{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:19:50Z","timestamp":1760059190947,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: The symptoms of cow\u2019s 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\u2014gastrointestinal, skin, and combined gastrointestinal and skin. The most significant improvement after AAF implementation was obtained in patients with a combined phenotype.<\/jats:p>","DOI":"10.3390\/nu17111809","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T03:34:46Z","timestamp":1748316886000},"page":"1809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Phenotypes of Severe Cow\u2019s Milk Protein Allergy with Various Responses to Amino Acid-Based Formula"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6387-2768","authenticated-orcid":false,"given":"\u0141ukasz","family":"B\u0142a\u017cowski","sequence":"first","affiliation":[{"name":"Department of Allergology and Pulmonology, National Research Institute of Tuberculosis and Lung Diseases, 34-700 Rabka-Zdroj, Poland"},{"name":"Department of Pathophysiology, Institute of Medical Sciences of Rzeszow University, 35-310 Rzeszow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Podlecka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Allergy, Medical University of Lodz, 90-419 Lodz, Poland"},{"name":"Korczak Pediatric Center, 92-328 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Brzozowska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Allergy, Medical University of Lodz, 90-419 Lodz, Poland"},{"name":"Korczak Pediatric Center, 92-328 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8042-406X","authenticated-orcid":false,"given":"Joanna","family":"Jerzy\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Allergy, Medical University of Lodz, 90-419 Lodz, Poland"},{"name":"Korczak Pediatric Center, 92-328 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"Seweryn","sequence":"additional","affiliation":[{"name":"Biobank Laboratory, Department of Molecular Biophysics, University of Lodz, 90-136 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"B\u0142a\u017cowski","sequence":"additional","affiliation":[{"name":"Specialist Hospital, 38-200 Jaslo, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2532-9983","authenticated-orcid":false,"given":"Pawe\u0142","family":"Majak","sequence":"additional","affiliation":[{"name":"Korczak Pediatric Center, 92-328 Lodz, Poland"},{"name":"Department of Pediatric Pulmonology, Medical University of Lodz, 90-419 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.jaci.2021.10.018","article-title":"Food allergy across the globe","volume":"148","author":"Sampath","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.anai.2023.09.015","article-title":"Anaphylaxis: A 2023 practice parameter update","volume":"132","author":"Golden","year":"2024","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.1111\/all.14857","article-title":"Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort","volume":"76","author":"Jonasson","year":"2021","journal-title":"Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1016\/j.jaip.2020.04.020","article-title":"Prevalence of Food Sensitization and Food Allergy in Children Across Europe","volume":"8","author":"Lyons","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pr."},{"key":"ref_5","first-page":"100785","article-title":"World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow\u2019s Milk Allergy (DRACMA) Guideline update\u2014VII\u2014Milk elimination and reintroduction in the diagnostic process of cow\u2019s milk allergy","volume":"16","author":"Meyer","year":"2023","journal-title":"WAO J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1111\/all.15939","article-title":"Systematic review and meta-analyses on the accuracy of diagnostic tests for IgE-mediated food allergy","volume":"79","author":"Riggioni","year":"2024","journal-title":"Allergy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jpeds.2021.01.059","article-title":"The Impact of Formula Choice for the Management of Pediatric Cow\u2019s Milk Allergy on the Occurrence of Other Allergic Manifestations: The Atopic March Cohort Study","volume":"232","author":"Nocerino","year":"2021","journal-title":"J. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/pai.12651","article-title":"Is there a march from early food sensitization to later childhood allergic airway disease? Results from two prospective birth cohort studies","volume":"28","author":"Alduraywish","year":"2017","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1111\/pai.13440","article-title":"The natural course of cow\u2019s milk allergy and the development of atopic diseases into adulthood","volume":"32","author":"Hansen","year":"2021","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_10","first-page":"100668","article-title":"Diagnosis and Rationale for Action against Cow\u2019s Milk Allergy (DRACMA) Guidelines update\u2014III\u2014Cow\u2019s milk allergens and mechanisms triggering immune activation","volume":"15","author":"Jensen","year":"2022","journal-title":"WAO J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e14100","DOI":"10.1111\/pai.14100","article-title":"Dietary management of IgE and non-IgE-mediated food allergies in pediatric patients","volume":"35","author":"Venter","year":"2024","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_12","first-page":"100888","article-title":"World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow\u2019s Milk Allergy (DRACMA) guideline update\u2014XII\u2014Recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA","volume":"17","author":"Bognanni","year":"2024","journal-title":"WAO J."},{"key":"ref_13","first-page":"100931","article-title":"World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow\u2019s Milk Allergy (DRACMA) guidelines update\u2014XVI\u2014Nutritional management of cow\u2019s milk allergy","volume":"17","author":"Venter","year":"2024","journal-title":"WAO J."},{"key":"ref_14","first-page":"642","article-title":"The clinical presentation, diagnostic approach, dietary treatment, and effectiveness of Nutramigen PURAMINO amino acid-based formula in the management of severe cow\u2019s milk allergy","volume":"20","author":"Dobrakowski","year":"2023","journal-title":"Stand. Med. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s11222-015-9585-2","article-title":"Model-based clustering of multivariate ordinal data relying on a stochastic binary search algorithm","volume":"26","author":"Biernacki","year":"2016","journal-title":"Stat. Comput."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1111\/all.12429","article-title":"EAACI food allergy and anaphylaxis guidelines: Diagnosis and management of food allergy","volume":"69","author":"Muraro","year":"2014","journal-title":"Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/WOX.0b013e3181defeb9","article-title":"World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow\u2019s Milk Allergy (DRACMA) Guidelines","volume":"3","author":"Fiocchi","year":"2010","journal-title":"World Allergy Organ. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1111\/j.1365-2222.2007.02724.x","article-title":"The efficacy of amino acid-based formulas in relieving the symptoms of cow\u2019s milk allergy: A systematic review","volume":"37","author":"Hill","year":"2007","journal-title":"Clin. Exp. Allergy."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/S0022-3476(95)70111-7","article-title":"Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulae in infants with cow milk allergy","volume":"127","author":"Isolauri","year":"1995","journal-title":"J. Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gold, M.S., Quinn, P.J., Campbell, D.E., Peake, J., Smart, J., Robinson, M., O\u2019Sullivan, M., Vogt, J.K., Pedersen, H.K., and Liu, X. (2022). Effects of an Amino Acid-Based Formula Supplemented with Two Human Milk Oligosaccharides on Growth, Tolerability, Safety, and Gut Microbiome in Infants with Cow\u2019s Milk Protein Allergy. Nutrients, 14.","DOI":"10.3390\/nu14112297"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/MPG.0b013e31825c9482","article-title":"European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Diagnostic approach and management of cow\u2019s-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines","volume":"55","author":"Koletzko","year":"2012","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13601-017-0162-y","article-title":"Better recognition, diagnosis and management of non-IgE-mediated cow\u2019s milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline","volume":"7","author":"Venter","year":"2017","journal-title":"Clin. Transl. Allergy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.jaip.2017.09.003","article-title":"When Should Infants with Cow\u2019s Milk Protein Allergy Use an Amino Acid Formula? A Practical Guide","volume":"6","author":"Meyer","year":"2018","journal-title":"J. Allergy Clin. Immunol. Pract."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/11\/1809\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:40:57Z","timestamp":1760031657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/11\/1809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":23,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["nu17111809"],"URL":"https:\/\/doi.org\/10.3390\/nu17111809","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2025,5,26]]}}}