今日の臨床サポート

気管支喘息

著者: 井上博雅 鹿児島大学大学院医歯学総合研究科 呼吸器内科学

監修: 長瀬隆英 東京大学 内科学専攻器官病態内科学講座

著者校正済:2022/07/20
現在監修レビュー中
参考ガイドライン:
患者向け説明資料
薬価収載情報:2022年11月16日 テゼスパイア 皮下注210mgシリンジ(テゼペルマブ(遺伝子組換え)製剤 ヒト抗TSLPモノクローナル抗体)

概要・推奨   

  1. いわゆる軽症喘息であっても重篤な増悪(発作)がみられ、吸入ステロイド薬を含んだ加療により、その増悪予防が可能である。喘息と診断したら、吸入ステロイド薬を含む加療を行うことが推奨される(推奨度1)
  1. 増悪時や喘息症状のある時は、速効性の気管支拡張薬(短時間作用性β2刺激薬または吸入ステロイド薬+フォルモテロールの配合薬)の吸入で対処することが推奨される(推奨度1)。 
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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
井上博雅 : 未申告[2022年]
監修:長瀬隆英 : 講演料(アストラゼネカ,日本ベーリンガー),奨学(奨励)寄付など(中外製薬)[2022年]

改訂のポイント:
  1. 日本の喘息予防・管理ガイドライン2021、及び、喘息管理の国際指針GINA2022に準拠して、加筆修正を行った。

病態・疫学・診察

疾患(疫学・病態)  
  1. 気管支喘息とは、気道の慢性炎症、可逆性のある気道狭窄と気道過敏性の亢進を本態として、咳嗽、喘鳴、呼吸困難などの症状を反復する呼吸器疾患である。
  1. 繰り返す発作性の喘鳴、呼吸困難、咳嗽などの症状がみられた場合は喘息を疑う。
  1. 病型には、環境アレルゲンに対する特異的なIgE抗体や血清総IgE値の高値を示すアトピー型喘息と、それがない非アトピー型喘息に分類される。
  1. 夜間、早朝の呼吸器症状は喘息でみられることが多い。
  1. 気管支拡張薬の吸入によって改善する気流制限、好酸球性気道炎症の存在、気道過敏性の亢進は診断に有用である。
  1. 診断においては、ほかの心肺疾患の鑑別が必要である。特に喫煙歴がある40歳以上の患者では慢性閉塞性肺疾患(COPD)との鑑別が難しいことがある。喘息とCOPDの合併もしばしばみられる。
  1. 急性増悪時のCOPDでは喘息様の症状を呈し得るが、この場合はまず喘息として治療を行ってよい。
病歴・診察のポイント  
下記のことを確認する。発作を起こして来院した場合は、治療を進めながら問診・診察を行う。
  1. 喘息の診断:症状からだけでは喘息かどうか判断しづらい症例では、小児期の喘息様の呼吸器症状の有無や家族歴の有無を確認する。

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。

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文献 

Romain A Pauwels, Søren Pedersen, William W Busse, Wan C Tan, Yu-Zhi Chen, Stefan V Ohlsson, Anders Ullman, Carl Johan Lamm, Paul M O'Byrne, START Investigators Group
Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial.
Lancet. 2003 Mar 29;361(9363):1071-6. doi: 10.1016/S0140-6736(03)12891-7.
Abstract/Text BACKGROUND: Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established.
METHODS: We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat.
FINDINGS: 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively).
INTERPRETATION: Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset.

PMID 12672309
R A Pauwels, C G Löfdahl, D S Postma, A E Tattersfield, P O'Byrne, P J Barnes, A Ullman
Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group.
N Engl J Med. 1997 Nov 13;337(20):1405-11. doi: 10.1056/NEJM199711133372001.
Abstract/Text BACKGROUND: The role of long-acting, inhaled beta2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide.
METHODS: After a four-week run-in period of treatment with budesonide (800 microg twice daily), 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 microg of budesonide plus placebo, 100 microg of budesonide plus 12 microg of formoterol, 400 microg of budesonide plus placebo, or 400 microg of budesonide plus 12 microg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma, symptoms, and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days.
RESULTS: The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent, respectively, when formoterol was added to the lower dose of budesonide. The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent, respectively. Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent, respectively. Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide, but the improvements with formoterol were greater.
CONCLUSIONS: In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial. The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma.

