A 28-year-old female patient visited the Department of Allergy and Clinical Immunology, Cheju Halla General Hospital, due to eosinophilia. In the past, she suffered from atopic dermatitis, allergic rhinitis and chronic urticaria for 24 years and from severe depression with numerous suicide attempts for 14 years.
In the diagnosis of chronic urticaria, all patients showed urticaria, skin rash (including urticaria) and itching over 6 weeks. The symptoms and signs of chronic urticaria, such as skin rash, itching and urticaria, were well controlled by antihistamine (levocetrizine, a H1 receptor blocker) and did not show any positive findings in prior diagnostic examinations in other hospitals. According to the definition of chronic urticaria , the patients were diagnosed with chronic urticaria.
Basic allergy tests (blood tests and skin prick tests) were conducted on all three patients before and after treatment. They underwent blood tests to determine the complete blood count with the differential count, serum eosinophil cationic protein, serum total IgE and IgE levels for specific allergens using a multiple allergosorbent test (MAST, Green Cross PD, Korea). In the MAST test, the specific IgEs for 41 allergens were evaluated, including Dermatophagoides pteronyssinus (Dp), Dermatophagoides farina (Df), cat, dog, egg white, milk, soybean, crab, shrimp, peach, mackerel, rye pollen, house dust mite, cockroach, Clasporium herbarum, Aspergillus fumigatus, Alternaria alternata, birch-alder mix, white oak, short ragweed, mugwort, Japanese hops, hazelnut, sweet vernal grass, Bermuda grass, orchard grass, timothy grass, reed, Penicillium notatum, sycamore, sallow willow, poplar mix, ash mix, pine, Japanese cedar, acacia, oxeye daisy, dandelion, Russian thistle, goldenrod and pigweed. The test results showed the level of specific IgE for each allergen, and a normal negative range was 0.000-0.349 IU/mL.
A skin prick test was also performed for 53 allergens. The allergens tested by the skin prick test were Alternaria alternata, Aspergillus fumigatus, Aspergillus nigre, Candida albicans, Cladosporium, Penicillium chrysogenum, German cockroach, Dp, Df, dog, cat, grey elder/silver birch, grass mix, mugwort, short ragweed, black willow pollen, orchard grass, Bermuda grass, timothy grass, English plantain, English rye grass, Holm oak, Japanese cedar, cotton flock, milk mix, egg mix, chicken, beef, pork, cod, oyster, salmon, prawn, mackerel, tuna, almond, peanut, bean, carrot, cabbage, walnut, maize, peach, tomato, black pepper, spinach, wheat flour, rabbit, kapok, hops, acacia, pine and poplar. Skin prick tests were performed on the back of the patient. The area to be tested was cleaned with alcohol and coded with a skin marker corresponding to the number of allergens being tested. The marks were 2 cm apart. A drop of allergen solution was placed beside each mark. A small prick through the drop was made into the skin using a Morrow Brown NeedleⓇ (Morrow BrownⓇ Allergy Diagnostics, USA) by holding the needle perpendicular to the test site and punching firmly through the tested extract and into the epidermis. The drop was removed immediately after the skin was pricked, and the used needle was discarded immediately. Histamine hydrochloride (1 mg/ml) was used as a positive control, and physiologic saline was used as a negative control. The results were determined according to the wheal size. Reactions were read after 15 min and described as negative (0, no reaction), 1+ (reaction greater than the control reaction but smaller than half the size of the reaction to histamine), 2+ (equal to or more than half the size of the histamine reaction), 3+ (equal to or more than the size of the histamine reaction) and 4+ (equal to or more than twice the size of the histamine reaction). The minimum size of a positive reaction was 3 mm.
In the laboratory tests, the elevation of the eosinophil fraction based on the complete blood counts with differential counts was as high as 11.05% (normal < = 5%), and the blood eosinophil cationic protein level was as high as 54.3 ng/ml (normal < = 24 ng/ml). The serum total IgE level was as high as 3112 IU/ml (normal < = 350). According to the MAST, the positive allergens were Dp (> 100), Df (> 100), cat (76.75), Clasporium herbarum (0.56), Alternaria alternata (0.35), short Ragweed (0.48), mugwort (2.82), hazelnut (1.67), orchard grass (0.54), timothy grass (0.49), Penicillium notatum (0.65), sallow willow (26.85), Japanese cedar (7.60), oxeye daisy (8.14), dandelion (3.63) and goldenrod (11.23). The skin prick test results were positive for allergens of Dp (7/5), Df (10/6), dog (2/3), cat (5/4), mugwort (24/9), short ragweed (4/4), black willow (3/3), Japanese cedar (6/4), almond (3/3), bean (3/3), and histamine (7/5), and the normal control results were 0/0.
The clinical progress of chronic urticaria was recorded as the frequency of allergic episodes, including the development of urticaria, skin rashes, and/or itching and the frequency of antihistamine intake.
Patients were evaluated before and after treatment to determine their mood using the Beck Depression Inventory (BDI)-2 for depression (normal < = 13, mild 14–19, moderate 20–28, severe 29<=) and the State-Trait Anxiety Inventory (STAI) for anxiety 
(state: normal < = 51, mild 52–56, moderate 57–61, severe 62<=; trait: normal < = 53, mild 54–58, moderate 59–63, severe 64<=). The patient in case 1 was the first case who presented symptoms and was the motivation for this study, and the BDI and STAI were not conducted. For the patient in the first case, the frequency of suicidal urges with depressive mood during one week was recorded as the 1st indicator for psychiatric evaluation.
Patients received 2 ml of Histobulin (12 mg human immunoglobulin/0.15 µg histamine complex) once a week by subcutaneous injection in the deltoid area of the upper arm. Patients were instructed to take a tablet of 5 mg levocetrizine every day if necessary when they felt uncomfortable due to urticaria, skin rash or especially itching that prevented them from engaging in activities of normal daily living.
Before Histobulin treatment, allergic symptoms and signs related to chronic urticaria and allergic rhinitis occurred nearly every day. Depressive mood changes occurred, and the patient had suicidal urges every day. By using antihistamines, the allergic symptoms and signs were well controlled, but the psychiatric manifestations such as depressed mood and suicidal urges were not changed.
Histobulin therapy was attempted for the treatment of allergic rhinitis and chronic urticaria. Allergic rhinitis began to improve after 3 injections of Histobulin. Surprisingly, the frequency of suicidal urges also decreased simultaneously. Thereafter, the severity of the psychiatric manifestations were correlated with the severity of the allergic status (Fig. 1A). Consequently, after 26 injections of histobulin, the allergic rhinitis and chronic urticaria had remitted, and the concomitant depression and suicidal urges also disappeared.