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American Journal of Epidemiology Advance Access originally published online on March 15, 2008
American Journal of Epidemiology 2008 167(10):1182-1187; doi:10.1093/aje/kwn042
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American Journal of Epidemiology © 2008 The Authors
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ORIGINAL CONTRIBUTIONS

Eczema, Birth Order, and Infection

Ann Maree Hughes, Simon Crouch, Tracy Lightfoot, Pat Ansell, Jill Simpson and Eve Roman

From the Epidemiology and Genetics Unit, Department of Health Sciences, University of York, Heslington, York, United Kingdom

Correspondence to Dr. Eve Roman, Epidemiology and Genetics Unit, Department of Health Sciences, Seebohm Rowntree Building (Area 3), University of York, Heslington, York YO10 5DD, United Kingdom (e-mail: er18{at}york.ac.uk).

Received for publication September 7, 2007. Accepted for publication February 6, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The association between infections occurring in the first 2 years of life and development of eczema was investigated in 1,782 control children from a national population-based case-control study in the United Kingdom conducted over the period 1991–1996. Dates of eczema and infectious diagnoses were ascertained from contemporaneously collected primary care records. Children diagnosed with eczema before the age of 2 years had more prior clinically diagnosed infections recorded than did children without eczema (rate ratio = 1.26, 95% confidence interval (CI): 1.18, 1.36). The difference in infection rates between children with and without eczema was apparent from birth and throughout the first 2 years of life. As expected, compared with children of second or higher birth order, those firstborn were at increased risk of eczema (p = 0.020); however, the relation between eczema and prior infection was evident only among children of second or higher birth order and not among firstborn children (rate ratio = 1.45, 95% CI: 1.32, 1.59, and rate ratio = 1.08, 95% CI: 0.98, 1.20, respectively). The authors' results are consistent with the notion that the association between birth order and eczema is unlikely to be attributable to variations in early infectious exposure.

birth order; child; eczema; hygiene; infection

Abbreviations: CI, confidence interval; GP, general practitioner; ICD-10, International Classification of Diseases, Tenth Revision; UKCCS, United Kingdom Childhood Cancer Study


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Against a background of apparent increasing allergy prevalence in developed countries, the "hygiene hypothesis" arose from the observations that allergic disease was less common in children from larger families and in those with older siblings (1, 2). Since then, the potential etiologic role of microbial exposure in infancy and subsequent allergy development has been the focus of several reports (3, 4). Underpinned by atopic sensitization studies (5, 6), there is now a substantial body of evidence supporting the inverse relation between birth order and allergic disease (7–10). At the same time, however, increased frequencies of infectious illness (11–16) and increased levels of breastfeeding (17–19) have both been associated with increased risks of allergy in later life.

With a view to shedding light on these apparently conflicting observations, we used data from United Kingdom primary care records collected as part of a national population-based case-control study (20–22) to examine the relation between clinically diagnosed infections and eczema in early life. We chose eczema as the marker of allergy for the current analyses as it is the earliest manifestation of atopic disease, typically presenting in the first 2 years.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The study population is composed of control children from the United Kingdom Childhood Cancer Study (UKCCS) who had their primary care medical records abstracted. The methods used by this national population-based case-control study, designed to examine cancers in children under 15 years of age diagnosed between 1991 and 1996, have been described in detail elsewhere (20). As part of the UKCCS, data on all primary care contacts from birth to "pseudodiagnosis" (corresponding to the date of diagnosis of their matched cancer case) were obtained for 2,393 controls (21). Overall, the average number of years of follow-up from birth to pseudodiagnosis was 6.0 years, reflecting the average age of childhood cancer diagnosis.

Information abstracted from primary care records included all visits to a general practitioner (GP) or practice nurse, referrals to hospital consultants and other specialists, dates of individual events, results of tests and investigations, and details relating to prescribed medicines and other treatments. Symptoms and diagnoses were coded by use of the International Classification of Diseases, Tenth Revision (ICD-10) (23). Data on livebirth order and breastfeeding history were obtained from mothers at interview, and enumeration district "deprivation" indices were calculated for the household at birth (24).

