Anaphylaxis

Japanese: アナフィラキシー

Definition and Concept Anaphylaxis is a systemic reaction affecting multiple organs, generally involving antigen exposure and release of mediators from mast cells and basophils, which can sometimes lead to death. It has been defined by an international group of experts as "a severe allergic reaction of rapid onset, sometimes leading to death" (Sampson et al., 2006; Kim et al., 2011). Correct diagnosis and appropriate and prompt treatment are required to save patients from this catastrophic condition, which is unpredictable and sudden onset, and sometimes leads to death.
Historically, in 1902, Protier and Richet found that when they injected sea anemone toxin into dogs, there were no problems the first time, but after two to three weeks, the dogs went into shock and often died. They named this reaction anaphylaxis, meaning "a reaction opposite (ana-) to the host defense reaction (phylaxis)."
Classification by causative agent
1) Food:
Common anaphylaxis inducers include peanuts, nuts, shellfish, fish, milk, eggs, buckwheat, and wheat. There are also a wide variety of hidden food allergens, including foods that cause cross-reactions (such as latex-fruit syndrome), food contaminants (such as dust mites that infest grains), food additives (such as colorings), and food parasites (such as parasites).
2) Drugs:
These are common triggering substances. These include various antibiotics, including β-lactams, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, and local anesthetics. Recently, caution has also been required regarding heparin contaminated with excessively sulfated chondroitin sulfate (OSCS), monoclonal antibodies used as molecular targeted drugs (such as omalizumab), and antigens used in desensitization therapy.
3) Poison:
Toxins and saliva from insects such as bees and mosquitoes, snake venom, shellfish poison, etc.
4) Physical stimulation:
Exercise, cold stimulation, heat, radiation, ethanol, etc.
5) Others (serum, high molecular weight compounds, etc.):
Occupational allergens include latex (natural rubber) and inhalant allergens derived from laboratory animals such as hamsters and mice. Other allergens include antisera, blood products, iodine-based contrast agents, and polysaccharides such as dextran.
For details on anaphylaxis caused by the above main causes, please refer to the separate section. [⇨10-28 to 10-33]
Mechanism of onset and pathology
1) Mechanism mediated by IgE antibody/high affinity IgE receptor (FcεRI):
This is the most frequent and common type. It is often induced by foods, drugs, poisons, and polymeric compounds such as latex. When IgE antibodies crosslink the high affinity IgE receptors (FcεRI) on the surface of mast cells and basophils, causing receptor aggregation, these cells are activated. First, histamine, tryptase, carboxypeptidase A, proteoglycan, phospholipase A, and other substances stored in secretory granules are released. Then, newly synthesized leukotrienes, prostaglandins, platelet activating factor (PAF), and other substances are secreted. In addition, various cytokines and chemokines are released, leading to capillary dilation, increased permeability, airway smooth muscle contraction, increased airway secretion, mucosal edema, and inflammation.
2) Other immune-mediated mechanisms:
Known mechanisms involve IgG antibody-antigen complexes, activation of the complement system, and activation of the fibrinolytic coagulation system. When immune complexes are formed in the bloodstream, the complement system is activated. During this process, C3, C4, and C5 are each cleaved into two fragments, and the larger fragments (C3b, C4b, and C5b) are involved in complement activation, but the smaller fragments (C3a, C4a, and C5a) are also physiologically active and can cause anaphylaxis. For this reason, C3a, C4a, and C5a are called anaphylatoxins. These substances induce degranulation of mast cells and basophils, but also have direct effects on smooth muscle contraction and increased vascular permeability.
3) Physical mechanism:
Anaphylaxis is also known to be directly induced by exercise, cold stimulation, heat, sunlight, etc. It is thought that these stimuli directly activate mast cells and basophils. Exercise-induced anaphylaxis, which occurs when exercising after a meal, is called food-dependent exercise-induced anaphylaxis (FDEIAn). It is thought that food allergies put the body in a preparatory state for an attack, and that exercise stimulation induces the onset of anaphylaxis, but the detailed mechanism is unknown. There is also idiopathic anaphylaxis, the cause of which is completely unknown.
