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To The Editor,
Food protein-induced enterocolitis syndrome (FPIES) is a non IgE-mediated food allergy that predominantly affects infants and is characterized by repetitive vomiting 1-4 hours after causative food ingestion which often leads to diarrhea, lethargy, and pallor. Although the involvement of cellular immunity is suggested, comprehensive mechanisms of the disorder have been poorly understood. Diagnosis is often hampered by delayed onset of non-specific symptoms after allergen exposure and lack of awareness of FPIES. In addition, reliable specific biomarkers are absent, although acute FPIES attack is accompanied by neutrophilia, thrombocytosis, methemoglobinemia, and metabolic acidosis.1
Thymus and activation-regulated chemokine (TARC), a member of the CC chemokine family, recruits CC chemokine receptor 4+Th2-polarized memory/effector T cells into inflamed tissues. A serum TARC level serves as a reliable biomarker of AD disease severity in clinical practice.2 Although high levels of serum TARC discriminate FPIES from vomiting associated with infectious gastroenteritis,4 TARC levels are influenced by several factors such as age and presence of eczema, which make it difficult to evaluate FPIES by a single measurement of TARC level. A recent report has demonstrated that serum levels of TARC elevate after oral food challenge (OFC) in two patients with FPIES, suggesting that serum TARC levels are potential biomarker of the disease.3 To validate the utility of TARC in the diagnosis of FPIES, we examined TARC ratio in a larger number of patients with FPIES.
The present study enrolled patients with solid FPIES diagnosed by positive OFC results in our hospital between April 2018 and April 2021. The open OFC was performed by ingestion at a single or three-divided doses with 30-minute intervals. OFC was considered positive for FPIES by delayed abdominal reactions without immediate skin or respiratory reactions. Tolerance acquisition was defined by both (1) negative OFC and (2) ability to repeatedly consume daily intakes without FPIES symptoms for three months at home. Serum TARC levels and C-reactive protein (CRP) were measured before (pre-OFC) and 24 hours after OFC (post-OFC). TARC ratio was defined as the ratio of post-OFC to pre-OFC TARC levels. In the present study, we excluded OFC which missed the data of TARC ratio. We compared TARC ratio and post-OFC serum CRP levels between the negative and positive OFC groups. We also collected data of sex, causative food, age of onset and diagnosis, the number of previous episodes before diagnosis, specific immunoglobulin E (sIgE) to causative foods by ImmunoCAP test, and current eczema. A sIgE values higher than 0.35 UA/ml were defined as positive. Statistical analyses were performed using GraphPad Prism8. Mann-Whitney U test was used for continuous data between two groups. A correlation of TARC ratio and serum CRP after OFC was evaluated by using the Spearman correlation coefficient. A P value of < 0.05 was considered statistically significant. This study was approved by the institutional review board of KKR Sapporo Medical Center (2020-54).
Of total 57 OFCs in 25 patients, seven OFC were excluded because of missing data of TARC ratio. As a result, TARC ratio was analyzed in 50 OFC of 23 patients which consisted of 22 OFC for diagnoses and 28 OFC for evaluations of tolerance. Characteristics of patients were shown in Table 1. Tested foods for OFC were 36 for egg yolk (EY), 10 for wheat, 3 for scallop, and 1 for soy. Forty-two (84.0%) of all OFC were positive. Eight negative OFC (eight patients) were all confirmed acquisition of tolerance later.
As shown in Figure 1, the median TARC ratio was significantly higher in the positive OFC group than in the negative OFC group (3.85 vs 1.15, p=0.018). The pre-OFC CRP levels were all negative (n=50, median 0.02 mg/dL, IQR 0.01-0.03 mg/dL). The median of post-OFC CRP levels in the negative and the positive OFC groups were 0.02 mg/dL (n=8, IQR 0.01-0.05 mg/dL) and 0.51 mg/dL (n=42, IQR 0.23-1.70 mg/dL), respectively (p=0.027). Additionally, there was a weak positive correlation between TARC ratio and post-OFC CRP levels (r2=0.699, p <0.0001).