今日の臨床サポート

気管支喘息(小児科)

著者: 安戸裕貴 山口大学大学院医学系研究科医学専攻小児科学講座

監修: 渡辺博 帝京大学老人保健センター

著者校正/監修レビュー済:2021/04/28
参考ガイドライン:
  1. 日本小児アレルギー学会:小児気管支喘息治療・管理ガイドライン 2020
患者向け説明資料

概要・推奨   

  1. 吸入ステロイド薬を使用すると、臨床症状、呼吸機能、気道過敏性が改善し、喘息死が減少する(推奨度2
  1. 吸入ステロイド薬の中断により、再び気道過敏性は亢進し、症状が再燃するとされている。吸入ステロイド薬が、喘息の自然経過を変化させ、小児喘息の寛解率を上昇させるというエビデンスはまだない。
  1. 吸入ステロイド薬の投与量と効果には用量依存性があるが、投与量が多くなると増量効果が乏しくなる。高用量に増量する代わりに、ステロイド薬/長時間作用性吸入β2刺激薬配合剤への切り替えロイコトリエン受容体拮抗薬の追加投与が提案される(推奨度2
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 吸入ステロイド薬/長時間作用性吸入β2刺激薬配合剤は気管支喘息治療に有用であるが、長期的な安全性に関するデータは乏しいため、漫然と使用せずにコントロール状態に応じて吸入ステロイド薬単独への切り替えを考慮する。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
安戸裕貴 : 特に申告事項無し[2021年]
監修:渡辺博 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 小児気管支喘息治療・管理ガイドライン 2020に基づき改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 気管支喘息とは、発作性の気道狭窄により、呼気性喘鳴呼吸困難を反復する疾患である。まれに致死的ですらある。
  1. 有症率は4~19.9%と高い[1][2][3]。喘息は乳幼児期に発症が多く、喘息を持つ学童の発症時期は2〜3歳をピークにその後緩やかに低下する傾向があり、発症の低年齢化がみられている[4]
 
気管支喘息発症年齢

近年では、気管支喘息発症の低年齢化が見られている。

 
  1. 喘息は、遺伝素因に環境因子が加わって発症する疾患で、その基本病態は気道過敏性と気道の慢性炎症と、その気道炎症により気道粘膜障害が生じることである。また、気管支平滑筋収縮、気道粘膜浮腫、気道分泌亢進によって起こる気道狭窄が生じることもある。気道炎症には好酸球、マスト細胞、T細胞などが関与することが知られており、好酸球などの活動をコントロールする治療が行われる[5][6][7][8]
  1. ライノウイルス、メタニューモウイルス、エンテロウイルス、コロナウイルス、マイコプラズマなどの感染、受動喫煙、運動、冷気、花火などの煙、気候変動などが喘息発作を誘発する。
問診・診察のポイント  
問診:
  1. 喘鳴などの症状が発作性・反復性に出現しているか問診する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
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文献 

著者: Angelo Barbato, Graziella Turato, Simonetta Baraldo, Erica Bazzan, Fiorella Calabrese, Maria Tura, Renzo Zuin, Bianca Beghe, Piero Maestrelli, Leonardo M Fabbri, Marina Saetta
雑誌名: Am J Respir Crit Care Med. 2003 Oct 1;168(7):798-803. doi: 10.1164/rccm.200305-650OC. Epub 2003 Jul 31.
Abstract/Text Airway pathology has been extensively investigated in adulthood asthma, whereas only few studies examined bronchial biopsies in childhood asthma. To evaluate the airway pathology in children with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other than asthma. Nine had mild/moderate asthma. Six had atopy without asthma, and eight had no atopy or asthma. We measured basement membrane thickness and quantified the number of eosinophils, mast cells, neutrophils, macrophages, T lymphocytes, and positive cells for transforming growth factor-beta1 (TGF-beta1) and its receptors I and II (TGFbeta-RI and TGFbeta-RII) in subepithelium. Children with asthma had an increase in basement membrane thickness and in the number of eosinophils compared with control subjects, but not compared with children with atopy. They also had a decreased expression of TGFbeta-RII compared with both those with atopy and control subjects. In children with asthma, the number of eosinophils correlated negatively with TGFbeta-RII and positively with symptom duration. In conclusion, airway eosinophilia and basement membrane thickening, which are the pathologic features that are characteristic of adulthood asthma, are already present in children with mild asthma, and even in children with atopy without asthma. Moreover, in children with asthma but not in children with atopy without asthma, there is a downregulation of TGFbeta-RII.

