10 HEP, except for Cladosporium herbarum and Alternaria, which were presented in a 1:20 dilution. A positive SPT corresponded to a wheal with a mean diameter exceeding the negative control by at least 3 mm.³⁵ Taking into account skin-test reactivity to histamine,³⁶ we also and alternatively defined a positive SPT as an average diameter corresponding to at least half of that caused by histamine. Children with at least 1 positive SPT were considered skin-prick positive.

Exposures
Early Respiratory Infections
The determinants of interest were respiratory infections, such as lower respiratory tract infections, otitis media, and croup, during the first year of life and the common cold during the first 6 months of life. Information on these early respiratory infections was registered in the 6- and 12-month follow-up questionnaires. The same determinants have been used for similar analyses of the data obtained at the 4-year follow-up of the cohort.¹³ Because almost all children had experienced an episode of the common cold during their first 12 months of life, information on the common cold was restricted to their first 6 months of life.

Indirect Measures of Exposure to Infectious Agents
Indirect measures of exposure to infectious agents were attendance to a child care center at the age of 1 year (measured as the number of hours per week in a child care center at the age of 1 year and categorized as 10 hours per week versus <10 hours per week) and having older siblings (measured as birth order when the child was included in the cohort). We did not investigate size of child care facility because, generally, child care centers in Norway were large (>30 children) and small child care centers (eg, home day care) were rarely used.

Covariates
Information on potential confounders was extracted from hospital records and the 6-month and the 1-year questionnaires. The covariates in the present analyses included gender, parental atopy, maternal age at delivery, maternal education, family income, single parenthood, length of breastfeeding, and environmental tobacco smoke (ETS) exposure at birth.³² Parental atopy was defined as a history of maternal or paternal asthma or hay fever. Length of breastfeeding was categorized into 0 to 6 and >6 months. Exposure to ETS was defined as living together with 1 smokers. The categorization of these covariates is presented in Table 1.

	RESULTS

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Table 1 presents the distributions of some characteristics and early exposures of the children at birth and 2, 4, and 10 years of life and among children who received SPT at the age of 10 years. Compared with the baseline registrations, parental income and maternal education were somewhat higher at all of the follow-ups. The distributions of the other variables were very similar for the variables at the different follow-ups. This was also the case for gender, birth weight, and keeping pets at home when the child was 6 months of age (figures not given). Information on asthma and allergic rhinitis was obtained for 2540 of the 2549 children with questionnaire information at the age of 10 years. Of these children, 292 (11.5%) reported ever having received a diagnosis asthma by a doctor, and 142 (5.6%) had experienced symptoms of asthma during the past 12 months. Corresponding figures for allergic rhinitis were 357 (14.1%) and 302 (11.9%). Among the 1740 children with a valid SPT result, 418 (24%) had a positive SPT, 182 (10.5%) had doctor-diagnosed asthma, and 84 (4.9%) had experienced asthma symptoms the past 12 months. In this group, 247 (14.3%) children had a doctor-diagnosed allergic rhinitis, and 207 (12.0.9%) had experienced symptoms the past 12 months (missing information: 12). A positive SPT was found among 51 (61%) of the children with current asthma, whereas 154 (74%) of the children with current allergic rhinitis had a positive SPT.

Tables 2 and 3 present the risk for a lifetime doctor diagnosis of asthma and allergic rhinitis and the risk for current asthma and allergic rhinitis at the age of 10 years in relation to early respiratory infections, birth order, and attendance to child care centers. All measures of early-life infections were positively associated with doctor-diagnosed asthma ever in life. Current asthma was significantly associated with early lower respiratory tract infections and croup; associations with otitis media and common cold were also positive without reaching statistical significance. Similar associations were found when hospitalization for lower respiratory tract infection was used as exposure (figures not given). For allergic rhinitis, the associations in general were weaker but also mainly positive. The association between early-life otitis media and allergic rhinitis was statistically significant.

