松永 佳世子

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening severe cutaneous adverse drug reactions. These diseases are rare, and their onset is difficult to predict because of their idiosyncratic reactivity. The Japan Severe Adverse Reactions Research Group, led by the National Institute of Health Sciences, has operated a nationwide to collect clinical information and genomic samples from patients with SJS/TEN since 2006. This study evaluated the associations of clinical symptoms with sequelae and specific causative drugs/drug groups in Japanese patients with SJS/TEN to identify clinical clues for SJS/TEN treatment and prognosis. Acetaminophen, antibiotics, and carbocisteine were linked to high frequencies of severe ocular symptoms and ocular sequelae (p < 0.05). For erythema and erosion areas, antipyretic analgesics had higher rates of skin symptom affecting <10% of the skin than the other drugs, suggesting narrower lesions (p < 0.004). Hepatic dysfunction, was common in both SJS and TEN, and antiepileptic drugs carried higher risks of hepatic dysfunction than the other drug groups (p = 0.0032). This study revealed that the clinical manifestations of SJS/TEN vary according to the causative drugs.

INTRODUCTION: Screening for ω-5 gliadin specific IgE antibody (sIgE) has high diagnostic utility in cases of suspected wheat-dependent exercise-induced anaphylaxis (WDEIA); however, negative cases may require confirmatory tests, such as the oral challenge test. Thus, newly identified allergens that can be used for the serological diagnosis of WDEIA are needed. This study aimed to identify additional sIgE biomarkers of WDEIA. METHODS: Forty-two patients with WDEIA (5 negative/37 positive for ω-5 gliadin sIgE) were enrolled. For comparison, 8 patients with immediate-type wheat allergy without WDEIA and 20 healthy controls without wheat allergy were also enrolled. Extracted wheat proteins were separated by 2D-PAGE. Proteins that reacted with serum IgE antibody in 2D Western blotting (2D-WB) were identified using mass spectrometry. Recombinant proteins were synthesized in Escherichia coli, and the antigenicity was tested using ELISA and the basophil activation test. RESULTS: In 2D-WB, nine proteins reacted with the serum IgE antibody from at least 60% of patients with WDEIA (n ≥ 25/42). ELISA revealed that alpha/beta gliadin MM1 exhibited the highest positive immunoreactivity in 23 of 26 patients who were positive for ω-5 gliadin sIgE (88%) and in 5 of 5 patients who were negative for ω-5 gliadin sIgE (100%). Alpha/beta gliadin MM1 exhibited significantly higher basophil activation in 14 patients with WDEIA when compared to 5 individuals without a wheat allergy. CONCLUSIONS: Alpha/beta gliadin MM1 sIgE exhibited the highest seropositivity, even among patients who were negative for ω-5 gliadin sIgE. The inclusion of alpha/beta gliadin MM1 in allergen-sIgE tests may improve the sensitivity for diagnosing WDEIA.

＜文献概要＞症例のポイント ・デュアック配合ゲル[クリンダマイシン(CLDM)リン酸エステル水和物1%-過酸化ベンゾイル(BPO)3%ゲル]によるアレルギー性接触皮膚炎(allergic contact dermatitis:ACD)の1例を経験した.・成分パッチテストの結果より,原因物質はBPOとCLDMリン酸エステルの両者と同定した.・ざ瘡治療薬は成分が重複するので,使用可能な薬剤を指導するためには,成分パッチテストが不可欠である.