The exact incidence is unknown, due to the lack of a uniform definition of the epidemiological disease, the lack of correct diagnosis, and insufficient reporting. However, anaphylaxis is by no means rare, and has recently been increasing. According to statistics in the United States, the number of cases per 100,000 people was 21 per year in the 1980s, but increased to 49.8 per year in the 1990s. The highest incidence is in those aged 0 to 19 years, at 70 per year. It has also been reported that it is more common in boys under the age of 15, and more common in girls over the age of 15. In children, adolescents, and young adults, food is the cause in many cases, while in middle-aged and elderly people, in addition to idiopathic cases, drugs and stinging insect venom such as bees are important. In Japan, there have been cases of anaphylaxis caused by wheat food allergy due to the use of soap containing hydrolyzed wheat components, and this has developed into a major social problem.
Clinical Symptoms Anaphylaxis is a systemic reaction, and symptoms and signs may appear in the skin, gastrointestinal tract, respiratory system, and cardiovascular system. Skin symptoms include urticaria (wheals), angioedema (swelling), erythema (redness), and pruritus (itching). Upper respiratory tract symptoms include nasal congestion, runny nose, hoarseness, and pharyngeal and laryngeal edema. Lower respiratory tract symptoms include airway spasm, wheezing, and chest tightness. Circulatory system symptoms include low blood pressure, lightheadedness, fainting, and tachycardia. Digestive system symptoms include nausea, vomiting, abdominal pain, and diarrhea. Nervous system symptoms include dizziness, dizziness, and confusion. Oral symptoms include itching, numbness, and swelling of the lips, tongue, and palate, and these may sometimes serve as precursor symptoms. Other systemic symptoms include cold sweats, chills, and anxiety. One of the characteristics of anaphylaxis is that it is accompanied by the "fear of death."
Diagnosis (Table 10-27-1)
Rapid diagnosis is important due to the sudden onset, rapid progression, and occasional death. Diagnostic criteria are shown in Table 10-27-1 (Sampson et al., 2006; Kim et al., 2011). Regardless of the presence or absence of a precipitating factor, if there are symptoms of skin and mucous membranes such as generalized urticaria, itching, redness, and swelling of the lips, tongue, uvula, etc., as well as sudden respiratory distress, wheezing/airway constriction, drop in blood pressure, or generalized collapse (hypotension/collapse, loss of consciousness, incontinence, etc.), anaphylaxis should be suspected and treatment should be initiated immediately. It is also important to ask family members (or the patient themselves if it is mild) about any history of anaphylaxis.
Test results: It is possible to identify some of the substances that cause anaphylaxis using intradermal reactions, antigen-specific IgE measurements, histamine release tests, etc. However, it is not possible to test for the majority of causative substances. Intradermal reactions can sometimes induce anaphylaxis, so great care must be taken. There have also been attempts to diagnose anaphylaxis by measuring histamine and tryptase derived from mast cells and basophils in serum.
Differential diagnosis includes vasovagal or neurocardiogenic vascular inhibitory reflexes manifesting as hypotension, facial pallor, bradycardia, nausea, and vomiting; acute respiratory depression due to severe asthma attack, foreign body aspiration, pulmonary embolism, vocal cord dysfunction, hyperventilation syndrome, acute heart failure, hypoglycemia, acute drug intoxication, and epileptic seizures.
Course and prognosis: If appropriate treatment is given, improvement will usually be seen within 10 to 15 minutes, and recovery will occur within a few hours. However, it is important to note that after acute symptoms have improved, symptoms may worsen again. Death from anaphylaxis often occurs within a few minutes to an hour of onset, and is due to respiratory or circulatory disorders. In Japan, 50 to 70 deaths are reported each year.
