Cohort study of sibling effect, infectious diseases, and risk of atopic dermatitis during first 18 months of life

Atopic dermatitis

In the fourth interview, the mothers were asked about itchy rash and atopic dermatitis in their child and when it had occurred. As described elsewhere, a dermatologist examined a subgroup of the children, and the combination of answers that resulted in the highest sum of sensitivity and specificity was determined.14 Cases of atopic dermatitis were defined as children whose mothers reported that the child had had an itchy rash or atopic dermatitis diagnosed by a doctor, or both, and recurrent rash or rash in at least four consecutive half month periods, or both, and relevant localisation of the rash in elbow and knee creases, on the hands, on the face, or in at least four places or generalised.14

Data on infectious diseases and use of antibiotics

In the fourth interview, the mothers were asked whether the child had had colds and diarrhoea, if these had lasted more than three days, and when they had occurred. They were also asked if the child had had otitis media, pneumonia, or other diseases (if so, which) and when they had occurred. We obtained date and diagnoses for admissions to hospital for infectious diseases from the national hospital discharge register. A variable for any type of infectious disease before 6 months of age was created. Furthermore, the mothers were asked about use of antibiotics in the child during the first 6 months of life.

Markers of microbial exposure

We obtained from the interviews data on number of siblings, pet keeping, farm residence, and, for a subgroup, day care before 6 months of age. Their effect was investigated separately and combined, defined as microbial exposure. The effect of number of siblings was explored as a classified variable with 0, 1, 2, 3, or ≥ 4 siblings. When we included this variable in the models as a confounder, and in the analyses combining the four variables, we grouped it into having ≥ 3 siblings or fewer.

Data on background factors

From the interviews we determined the date of birth and sex of the child and, for a subgroup, information on breast feeding. For parents, we determined the date of birth of the mother and details of allergic diseases (asthma, hay fever, atopic dermatitis), occupational class, educational level, smoking, cohabitation, and household income. Data on birth characteristics were obtained from the Danish medical birth registry.

Statistical methods

We used χ² tests to analyse the prevalence ratios for having had an infectious disease at 6 months of age according to characteristics of the child and its family. We used Cox proportional hazards models with age as the underlying time (that is, estimated non-parametric) and reported incidence rate ratios to examine the effect of infectious diseases on atopic dermatitis. We retained in the model any variables (of sex, parental history of allergy, number of siblings, maternal education, and background factors) that changed the estimate of the incidence rate ratio for atopic dermatitis by more than 5%. Potential effect modification was investigated by testing the homogeneity of the effect of infectious diseases within different strata. When we analysed the data according to sex, we became aware of a significant interaction between sex, age, and atopic dermatitis: more boys than girls had atopic dermatitis in the first months of life, whereas this was not the case later. Subsequently we controlled for this in all analyses where results were different by time and sex. Furthermore, we presented the main associations separately for boys and girls.

Main findings

Infectious diseases in the first 6 months of life are associated with an increased risk of atopic dermatitis, while the opposite is true for several environmental factors indicative of microbial exposure. Our findings support the importance of microbial exposure for preventing atopic dermatitis but challenge the hypothesis that infectious diseases in infancy protect against its development.

Strengths and limitations of the study

The strengths of our study include the large sample size and the population based cohort design. Information on all types of infectious disease and symptoms of atopic dermatitis was obtained in early infancy. The diagnosis of atopic dermatitis was based on a set of diagnostic criteria, which we have found to be robust and reasonably specific.14 The observed cumulative prevalence of 10.8% is lower than reported in other cohort studies of children of similar ages. However, many cohorts tend to contain more children with risk factors for allergy or with atopic dermatitis defined by the mother or diagnosed by a doctor; both diagnoses being non-specific.15 Because of the large sample size we were able to control for numerous potential confounders. Importantly, we conducted the analyses as survival analyses including only infectious diseases occurring before the appearance of atopic dermatitis. We addressed the effect of all reported early infectious diseases on the risk of an allergic disease in a population with an evident sibling effect, while previous similar studies have addressed only the potential effect of subgroups of infectious diseases. In such studies, the presence of systemic childhood diseases could not explain the protective effect of siblings on allergic diseases4 and asthma,6 though a protective effect of measles infection was observed. Seropositivity to hepatitis A virus, Helicobacter pylori, and Toxoplasma gondii seemed to explain the sibling effect to some extent in one study10 but not in another.5 Neonatal infectious disease could not explain an observed sibling effect on hay fever.7 Furthermore, respiratory tract infections could not explain the sibling effect on atopy,8 rhinitis,11 or asthma.9 Finally, infectious diseases in infancy that resulted in the child being seen by a general practitioner could not explain a sibling effect on allergic diseases diagnosed by a doctor.12

Possible explanations of the findings

Most of the infectious diseases occurring in our population were respiratory tract infections and diarrhoea. Systemic childhood diseases, such as measles, may be more likely to have long lasting effects on the immune system. However, we found evidence for a sibling effect before 6 months of age. Hence, systemic childhood diseases, which mostly occur later in childhood, cannot explain the sibling effect.

The tendency for reduced risk associated with number of siblings, early day care, pet keeping, and farm residence could reflect microbial stimulation by environmental micro-organisms or microbial products, or both, which does not result in clinically apparent disease, but anyhow stimulates the immune system. Such stimulation may take place in the gut, where the permanent and enormous load ensures a constant source of stimulation.16^–19

The inverse association between number of siblings and risk of atopic dermatitis early in life and the lack of effect of infectious diseases on allergic diseases could suggest a “parity effect” originating in utero. Several studies have found evidence for altered immune function as a function of birth order.20 21 However, even if the sibling effect originated in utero, it would explain neither the increasing incidence of allergic diseases in recent years nor the effect of the indicators of microbial exposure.

We measured clinically apparent infections and not merely exposure to microbes. Previously, it was noted that adults with atopic dermatitis had a higher incidence of recurrent cold sores and upper respiratory tract infections, which led to the suggestion that this could be due to dysfunctioning cell mediated immunity.22 A recent study reported concomitant diseases in children with atopic dermatitis.23 The observed association between clinically apparent infectious diseases and atopic dermatitis may be caused by an underlying immature immune system.

Overall, boys had more infectious diseases and more atopic dermatitis, but these were associated only in girls. Interestingly, a Swedish group recently reported pneumonia to be significantly more common in girls with atopic dermatitis than in girls without, whereas this was not the case in boys.23

Conclusions

In conclusion, we found that infectious diseases occurring early in life were associated with an increased risk of atopic dermatitis before 18 months. This contrasts with the previously held belief of a protective effect of early infections on the development of allergic diseases. The inverse association between atopic dermatitis and number of siblings, early day care, pet keeping, and farm residence remained after we controlled for number of clinically apparent infectious diseases, suggesting that these effects are mediated early in life and independently of clinically apparent infectious diseases.