<p><strong>BACKGROUND: </strong>Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. Its relationship to the major atopic manifestations (atopic dermatitis, AD; IgE-mediated food allergy, IgE-FA; allergic rhinitis, AR; asthma) is not understood.</p>

<p><strong>OBJECTIVE: </strong>Determine the clinical characteristics, epidemiologic features, and natural history of FPIES in relation to the major atopic manifestations.</p>

<p><strong>METHODS: </strong>We examined our primary care birth cohort of 158,510 pediatric patients, of which 214 patients met 2017 FPIES diagnostic criteria. We measured the influence of FPIES on developing subsequent atopic disease.</p>

<p><strong>RESULTS: </strong>Pediatric FPIES incidence was between 0.17% and 0.42% depending on birth year. As in prior reports, most patients had an acute presentation (78%) and milk, soy, oat, rice, potato, and egg were common triggers. The mean age of diagnosis was 6.8 months. Atopic comorbidity was higher in FPIES patients compared to healthy children (AD, 20.6% vs. 11.7%; IgE-FA, 23.8% vs. 4.0%; asthma, 26.6% vs. 18.4%; AR, 28.0% vs. 16.7%; p&lt;0.001 Chi-squared). However, longitudinal analyses indicated that prior FPIES did not influence the rate of atopy development.</p>

<p><strong>CONCLUSIONS: </strong>The incidence of FPIES in our cohort was initially low, but is increasing. Food allergen distribution, presentation, and age of onset are similar to prior reports. FPIES patients have high rates of atopic comorbidity, however, longitudinal analysis does not support direct causation as the etiology of these associations. Rather it suggests a shared predisposition to both types of allergy, or associative bias effects. This work refines our understanding of the natural history of FPIES by elucidating associations between FPIES and atopy.</p>