Naoko Inomata

Recent Advances in Drug-Induced Angioedema

Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life-threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs) in the causation of life-threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin-dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

Poor adherence to medication as assessed by the Morisky Medication Adherence Scale-8 and low satisfaction with treatment in 237 psoriasis patients

Previously we assessed the medication adherence for oral and topical remedies by a translated Japanese version of the Morisky Medication Adherence Scale‐8 (MMAS‐8) together with socioeconomic backgrounds in 3096 Japanese dermatological patients, and found the medication adherence, especially to topical drugs, was poor in these patients. In order to elucidate the disease‐specific sociomedical factors, we further sub‐analyzed the medication adherence in 237 psoriasis patients and compared it with that in other dermatological diseases such as atopic dermatitis, urticaria or tinea. This study was conducted among patients registered in monitoring system and 3096 eligible patients were enrolled. Our web‐based questionnaire included the following items such as age, sex, annual income, main health‐care institution, experience of effectiveness by oral or topical medication, overall satisfaction with treatment, and MMAS‐8 for oral or topical medication. Mean adherence score by MMAS‐8 was 5.2 for oral and 4.3 for topical medication. More patients with psoriasis used a university hospital and fewer used a private clinic compared with those with the other skin disease patients. Experience of drug effectiveness by oral medication and overall satisfaction with treatment was lower in psoriasis patients than in other patients. In oral medication, significantly better adherence was observed in those of higher age and with higher annual income. The adherence to medication, especially to topical drugs, was poor in 237 psoriasis patients. We speculated that some severe psoriasis patients were not sufficiently treated systemically and were resistant to topical therapy, leading to poor adherence.

Correlation of oral allergy syndrome due to plant-derived foods with pollen sensitization in Japan

BACKGROUND The clinical features of patients with oral allergy syndrome (OAS) due to plant-derived foods related to pollen allergy have been rarely reported in Japan. OBJECTIVES To evaluate the characteristics of OAS and to investigate whether pollen sensitizations are correlated with the prevalence of OAS in Japan. METHODS We measured specific IgE antibodies against 5 pollens in 622 outpatients (277 males and 345 females; mean age, 37 years) with atopic dermatitis, urticaria, angioedema, and food allergy during a 2-year period. Furthermore, OAS is diagnosed based on anamnesis and positive skin prick test reactions to suspected foods. RESULTS Eighteen of the 436 patients (4.1%) sensitized to pollens were diagnosed as having OAS. Rates of specific IgE antibody-positive responses against Japanese cedar, ragweed, orchard grass, mugwort, and alder pollen were 69.8%, 35.3%, 29.1%, 24.1%, and 19.6%, respectively. The prevalence of OAS showed a significant positive correlation with sensitization to alder (P < .001). In addition, the most frequent causative foods were found to be apple, peach, and melon. The prevalence of OAS due to apple showed a significant positive correlation with sensitization to alder (P < .001) pollen, due to peach showed a significant positive correlation with sensitization to alder (P < .001) and orchard grass (P < .05) pollen, and due to melon showed a significant positive correlation with sensitization to alder (P < .005), orchard grass (P < .05), and ragweed (P < .05) pollen. CONCLUSION Sensitization to pollens from species in the Betulaceae family is most strongly implicated in causing OAS in Japan.

Clinical Features of Four Cases with Cashew Nut Allergy and Cross-Reactivity between Cashew Nut and Pistachio

BACKGROUND Few cases of cashew nut (CN) allergy have been reported in Japan. We evaluated the clinical features of 4 cases with CN allergy and investigated the allergens involved. METHODS In order to investigate the cross-reactivity between CN and pistachios, we performed ImmunoCAP inhibition tests using sera of 4 cases with positive histories of CN allergy and positive results of specific IgE measurement (ImmunoCAP) and skin prick tests. Furthermore, we analyzed the molecular weights of allergens of CN and pistachios by IgE-immunoblotting. RESULTS Of the 4 cases (male : female = 1:3), there were 3 cases (patient #2-4) and 1 case (patient #1) of anaphylaxis and oral allergy syndrome, respectively. The initial symptom was an oropharyngeal symptom in 3 of the 4 cases, of which 2 cases developed anaphylaxis within 10 minutes after eating only a few pieces of CN. All 4 cases reacted positively to the skin prick test with CN, although 1 case of anaphylaxis tested negatively for CN by ImmunoCAP. Additionally, in 2 cases, IgE-binding to CN and pistachio were inhibited with both pistachios and CN, indicating cross-reactivity between CN and pistachios. IgE-immunoblotting of CN using sera from the 4 cases revealed 2 bands at molecular weights of approximately 33 kd and 42 kd, whereas that of pistachios showed a single band at 36 kd. However, IgE in all 4 sera did not bind to rAna o 2. CONCLUSIONS In CN allergy, a small amount of CN could induce a severe anaphylactic reaction. Moreover, in cases of suspected CN allergy, reactions to not only CN but also pistachio, which could be cross-reactive to CN, should be examined.