TreatmentAnaphylaxis develops suddenly and can be fatal within a few minutes, so immediate diagnosis and treatment are necessary. Epinephrine injection is the first choice and should be administered immediately in cases suspected of this condition. 0.2-0.5 mL of 0.1% epinephrine is injected subcutaneously or intramuscularly (in the thigh or upper arm, intramuscular injection is preferable, as absorption through the skin decreases during circulatory collapse). The same amount is repeated every 10-15 minutes while monitoring the progress. At the same time, following the ABCs of emergency care, respiratory measures should be taken to ensure airway access, administer oxygen, and assisted ventilation, and circulation should be maintained by securing peripheral veins, providing fluids, and administering vasopressors. Antihistamines may also be effective. Rapid-acting corticosteroids may also be administered intravenously or by infusion.
For patients with a history of anaphylaxis and for whom the causative substance has been identified, self-injection of adrenaline (EpiPen) has been covered by insurance since 2011. It is available in two doses, 0.15 mg for children and 0.3 mg for adults, and is administered intramuscularly from the anterior lateral side of the thigh. Patients must be fully instructed on how to use it beforehand, and only doctors who have received training on the use of EpiPen can prescribe it. Identifying the cause through challenge tests and desensitization therapy carry the risk of inducing anaphylaxis, so it is best to ask an allergy specialist. [Munakata Mitsuru]
■ References
Kim H, Fischer D: Anaphylaxis. Ann Asthma Clin Immunol, 7(suppl 1): S6, 2011.
Sampson HA, et al: Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol, 117: 391-397, 2006.

Table 10-27-1
Clinical diagnostic criteria for anaphylaxis (Sampson et al., 2006)

Table 10-27-1

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　アナフィラキシーは多臓器にわたる全身反応であり，一般的には抗原暴露とマスト細胞や好塩基球からのメディエーターの放出を伴い，ときに死に至る．国際専門家グループにより「急激に発症し，ときに死に至る重篤なアレルギー反応」と定義されている（Sampsonら，2006；Kimら，2011）．予期不能かつ突然の発症と，ときに死に至る破滅的病態から患者を救済するためには，正しい診断と適切かつ迅速な治療が必要とされる．