PMID 12893650  Am J Respir Crit Care Med. 2003 Oct 1;168(7):798-803. d・・・
著者: L M van den Toorn, S E Overbeek, J C de Jongste, K Leman, H C Hoogsteden, J B Prins
雑誌名: Am J Respir Crit Care Med. 2001 Dec 1;164(11):2107-13. doi: 10.1164/ajrccm.164.11.2006165.
Abstract/Text Symptoms of atopic asthma often disappear at puberty. However, asthmatic subjects in clinical remission will frequently have a relapse later in life. The aim of this study was to investigate whether subjects in clinical remission of atopic asthma have persistent airway inflammation and/or airway remodeling. Bronchial biopsies were obtained from subjects in clinical remission, asthmatic subjects, and healthy control subjects. The presence and/or activation state of eosinophils, mast cells, macrophages, T lymphocytes, interleukin (IL)-5, eotaxin, and inducible nitric oxide synthase (iNOS) were analyzed. Results were compared with less invasive indicators of airway inflammation. Also aspects of airway remodeling were determined. Eosinophils, T cells, mast cells, and IL-5 were significantly elevated in the airway mucosa of subjects in remission compared with control subjects. Also, blood eosinophil cell counts were significantly higher in subjects in clinical remission. Blood eosinophil cell counts, exhaled nitric oxide (eNO) levels, and bronchial response to adenosine-5'-monophosphate correlated significantly with the quantity of tissue eosinophils. Significant airway remodeling was found in subjects in clinical remission. Our study has shown ongoing airway inflammation and airway remodeling in adolescents in clinical remission of atopic asthma. Subclinical airway inflammation may well determine the risk of an asthma relapse later in life.

PMID 11739143  Am J Respir Crit Care Med. 2001 Dec 1;164(11):2107-13. ・・・
著者: A Bush, J C de Jongste, K-H Carlsen
雑誌名: Thorax. 2003 Feb;58(2):187; author reply 187; discussion 187-8.
Abstract/Text
PMID 12554909  Thorax. 2003 Feb;58(2):187; author reply 187; discussio・・・
著者: D N R Payne, Y Qiu, J Zhu, L Peachey, M Scallan, A Bush, P K Jeffery
雑誌名: Thorax. 2004 Oct;59(10):862-9. doi: 10.1136/thx.2003.017244.
Abstract/Text BACKGROUND: The effective management and development of new treatments for children with difficult asthma requires investigation of the underlying airway pathology and its relationships with persistent symptoms and airflow limitation.
METHODS: The density of immunologically distinct inflammatory cells and cells expressing interleukin (IL)-4, IL-5, and RANTES was determined in paraffin-embedded endobronchial biopsy specimens from 27 children with difficult asthma (6-16 years) following treatment with systemic corticosteroids. Eleven non-asthmatic children (7-16 years) acted as controls. Reticular basement membrane (RBM) thickness was also recorded and forced expiratory volume in 1 second (FEV(1)) and exhaled nitric oxide (FE(NO)) measured, the latter in asthmatic children only.
RESULTS: RBM thickness was greater in the asthmatic than the control group (median (range) 7.4 (3.1-11.1) v 5.1 (3.5-7.5) microm, p = 0.02). No other significant tissue difference was seen, nor was there a difference between asthmatic subjects with daily symptoms after systemic corticosteroids and those who became asymptomatic. CD4+ T lymphocyte density was higher in asthmatic subjects with persistent airflow limitation (post-bronchodilator FEV(1)<80% predicted) than in those without (9.1 (5.5-13.6) v 3.5 (0.6-34.9)%, p = 0.027). Analysing all asthmatic subjects together, there were negative correlations between CD4+ T lymphocytes and both pre-bronchodilator FEV(1) (r = -0.57 (95% CI -0.79 to -0.23), p = 0.002) and post-bronchodilator FEV(1) (r = -0.61 (95% CI -0.81 to -0.29), p<0.001). There were no significant correlations between FE(NO) and inflammatory cells of any type.
CONCLUSION: In children with difficult asthma treated with systemic corticosteroids, persistent airflow limitation is associated with a greater density of CD4+ T lymphocytes in endobronchial biopsy specimens.

PMID 15454652  Thorax. 2004 Oct;59(10):862-9. doi: 10.1136/thx.2003.01・・・
著者: Donald N R Payne, Andrew V Rogers, Ellinor Adelroth, Venkata Bandi, Kalpalatha K Guntupalli, Andrew Bush, Peter K Jeffery
雑誌名: Am J Respir Crit Care Med. 2003 Jan 1;167(1):78-82. doi: 10.1164/rccm.200205-414OC.
Abstract/Text Remodeling of the airway wall occurs in adults with asthma, and reticular basement membrane (RBM) thickening is pathognomonic of the asthma process. To investigate whether RBM thickening is present in children with difficult asthma and comparable to that seen in adults with asthma, we used light microscopy to measure RBM thickness in plastic-embedded endobronchial biopsy sections from 19 children with difficult asthma who were prescribed 1,600 microg/day or more of inhaled steroids (age range, 6-16 years), 10 children without asthma (7-16 years), and three adult groups: 8 healthy control subjects (21-42 years), 10 mild steroid-naive subjects with asthma (18-41 years), and 6 adults (3 steroid naive and 3 on inhaled steroids) intubated after a life-threatening attack of asthma (20-64 years). RBM thickness in the children with asthma was similar to that in adults with either mild or life-threatening asthma (median 8.2 [range 5.4-11.1] versus 8.1 [5.8-10.0] and 7.2 [2.8-10.0] microm, respectively) and greater than either adult or pediatric control subjects (8.2 [5.4-11.1] versus 4.4 [3.2-6.3] microm, p < 0.01, and 4.9 [3.7-8.3] microm, p < 0.01). We conclude that RBM thickening is already present in children with difficult asthma and to a similar extent to that seen in adults with asthma. In addition, we find no association with age, symptom duration, lung function, or concurrent eosinophilic airway inflammation.