Associations between SPT positivity and early-life respiratory infections, birth order, and child care attendance were weak (Table 4). This was also the case when positive SPT was defined as at least half the size of the histamine reaction and when reaction to pollen (grass/birch) and furred pets (dog/cat) was used as outcome (figures not shown). Of the children who were not tested because of reports of severe allergic reactions, 47% (20 of 43) had asthma and/or allergic rhinitis. Early respiratory infections and indicators of infections did not reduce the chance of asthma and allergic rhinitis among these children either (figures not given).

	DISCUSSION

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Childhood asthma is a heterogeneous disease, which can start early or late in childhood and be transient or persistent.³⁷ A 4-year follow-up of the Oslo Birth Cohort showed that early-life respiratory infections increased the risk for asthma-like disorders in the first 4 years of life.¹³ Other studies have found that indicators of infections early in life protect against the development of asthma and other allergic diseases, especially in subgroups of high-risk children. Because the diagnosis of asthma notably is more difficult in young children than in older children, we wanted to study the associations between early respiratory infections and having asthma later in childhood and how these infections were related to other atopy-related disorders.

By design, prospective cohort studies such as ours exclude recall bias as an alternative explanation of the positive associations between early-life infections and asthma that we observed, because information on exposures and potential confounders are measured in time before and independent of the disease outcome measurements. Large cohort studies have to use simple and practical data-collection methods, which may lead to some misclassification of both exposures and outcomes. However, this type of misclassification is most likely nondifferential, which will make associations weaker but not change direction. The distributions of the covariates at the different follow-ups and among children who received SPT do not indicate selective losses to follow-up. The subgroup of children who participated in the clinical examinations reported a somewhat higher occurrence of atopic diseases. We do not see reasons for why this should affect the studied associations, besides reducing statistical power and precision of risk estimates. SPT results for the 43 children who reported severe allergic reactions may have influenced the associations among the children who received SPT. However, analyses among these 43 children did not indicate so. Furthermore, <50% of these children had asthma and/or allergic rhinitis, indicating that some families had considered, for instance, adverse drug reactions as severe allergic reactions.

As we found before for asthma at the age of 4 years,¹³ respiratory infections increased the risk for both ever asthma and current asthma at the age of 10 years, and the effect was strongest in children who had experienced >1 type of infection. Associations were strongest for infections that affect the lower parts of the airways, including croup. For the infections that affect the upper part of the respiratory tract, the effect was less clear. This seems reasonable and could indicate that some infections affect the lower part of the airways in a way that increases the risk for developing asthma in the following years. Studies of respiratory syncytial virus infections support this view.³⁸ As for respiratory syncytial virus infections, croup symptoms may indicate hyperreactivity in the airways, including the lower airways, which may explain the association with asthma.^39,40

As in other studies,^14,30 we found that asthma had been diagnosed in a substantial proportion of SPT-negative children. Stratified analyses of SPT-positive and -negative children gave no indication of protective effects of early-life infections in either of the 2 groups. It is interesting that early-life experience of croup seemed to have the strongest effect among SPT-negative children.

If early-life infections have effect on the development of allergy in childhood, then one would expect that this would also be the case for other atopy-related disorders. We therefore analyzed associations with allergic rhinitis at the age of 10 years as well. The overlap between current and ever allergic rhinitis was substantial, which indicates that most children who develop allergic rhinitis before the age of 10 years will continue to have symptoms during childhood. The large overlap resulted in similar associations for both ever and current allergic rhinitis. Most children with reported rhinitis were SPT positive. As for asthma, we did not find protective effects of these early-life infections that could indicate immunologic reactions that reduce the risk for allergy development. Early-life otitis media was positively associated with allergic rhinitis, and the effect seemed to have the strongest impact among SPT-positive children. These findings are somewhat in contrast with other findings, including Norwegian studies based on retrospective reporting of infections, which indicate protective effects on sensitization in subgroups of children with asthma.^41,42 Conversely, several studies have indicated a positive link between allergic rhinitis and otitis media, which is what we found in this study.^43,44 As for asthma, early-life experience of croup seems to increase the risk for allergic rhinitis, especially among nonatopic children.