Background: Allergic contact dermatitis (ACD) caused by hexavalent chromium (Cr(VI)) is often severe and difficult to treat. The content of Cr(VI) in cement can be reduced by, for example, addition of iron(II) sulfate. Since 2005 the content of Cr(VI) in cement is regulated in the EU Directive 2003/53/EC and must not exceed 2 ppm. Since this regulation came into force, ACD caused by cement has markedly been reduced. Objective: To investigate Cr(VI) and total chromium content in samples of cement from countries within and outside the EU. Methods: The members of the International Contact Dermatitis Research Group (ICDRG) were invited to participate in the study with the aim to collect cement samples from geographically different areas. The content of Cr(VI) in the samples was estimated by the diphenyl carbazide spot test, atomic absorption spectroscopy was used to assess the total chromium content. Results: Forty-five cement samples were analyzed, containing amounts of Cr(VI) from <0.1 to >70 ppm. Twenty-one samples contained >2 ppm Cr(VI), 24 contained less. Four of 17 samples from within the EU contained >2 ppm Cr(VI), that is, higher amounts than stipulated in the EU directive, as compared with 17 samples from countries outside the EU. Conclusion: In countries outside the EU, significantly more cement samples contained >2 ppm Cr(VI).

BACKGROUND: Immediate allergy caused by natto, a popular Japanese food prepared by fermenting soybeans with Bacillus subtilis var. natto, has been reported. Polygamma glutamic acid (PGA) in the sticky substance around natto beans has been reported to be a causative allergen of natto allergy. However, some of our patients with natto allergy were negative for PGA in the skin prick test (SPT). The sticky substance of natto beans contains a subtilisin family serine protease, nattokinase, along with PGA. In this study, we aimed to examine the antigenicity of nattokinase in natto allergy. METHODS: Eight patients, who developed symptoms after ingesting natto and positively reacted to natto (seven to the sticky substance in natto and one to the whole natto product) in their SPT, were enrolled in this study. To analyze IgE reactivity, we performed immunoblotting, ELISA, and SPT for natto (bean and sticky substance), and/or PGA, and/or nattokinase and/or cultured B. subtilis var. natto extract. RESULTS: In the SPT, four cases each were PGA-positive and PGA-negative. Immunoblotting of the sera from PGA-negative patients showed a protein band at 30 kDa, which was identified as nattokinase. Three PGA-negative cases, but not three PGA-positive cases, showed a positive reaction to nattokinase in the SPT and had a history of atopic dermatitis. The ELISA for nattokinase revealed a positive reaction of PGA-negative cases and negative reaction of PGA-positive cases in the SPT. CONCLUSIONS: We identified a subtilisin family serine protease, nattokinase, as a novel allergen in natto allergy patients unsensitized to PGA.

Background: Most cases of food-dependent exercise-induced anaphylaxis (FDEIA) are caused by eating wheat or crustaceans. However, fruits or vegetables may rarely act as allergens for FDEIA. We report a rare case of FDEIA caused by eating carrots. Case Presentation: An 8-year-old boy developed an anaphylactic reaction while playing, after eating lunch that included cooked carrots. Serum carrot-specific immunoglobulin E level was 0.19 UA/mL. The prick-by-prick test for raw carrots was positive (wheal diameter: 4 mm). The patient developed urticaria after exercise provocation tests following ingestion of raw carrots. Carrot proteins were analyzed by 2-dimensional Western blotting to identify the causative allergens. Nine proteins were identified as candidate antigens at 21-66 kDa. Conclusions: Our patient presented with FDEIA symptoms after ingesting both raw and cooked carrots. Both raw and cooked carrots contain 9 proteins that may induce FDEIA.

BACKGROUND: Some patients with wheat allergy have been reported to show clinical cross-reactivity to barley. However, it is not clear whether the development of barley allergy in patients with wheat allergy is due to cross-antigenicity between wheat and barley. This study aimed to determine the clinical cross-reactivity and immunological cross-antigenicity of wheat and barley. METHODS: The results of barley oral food challenges (OFCs) were compared before and after oral immunotherapy (OIT) for wheat in nine patients with wheat allergy to estimate the clinical cross-reactivity of wheat and barley. Moreover, we performed enzyme-linked immunosorbent assay (ELISA) inhibition and immunoblotting inhibition using serum from seven patients allergic to wheat and barley. RESULTS: Nine patients who had positive barley-OFC results performed before OIT for wheat were all negative on barley-OFC performed after OIT. In ELISA inhibition, preincubation of serum from patients allergic to wheat and barley with a high barley extract concentration inhibited binding of IgE to wheat extract by less than 10%. On the other hand, wheat and barley extracts equally inhibited binding to barley sIgE at high concentrations. In the immunoblotting inhibition test, the spots of wheat were inhibited but weakly by barley extracts, and most of the spots of barley were inhibited even by low concentrations of the wheat and barley extract. CONCLUSIONS: We showed that barley allergy associated with wheat allergy is caused by cross-reactivity from wheat. The OIT for wheat is one of the promising options for barley allergy.