PMID 12502479  Am J Respir Crit Care Med. 2003 Jan 1;167(1):78-82. doi・・・
著者: Henry A Jenkins, Carlyne Cool, Stanley J Szefler, Ronina Covar, Susan Brugman, Erwin W Gelfand, Joseph D Spahn
雑誌名: Chest. 2003 Jul;124(1):32-41.
Abstract/Text BACKGROUND: To date, little has been published describing the pathology of severe childhood asthma. The currently accepted model of asthma holds that persistent airway inflammation leads to various symptoms of asthma, airway hyperresponsiveness, and airway remodeling that ultimately results in permanent loss of lung function.
METHODS: Evaluation of six children referred to the National Jewish Medical and Research Center with difficult-to-control asthma, despite aggressive anti-inflammatory therapy, who underwent bronchoscopy with endobronchial biopsy to better characterize their disease.
RESULTS: In every case, endobronchial biopsies revealed changes consistent with airway remodeling characterized by thickening of the basement membrane, smooth-muscle hypertrophy, with varying degrees of goblet-cell and submucous gland hyperplasia. The degree of subbasement membrane thickening did not appear to correlate with baseline FEV(1), ultimate FEV(1) following aggressive therapy, or lability in lung function. In five of six cases, there was minimal to no histologic evidence for airway inflammation with mild and patchy submucosal lymphocytic infiltration noted; eosinophils and neutrophils were not present. Further, the majority of the patients achieved normal FEV(1) values despite significant subbasement membrane thickening, counter to the current beliefs regarding airway remodeling and irreversible loss of lung function.
CONCLUSIONS: This case report highlights some of the shortcomings of the current inflammatory paradigm for severe asthma. Despite little evidence of ongoing airway inflammation, many of the subjects displayed significant lung function lability. The lack of inflammation argues against steroid resistance at a cellular level, although it could be argued that inflammation may have been distal to the site sampled. Additionally, normal to nearly normal lung function was achieved despite the presence of significant remodeling. These findings suggest the need to look beyond inflammation to fully treat severe asthma and ultimately alter its progression.

PMID 12853499  Chest. 2003 Jul;124(1):32-41.
著者: J M Vonk, D S Postma, H M Boezen, M H Grol, J P Schouten, G H Koëter, J Gerritsen
雑誌名: Thorax. 2004 Nov;59(11):925-9. doi: 10.1136/thx.2003.016246.
Abstract/Text BACKGROUND: Factors contributing to either "complete" or "clinical" remission of asthma are important to know since there is no cure for the disease.
METHODS: A cohort of 119 allergic asthmatic children was examined three times with a mean follow up of 30 years. They were aged 5-14 years at visit 1 (1966-9), 21-33 years at visit 2 (1983-6), and 32-42 years at visit 3 (1995-6). Complete remission of asthma at visit 3 was defined as no asthma symptoms, no use of inhaled corticosteroids, normal lung function (FEV1 >90% predicted), and no bronchial hyperresponsiveness (PC10 >16 mg/ml). Clinical remission was defined as no asthma symptoms and no use of inhaled corticosteroids.
RESULTS: 22% of the group was in complete remission of asthma at visit 3 and a further 30% was in clinical remission (total 52%); 57% of subjects in clinical remission had bronchial hyperresponsiveness and/or a low lung function. Logistic regression analyses showed that a higher FEV1 in childhood and more improvement in FEV1 from age 5-14 to 21-33 were associated with both complete and clinical asthma remission at age 32-42.
CONCLUSIONS: Complete remission of asthma was present in a small subset of asthmatics while half the subjects showed clinical remission. Both complete and clinical remission were associated with a higher lung function level in childhood and a higher subsequent increase in FEV1. These results support the view that defining remission only on the basis of symptoms and medication use will overlook subjects with subclinical active disease and possibly associated airway remodelling.

PMID 15516465  Thorax. 2004 Nov;59(11):925-9. doi: 10.1136/thx.2003.01・・・
著者: Peter D Phelan, Colin F Robertson, Anthony Olinsky
雑誌名: J Allergy Clin Immunol. 2002 Feb;109(2):189-94.
Abstract/Text A group of children with a past history of wheezing was randomly selected from the Melbourne community at the age of 7 years in 1964, and a further group of children with severe wheezing was selected from the same birth cohort at the age of 10 years. These subjects have been followed prospectively at 7-year intervals, with the last review in 1999, when their average age was 42 years. Eighty-seven percent of the original cohort who were still alive participated in the 1999 review. This study showed that the majority of children who had only a few episodes of wheezing associated with symptoms of a respiratory infection had a benign course, with many ceasing to wheeze by adult life. Most who continued with symptoms into adult life were little troubled by them. Conversely, those children with asthma mostly continued with significant wheezing into adult life, and the more troubled they were in childhood, the more likely symptoms continued. There was a loss in lung function by the age of 14 years in those with severe asthma, but the loss did not progress in adult life. The childhood asthma had been treated before the availability of inhaled steroids. There was no significant loss of lung function in those with milder symptoms.

