Objective: Non-IgE-mediated cow’s milk protein allergy (CMPA) is difficult to diagnose in infancy because its manifestations are often nonspecific and overlap with common functional gastrointestinal disorders. The Cow’s Milk-related Symptom Score (CoMiSS) was developed as an awareness tool to support recognition of symptoms potentially related to CMPA. This study aimed to evaluate the diagnostic performance of CoMiSS in infants with suspected non-IgE-mediated CMPA.

Materials and Methods: This prospective study included 51 infants aged ≤18 months with suspected non-IgE-mediated CMPA who were evaluated in a tertiary pediatric allergy clinic between November 2023 and February 2024. CoMiSS was calculated at presentation. All infants underwent a 4-week cow’s milk elimination diet followed by oral food challenge (OFC) as the reference diagnostic method. In the primary analysis, a CoMiSS score of ≥12 was considered positive in accordance with previous literature. ROC analysis was also performed to assess diagnostic performance and determine the optimal cut-off value.

Results: After elimination diet and OFC, CMPA was confirmed in 37 of 51 infants (72.5%). The CoMiSS score was positive in 28 of 37 infants with CMPA and negative in 12 of 14 infants without CMPA, demonstrating a sensitivity of 75.7%, specificity of 85.7%, positive predictive value (PPV) of 93.3, and negative predictive value (NPV) of 57.1. ROC analysis demonstrated good discriminative ability, with an area under the curve (AUC) of 0.876 (95% CI: 0.767-0.986; p<0.001). The optimal cut-off value determined by the Youden index was 10.5 (practical cut-off ≥11), yielding a sensitivity of 83.8% and specificity of 85.7%. The PPV and NPV at this threshold were 93.9% and 66.7%, respectively.

Conclusion: CoMiSS showed good diagnostic performance in infants with suspected non-IgE-mediated CMPA. While the predefined cut-off of ≥12 remained clinically useful, ROC analysis suggested that a threshold of ≥11 may improve sensitivity while maintaining high specificity. CoMiSS may serve as a practical supportive tool for clinical suspicion, but it should not replace an elimination diet and oral food challenge for definitive diagnosis.