A case of episodic angioedema associated with eosinophilia Takanori Shikiji, Yoshio Urano, Hirotsugu Takiwaki and Seiji Arase Department of Dermatology, The University of Tokushima School of Medicine, Tokushima, Japan. Abstract:Background Gleich et al. first described 4 cases of episodic angioedema associated with eosinophilia as a distinct entity in1984. Since then, several cases of this disorder have been reported in the United States, Europe and Japan. Observations We report a case of a22-year-old pregnant Japanese woman with this disorder. She had no fever and her general condition was good except the angioedema which was limited to her limbs. During an acute episode, her white blood cell count increased to 29,500/mm3 with 50%eosinophils, following an elevated serum interleukin-5 (IL-5) level. Spontaneous resolution occurred in1month after the onset. In a5month follow-up, no evidence of cardiac or other visceral organ involvement was found, and no recurrence occurred. Conclusions Our case, combined with those reported in the literature, suggests that Japanese cases of episodic angioedema associated with eosinophilia differ from Caucasian cases in clinical symptoms and some other points. J. Med. Invest. 44:103-108, 1997 Keywords:episodic angioedema, eosinophilia, interleukin-5 INTRODUCTION Episodic angioedema with eosinophilia was described by Gleich, et al. (1) as a distinct entity characterized by recurrent angioedema, urticaria, leukocytosis with remarkable eosinophilia, fever and periodically increased body weight. Since then several authors have also reported similar cases in Caucasoids (2-7). Most of the patients with this disorder had angioedema extending to the face and trunk as well as the extremities, with episodes recurring in all of them. Serum immunoglobulin levels were elevated in all Caucasian cases. Corticosteroid was administerd in most cases, which proved quite beneficial. Recently, 17cases of this disorder have been reported in Japan (8-18). We presented an additional Japanese case along with a literary review of other cases. This study revealed some differences between Japanese and Caucasian patients. CASE REPORT A22-year-old female, in her fifth month of pregnancy, presented with a10-day history of continuous edema of the limbs. The ailment began with severe pruritus of the soles, followed by the non-pitting edema of the feet, lower legs, hands and forearms. She had no fever and her general condition was good. Her family history did not include autoimmune, malig-nant, hematologic, or eosinophilic diseases. However, at the age of 12, she had uveitis which was not associated with blood eosinophilia, requiring treatment with prednisolone for the following 3years. On admission, a non-pitting, painless but pruritic edema, together with faint erythemas of various size and shape, were present on the bilateral lower legs and feet (Fig.1,A), and also on the bilateral forearms and hands (Fig.1,B) . The face and trunk were not affected, and none of the cervical, axillary or inguinal lymph nodes were palpable. Although she had gained2kg in weight over the previous7days, her urinary output was normal. On admission, her white blood cell count was17,000/mm3 with 4% eosinophils. Serum IgG, IgA, IgM, and IgE levels were normal, with a radioallergosorbent test detecting no specific IgE antibodies against house dusts, mites, several molds, animal epithelia and feathers. Levels of circulating complements (C3, C4, total hemolytic complement CH50) and C1-esterase inhibitor were within the normal range. Anti-nuclear antibody (ANA) was positive with a titer of1:80 (speckled pattern), but other autoantibodies including anti-DNA, SS-A, SS-B, RNP and Sm were negative. The level of lactate dehydrogenase was elevated to 602IU/L (normal, 237 to 454IU/L). The results of the following tests performed during the episode were also negative or within normal range: urinalysis, stool tests for ova and parasites, red blood cell and platelet counts, liver and renal function tests, serum electrolyte concentration, C-reactive protein and plasma histamine levels. Electrocardiograms, echocardiograms, chest roentgengrams and abdomen ultrasoundgrams were all normal. Biopsy specimen taken from the dorsum of the foot (lacking in erythema) showed edema and a slight