Antibiotic prescription and food allergy in young children

In the United States, food allergy affects between 4 and 8 % of children and is most prevalent during the first years of life. From 1997 to 2007, the prevalence of reported food allergy increased 18 % among children under age 18 years [1]. In a prospective study of 480 consecutive newborns followed through their third birthday, nearly 8 % of the cohort was food allergic [2]. Food allergy contributes significantly to healthcare utilization with an estimated average of 317,000 ambulatory visits per year to emergency departments or physician offices [3]. A threefold increase in overall hospitalizations related to food allergy has been reported from 1998 to 2000 through 2004–2006 [1, 3].

Newborn children need exposure to immunogenic material to develop a healthy, functional immune system. Changes in the composition, richness, and abundance of microbiota that colonize the human gut during infancy has been theorized to play a role in development in atopic disease, including food allergen sensitization [4]. Commensal bacteria have been shown to protect against food allergen sensitization in mice [5]. Attempts to translate these findings to early infancy in one study revealed that infants with low gut microbiota richness and elevated proportion of Enterobacteriaceae relative to Bacteroides spp. were associated with subsequent food allergen sensitization at 1 year of age [6]. In this study, we sought to explore the association between antibiotic prescription in the first year of life and the presence of any food allergy diagnosis code in young children.

In our sample of children enrolled in the South Carolina Medicaid Program, we identified an association between antibiotic prescription and presence of food allergy diagnosis code in young children. Children with diagnosis of food allergy received significantly more antibiotics than controls even though we censored further antibiotics after the initial FA diagnosis in the case group. Our approach could have reduced the observed association between antibiotics and food allergy, since controls had an unlimited number of antibiotic exposures up to the end of month 12, while for cases the potential for exposure continued only until the initial food allergy diagnosis. However, we felt it was important to enforce this restriction since considering antibiotic prescriptions filled after the initial food allergy diagnosis as potential risk factors would have been nonsensical.

In our study, increasing quantity of antibiotic prescriptions was associated with a higher incidence of food allergy. We theorize that this could affect the likelihood of food allergen sensitization in several ways. Multiple courses of antibiotics increase the likelihood that children are on an antibiotic while introducing a new food. Secondly, there are more opportunities for microbiota dysbiosis with more frequent antibiotic administration.

Commensal gut flora serves an important role in both immune system development and immune tolerance. Studies with germ free animals show impaired humoral and cell mediated immune function [7, 8]. Also, the interaction with normal gut flora is important in the development of regulatory T-cells and IgA antibody, both of which are important in developing tolerance to foreign proteins such as food [9, 10]. Emerging evidence suggests that alterations in commensal flora due to early antimicrobial use may increase the risk of obesity, inflammatory bowel disease, and allergic diseases [11–18]. Recent articles suggest that even antimicrobial food additives or antimicrobials in health care products may be associated with increased allergic disease [19, 20]. In addition, children born via Caesarian section may have increased food allergy in addition to other atopic disease, possibly due to the lack of early colonization with beneficial bacteria from the mother’s urogenital tract [21, 22].

Conflicting findings are available for the few studies which have examined the association between antibiotic exposure and diagnosis of food allergy. In one small retrospective case control study (n = 99 cases) utilizing the same ICD-9-CM diagnoses codes as our study, neither postnatal nor perinatal antibiotic exposure was associated with subsequent food allergy diagnosis [23]. Another study was designed to look at several allergic diseases and was not powered to identify food allergy specifically. Of the 3306 children studied, 173 had food allergy at age 4, and 230 had food allergy at age 8. While antibiotic use was associated with food allergy, the association was not significant in adjusted models [24]. More recently, in a large nested case–control study (n = 16,237) maternal exposure to antibiotics and increasing antibiotic exposure in children were associated with cow’s milk allergy [25]. Our results are consistent with these previous findings, and suggest that other types of food allergen sensitization besides cow’s milk may be associated with antibiotic exposure early in life.

Infections represent one of the most frequently encountered diseases in childhood, and prescriptions for systemic antimicrobials account for about 30 % of all prescriptions in pre-school children. In the US, children aged 3 months to 3 years of age received, on average, 2.2 antimicrobial prescriptions per year between 1996 and 2000 [26], and between 10 and 20 courses of antibiotics by the age of 18 [27]. Most of these prescriptions are for otitis media, although most cases are caused by viral infection. Additionally, some studies have suggested high rates of antimicrobial prescribing for viral infections such as bronchitis and upper respiratory infection. In one study, 44 % of children with common colds, 46 % of those with upper respiratory infections, and 75 % of children with bronchitis were treated with antibiotics [28]. Data suggests that this pattern continues despite educational efforts and increasing reports of bacterial resistance [29–31]. Antibiotics are not devoid of adverse effects: Nausea, vomiting, diarrhea, and rash are common and well known short-term side effects reported in children receiving antimicrobial agents. Antibiotics are known to affect the GI flora, with the potential to cause antibiotic–induced diarrhea or Clostridium difficile associated disease [32–35]. Antibiotics with broader spectrum of activity are more likely to have an impact on commensal flora than narrower spectrum agents. We are just beginning to understand the potential long-term effects of microbiotia dysbiosis due to antibiotic exposure.

Strengths of our study include matching on demographic variables including month and year of birth, multivariate analysis that controlled for variables previously associated with food allergen sensitization in other studies, and a large sample of FA children; however, our study has several limitations. First, we defined food allergy using ICD-9 codes; thus, we cannot determine whether patients had food allergy versus food intolerance. The only definitive diagnostic test for food allergy is a double-blind, placebo-controlled challenge [36], but this is not frequently done in clinical practice. Additionally, there is not one single diagnostic code for food allergy, but rather several codes exist which define the allergen or clinical presentation of allergy. In clinical practice, inconsistent or varied use of diagnosis codes between providers could lead to under or over reporting of true food allergy. On the other hand, we chose FA diagnosis codes for our study based upon prior retrospective analyses of administrative records, and we conducted sensitivity analyses comparing diagnosis by provider type, receipt of epinephrine, and exclusion of diagnoses to examine this. Second, children at risk for food allergy often have other associated allergic diseases; therefore, such children may receive more antibiotics simply because of these illnesses. Atopic dermatitis predisposes to recurrent skin infections such as impetigo and Staphylococcal abscesses, and asthma exacerbations or wheezing episodes are often treated with antibiotics. We controlled for asthma, wheezing and atopic dermatitis in all logistic regression models to account for this. Finally, our study population consisted of patients receiving Medicaid benefits, thus our study may be more representative of a lower socioeconomic group than the general population. Lower socioeconomic status has been associated with higher rates of asthma and allergic rhinitis [37], but recent data cite higher rates of peanut sensitization among higher socioeconomic families [38–40]. Additional investigation in a more socioeconomically diverse population would also be beneficial.

In summary, we identified an association between antibiotic prescription and presence of food allergy diagnosis code in young children. Our results require cautious interpretation due to the limitations as discussed; however, our findings offer a plausible hypothesis for increasing food allergy prevalence since increased antibiotic use is common in many westernized countries. Further research is needed to examine this association in larger, more diverse patient populations with confirmed food allergy.