PMID 9358137
S Suissa, P Ernst, S Benayoun, M Baltzan, B Cai
Low-dose inhaled corticosteroids and the prevention of death from asthma.
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
Sean D Sullivan, Martin Buxton, L Fredrik Andersson, Carl Johan Lamm, Bengt Liljas, Yu Zhi Chen, Romain A Pauwels, Kevin B Weiss
Cost-effectiveness analysis of early intervention with budesonide in mild persistent asthma.
J Allergy Clin Immunol. 2003 Dec;112(6):1229-36. doi: 10.1016/j.jaci.2003.09.025.
Abstract/Text BACKGROUND: The Inhaled Steroid as Regular Therapy in Early Asthma (START) study reported that early intervention with budesonide in mild persistent asthma reduces severe asthmatic events and improves symptom outcomes and lung function in adults and children.
OBJECTIVE: We sought to estimate the incremental cost-effectiveness of early intervention with budesonide, as observed within the START study.
METHODS: START was a randomized, 3-year controlled trial of budesonide in early onset mild asthma among 7165 subjects ages 5 to 66 years. Three age groups (5-10, 11-17, and >or=18 years) were studied separately and overall. Differences in the probability of emergency treatments, symptom-free days (SFDs), and costs of health care were determined. Incremental cost-effectiveness ratios were estimated from the health care payer and societal perspectives.
RESULTS: Compared with usual therapy, patients receiving budesonide experienced an average of 14.1 (SE, 1.3) more SFDs per year (P <.001), fewer hospital days (69%, P <.001), and fewer emergency department visits (67%, P <.05). From the health care payer perspective, the net cost of early use of budesonide was an additional US dollars 0.42 (SE, dollars 0.04) per day, and the resultant cost-effectiveness ratio was US dollars 11.30 (95% CI, US dollars 8.60-US dollars 14.90) per SFD gained. From the societal perspective, the cost offsets of lower absence from school or work reduced the net cost of early budesonide to US dollars 0.14 (SE, US dollars 0.07) per day and decreased the cost-effectiveness ratio to US dollars 3.70 (95% CI, US dollars 0.10-US dollars 8.00). Early intervention was more effective and cost saving in the youngest age group.
CONCLUSION: Long-term treatment with budesonide appears to be cost-effective in patients with mild persistent asthma of recent onset.

PMID 14657888
Abstract/Text We evaluated asthma control and medication use 5 years after introduction of an inhaled corticosteroid (budesonide via Turbuhaler) in 462 patients with persistent asthma and symptoms of different duration. An early treatment group with symptoms for <2 years (group A) was compared with a delayed treatment group (group B) (median duration 5 years and 3 months). Most patients received budesonide 400 microg twice daily as initial dose. We report 5-year follow-up data on 404 patients (group A n = 253; group B n = 151) and on a few more patients after treatment for 6 months, 1 year and 3 years. At 5 years the mean maintenance doses of budesonide were 412 microg (A) and 825 microg (B), respectively (P<0.001). Nevertheless, treatment goals (normal lung function, normal exercise tolerance, minimal use of reliever medication, no asthma exacerbations) were all statistically significantly more frequently achieved in group A. At 5 years group B patients also used significantly more additional asthma medications, e.g. inhaled long-acting beta2-agonists by 64% compared with 6% in group A. In group A 43 patients (17%) had been able to stop budesonide treatment compared to five patients (3%) in group B. A subgroup of group B patients with higher mean baseline FEV1 values than group A showed nevertheless significantly poorer response. No treatment-related serious adverse events were reported. Budesonide was well tolerated in both groups. Conclusion: Duration of asthma symptoms when starting treatment with an inhaled corticosteroid is an important determinant for the response. Early treatment gives significantly better airway function and asthma control than delayed treatment and at lower maintenance doses.