　歴史的には，1902年にProtierとRichetがイヌにイソギンチャク毒素を注射していくと，初回は問題ないが，2～3週間後の注射ではイヌがショック症状を呈し，しばしば死亡することを見いだした．彼らはこの反応を「生体防御反応（phylaxis）とは逆（ana-）の反応」という意味でアナフィラキシー（anaphylaxis）と命名した．
原因物質による分類
1）食物：
一般的なアナフィラキシー惹起物質としては，ピーナッツ，木の実，甲殻類，魚類，牛乳，卵，そば，小麦，などがある．その他，隠れた食物抗原として，交叉反応を起こす食物（ラテックス・フルーツ症候群など），食物汚染物（穀物につくコナダニなど），食物添加剤（色素など），食物寄生物（寄生虫など），など多彩である．
2）薬物：
頻度の高い惹起物質である．βラクタム系をはじめとする各種抗菌薬，アスピリンなどの非ステロイド系抗炎症薬（NSAIDs），局所麻酔薬などがある．最近では，過度に硫酸化されたコンドロイチン硫酸（OSCS）に汚染されたヘパリン，分子標的薬として用いられている単クローン抗体（オマリズマブなど），脱感作療法に用いられる抗原などにも注意が必要である．
3）毒物：
ハチや蚊などの昆虫由来の毒素・唾液，ヘビ毒，貝毒など．
4）物理的刺激：
運動，寒冷刺激，熱，放射線，エタノールなど．
5）その他（血清，高分子化合物，など）：
職業性抗原としては，天然ゴムであるラテックス，ハムスター・マウスなど実験動物由来の吸入性抗原など．その他，抗血清，血液製剤，ヨウ素系造影剤，デキストランなどの多糖類などがある．
　上記の主要な原因によるアナフィラキシーの詳細については別項参照のこと．【⇨10-28〜10-33】
発症機序・病態
1）IgE抗体/高親和性IgE受容体（FcεRI）を介する機序：
最も頻度が高く一般的なタイプである．食物・薬物・毒物・ラテックスなどの高分子化合物などで惹起されることが多い．IgE抗体がマスト細胞や好塩基球表面の高親和性IgE受容体（FcεRI）を架橋し受容体が凝集すると，これらの細胞が活性化される．まず，分泌顆粒に蓄えられているヒスタミン，トリプターゼ，カルボキシペプチダーゼA，プロテオグリカン，ホスホリパーゼAなどが放出される．その後，新たに合成されるロイコトリエン，プロスタグランジン，血小板活性化因子（platelet activating factor：PAF）などが分泌される．さらに，各種サイトカイン・ケモカインなどが放出され，毛細血管の拡張や透過性亢進，気道平滑筋収縮，気道分泌亢進，粘膜浮腫，炎症などがもたらされる．
2）その他の免疫現象を介する機序：
IgG抗体・抗原複合物，補体系活性化，線溶凝固系活性化，などが関与するメカニズムが知られている．流血中に免疫複合物が形成されると補体系が活性化される．この経過で，C3，C4，C5はそれぞれ2つの断片に切断され，大きな断片（C3b，C4b，C5b）は補体活性化にかかわるが，小さな断片（C3a，C4a，C5a）も生理活性をもち，アナフィラキシーを惹起することがある．このため，C3a，C4a，C5aはアナフィラトキシンとよばれている．これらの物質はマスト細胞・好塩基球の脱顆粒を惹起するが，直接的な平滑筋収縮，血管透過性亢進作用も有する．
3）物理的機序：
運動，寒冷刺激，温熱，日光などにより直接的に惹起されるアナフィラキシーも知られている．これらの刺激が直接的にマスト細胞・好塩基球の活性化を惹起すると考えられる．運動誘発では，食後に運動してアナフィラキシーを起こす食物依存性運動誘発アナフィラキシー（food dependent exercise induced anaphylaxis：FDEIAn）とよばれる．食物アレルギーにより発作準備状態となり，運動刺激がアナフィラキシー発現を誘発すると考えられているが，詳細な機序は不明である．また，原因がまったく不明な特発性アナフィラキシーも存在する．
疫学
　疾患の定義が一定しておらず正しい診断がなされていないこと，報告も不十分なことなどもあり，正確な発生頻度は不明である．しかし，アナフィラキシーは決してまれなものではなく，最近増加傾向にある．米国での統計では，対10万人で1980年代には21人/年であったものが，1990年代には49.8人/年に増加している．0歳～19歳では70人/年で最も多い．また，15歳以下では男児に多く，15歳以上では女子に多いとの報告もある．小児・思春期・若年成人では食物を原因とするものが多く，中高年では，特発性に加え，薬物やハチなどの刺咬昆虫毒が重要である．わが国では，加水分解小麦成分を含む石鹸の使用により，小麦食物アレルギーによるアナフィラキシーが生ずる事例が発生し，大きな社会問題に発展している．
