We report a case of a 75 year old woman addressed to Allergology Department of our hospital in January 2014 for recurrent episodes of angioedema since the age of 66, with progressively increased severity and frequency. It was first considered to be induced by treatment with angiotensin-converting-enzyme inhibitors (ACEI) for mild hypertension, but she continued to have angioedema attacks for the next 6 years after discontinuation of ACE, with progressive aggravation during the last year. The previous multiple evaluations by many specialists in other hospitals did not succeed to give a clear diagnosis and treatment.\nThe patient had no relevant medical history and took no medication, except ACEI that was stopped some months after angioedema onset. No relation with possible allergic stimuli could be identified and she had no clinical manifestations between attacks. Angioedema was painful, not accompanied by urticaria or abdominal symptoms, located variably to neck, arms or buttocks, without facial involvement during 6 years. The attacks occurred at weeks or months intervals and usually lasted between 48 and 72 h, irrespective of corticosteroids and antihistamines treatment usually administered. The frequency of attacks had progressively increased from one at 2–3 months intervals to almost weekly during the last year before presentation. The last angioedema attack, determining emergency hospitalization in September 2014, was more severe and prolonged, accompanied for the first time by laryngeal edema and respiratory symptoms. The extended medical evaluation, including complete blood tests for inflammation, allergy, autoimmunity and cancer, were all negative (Table ). Full body CT scan and bone marrow examination were normal. No criteria for lymphoproliferative, mieloproliferative or autoimmune diseases could be found. Measurement of C1 inhibitor (C1INH) in plasma showed significantly decreased level at all measurements, with low activity ranging from 58 to 4% and constantly low C4 (Fig. ). Complement fraction C1q plasma level was measured twice and had normal value. Genetic tests were not performed, given the patient advanced age and lack of family history of angioedema, which are against HAE. A spontaneous mutation in SERPING 1 gene is noticed in up to 25% cases of HAE without family history, but we considered this probability very low in our case, due to late onset of angioedema.\nTreatment of angioedema attacks before hospitalization consisted of antihistamines and systemic corticosteroids, which proved to be ineffective. Since no pathogenic therapy with C1INH concentrate, antagonists of bradikinin receptors (icatibant) or selective inhibitor of plasma kallikrein (ecallantide) was available in 2014, we first initiated daily prophylactic treatment with tranexamic acid for 3 months, with no amelioration. During the more severe attack with laryngeal edema, in September 2014, we have switched to attenuated androgen danazol, given 400 mg the initial dose, reduced to 200 mg daily after 1 week and then to 100 mg daily. The clinical evolution was very good, no angioedema attack occurred since the introduction of danazol. C1INH and C4 plasma levels increased after 2 weeks of treatment and became normal after 1 month. After some months, the patient decided herself to discontinue danazol for short time, in order to check effects and to taper the minimal dose. Serum C1-INH and C4 plasma levels were measured after 2 and 4 weeks and showed significant lower levels, but no angioedema attack occurred during this period of time. She therefore restarted danazol prophylactic therapy at a minimum of 50 mg dose daily, ongoing after 3 years. The patient was closely monitored during the next 3 years, with complete clinical and laboratory control twice a year. We took into consideration the possible side effects of danazol, mainly dislipidemia, haematological and liver malignancies and any other complications or concomitant diseases. The clinical evaluation was very good, except two episodes of pulmonary cysts infection, remitted with broad spectrum antibiotherapy, which could not be related to danazol treatment. The clinical outcome of angioedema after 3 years of danazol treatment is very good, with no attacks or other related symptoms. No clinical or laboratory sign of any disease that could induce C1 INH deficiency occurred. No relevant side effects of danazol were noticed. The patient has an improved quality of life due to therapeutic compliance and general management plan.
A 47-year-old man had symptoms of weekly recurrent angioedema attacks in lips, tongue, larynx, and scrotum for seven years and experienced swelling of larynx twice weekly in the last 3 months. He had been receiving antihistamines and the symptoms were relapsing during the antihistamine treatment. His signs and symptoms did not improve during administration of different nonsedating H1-antihistamines or increasing of the standard dosage up to fourfold of the daily. Emergency treatment with prednisolone and short acting antihistamines led him to a remission in emergency department visits. Urticaria was absent. Physical examination was unremarkable. He had no other disease and did not receiving drugs such as angiotensin-converting-enzyme inhibitors. Any of the relatives had no angioedema. Laboratory findings included normal values for complete blood count with differential, comprehensive metabolic panel including antinuclear antibody, thyroid stimulating hormone level, C4 level, C1 inhibitor function and level and total immunoglobulin (Ig) E level of 183 kU/L. Also C4 levels were all in normal range during the angioedema attacks. The patient did not attribute his angioedema to certain foods. But the stress is a trigger for him. Fluoksetine and 0.5 mg/kg prednisolon therapy was initiated and clemastine was recommended for the emergency new attacks during corticosteroid therapy. Soon after corticosteroid therapy patient's angioedema regressed. However he felt more depressed after the therapy and the treatment started to be tapered for this side effect. After reducing the corticosteroid dose angioedema attacks again progressed. Because of the patient's angioedema, 300 mg of omalizumab every 4 weeks administered subcutaneously after obtaining written informed consent. His last episode of angioedema was seen 3 days before initiation of therapy. He has tolerated tapering and cessation of his oral steroids and he has remained free of angioedema during 4 months of omalizumab therapy. After 3 months of stopping omalizumab therapy, during the 4-week period he had two mild lip swelling in his lips that resolved with antihistamines.