We focus here on events occurring in the first 2 years of life and, because the primary care records of older children were less uniformly complete in their early years, analyses are restricted to the 1,782 (75 percent) children born in the 12 years, 1985–1996 (average length of follow-up: 3.9 years). For the purposes of the present investigation, a positive history of eczema (ICD-10 code L20.8, atopic eczema) was defined as at least one visit to the GP for this condition before the age of 2 years (414 children) (25). Infections included all relevant ICD-10 codes (A00–B99, H10, H66, J00–J11, J18–J22, L00–L03, L08, and P35–39). We repeated all analyses for children with two or more GP visits for eczema before the age of 2 years (167 children) and also excluding fungal infections (ICD-10 codes B35, B37, B49, and P37.5).

Data were analyzed by use of both Poisson and logistic regression (26). In the Poisson regression, infection rates were taken to be the outcome, under the hypothesis that a mechanism underlying eczema development might also manifest itself through differential infection rates. Infection rates were modeled for the first 2 years of life, adjusting for the manifest time dependence of these rates with a quadratic function of time fitted to monthly infection counts aggregated over all individuals. With this adjustment for time dependence, infection rate ratios between children with and without eczema were then estimated from fitted model parameters. In addition, infection rate ratios were adjusted for the time variation and for all covariates (case-control status, sex, birth order, deprivation index, and breastfeeding status) by use of Poisson regression with individual subject level data. The main-effects model was calculated, as were models with time variation correction together with all two-way, three-way, four-way, and five-way interactions among covariates. Also, rate ratios for infection, adjusted for time variation, were calculated for the aggregated data overall and stratified by the covariates. A certain amount of within-patient correlation was detected for monthly infection status (i.e., whether an individual had one or more infections in a particular month) by comparing the distribution of runs of months containing an infection with the distribution of nonzero runs in independently generated random data with the same event intensities. Therefore, it was anticipated that standard errors would require correction. Standard errors for the rate ratio estimates presented here were corrected by use of the measured overdispersion (26) and approximate 95 percent confidence intervals calculated. Alternative methods of modeling the correlation structure by refitting the models with an individual-level random effect and by the use of generalized estimating equations (using both unstructured and AR(1) correlation structures (27)) led to inflated estimates of standard errors, but these made no difference to the assessment of statistical significance. (Indeed, in the case of the generalized estimating equation models, eczema status effects were themselves inflated relative to the Poisson models.)

For a confirmatory analysis, recurrent event data may be modeled as realizations of an underlying continuous-time Poisson process, using techniques adapted from survival analysis (28). In particular, individual sequences of recurrent events may be written in a counting process format using the times of the event (measured in days since birth), and the intensity of the Poisson process may be estimated using standard software for the Cox proportional hazards model (28, 29). Clustering the events by individual leads to the Andersen-Gill model (28, chapter 8; 29, chapter 3), whereas inclusion of an individual-level random effect leads to a frailty model (28, chapter 9; 29, chapter 3). Fitting Andersen-Gill and frailty models to the data, considering the infection occurrences to be realizations of an underlying Poisson process with time since birth as the natural time parameter, gave results consistent with the Poisson analysis above.

In the logistic regression, the hypothesis that the infection rate might be predictive of eczema as an outcome was investigated. The probability of eczema diagnosis was modeled using as a covariate an infection score derived for each individual to correct for the time-varying nature of the infection profile. For each individual, the ratio between the number of infections he/she had in each month and the average number of infections per individual in that month was calculated and then averaged over the months the individual was observed. Odds ratios and their 95 percent confidence intervals for the infection score and other covariates were estimated from fitted model parameters. The effect of infection score in the logistic model was checked for functional form by refitting with a binary generalized additive model, and interaction models with all two-way, three-way, four-way, and five-way interactions among covariates were fitted. Overdispersion was not found to be present in the logistic models.