Gibberellin-regulated protein (GRP) is a fruit severe allergen. The amounts of GRP expression normalized against actin in peach were determined by reverse transcription-quantitative PCR (RT-qPCR). The results were consistent with those determined by enzyme-linked immunosorbent assay (ELISA). The GRP expression was more evident in flesh than peel and increased rapidly in the maturing period. This approach is applicable to estimate the amount of GRP in other plants.

塩化リゾチームは殺菌作用のある物質で,かつては多くの医薬品に有効成分として含まれていた.今回,塩化リゾチームを含有するデオドラントスプレーによりアナフィラキシー症状を呈した症例を経験した.【症例】鶏卵アレルギーで卵を部分解除中の10歳女児.卵白由来塩化リゾチームを含有するデオドラントスプレーを散布した直後から噴霧部の膨疹と喘鳴,呼吸困難が出現し顔面蒼白となったため救急外来を受診した.原因としてデオドラントスプレーが疑われたため,同製品と塩化リゾチームでプリックテストおよび好塩基球活性化試験を実施したところ,いずれの検査でも両者ともに陽性であった.【考察】病歴と検査結果よりデオドラントスプレーに含まれる塩化リゾチームによるアナフィラキシーと診断した.医薬部外品に含有される塩化リゾチームは表示指定成分としての表示義務はあるが,卵白由来である記載がない場合も多い.鶏卵アレルギー患者に対しては塩化リゾチームを含む商品の使用を控えるよう,注意喚起が重要である.(著者抄録)

Cocamidopropyl betaine (CAPB) is an amphoteric surfactant. It has several functions, including producing effervescence and washing effects, and thus, it is used in many cleansing products, such as shampoo and liquid body cleansers. Recently, it has become clear that some impurities that arise during the manufacturing process can have sensitizing effects. Herein, we report a case of allergic contact dermatitis caused by detergents containing CAPB, in which an impurity was determined to be the possible causative agent by patch testing and chemical analysis.A 64-year-old Japanese female developed a skin rash on the hairlines of her forehead and nuchal region one month before her first visit to our clinic. Later, the rashes, which were composed of desquamative erythema, expanded to her face, neck, upper back, and chest. Patch tests produced positive results for a shampoo and liquid body cleanser (1% aq.) that she had used as well as for CAPB (1% aq.); lauramidopropyl betaine (LAPB) (1% aq.); and lauramidopropyl dimethylamine (LAPDMA) (0.05% aq.), which is an impurity of CAPB. The rashes resolved completely after we instructed her to use products without CAPB and LAPB. When issuing such instructions, clinicians should have correct knowledge about surfactants, such as the differences between cosmetic ingredient names and quasi-drug ingredient names.

BACKGROUND: Lysozyme chloride is a bactericidal substance that is included as an active ingredient in many medicines and quasi-drugs. We experienced a case of anaphylactic reaction caused by deodorant spray-containing lysozyme chloride. CASE: The patient was a 10-year-old girl who had an egg allergy. She visited an emergency department because of urticaria, wheezing, dyspnea, and pallor after she used deodorant spray that contained lysozyme chloride derived from hen's egg white. Results for deodorant spray and lysozyme chloride were positive in both skin prick tests and basophil activation tests. According to the medical history and the results, her condition was diagnosed as an anaphylactic reaction to lysozyme chloride in the deodorant spray. DISCUSSION: Although ingredient labelling is obligatory for lysozyme chloride in quasi-drugs, lysozyme chloride is not often described to be derived from egg white. It is important to alert patients with egg allergy to avoid lysozyme chloride-containing products.