Improvement of digestibility, reduction in allergenicity, and induction of oral tolerance of wheat gliadin by deamidation

Wheat gliadin was deamidated by using a cation-exchange resin in the presence or absence of added cysteine, with the change in digestibility being measured. The allergenicity of the gliadin was evaluated by using sera from patients RAST-positive to wheat. Gliadin-specific IgE was measured after the gliadin had been orally administered to rats. The addition of cysteine before the treatment with a cation exchanger effectively increased the deamidation level of gliadin. Deamidated gliadin showed higher solubility than the undeamidated form. There was no difference in the peptic digestibility of the gliadin, whereas deamidation enhanced the pancreatic digestibility in vitro and the digestibility in the mouse stomach in vivo. Deamidation of gliadin reduced its reactivity toward the sera of patients with wheat allergy. Rats administered with deamidated gliadin showed suppressed elevation of the gliadin-specific IgE level.

Multiple H1‐antihistamine‐induced urticaria

H1‐antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H1‐antihistamines. However, a few cases of H1‐antihistamine‐induced urticaria have been reported. A 34‐year‐old woman presented with a 4‐month history of recurrent urticaria, which was prominently exacerbated by the administration of H1‐antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one‐fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H1‐antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E‐mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H1‐antihistamine‐induced urticaria may have been due to cross‐reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H1‐antihistamines should be considered when urticarial lesions worsen after H1‐antihistamine treatment.

Food allergy preceded by contact urticaria due to the same food: Involvement of epicutaneous sensitization in food allergy

BACKGROUND There have recently been reports suggesting that sensitization to food allergens may occur outside the intestinal tract, especially through the skin. To clarify the role of epicutaneous sensitization in food allergy, we investigated the clinical characteristics of adult patients with food allergies preceded by contact urticaria due to the same foods. METHODS We investigated clinical characteristics of 15 patients (20-51 years of age; 5 men and 10 women), who had food allergies preceded by contact urticaria. RESULTS Fourteen patients were contact urticaria due to the causative foods during occupationally cooking, whereas 1 patient during face pack. In the occupational group, causative foods included rice, wheat, fruits, vegetables, fish, shrimp and cuttlefish; in the fresh cucumber paste case the cause was cucumber. In the 15 patients, the causative foods were fresh, not processed, and were tolerated by most (9/15, 60%) after heating. Regarding to symptoms after ingestion of the causative foods, the most frequently induced symptoms was oral symptoms (14/15, 93.3%), followed by urticaria (4/15, 26.7%), abdominal symptoms (3/15, 20%). The duration between the start of jobs or face pack, and the onset of contact urticaria was from 1 month to 19 years (mean, 8.7 years). The duration between the onset of contact urticaria and the onset of food allergy was from a few weeks to 6 years (mean, 11 months). One sushi cook experienced severe anaphylactic shock after ingestion of fish. In the occupational group, 13 of 15 patients (86.7%) had atopic dermatitis or hand eczema, indicating that the impaired skin barrier might be a risk for food allergies induced by epicutaneous sensitization. CONCLUSIONS Epicutaneous sensitization of foods could induce food allergy under occupational cooking and skin-care treatment with foods in adults.

Sweet’s syndrome with gastric cancer

Solid tumors are found in about 15% of malignancy-associated Sweets syndrome, but only 3 cases of Sweets syndrome with gastric cancer have been reported. We describe a 59-year-old Japanese man with gastric cancer associated with Sweets syndrome.

Anaphylaxis caused by ingesting jellyfish in a subject with fermented soybean allergy: possibility of epicutaneous sensitization to poly-gamma-glutamic acid by jellyfish stings.

