The patient was a 27-year-old man with a history of recurrent episodes of angioedema. The episodes begun when he was 19 years old, and their frequency and severity had been rising over the previous six months. There was a history of urticaria following penicillin administration in early childhood, but there were no other known allergies.\nInitially, the episodes were manifested by mild urticaria which resolved spontaneously. But the severity and frequency of attacks increased over the years. In the last few months, the attacks became more frequent, at least twice a month, and included autonomic dysfunction: one episode of syncope and a few presyncopal episodes associated with scrotal and neck swelling and abdominal pain. Two of the episodes were considered “life threatening” due to imminent airway obstruction and were treated with subcutaneous epinephrine and intravenous steroids, which were tapered down gradually after each episode. Due to the severity of the episodes, the patient was instructed to carry epinephrine 0.3 mg autoinjector (EpiPen) at all times.\nExtensive search for possible etiology was carried out. Ancillary studies were nonproductive. Blood tests included a complete blood count, full chemistry panel, serum levels of thyroid stimulating hormone, antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, C-1 inhibitor activity, tryptase, and chromogranin. Urinary vanillylmandelic acid and 5-hydroxyindoleacetic acid were also negative, as were urine and stool tests for OVA and parasites. Imaging studies (chest roentgenograms, abdominal ultrasound) did not show evidence of echinococcal infection, and endoscopically obtained biopsies from the GI tract did not show eosinophils or mast cells. Skin biopsy was negative for C-KIT, and bone marrow aspiration showed no evidence of increased mast cell count and was negative for tryptase and C-KIT. While the workup was in progress, the patient was placed on prophylactic antihistamines, using several preparations, but the attacks persisted, and periodically supplemental steroids were necessary.\nThe patient disclosed that from time to time he was using marijuana socially and that it seemed to him that the attacks were less frequent when he did. The patient declared that he did not prepare the cigarette himself, so we presumed he did not have a significant skin contact with cannabis. The history was consistent with the known effect of cannabis on the immune system as described in the introduction, so we conjectured that marijuana may have had a modulatory effect facing failure of other treatment modalities. We suggested that the patient should try medical grade marijuana inhalations (cannabis products for medical indications may be legally used in Israel, but authorization by the Ministry of Health is required for each individual patient and prescription must be renewed monthly). The patient was informed that there was no supporting evidence in the medical literature for this treatment in his condition but that the potential risk for side effects was minimal and he consented to try. He was instructed not to drive or engage in other potentially risky activities during treatment.\nWe prescribe a total of 20 grams of medical grade marijuana per month, inhaled two to three times a week, which in Israel is the minimal accepted dosage for medical indications. The patient stayed on this dose for two years during which the patient did not have a single attack and no adverse effects were observed. After two years, the patient tried to stop treatment, on his own initiative, but developed a recurrent severe attack a week later. After resuming the treatment no further attacks were observed over the next 4 months of close followup (the regulations for legal use of medical marijuana stipulate that the prescription must be renewed monthly). The timeline of the course of the disease is depicted in .
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.