BACKGROUND: The Japanese baseline series (JBS), established in 1994, was updated in 2008 and in 2015. The JBS 2015 is a modification of the Thin-layer Rapid Use Epicutaneous (TRUE) test (SmartPractice Denmark, Hillerød, Denmark). No nationwide studies concerning the TRUE test have previously been reported. OBJECTIVES: To determine the prevalence of sensitizations to JBS 2015 allergens from 2015 to 2018. METHODS: We investigated JBS 2015 patch test results using the web-registered Skin Safety Case Information-Net (SSCI-Net) from April 2015 to March 2019. RESULTS: Patch test results of 5865 patients were registered from 63 facilities. The five allergens with the highest positivity rates were gold sodium thiosulfate (GST, 25.7%), nickel sulfate (24.5%), urushiol (9.1%), p-phenylene diamine (PPD, 8.9%) and cobalt chloride (8.4%). The five allergens with the lowest positivity rates were mercaptobenzothiazole (0.8%), formaldehyde (0.9%), paraben mix (1.1%), mercapto mix (1.1%), and PPD black rubber mix (1.4%). CONCLUSIONS: Nickel sulfate and GST had the highest positivity rates. The JBS 2015, including a modified TRUE test, is suitable for baseline series patch testing. This article is protected by copyright. All rights reserved.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

Individuals who used skin-whitening cosmetics (quasi-drugs) containing 2% rhododendrol-containing agents, developed leukoderma at a higher frequency than those who have used other skin-whitening cosmetics. The Rhododenol Research Team (RD-Team) was formed and commissioned by Kanebo Cosmetics Inc. to conduct research in treatments of rhododendrol-induced leukoderma (RDL), to evaluate effective treatment options from a medical standpoint, and provide information to a wide range of people. In this study, we evaluated the efficacy of various treatments for RDL from a medical perspective, based on the information published in the literature as original or review articles. We searched the PubMed (international) and the Igaku Chuo Zasshi (ICHUSHI) (Japanese) databases using the keywords "Rhododenol" and "rhododendrol", for articles published between July 2013 and November 2020. We discuss the main clinical findings and treatments (topical, oral, phototherapy, and surgical) of this condition based on the literature review. We found that ultraviolet light therapy is the most effective treatment for RDL. We have also summarized reports of the efficacy of oral vitamin D3 in RDL. A topical prostaglandin derivative has been reported in a new study to be effective. We have provided guidance for patients using self-tanning and skin-whitening agents to improve their quality of life. Finally, we have highlighted the importance of providing patients with information on contact dermatitis and instructing them to discontinue product use immediately if they develop any symptoms of contact dermatitis while using skin-whitening agents.

A small proportion of individuals utilizing cosmetics containing rhododendrol developed leukoderma with various pathological conditions, in some cases indistinguishable from vitiligo. In this review, we investigate and evaluate the major considerations for developing rhododendrol-induced leukoderma based on data from original or review articles published in the literature to provide a wide range of information regarding the pathophysiology, mechanisms, risk evaluation, and possible mechanism-based treatments. We compile and discuss the latest information, including data related to the cytotoxicity of rhododendrol, cytoprotective functions, and involvement of the immune system, and consider the possibility of novel treatments based on the differences between individual patients and on the mechanism underlying the onset of the condition. Understanding the pathophysiology of rhododendrol-induced leukoderma helps not only elucidate the mechanisms of non-segmental vitiligo onset and progression, but also suggests prevention and treatment.