For both Poisson and logistic regressions, investigation of complex interaction models was facilitated by dichotomizing birth order (birth order: firstborn and second or higher), breastfeeding status (<1 month, ≥1 month), and deprivation indices 1–4 and 5. No adjustment for GP practice clustering was made, as few subjects were associated with the same GP practice. Analyses were conducted by use of STATA, version 9.2, software (StataCorp LP, College Station, Texas) and R language, version 2.5.1 (http://www.R-project.org).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The sex, year of birth, and deprivation distributions shown in table 1 reflect those of the larger study from which the present population was drawn (21). There were no differences between children with a clinical record of eczema and those without. Further, maternal reports of breastfeeding duration were similar. However, children with a record of eczema were more likely to be firstborn (birth order one) (for at least one GP visit: odds ratio = 1.31, 95 percent confidence interval (CI): 1.04, 1.64; p = 0.020; for at least two GP visits: odds ratio = 1.53, 95 percent CI: 1.10, 2.15; p = 0.010).


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  		TABLE 1. Background characteristics and clinically diagnosed infection in children with no, one, and two or more general practitioner visits for eczema in their first 2 years, United Kingdom Childhood Cancer Study, 1991–1996

 
With respect to infection, by the end of the first year, approximately 80 percent of the children without an eczema record, compared with 90 percent of those with an eczema record, had visited their GP at least once with an infection (difference of proportions = 0.09, 95 percent CI: 0.06, 0.14; p < 0.0001) (table 1). This had risen to 89 percent and 98 percent, respectively, by the end of the second year. The excess among children with eczema was not confined to any specific diagnosis, as can be seen from the data at the bottom of table 1, where the frequencies for the five most commonly diagnosed infections in the first 12 months are presented. Upper respiratory tract infections were the most common, and the pattern was similar for children with one or more than one eczema record.

The modeled infection counts per 100 children per month for children with and without eczema in the first 2 years of life, excluding infections occurring after the first eczema diagnosis, are presented in figure 1. In both groups, the rate increases gradually, peaking at around 10 months of age before falling to its lowest point at 24 months. Differences between children with and without eczema were marked throughout the 2-year period, with a clear excess of GP visits for infections evident at all times from birth to 2 years in children with eczema.


Figure 1
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  		FIGURE 1. Prior infection rates (and 95% confidence intervals) by month over the first 2 years of life in children diagnosed with eczema before age 2 compared with children with no eczema diagnosis before age 2, United Kingdom Childhood Cancer Study, 1991–1996.

 
Rate ratios (and 95 percent confidence intervals) for infections in the first 2 years of life, adjusted for the time variation of infection rate, are shown in table 2. Findings were similar for all infections (before and after eczema diagnosis) and excluding infections occurring after the first visit with an eczema diagnosis, the overall excess ranging from 20 to 26 percent. Repeating the analysis restricting eczema cases to those who had at least two diagnoses did not affect the results. However, stratification by birth order revealed that the excess was confined largely to children of second or higher birth order, where the rate ratios among those who developed eczema were around 40 percent higher than the rate ratios among those who did not. The rate ratio for infections using the model with at least one eczema visit and adjusting for all covariates (birth order, breastfeeding, sex, deprivation) was 1.28 (95 percent CI: 1.19, 1.38).


