The patient was a 31-year-old lactating woman who had delivered her first child 4 months before. Her medical history included infantile asthma, and her family history revealed hyperuricemia and hypertension in her father, and Hashimoto's disease in her mother.
Upon developing pruritis on bilateral lower limbs, she visited a dermatology clinic and was prescribed a steroid cream. One week after the onset of pruritis, she developed lower limb edema. She visited our hospital two weeks after the onset of edema. She reported no history of parasitic or non-parasitic infections.
Physical examination revealed striking, non-pitting edema of both lower legs and feet ( Figure 1A ). She did not have fever or urticaria. Her weight had not changed significantly. Otherwise, she showed no symptoms, and her vital signs were normal. Initial laboratory findings were as follows: white blood cell count was 1.82x104/muL, and it increased to 1.91x104/muL with 68.6% eosinophils later (eosinophil count was as high as 1.31x104/muL) ( Figure 1A ). Serum lactate dehydrogenase was slightly elevated ( Figure 1B ). Serum immunoglobulin G (IgG), IgM, rheumatoid factor, antinuclear antibody, complement component 4, and erythrocyte sedimentation rate were within normal range. The maximum C-reactive protein level was only 0.51 mg/dL throughout the course of illness ( Supplementary Table 1 ). There was no evidence of anemia, hypoalbuminemia, or thyroid dysfunction ( Figure 1B ).
Chest radiography showed no signs of heart failure or renal failure, and ultrasound cardiography was negative for postpartum cardiomyopathy.
Since she had edema with eosinophilia but no involvement of internal organs, we diagnosed her with angioedema with eosinophilia. She had no fever, urticaria, or weight gain. Serum IgM concentration was normal. Based on these findings, the final diagnosis was NEAE. She gradually recovered in approximately three months without any medication throughout the course. The follow-up period of 1 year was completely uneventful. Written informed consent was obtained from the patient.
To measure the degree of edema objectively, we used bioimpedance analysis using InBody  (InBody, Seoul, Korea). The high ratio of extracellular water to total body water (ECW/TBW) in the trunk and lower limbs, especially on the left side, concurred with the finding of edema (  Figure 2A ). Although the total amount of body water and intra- and extra-cellular water remained unchanged ( Figure 2B ), bioimpedance analysis revealed edema of the trunk and lower legs.
Next, we investigated the role of various cytokines and chemokines. We found that interleukin-5 (IL-5), thymus- and activation-regulated chemokine/C-C motif chemokine ligand-17 (TARC/CCL-17), eotaxin-3/CCL-26, tumor necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor (VEGF) showed correlation with the extent of disease ( Figure 2C ). Furthermore, we found the relationship between monocyte chemotactic protein-4/CCL-13 (MCP-4/CCL-13), eotaxin-1/CCL-11, and regulated on activation, normal T expressed and secreted/CCL-5 (RANTES/CCL-5), and the extent of disease ( Figure 2D ).
We explored the correlation between the index of edema (ECW/TBW) and these cytokines/chemokines. We found that each parameter we measured had a positive correlation with ECW/TBW. In particular, eotaxin-3/CCL-26, eotaxin-1/CCL-11, TARC/CCL-17, and MCP-4/CCL-13 were highly correlated (rho value>0.9) with the index of edema ( Table 1 ). In contrast, VEGF and RANTES/CCL-5 demonstrated a weak positive correlation (rho value <0.5) with ECW/TBW.