An 8-year-old boy with poor control of atopic dermatitis could eat potato products such as French fries without restrictions until 21 months of age. However, he developed generalized urticaria after eating potato products at the same age. Therefore, potatoes were excluded from his diet; nevertheless, he continued to consume a very small amount of potato starch but was without symptoms until the age of 8 years. At this age, he developed anaphylaxis after consuming potato starch and required administration of intramuscular epinephrine. He tested positive for potato-specific immunoglobulin E, skin prick test, and basophil activation test. He developed severe eczema with dry skin and erosion. We later discovered that potato starch had been used for play clay at his nursery school. Although he discontinued using potato starch play clay, it remained present in his surroundings for 6 years. His potato allergy may have developed and continued to worsen as a result of making indirect contact with surfaces that had previously been exposed to the allergen. Two-dimensional Western blot analysis on potato starch revealed the presence of proteins binding to the immunoglobulin E of the patient. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis findings showed that 5 of the 6 protein bands had a similar molecular weight as that of potato proteins. Thus far, there are no reports of anaphylaxis due to potato starch. Children with atopic dermatitis or damaged skin may have sensitivity to potato starch and could develop anaphylaxis as noted in this case.

BACKGROUND: There is controversy over late and long-lasting reactions to gold sodium thiosulfate (GST). OBJECTIVES: To study the GST patch-test reaction by observing the application site after 1 month, and to clarify the relevance of GST sensitization by piercings and dental metals. PATIENTS: A retrospective analysis was performed on 746 patients (143 male; 603 female) who were patch tested using GST of the TRUE Test. We conducted a questionnaire on the presence of piercings or dental metals in these patients. RESULTS: The GST positive rate was 27.9% at day (D)3 and/or D7 and 40.3% up to the 1-month reading. The positive rate was significantly higher in female patients and increased with age. Sixty-two percent of cases with a positive reaction at D7 continued to show a positive reaction after 1 month. Eleven percent of cases with a negative reaction at D3 and D7 showed a late reaction. Both piercings and dental metals were related to gold sensitization. CONCLUSIONS: The GST of the TRUE Test had a high positive and low false-negative rate. The 1-month reading after the patch test was important for identifying late reactions. Piercing history and dental metal were associated with gold sensitization.

皮下間質液中のグルコースを測定する持続血糖モニターのFreeStyleリブレは2017年から使用され始めた。本邦でのアレルギー性接触皮膚炎の報告は今のところは稀であるが、今回、接着部テープによるアレルギー性接触皮膚炎を発症した糖尿病患者3例を報告する。3例中2例で行った成分パッチテストからテープ部に含まれるアクリル酸イソボルニル(IBOA)が原因アレルゲンであることが判明した。当院では15例が使用し、ほか2例も紅斑やそう痒が出現していた。今後もFreeStyleリブレの使用例の増加が予想され、IBOAは注意すべきアレルゲンとして重要である。(著者抄録)

2015年に化粧品による接触皮膚炎を疑った69例(男性2例、女性67例、平均年齢44.6歳)を対象に、背部または上腕外側に48時間閉鎖貼付によるパッチテスト(PT)を施行した。試料は患者が持参した化粧品とJapanese standard allergens 2008または2015および化粧品関連アレルゲンとした。判定は72時間または1週間後にInternational Contact Dermatitis Research Group基準で+以上を陽性とした。化粧品または関連アレルゲンのPTが陽性で臨床的に関連性があると考えられた症例は14例で、原因製品は9製品であった。最も多い原因製品はヘアカラー剤であった。例年と比較して特に増加傾向の陽性製品や新規のアレルゲンは認めなかった。

Fish collagen is one of the major allergens involved in fish allergies; however, it has not been well-established whether fish collagen can cause anaphylaxis among individuals with fish allergies, especially children. A 9-year-old girl experienced anaphylaxis after consuming 2 fruit-flavored gummy tablets. Contacting the manufacturing company revealed that fish-derived collagen was used in the gummy tablets, and an oral fish collagen challenge test confirmed that the anaphylaxis was induced by fish collagen. Immunoblot analysis showed a 120-kDa band in a sample of the fish collagen in the gummy tablets, and no reactive band of the pork gelatin was observed. Additionally, salmon collagen and other fish samples that provoked symptoms were detected as a 120-kDa band in the immunoblot analysis. The 120-kDa band was identified as fish collagen by mass spectrometry confirming that it was the causative antigen of our patient's allergy. This case study confirms that fish collagen can cause anaphylaxis in children with fish allergies. Physicians and allergic individuals need to be aware that processed foods may contain fish collagen to avoid allergic reactions.