PMID 11842286  J Allergy Clin Immunol. 2002 Feb;109(2):189-94.
著者: H William Kelly, Alice L Sternberg, Rachel Lescher, Anne L Fuhlbrigge, Paul Williams, Robert S Zeiger, Hengameh H Raissy, Mark L Van Natta, James Tonascia, Robert C Strunk, CAMP Research Group
雑誌名: N Engl J Med. 2012 Sep 6;367(10):904-12. doi: 10.1056/NEJMoa1203229. Epub 2012 Sep 3.
Abstract/Text BACKGROUND: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height.
METHODS: We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry.
RESULTS: Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants.
CONCLUSIONS: The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).

PMID 22938716  N Engl J Med. 2012 Sep 6;367(10):904-12. doi: 10.1056/N・・・
著者: C Calpin, C Macarthur, D Stephens, W Feldman, P C Parkin
雑誌名: J Allergy Clin Immunol. 1997 Oct;100(4):452-7.
Abstract/Text BACKGROUND: There has been no systematic appraisal of the evidence regarding the effectiveness of prophylactic inhaled steroids in childhood asthma.
OBJECTIVE: We sought to evaluate the effectiveness of prophylactic inhaled steroids in childhood asthma.
METHODS: A MEDLINE search from January 1966 through December 1996 was used to identify pertinent English-language publications. All randomized, double-blind, placebo-controlled trials of prophylactic inhaled steroid therapy for childhood asthma that included data on clinical outcomes (symptom scores and concomitant drug use) or laboratory outcomes (peak expiratory flow rate) were included.
RESULTS: In total, 24 of 93 studies retrieved met the inclusion criteria. The overall weighted relative improvement in mean total symptom score (inhaled steroid vs placebo) was 50% (95% confidence interval [CI]: 49%, 51%), the overall weighted relative decrease in mean concomitant beta2-agonist use (inhaled steroid vs placebo) was 37% (95% CI: 36%, 38%), and the overall weighted relative decrease in mean concomitant oral steroid use (inhaled steroid vs placebo) was 68% (95% CI: 66%, 70%). The overall weighted absolute improvement in mean peak expiratory flow rate (inhaled steroid vs placebo) was 38 L/min (95% CI: 34.3 L/min, 41.7 L/min).
CONCLUSIONS: Prophylactic inhaled steroids are effective, compared with placebo, in improving both clinical and laboratory outcomes in childhood asthma.

PMID 9338536  J Allergy Clin Immunol. 1997 Oct;100(4):452-7.
著者:
雑誌名: N Engl J Med. 2000 Oct 12;343(15):1054-63. doi: 10.1056/NEJM200010123431501.
Abstract/Text BACKGROUND: Antiinflammatory therapies, such as inhaled corticosteroids or nedocromil, are recommended for children with asthma, although there is limited information on their long-term use.
METHODS: We randomly assigned 1041 children from 5 through 12 years of age with mild-to-moderate asthma to receive 200 microg of budesonide (311 children), 8 mg of nedocromil (312 children), or placebo (418 children) twice daily. We treated the participants for four to six years. All children used albuterol for asthma symptoms.
RESULTS: There was no significant difference between either treatment and placebo in the primary outcome, the degree of change in the forced expiratory volume in one second (FEV1, expressed as a percentage of the predicted value) after the administration of a bronchodilator. As compared with the children assigned to placebo, the children assigned to receive budesonide had a significantly smaller decline in the ratio of FEV1 to forced vital capacity (FVC, expressed as a percentage) before the administration of a bronchodilator (decline in FEV1:FVC, 0.2 percent vs. 1.8 percent). The children given budesonide also had lower airway responsiveness to methacholine, fewer hospitalizations (2.5 vs. 4.4 per 100 person-years), fewer urgent visits to a caregiver (12 vs. 22 per 100 person-years), greater reduction in the need for albuterol for symptoms, fewer courses of prednisone, and a smaller percentage of days on which additional asthma medications were needed. As compared with placebo, nedocromil significantly reduced urgent care visits (16 vs. 22 per 100 person-years) and courses of prednisone. The mean increase in height in the budesonide group was 1.1 cm less than in the placebo group (22.7 vs. 23.8 cm, P=0.005); this difference was evident mostly within the first year. The height increase was similar in the nedocromil and placebo groups.
CONCLUSIONS: In children with mild-to-moderate asthma, neither budesonide nor nedocromil is better than placebo in terms of lung function, but inhaled budesonide improves airway responsiveness and provides better control of asthma than placebo or nedocromil. The side effects of budesonide are limited to a small, transient reduction in growth velocity.