Dear Editor, Jellyfish stings are known to induce delayed allergic skin reactions, however, there have been few reports of reactions after jellyfish ingestion. We report herein on anaphylaxis after jellyfish ingestion in a subject allergic to fermented soybeans (natt o). A 45-year-old man presented with two episodes of anaphylactic reaction 2 h after dinners including jellyfish salad, accompanied by dyspnea, chest tightness, abdominal cramps, palpitations, vomiting, dizziness, headache and loss of consciousness. These reactions required emergency hospital care including hydration and i.v. antihistamines after self-injected adrenaline. The patient’s medical history revealed childhood bronchial asthma and adult-onset food allergies to natt o, crab and shrimp. The onset of the natt o allergy was 8 years prior to the episodes under consideration, and poly-gamma-glutamic acid (PGA) was identified as the causative allergen. The patient had surfed since the age of 20 years and had been frequently stung by jellyfish. The patient’s diet diaries revealed that jellyfish, which he consumed infrequently, was common to the two episodes, while he ate the other foods in the meals daily without incident. To identify the causative food in these two episodes, a skin prick test and a basophil activation test (BAT) were performed. The patient’s serum total immunoglobulin (Ig)E concentration was 4182 IU/mL. Specific IgE antibodies were detected against shrimp, crab, soybean and rice, but not against other ingredients (ImmunoCAP; Phadia, Uppsala, Sweden). Skin prick testing for desalted jellyfish (Kanetoku, Hyogo, Japan), natt o and PGA was positive with wheal diameters of 3.3 9 3.2, 8.1 9 5.1 and 11.9 9 5.8 mm, respectively (positive control, 10 mg/mL histamine hydrochloride, wheal diameter 6.9 9 5.6 mm; negative control, saline, wheal diameter 0 9 0 mm). In three healthy controls, skin prick testing for them was negative. BAT was performed using an Allergenicity Kit (Beckman Coulter, Fullerton, CA, USA) to quantify basophil CD203c expression as described previously (Fig. 1). Extract of jellyfish was found to enhance basophil CD203c expression in a concentration-dependent manner. Whole-blood BAT showed 35.7% CD203c-positive cells at 100 lg/mL of jellyfish extract in the patient. Anaphylactic reactions after jellyfish ingestion are rare. Imamura et al. reported a female surfer with jellyfish allergy, and speculate that she was sensitized by jellyfish stings; IgE immunoblotting suggested that the causative allergen was a high molecular weight of 200-kDa protein. Interestingly, PGA is known to be a major allergen of natt o with a high molecular weight ranging from 100 to over 1000 kDa, and has been detected only extracellularly in some prokaryotes, including natt o bacteria (Bacillus subtilis) and intracellularly in cnidarian nematocyte capsules. By attracting cations within the capsule, PGA is critical for nematocyte discharge, which involves rapid changes in intracapsular osmotic pressure. Furthermore, 10 of 12 natt o allergy cases (83.3%) in our hospital were surfers and/or divers frequently stung by jellyfish. Therefore, we speculate that our patient also might have been sensitized to jellyfish nematocyte PGA by stings via the skin during surfing, and consequently developed the anaphylactic reactions to ingested jellyfish and natt o. Further investigation is needed to clarify whether the causative allergen of jellyfish may be PGA and may be cross-reactive to natt o PGA.

High prevalence of sensitization to gibberellin‐regulated protein (peamaclein) in fruit allergies with negative immunoglobulin E reactivity to Bet v 1 homologs and profilin: Clinical pattern, causative fruits and cofactor effect of gibberellin‐regulated protein allergy

Gibberellin‐regulated protein (GRP) is a new allergen in peach allergy, with an amino acid sequence very well conserved through several botanical species. We investigated the allergenicity of GRP in fruit allergies other than peaches and identified the clinical characteristics of fruit allergy patients with GRP sensitization. One hundred consecutive Japanese patients with fruit allergies were enrolled in the present study. To identify the features of GRP sensitization, we selected patients with negative ImmunoCAP results for Bet v 1 homologs and profilin, which are marker allergens for pollen‐food allergy syndrome (PFAS), or lipid transfer protein. These patients underwent specific immunoglobulin E measurements by enzyme‐linked immunosorbent assay (ELISA) and skin prick tests (SPT) using purified nPru p 7. Twenty of 100 consecutive patients with fruit allergies had negative ImmunoCAP results for Bet v 1 homologs and profilin. Thirteen (65.0%) of the 20 patients had positive ELISA and/or SPT results using nPru p 7, whereas one of the 20 patients had positive ImmunoCAP results for Pru p 3. In 13 nPru p 7‐sensitized patients, the causative foods were peaches (92.3%), apricots (61.5%), oranges (46.2%) and apples (30.8%). Ten patients (76.9%) had multiple causative fruits. Frequent symptoms included facial edema (92.3%) and laryngeal tightness (66.7%). In eight patients (61.5%), exercise or aspirin intake enhanced the allergic reaction onset as cofactors. The prevalence of GRP sensitization was high in Japanese fruit allergy patients except for PFAS patients. In conclusion, GRP‐sensitized patients may have allergies to multiple fruits and may show peculiar characteristics such as facial swelling and cofactor dependence.