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  		TABLE 2. Poisson model rate ratios for all infections and excluding infections occurring after the first occurrence of eczema, adjusting for temporal infection rate variation, United Kingdom Childhood Cancer Study, 1991–1996

 
As there was clear evidence from the stratification of the Poisson model by birth order for an interaction between birth order and infection score, odds ratios for the logistic model with main effects and the birth-order infection score interaction are given in table 3. The interaction effect between birth order and infection score meant that the dependence on infection score was clearly statistically significant at the 5 percent level for latter-born children but only marginally so among firstborn children. So, for example, for at least one eczema diagnosis, an increment of one in the infection score (recalling that a score of 1 represents an average infection rate, and a score of 2 represents twice the average infection rate) resulted in an odds ratio of 1.15 (95 percent CI: 0.98, 1.35) among firstborns and an odds ratio of 1.45 (95 percent CI: 1.26, 1.67) among the latter born. A second or higher birth order, compared with firstborn birth order, led to a reduction in risk of eczema (odds ratio = 0.60, 95 percent CI: 0.43, 0.83), and breastfeeding for more than a month led to an apparent increase (odds ratio = 1.29, 95 percent CI: 1.03, 1.62). Sex and deprivation had no statistically significant effect on the risk of eczema. As with Poisson count modeling, specification of two eczema diagnoses made no substantial difference to the results, with the possible exception of breastfeeding, which was no longer statistically significant at the 5 percent level.


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  		TABLE 3. Logistic model odds ratios with eczema as the outcome, United Kingdom Childhood Cancer Study, 1991–1996

 
For both types of model, there was some evidence (for the logistic model: likelihood ratio test = 44.4 on 25 df, p = 0.01; for the Poisson model: likelihood ratio test = 193 on 25 df, p < 0.0001) that models fitting all interactions up to and including four-way interactions provided better fits to the data than the corresponding main effects models. Inspection of sample sizes in each of the categories defined by the covariate values confirmed that inference could reasonably be made for such models. For the logistic model, however, whether the interaction model was best depended upon censoring and specification of two eczema diagnoses. These interaction models allowed us to confirm the effects seen in the stratified analysis, especially that due to stratifying by birth order. We were also able to show that the history of infections for any individual can be seen as a complex interaction between the covariates entered into the model.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our findings for infection and eczema are consistent with those of previous reports examining this topic (3, 4, 12, 14, 15, 30). Similarly, both the incidence of eczema and counts of recorded infections in the first year are analogous to those observed in other United Kingdom general practice populations (14, 31). Taken at face value, however, the observation that children who develop eczema have more infections prior to their eczema diagnosis does not sit comfortably with the "hygiene hypothesis" that is predicated on the notion that a lack of microbial exposure in infancy increases risk of allergic disease in later life (2). Furthermore, the relation between infection and eczema was apparent from birth and throughout the first 2 years of life, the excess being evident both before and after eczema diagnosis. Importantly, the nature of the data also provided the opportunity to look at individual diagnoses, but no evidence implicating any specific infection was found. Likewise, exclusion of specific groups of infections (e.g., fungal infections) did not impact on the results.

As expected, compared with children of second or higher birth order, those firstborn were at increased risk of eczema (32, 33); however, the relation between eczema and prior infection was evident only among children of second or higher birth order. Whether or not susceptibility to infection and eczema are both manifestations of the same underlying predisposition remains to be clarified in further research. Overall, therefore, we conclude that the well-established inverse relation between birth order and eczema is not mediated by a deficit of prior infectious exposure. Rather, it seems likely that other immunologic factors, such as changes in maternal immune tolerance during pregnancy, may be involved (6, 34–36).


   ACKNOWLEDGMENTS
 
Supported by the Children's Cancer and Leukaemia Group and the Health Protection Agency (formally the National Radiological Protection Board). Ann Maree Hughes has an Australian National Health and Medical Research Council Sidney Sax Postdoctoral Research Fellowship (grant 358672).

The authors would like to thank the members of the Children's Cancer and Leukaemia Group for their support and the staff of local hospitals, general practitioners, general practice staff, and UKCCS interviewers and technicians. They would especially like to thank the families of the children included in the study, without whom the UKCCS would not have been possible.

The UKCCS was conducted by 12 teams of investigators based in United Kingdom universities, research institutes, and the National Health Service. The work is coordinated by a research committee.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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