PMID 11027739  N Engl J Med. 2000 Oct 12;343(15):1054-63. doi: 10.1056・・・
著者: S Suissa, P Ernst, S Benayoun, M Baltzan, B Cai
雑誌名: N Engl J Med. 2000 Aug 3;343(5):332-6. doi: 10.1056/NEJM200008033430504.
Abstract/Text BACKGROUND: Although inhaled corticosteroids are effective for the treatment of asthma, it is uncertain whether their use can prevent death from asthma.
METHODS: We used the Saskatchewan Health data bases to form a population-based cohort of all subjects from 5 through 44 years of age who were using antiasthma drugs during the period from 1975 through 1991. We followed subjects until the end of 1997, their 55th birthday, death, emigration, or termination of health insurance coverage; whichever came first. We conducted a nested case-control study in which subjects who died of asthma were matched with controls within the cohort according to the length of follow-up at the time of death of the case patient (the index date), the date of study entry, and the severity of asthma. We calculated rate ratios after adjustment for the subject's age and sex; the number of prescriptions of theophylline, nebulized and oral beta-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled beta-adrenergic agonists used in the year before the index date; and the number of hospitalizations for asthma in the two years before the index date.
RESULTS: The cohort consisted of 30,569 subjects. Of the 562 deaths, 77 were classified as due to asthma. We matched the 66 subjects who died of asthma for whom there were complete data with 2681 controls. Fifty-three percent of the case patients and 46 percent of the control patients had used inhaled corticosteroids in the previous year, most commonly low-dose beclomethasone. The mean number of canisters was 1.18 for the patients who died and 1.57 for the controls. On the basis of a continuous dose-response analysis, we calculated that the rate of death from asthma decreased by 21 percent with each additional canister of inhaled corticosteroids used in the previous year (adjusted rate ratio, 0.79; 95 percent confidence interval, 0.65 to 0.97). The rate of death from asthma during the first three months after discontinuation of inhaled corticosteroids was higher than the rate among patients who continued to use the drugs.
CONCLUSIONS: The regular use of low-dose inhaled corticosteroids is associated with a decreased risk of death from asthma.

PMID 10922423  N Engl J Med. 2000 Aug 3;343(5):332-6. doi: 10.1056/NEJ・・・
著者: Theresa W Guilbert, Wayne J Morgan, Robert S Zeiger, David T Mauger, Susan J Boehmer, Stanley J Szefler, Leonard B Bacharier, Robert F Lemanske, Robert C Strunk, David B Allen, Gordon R Bloomberg, Gregory Heldt, Marzena Krawiec, Gary Larsen, Andrew H Liu, Vernon M Chinchilli, Christine A Sorkness, Lynn M Taussig, Fernando D Martinez
雑誌名: N Engl J Med. 2006 May 11;354(19):1985-97. doi: 10.1056/NEJMoa051378.
Abstract/Text BACKGROUND: It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma.
METHODS: We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year.
RESULTS: During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively.
CONCLUSIONS: In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).

Copyright 2006 Massachusetts Medical Society.
PMID 16687711  N Engl J Med. 2006 May 11;354(19):1985-97. doi: 10.1056・・・
著者: S Pedersen, O R Hansen
雑誌名: J Allergy Clin Immunol. 1995 Jan;95(1 Pt 1):29-33.
Abstract/Text OBJECTIVE: The purpose of the study was to evaluate the dose-response relationships of the inhaled corticosteroid budesonide in a double blind crossover study in 19 children with moderate and severe asthma.
METHODS: A 2-week placebo treatment period (run-in) was followed by three 4-week treatment periods during which 100, 200, and 400 micrograms of budesonide were given per day in randomized order. Urinary cortisol excretion, lung functions, and protection against exercise-induced asthma were assessed at the end of run-in and each treatment period. Furthermore, morning and evening peak expiratory flow rates, day and night symptoms, and use of rescue beta 2-agonists were recorded throughout the study.
RESULTS: One hundred micrograms of budesonide per day markedly improved symptoms, morning and evening peak expiratory flow rates, and use of rescue beta 2-agonists (p < 0.01). No further improvement was seen in these parameters with increasing doses of budesonide. In contrast, a significant dose-response effect was found on lung functions measured at the hospital and fall in lung functions after exercise (p < 0.001); 200 micrograms was significantly better than 100 micrograms, and 400 micrograms was significantly better than 200 micrograms. About 53% of the maximum effect against exercise-induced asthma was achieved by the lowest budesonide dose (p < 0.001), and about 83% by the highest dose. No significant differences were seen in urinary cortisol excretion between run-in and the various budesonide doses.
CONCLUSIONS: Low doses of budesonide, which are not associated with any systemic side effects, have a marked antiasthma effect in children. Protection against exercise-induced asthma requires higher doses than achievement of symptom control.