All ORs between early-life respiratory infections and sensitization to common allergens were near 1, with narrow CIs. Thus, this study does not support the view that early respiratory infections protect against sensitization. In fact, the only borderline significant association that was found was a positive association between SPT positivity and early-life otitis media, which further raises the question of how allergy and otitis media are related.

Neither birth order nor child care attendance at 1 year was significantly associated with any of the health outcomes, which is in contrast with findings from several other studies. The finding of protective effects of having older siblings was in fact important for the development of the hygiene hypothesis.^2,3 Our findings seem to be in contrast with these findings. In fact, there was a tendency that second and higher birth order increased the risk for asthma and allergic rhinitis in SPT-negative children. However, the sibling effect mostly has been found in families with many children. In our cohort, there were few large families. It therefore could be argued that we could not address fully the sibling effect in this study and that we in fact had the advantage of addressing the effects of respiratory infections in a population without a strong sibling effect. Child care attendance outside home seldom starts before the age of 1 year in Norway because of a long and fully paid maternity leave. One thus could argue that this ensures that early child care attendance exposure could not affect the results and that our results express a true relation between early-life respiratory infection and atopy-related diseases. A recent, comprehensive review of the literature has argued that it is inappropriate to equate having older siblings or attending a large child care center with increased exposure to infections, in the absence of more direct measures of exposure to infections or microbial agents such as bacterial endotoxin.⁴⁵

Our results do not support the view that early-life respiratory infections, the most common infections in early childhood, cause immunologic reactions that protect against the development of atopic disease, which is in agreement with recent results from a Dutch cohort study.⁴⁶ The findings are more in support of the view that certain respiratory infections affect the airways in a way that increases the risk for developing asthma and that the effect may be different in atopic and nonatopic children. Apart from lower respiratory infections, we found that croup, which often is caused by parainfluenza viruses, was positively associated with asthma and partly with allergic rhinitis. Similar results were also found in the 4-year follow-up of the cohort as well as in some other studies,^13,39,40,47 and the findings indicate that other infectious agents than respiratory syncytial viruses can cause long-term airway effects. Early-life otitis media was positively associated with allergic rhinitis. We even found a weak relation between allergen sensitization and early-life otitis media. The result raises the question of the role of atopy in the pathogenesis of otitis media and vice versa.

We were unable to address microbial exposure of the developing gut in this study. It has been argued that the type of gastrointestinal flora in early life influences the development of the immune system.⁴⁸ Also, child care center attendance has long been associated with increased incidence of gastrointestinal infections.⁴⁹ Some have suggested that the difference in infection incidence between home child care and attending large child care is restricted to children who are younger than 18 months,⁵⁰ which would be in line with the absence of a child care effect in this study in which few children went into child care before 12 months of age. Nevertheless, our study cannot exclude that infections other than respiratory or microbial load in general influence development of sensitization and atopic disorders later in childhood.

	ACKNOWLEDGMENTS

 
This study was supported with grants from the Norwegian Research Council. The Oslo Birth Cohort was initiated in 1992 by the Norwegian Institute of Public Health in cooperation with Aker and Ullevål University Hospitals.

We thank head physician Per G. Lund-Larsen and his staff at the Norwegian Institute of Public Health for conducting excellent data collection at the 10-year follow-up of the cohort.

	FOOTNOTES

 
Accepted Feb 28, 2005.

Address correspondence to Per Nafstad, MD, PhD, Department of General Practice and Community Medicine, Medical Faculty, University of Oslo, Pb 1130 Blindern, 0316 Oslo, Norway. E-mail: per.nafstad{at}fhi.uio.no

No conflict of interest declared.

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				P. S. Noakes, J. Hale, R. Thomas, C. Lane, S. G. Devadason, and S. L. Prescott Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses Eur. Respir. J., October 1, 2006; 28(4): 721 - 729. [Abstract] [Full Text] [PDF]

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