infiltration of eosinophils in the lower dermis and subcutaneous fat (Fig. 2). There was no evidence of vasculitis. A few mast cells were also seen in the lower dermis. WBC and eosinophil counts gradually increased, reaching 29,500/mm3 with 50% eosinophils on day10 (Fig 3). Bone marrow biopsy revealed an increased number of immature and mature eosinophils without evidence of leukemia. No drugs were administerd because of her pregnancy and because of her good general condition. The angioedema improved gradually in parallel with a decrease in WBC and eosinophil counts. About1month after the onset, all skin symptoms disappeared completely but slight leukocytosis (11,100/mm3) with eosinophilia(11%) was still noticed. Three months after the onset and2months before the expected date of delivery, she gave birth to a child without any abnormalities or eosinophilia. We measured serum IL-5levels during and after the episode by a sandwich enzyme-linked immunosorbent assay as described previously (19) (Fig. 3). The levels in2normal subjects (non-pregnant) were both less than0.3ng/ml. On day4, about1week before the maximal blood eosinophilia, the level of the IL-5was significantly higher than that of the normal controls. It decreased 3 months after the onset, though, it was still a little higher than the normal value. DISCUSSION This patient clinically demonstrated persistent angioedema on the limbs associated with blood leukocytosis and eosinophilia. Histological examination showed a slight infiltration of eosinophils in the lower dermis and subcutaneous fat. Eosinophilic leukemia and parasitic diseases were excluded in the clinical course and diagnostic examinations. Hypereosinophilic syndrome (HES) and Well's syndrome were important in the differential diagnosis. HES, in which cardiac and/or lung involvement is common, shows persistent eosinophilia with various skin manifestations including angioedema(20), and carries a poor prognosis (21). Transient eosinophilia and absence of visceral organ involvement in our patient were inconsistent with HES. Well's syndrome(22) is a disorder characterized by the existence of frame figure, histologically. This was not the case with our patient. Judging from the findings above, we diagnosed this case as episodic angioedema with eosinophilia. A review of the literature has disclosed 28 cases reported as episodic angioedema with eosinophilia, covering 12 Caucasian and 16 Japanese cases (Table1). We noticed that the Japanese cases differed from the Caucasian ones in some points. In the Caucasian cases, for instance, the male-to female ratio was1:2. The angioedema was seen not only on their limbs but also on their faces and trunks. The patients usually demonstrated monthly episodes of angioedema and eosinophilia accompanied by systemic symptoms such as fever and malaise. Various types of immunological abnormalities, including increased serum IgM (1-7) and IgE (1-4, 7) levels and elevated levels of circulating activated T-helper cells, were commonly found among these cases (2-4, 6). The patients required systemic corticosteroid therapy at each episode. However, Japanese patients were all young females in their twenties, except for 2 cases. The angioedema was limited to their limbs and did not extend over their faces and trunks. In contrast with the Caucasian cases, most of the patients had no fever or malaise during the episode, and their symptoms resolved spontaneously or with antihistamines in about1month. Moreover, they experienced no recurrence of the disorder. The cause of the difference between the two groups remains to be answered. The patient described here was pregnant. Various types of specific dermatoses may occur during pregnancy, including pruritus, prurigo, papule, erythema and herpes(23). However, angioedema is not common in pregnancy. In the literature, we found 1 Japanese case with this disorder associated with pregnancy (12), but possible correlations between the angioedema and pregnancy remain unclear. IL-5possesses a wide variety of biological activities including the induction of eosinophil differentiation and proliferation. Butterfield et al. (6) demonstrated that, in the patients with this disorder, IL-5levels peaked several days before maximal eosinophilia. From our patient, we have obtained