PMID 7822661  J Allergy Clin Immunol. 1995 Jan;95(1 Pt 1):29-33.
著者: M Laviolette, K Malmstrom, S Lu, P Chervinsky, J C Pujet, I Peszek, J Zhang, T F Reiss
雑誌名: Am J Respir Crit Care Med. 1999 Dec;160(6):1862-8. doi: 10.1164/ajrccm.160.6.9803042.
Abstract/Text The primary objective of this study was to determine whether montelukast, an oral leukotriene receptor antagonist, provides additional clinical benefit to the effect of inhaled corticosteroids. A total of 642 patients with chronic asthma (FEV(1) 50 to 85% of predicted value and at least a predefined level of asthma symptoms) incompletely controlled with inhaled beclomethasone, 200 microg twice daily using a spacer device, during the 4-wk run-in period were randomly allocated, in a double-blind, double-dummy manner to one of four treatment groups: (1) montelukast 10 mg plus continuing inhaled beclomethasone; (2) placebo tablet plus continuing inhaled beclomethasone; (3) montelukast 10 mg and inhaled placebo (after blind beclomethasone removal); and (4) placebo tablet and inhaled placebo (after blind beclomethasone removal). The primary endpoints were FEV(1) and daytime asthma symptoms score. Montelukast provided significant (p < 0.05) clinical benefit in addition to inhaled beclomethasone by improving FEV(1), daytime asthma symptom scores, and nocturnal awakenings. Blind removal of beclomethasone in the presence of placebo tablets caused worsening of asthma control, demonstrating that patients received clinical benefit from inhaled corticosteroids. Blind removal of beclomethasone in the presence of montelukast resulted in less asthma control but not to the level of the placebo group. All treatments were well tolerated; clinical and laboratory adverse experiences were generally similar to placebo treatment in this study. In conclusion, montelukast provided additional asthma control to patients benefitting from, but incompletely controlled on, inhaled beclomethasone.

PMID 10588598  Am J Respir Crit Care Med. 1999 Dec;160(6):1862-8. doi:・・・
著者: Jacques de Blic, Ludmila Ogorodova, Rabih Klink, Irina Sidorenko, Arunas Valiulis, Jerzy Hofman, Olav Bennedbaek, Sally Anderton, Valerie Attali, Jean-Luc Desfougeres, Marc Poterre
雑誌名: Pediatr Allergy Immunol. 2009 Dec;20(8):763-71. doi: 10.1111/j.1399-3038.2009.00861.x. Epub 2009 Feb 20.
Abstract/Text There is a large body of data to support the use of an inhaled corticosteroid (ICS) plus a long-acting beta(2)-agonist vs. increasing the dose of ICS in adults, but less data in children. This double-blind, parallel group, non-inferiority study compared lung function and asthma control, based on Global Initiative for Asthma guidelines, in children receiving either salmeterol/fluticasone propionate (SFC) 50/100 microg bd (n = 160) or fluticasone propionate (FP) 200 microg bd (n = 161) for 12 wks. Change from baseline in mean morning peak expiratory flow increased following both treatments, but was significantly greater in the SFC group compared with FP [Adjusted mean change (s.e.) (l/min): SFC: 26.9 (2.13), FP: 19.3 (2.12); treatment difference: 7.6 (3.01); 95% CI: 1.7, 13.5; p = 0.012)]. Asthma control improved over time in both groups. Mean pre-bronchodilator maximal-expiratory flow at 50% vital capacity and percentage rescue-free days showed significantly greater improvements in the SFC group compared with FP. All other efficacy indices showed comparable improvements in each group. Treatment with SFC 50/100 microg bd compared with twice the steroid dose of FP (200 microg bd), was at least as effective in improving individual clinical outcomes and overall asthma control, in asthmatic children previously uncontrolled on low doses of ICS.

PMID 19239660  Pediatr Allergy Immunol. 2009 Dec;20(8):763-71. doi: 10・・・
著者: Bo Lundbäck, Eva Rönmark, Anne Lindberg, Ann-Christin Jonsson, Lars-Gunnar Larsson, Frank Pétavy, Mark James
雑誌名: Respir Med. 2006 Jan;100(1):2-10. doi: 10.1016/j.rmed.2005.09.006. Epub 2005 Oct 21.
Abstract/Text OBJECTIVE: The aim of this study was to assess asthma control using salmeterol plus fluticasone propionate (FP) in combination (SFC) versus salmeterol or FP as monotherapy in patients with mild to moderate asthma.
METHODS: In this randomised, double-blind, parallel-group study, 322 symptomatic patients were recruited, of which 282 were randomised to receive either salmeterol (50 microg), FP (250 microg), or SFC (50 microg/250 microg), via a single Diskus inhaler twice daily for 12 months. Outcome variables included the number of patients requiring an increase in study medication and the number experiencing 2 exacerbations during the 12-month treatment period. Airway hyper-responsiveness (AHR) and lung function tests were performed at clinic visits. Peak expiratory flow, rescue medication use, symptom scores and adverse events were recorded in diary cards.
RESULTS: Fewer patients required an increase in study medication with SFC (10.5%) than with either FP (34.8%) or salmeterol (61.1%) (P<0.001). Significantly fewer patients experienced 2 exacerbations with SFC (4.2%), compared with FP (17.4%; P<0.01) or salmeterol (40%; P<0.001). SFC improved AHR to a significantly greater extent than FP (methacholine PC20=1.8 mg/ml vs. 1.1 mg/ml; P<0.05) or salmeterol (methacholine PC20=1.8 mg/ml vs. 0.7 mg/ml; P<0.001).
CONCLUSIONS: The protection against exacerbations may be attributed to better control of inflammation, AHR and lung function parameters achieved with salmeterol and FP in combination, compared with either treatment alone.