＜文献概要＞症例のポイント ・顔面全体の発赤と顕著な浮腫を伴う,デュアック配合ゲル(クリンダマイシンリン酸エステル水和物/過酸化ベンゾイル,サンファーマ株式会社)によるアレルギー性接触皮膚炎の2例を経験した.・パッチテストを施行し,原因成分は2症例とも過酸化ベンゾイルおよびクリンダマイシンリン酸エステルと同定した.・過酸化ベンゾイルの外用によるケラチノサイトの障害でバリア機能が低下することで,経皮感作がおこりやすくなり,比較的短期間で接触皮膚炎を発症した可能性が考えられた.

Racemic RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol; trade name: Rhododenol [RD]), which is used in topical skin-lightening cosmetics, was unexpectedly reported in Japan to induce leukoderma or vitiligo called RD-induced leukoderma (RIL) after repeated application. To our knowledge, no studies have investigated chemical-induced vitiligo pathogenesis on a genome-wide scale. Here, we conducted a genome-wide association study (GWAS) for 147 cases and 112 controls. CDH13, encoding a glycosylphosphatidylinositol-anchored protein called T-cadherin (T-cad), was identified as the strongest RIL susceptibility gene. RD sensitivity was remarkably increased by T-cad knockdown in cultured normal human melanocytes. Furthermore, we confirmed tyrosinase upregulation and downregulation of the anti-apoptotic molecules (BCL-2 and BCL-XL), suggesting that T-cad is associated with RD via tyrosinase or apoptotic pathway regulation. Finally, monobenzyl ether of hydroquinone sensitivity also tended to increase with T-cad knockdown, suggesting that the T-cad could be a candidate susceptibility gene for RIL and other chemical-induced vitiligo forms. This is the first GWAS for chemical-induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.

コチニール色素は雌のエンジムシ由来の赤色の着色料で、多くの食品や化粧品に使用される。コチニール色素による即時型アレルギーは成人女性に多く発症することから化粧品による経皮感作が考えられており、本邦では現在までに30例の報告があり、1例を除く全例が成人女性に生じ、90%にアナフィラキシーを生じた。原因食品は国内製造のイチゴ飲料、魚肉ソーセージ、フランス産のマカロンの報告が多い。化粧品による局所症状の既往は約半数に認められた。診断にはプリックテストとコチニール特異的IgE抗体の測定が有用である。(著者抄録)

Background: Serological testing for immunoglobulin (Ig) E or IgG is useful for diagnosing allergic bronchopulmonary aspergillosis (ABPA), as it detects type I and III allergic reactions to Aspergillus species. However, few reports have investigated the allergen component and cross-reactivity among Aspergillus species. We aimed to measure and analyze the levels of IgGs specific to each Aspergillus species and investigate the prevalence of IgEs specific to each allergen component of A. fumigatus (Af) in ABPA patients.Methods: Serum samples were collected from 12 ABPA patients who visited our hospital between February and December 2017, and 16 with Af-sensitized asthma and 41 with Af-unsensitized asthma were controls. Immuno-CAP was performed to analyze the IgEs and IgGs specific to Af, A. niger, A flavus and A. terreus, and IgEs specific to allergen components Asp f 1, 2, 3, 4 and 6.Results: The ABPA group was significantly more frequently sensitized to Asp f 1 and 2 than the control groups. Af-specific IgEs were significantly positively correlated to the IgEs specific to A. flavus, A. niger and A. terreus. Af-specific IgGs were positively correlated to the IgGs specific to all the other species.Conclusions: Tests using allergen components were useful for ABPA diagnosis. Both IgE and IgG were highly cross-reactive among the Aspergillus species. There were many patients apart from asthmatic patients with ABPA, who displayed high Aspergillus IgG values.