# Clinical Phenotypes of Severe Cow’s Milk Protein Allergy with Various Responses to Amino Acid-Based Formula

## TL;DR

This study identifies three distinct symptom patterns in severe cow's milk allergy and finds that children with combined gastrointestinal and skin symptoms improve most with amino acid-based formula.

## Contribution

The study introduces a new classification of severe CMA phenotypes and shows differential treatment response to amino acid-based formula.

## Key findings

- Three distinct CMA phenotypes were identified: gastrointestinal, skin, and combined.
- Children with the combined phenotype showed the greatest improvement after amino acid-based formula treatment.
- The clustering pattern was validated in a separate cohort of infants with CMA.

## Abstract

Background: The symptoms of cow’s milk allergy (CMA) can vary widely in severity and course, so diagnosis and treatment are still challenging. Objective: This study aims to establish the phenotype of severe CMA in children with the greatest improvement following the application of amino acid-based formula (AAF). Methods: This is a post hoc analysis of data from the multicenter, real-life study assessing the clinical effectiveness of a 5-week AAF intervention in 232 infants with severe CMA. A cluster analysis based on symptom severity at the 1st visit was performed. The differences in the severity scale of each symptom before and after the intervention were assessed and compared within and between clusters. The clustering results were validated in a separate cohort of infants with CMA (n = 157). Results: Three clusters were identified: cluster A (38.8% of patients) with moderate-to-severe gastrointestinal symptoms, cluster B (34.1%) with severe skin symptoms, and cluster C (25.9%) with combined moderate-to-severe gastrointestinal and severe skin symptoms. In the validation cohort, three clusters with the same pattern of symptoms were observed among children with moderate-to-severe CMA. The multivariate model of linear regression showed that severity score reductions after AAF treatment were significantly higher in cluster C than in clusters A and B, in children with a positive family history of allergy, and in children with growth retardation at baseline. Conclusion: Symptoms of severe CMA in children are grouped into three distinct phenotypes—gastrointestinal, skin, and combined gastrointestinal and skin. The most significant improvement after AAF implementation was obtained in patients with a combined phenotype.