PMID 16243498  Respir Med. 2006 Jan;100(1):2-10. doi: 10.1016/j.rmed.2・・・
著者: Annika Wallin, Malcolm Sue-Chu, Leif Bjermer, Jonathan Ward, Thomas Sandström, Anne Lindberg, Bo Lundbäck, Ratko Djukanović, Stephen Holgate, Susan Wilson
雑誌名: J Allergy Clin Immunol. 2003 Jul;112(1):72-8.
Abstract/Text BACKGROUND: The clinical benefit of combining long-acting beta(2)-agonists with inhaled corticosteroids rather than doubling the dose of corticosteroid has been well-documented. However, there are concerns that this might result in a masking of underlying airway inflammation.
OBJECTIVE: The aim of this study was to test the hypothesis that the addition of the long-acting beta(2)-agonist salmeterol (SALM) to a low dose of the inhaled corticosteroid fluticasone propionate (FP) has a steroid-sparing effect and does not result in a worsening of bronchial inflammation compared to doubling the dose of inhaled corticosteroid.
METHODS: Fifty-six asthmatic subjects, previously not well-controlled on inhaled corticosteroids, were randomized to receive 3 months of treatment with inhaled FP 500 microg twice a day (FP 1000) or FP 200 microg twice a day plus SALM 50 microg twice a day (FP 400 + SALM). Fluticasone propionate 200 microg twice a day served as the control (FP400). Bronchial mucosal biopsy specimens, bronchial washings (BW), and bronchoalveolar lavage were obtained before and after treatment. The primary end points for the study were submucosal mast cell and eosinophil counts.
RESULTS: There was a significant improvement in FEV(1) in the FP400 + SALM group compared to both the FP400 and FP1000 groups. This was accompanied by a significant improvement in peak expiratory flow in the FP400 + SALM group in both the morning and evening compared to the FP1000 group. There were no significant between treatment differences in the change in the number of submucosal mast cells or eosinophils. However, in the FP400 + SALM group there was a significant decrease in submucosal mast cells after 12 weeks of treatment. The addition of SALM to FP was not associated with any increases in airway inflammation in the biopsy specimens, bronchoalveolar lavage, or bronchial washings.
CONCLUSION: These findings confirm that addition of SALM to FP has clinical benefits but does not mask or exacerbate airway inflammation and suggest that long-acting beta(2)-adrenoceptor agonists might influence mast cell numbers.

PMID 12847482  J Allergy Clin Immunol. 2003 Jul;112(1):72-8.
著者: Anna A P H Vaessen-Verberne, Norbert J van den Berg, Jan C van Nierop, Hein J L Brackel, Gerardus P J M Gerrits, Wim C J Hop, Eric J Duiverman, COMBO Study Group
雑誌名: Am J Respir Crit Care Med. 2010 Nov 15;182(10):1221-7. doi: 10.1164/rccm.201002-0193OC. Epub 2010 Jul 9.
Abstract/Text RATIONALE: For children with symptomatic asthma despite low to moderate doses of inhaled corticosteroids, evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of inhaled corticosteroids.
OBJECTIVE: To evaluate whether salmeterol/fluticasone propionate (SFP), 50/100 μg twice a day, is noninferior regarding symptom control compared with fluticasone propionate (FP), 200 μg twice a day Diskus in children with symptomatic asthma.
METHODS: A multicenter, randomized, parallel-group, double-blind study was performed comparing SFP and FP treatment during 26 weeks on asthma control and lung function.
MEASUREMENTS AND MAIN RESULTS: A total of 158 children, 6-16 years old, still symptomatic on FP, 100 μg twice a day, during a 4-week run-in period, were included. Percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups (per protocol analysis: adjusted mean difference [FP minus SFP] 2.6%; 95% confidence interval, -8.1 to 13.4). Both groups showed substantial improvements of about 25 percent points in symptom-free days (both P < 0.001 from baseline). Lung function measurements (FEV(1), FVC, PEF rate, and maximal expiratory flow) did not differ between groups except for a slight advantage in maximal expiratory flow in the SFP group at 1 week. No differences were found between FP and SFP regarding exacerbation rates, adverse events, or growth.
CONCLUSIONS: In our study the efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid.