臨床症状
　アナフィラキシーは全身反応であるため，皮膚，消化管，呼吸器，心血管系などの症状と徴候がみられる．皮膚症状としてはじんま疹（膨疹），血管浮腫（腫脹），紅斑（発赤），瘙痒感（かゆみ）など，上気道症状としては鼻閉，鼻汁，嗄声，咽頭・喉頭浮腫など，下気道症状としては気道攣縮，喘鳴，胸部圧迫感などがある．循環系では低血圧，ふらつき，失神，頻脈など，消化器系では悪気，嘔吐，腹痛，下痢など，神経系では朦朧感，めまい，混乱などの症状・徴候がみられる．口腔では，かゆみ，唇・舌・口蓋のしびれや腫脹などがみられ，ときにこれらが前駆症状となる．その他，全身症状として冷汗，悪寒，不安感などがある．「死の恐怖」を伴うことも特徴の1つとされている．
診断（表10-27-1）
　突然の発症，急激な進行，ときに死に至ることなどから，迅速な診断が重要である．表10-27-1に診断基準を示す（Sampsonら，2006；Kimら，2011）．誘発要因の有無にかかわらず，全身性じんま疹，かゆみ，発赤，唇・舌・口蓋垂などの腫脹などの皮膚・粘膜症状に加え，急激な呼吸困難・喘鳴/気道攣縮，血圧低下あるいは全身虚脱症状（低血圧/虚脱，意識消失，失禁など）がある場合はアナフィラキシーを考え，即座に治療を開始する．家族（軽度の場合は本人）などからアナフィラキシーの既往を聴き取ることも重要である．
検査成績
　皮内反応，抗原特異的IgE測定，ヒスタミン遊離試験などで，一部のアナフィラキシー原因物質の特定が可能である．しかし，大部分の原因物質については検査不能である．皮内反応は，ときにアナフィラキシーを誘発することがあるため，十分な注意が必要である．また血清で，マスト細胞・好塩基球由来のヒスタミンやトリプターゼなどを測定し，アナフィラキシーを診断しようとする試みもある．
鑑別診断
　鑑別診断としては，低血圧・顔面蒼白・徐脈・悪気・嘔吐症状などを呈する血管迷走神経性あるいは神経心原性の血管系抑制反射，重症喘息発作・異物誤嚥・肺塞栓症・声帯機能異常（vocal cord dysfunction）・過換気症候群などによる急性呼吸抑制，急性心不全，低血糖，急性薬物中毒，てんかん発作などがある．
経過・予後
　適切な治療がなされれば，通常は10～15分程度で改善が認められ，数時間で回復する．注意が必要なのは，急性症状が改善した後，再度症状が悪化する場合がある点である．アナフィラキシーによる死亡は発症数分間～1時間以内のことが多く，呼吸障害や循環障害による．わが国では年間50～70例の死亡が報告されている．
治療
　アナフィラキシーは急激に発症し，数分以内に死亡するため，即座の診断と治療が必要である．アドレナリン注射が第一選択であり，この病態が疑われる症例には即時に行うべきである．0.1％アドレナリン0.2～0.5 mLを皮下注あるいは筋注する（循環虚脱時には皮膚からの吸収が低下するので，筋注（大腿・上腕）がよい）．経過をみながら10～15分ごとに同量を反復する．並行して，救急のABCに従い気道確保・酸素投与・補助換気などによる呼吸確保，末梢静脈確保・補液・昇圧薬投与などによる循環確保を行う．抗ヒスタミン薬も有効なことがある．即効型の副腎皮質ステロイド薬の静脈注射・点滴静注を追加する場合もある．
　アナフィラキシーの既往があり，原因物質が特定されている患者には，アドレナリン自己注射（エピペン）が平成23年から保険適応となった．小児用0.15 mgと成人用0.3 mgの2用量があり，大腿前外側から自分で筋注する．事前に患者に十分使用法を指導しておく必要があり，あらかじめエピペンの使用に関する講習を受けた医師でなければ処方することができない．　チャレンジテストによる原因の特定や減感作療法はアナフィラキシー誘発の危険があるため，アレルギー専門医に依頼するのがよい．［棟方　充］
■文献
Kim H, Fischer D: Anaphylaxis. Ann Asthma Clin Immunol, 7(suppl 1): S6, 2011.
Sampson HA, et al: Second symposium on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol, 117: 391-397, 2006.

表10-27-1
アナフィラキシーの臨床診断基準（Sampson ら，2006）">

表10-27-1

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