results consistent with such findings. These observations suggest that IL-5plays an important role in eosinophilia in episodic angioedema with eosinophilia. ACKNOWLEDGMENTS We wish to thank Dr. N. Tsuruoka (Suntory Institution for Biomedical Research, Osaka, Japan) for providing monoclonal and polyclonal antibodies to recombinant human interleukin-5. REFERENCES 1. Gleich GJ, Schroeter AL, Marcoux JP, Sachs MI, O'Connell EJ, Kohler PF:Episodic angioedema associated with eosinophilia. N Engl J Med 310:1621-1636, 1984 2. Katzen DR, Leiferman KM, Weller PF, Leung DYM:Hypereosinophilia and recurrent angioneurotic edema in a2-year-old girl. Am J Dis Child140:62-64, 1986 3. Wolf C, Pehamberger H, Breyer S, Leiferman KM, Wolf K:Episodic angioedema with eosinophilia. J Am Acad Dermatol20:21-27,1989 4. Schiavino D, Gentiloni N, Murzilli F, Gebreselassie M, Rocca LML, Patriarca G:Episodic angioedema with eosinophilia (Gleich syndrome). Allergol ET Immunopathol18:233-236, 1990 5. Lassalle P, Gosset P, Gruart V, Plin L, Capron M, Lagrue G, Kusnierz LP: Presence of antibodies against endothelial cells in the sera of patients with episodic angioedema and hypereosinophilia. Clin Exp Immunol 82:38-43, 1990 6. Butterfield JH, Leiferman KM, Abrams J, Silver JE, Bower J, Gonchoroff N, Gleich GJ:Elevated serum levels of interleukin-5in patients with the syndrome of episodic angioedema and eosinophilia. Blood79:688-692, 1992 7. Putterman C, Barak V, Caraco Y, Neuman T, Shalit M:Episodic angioedema with eosinophilia:a case associated with T cell activation and cytokine production. Ann Allergy 70:243-248, 1993 8. Tsurumachi K, Sakurai M, Nogi N, Nakayama H, Sugi T:Two cases of hyperiosinophilic syndrome with transient swelling of legs. Jpn J Clin Dermatol (Tokyo) (in Japanese) 32:999-1002, 1990 9. Tabe Y, Imayama S, Hori Y:Two cases of hypereosinophilic syndrome associated with prolonged edematous skin eruption. Nishinihon J Dermatol (Fukuoka,) (in Japanese) 52:896-900, 1990 10. Tsuda M, Mimura M. A case of episodic angioedema. Rinsho Derma (Tokyo) (in Japanese) 32:999-1002, 1990 11. Tsuda M, Mimura M. Two cases of episodic angioedema. Jpn J Dermatol (in Japanese) 100:408, 1990 12. Yamashita N, Yamaguchi R, Kawashima S, Hidano S:A case of angioedema with limbs with eosinophilia. Jpn J Dermatol (in Japanese) 101:663, 1991 13. Ohashi A, Ishida T, Yamamoto M, Tamaki S:Three cases of episodic angioedema with eosinophilia. Rinsho Derma (Tokyo) (in Japanese) 34:1751-1754, 1992 14. Nishimoto M, Nakashima K, Sasaki K, Sasaki M, Takaiwa T:Angioedema with eosinophilia. Jpn J Dermatol (in Japanese)103:533-538, 1993 15. Nishii Y, Kawatsu T:A case of Episodic angioedema associated with eosinophilia. Jpn J Clin Dermatol (Tokyo) (in Japanese) 47:991-995, 1993 16. Hara Y, Inoue T:Two cases of episodic angioedema associated with eosinophilia. Jpn J Clin Dermatol (Tokyo) (in Japanese) 48:367-370, 1994 17. Okahara K, Horiuchi K, Iwamoto T, Yamura M:Two cases of episodic angioedema associated with eosinophilia. Nishinihon J Dermatol (Fukuoka) (in Japanese) 58:764-766, 1996 18. Kawano M, Muramoto H, Tsunoda I, Koni I, Mabuchi H, Yachie A, Miyawaki T:Absence of CD 69expression on peripheral eosinophils in episodic angioedema and eosinophilia. Am J Hematology53:43-45, 1996 19. Fukuda Y, Hashino J, Haruyama M, Tsuruoka N, Nakazato H, Nakanishi T:A sandwich enzyme-linked immunosorbent assay for human interleukin-5. J Immunol Methods 143:89-94, 1991 20. Kazmierowski JA, Chusid MJ, Parrillo JE, Fausi AS, Wolff SM:Dermatologic manifestations of the hypereosinophilic syndrome. Arch Dermatol 114:531-535, 1978 21. Chusid MJ, Dale DC, West BC, Wolff SM:The hypereosinophilic Syndrome:Analysis of fourteen cases with review of the literature. Medicine 54:1-27, 1975 22. Wells GC, Smith NP:Eosinophilic cellulitis. Br J Dermatol 100:101-109, 1975 23. Burton JL, Rook A:The ages of man and their dermatoses. In:Rook A, Wilkinson DS, Ebling FJG, Champion RH, eds. Textbook of Dermatology 4th ed., Blackwell Scientific Publication, Boston, Mass1986, pp.275-277 Received for publication July 10, 1997;accepted July 31, 1997. 1 Address correspondence and reprint requests to Takanori Shikiji, M.D.,Department of Dermatology, The University of Tokushima School of Medicine, 3-18-15, Kuramoto-cho, Tokushima, Japan.