PMID 20622031  Am J Respir Crit Care Med. 2010 Nov 15;182(10):1221-7. ・・・
著者: M Turpeinen, K Nikander, A S Pelkonen, P Syvänen, R Sorva, H Raitio, P Malmberg, K Juntunen-Backman, T Haahtela
雑誌名: Arch Dis Child. 2008 Aug;93(8):654-9. doi: 10.1136/adc.2007.116632. Epub 2007 Jul 18.
Abstract/Text OBJECTIVE: To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and
INTERVENTIONS: 176 children aged 5-10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg twice daily for months 7-18); (2) budesonide, identical treatment to group 1 during months 1-6, then budesonide for exacerbations as needed for months 7-18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1-18. Exacerbations were treated with budesonide 400 microg twice daily for 2 weeks.
MAIN OUTCOME MEASURES: Lung function, the number of exacerbations and growth.
RESULTS: Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7-18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth.
CONCLUSIONS: Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.

PMID 17634183  Arch Dis Child. 2008 Aug;93(8):654-9. doi: 10.1136/adc.・・・
著者: Fernando D Martinez, Vernon M Chinchilli, Wayne J Morgan, Susan J Boehmer, Robert F Lemanske, David T Mauger, Robert C Strunk, Stanley J Szefler, Robert S Zeiger, Leonard B Bacharier, Elizabeth Bade, Ronina A Covar, Noah J Friedman, Theresa W Guilbert, Hengameh Heidarian-Raissy, H William Kelly, Jonathan Malka-Rais, Michael H Mellon, Christine A Sorkness, Lynn Taussig
雑誌名: Lancet. 2011 Feb 19;377(9766):650-7. doi: 10.1016/S0140-6736(10)62145-9. Epub 2011 Feb 14.
Abstract/Text BACKGROUND: Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment.
METHODS: In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5-18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 μg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 μg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329.
RESULTS: 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)-555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37-61), the frequency of exacerbations was lower in the daily (28%, 18-40, p=0·03), combined (31%, 21-43, p=0·07), and rescue (35%, 24-47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14-43) in the placebo group, compared with 5·6% (1·6-14) in the combined (p=0·012), 2·8% (0-10) in the daily (p=0·009), and 8·5% (2-15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis.
INTERPRETATION: Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided.
FUNDING: National Heart, Lung and Blood Institute.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21324520  Lancet. 2011 Feb 19;377(9766):650-7. doi: 10.1016/S0140・・・
著者: Hiroshi Odajima, Motohiro Ebisawa, Toshikazu Nagakura, Takao Fujisawa, Akira Akasawa, Komei Ito, Satoru Doi, Koichi Yamaguchi, Toshio Katsunuma, Kazuyuki Kurihara, Naomi Kondo, Kazuko Sugai, Mitsuhiko Nambu, Akira Hoshioka, Shigemi Yoshihara, Norio Sato, Noriko Seko, Sankei Nishima
雑誌名: Allergol Int. 2015 Oct;64(4):364-70. doi: 10.1016/j.alit.2015.05.006. Epub 2015 Jun 10.
Abstract/Text BACKGROUND: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression).
METHODS: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 μg/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study.
RESULTS: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study.
CONCLUSIONS: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well.

Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
PMID 26433533  Allergol Int. 2015 Oct;64(4):364-70. doi: 10.1016/j.ali・・・
著者: Ken Ohta, Terumasa Miyamoto, Taro Amagasaki, Manabu Yamamoto, 1304 Study Group
雑誌名: Respirology. 2009 Nov;14(8):1156-65. doi: 10.1111/j.1440-1843.2009.01633.x.
Abstract/Text BACKGROUND AND OBJECTIVE: The efficacy and safety of the anti-IgE antibody, omalizumab, has been widely studied in patients with asthma. However to date, no large studies have been performed in Asian populations. The aim of this study was to compare the efficacy and safety of omalizumab with placebo, as add-on therapy in Asian patients with moderate-to-severe persistent asthma.
METHODS: Japanese patients (20-75 years of age) with uncontrolled asthma, despite receiving high-dose inhaled corticosteroids and other standard therapies, were randomized to receive add-on treatment with omalizumab or placebo in a 16-week, double-blind, parallel-group, multicentre study.
RESULTS: Altogether, 315 treated patients were included in the efficacy and safety analyses. The change from baseline in morning PEF was 15.45 L/min (least squares mean) with omalizumab versus 2.25 L/min with placebo, a statistically significant difference of 13.19 L/min (P = 0.0004). Clinically significant asthma exacerbations occurred in six patients (4.0%) treated with omalizumab and in 18 patients (11.0%) treated with placebo. The odds ratio for the risk of experiencing an asthma exacerbation was 0.32 in favour of omalizumab (P = 0.0192). Changes in asthma symptom scores, daily life activity scores, sleep scores and rescue medication use were in favour of omalizumab, but group differences did not reach statistical significance. Adverse event rates were similar between omalizumab and placebo, except for injection site reactions, which were more frequently observed in the omalizumab group.
CONCLUSIONS: Add-on treatment with omalizumab improved asthma control without significant adverse events in Japanese patients with moderate-to-severe persistent asthma.

PMID 19909462  Respirology. 2009 Nov;14(8):1156-65. doi: 10.1111/j.144・・・

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