PMID 15002762
Abstract/Text OBJECTIVE: To appraise the data on systemic adverse effects of inhaled corticosteroids.
METHODS: A computerized database search from January 1, 1966, through July 31, 1998, using MEDLINE, EMBASE, and BIDS and using appropriate indexed terms. Reports dealing with the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate. Studies were included that contained evaluable data on systemic effects in healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies.
RESULTS: Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1.5 mg/d (0.75 mg/d for fluticasone propionate), although there is a considerable degree of interindividual susceptibility. Meta-analysis showed significantly greater potency for dose-related adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone propionate were approximately equivalent on a 10:1-mg basis. Inhaled corticosteroids in doses above 1.5 mg/d (0.75 mg/d for fluticasone propionate) may be associated with a significant reduction in bone density, although the risk for osteoporosis may be obviated by post-menopausal estrogen replacement therapy. Although medium-term growth studies showed suppressive effects with 400-microg/d beclomethasone dipropionate, there was no evidence to support any significant effects on final adult height. Long-term, high-dose inhaled corticosteroid exposure increases the risk for posterior subcapsular cataracts, and, to a much lesser degree, the risk for ocular hypertension and glaucoma. Skin bruising is most likely to occur with high-dose exposure, which correlates with the degree of adrenal suppression.
CONCLUSIONS: All inhaled corticosteroids exhibit dose-related systemic adverse effects, although these are less than with a comparable dose of oral corticosteroids. Metaanalysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.8 mg/d. The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life.

PMID 10326936
R F Lemanske, C A Sorkness, E A Mauger, S C Lazarus, H A Boushey, J V Fahy, J M Drazen, V M Chinchilli, T Craig, J E Fish, J G Ford, E Israel, M Kraft, R J Martin, S A Nachman, S P Peters, J D Spahn, S J Szefler, Asthma Clinical Research Network for the National Heart, Lung, and Blood Institute
Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.
JAMA. 2001 May 23-30;285(20):2594-603.
Abstract/Text CONTEXT: Inhaled long-acting beta(2)-agonists improve asthma control when added to inhaled corticosteroid (ICS) therapy.
OBJECTIVE: To determine whether ICS therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting beta(2)-agonist to their treatment regimen.
DESIGN AND SETTING: A 24-week randomized, controlled, blinded, double-dummy, parallel-group trial conducted at 6 National Institutes of Health-sponsored, university-based ambulatory care centers from February 1997 through January 1999.
PARTICIPANTS: One hundred seventy-five patients aged 12 through 65 years with persistent asthma that was suboptimally controlled during a 6-week run-in period of treatment with inhaled triamcinolone acetonide (400 microg twice per day).
INTERVENTION: Patients continued triamcinolone therapy and were randomly assigned to receive add-on therapy with either placebo (placebo-minus group, n = 21) or salmeterol xinafoate, 42 microg twice per day (n = 154) for 2 weeks. The entire placebo-minus group was assigned and half of the salmeterol group (salmeterol-minus group) was randomly assigned to reduce by 50% (for 8 weeks) then eliminate (for 8 weeks) triamcinolone treatment. The other half of the salmeterol group (salmeterol-plus group) was randomly assigned to continue both salmeterol and triamcinolone for the remaining 16 weeks (active control group).
MAIN OUTCOME MEASURE: Time to asthma treatment failure in patients receiving salmeterol.
RESULTS: Treatment failure occurred in 8.3% (95% confidence interval [CI], 2%-15%) of the salmeterol-minus group 8 weeks after triamcinolone treatment was reduced compared with 2.8% (95% CI, 0%-7%) of the salmeterol-plus group during the same period. Treatment failure occurred in 46.3% (95% CI, 34%-59%) of the salmeterol-minus group 8 weeks after triamcinolone therapy was eliminated compared with 13.7% (95% CI, 5%-22%) of the salmeterol-plus group. The relative risk (95% CI) of treatment failure at the end of the triamcinolone elimination phase in the salmeterol-minus group was 4.3 (2.0-9.2) compared with the salmeterol-plus group (P<.001).
CONCLUSIONS: Our results indicate that in patients with persistent asthma suboptimally controlled by triamcinolone therapy alone but whose asthma symptoms improve after addition of salmeterol, a substantial reduction (50%) in triamcinolone dose can occur without a significant loss of asthma control. However, total elimination of triamcinolone therapy results in a significant deterioration in asthma control and, therefore, cannot be recommended.

PMID 11368733
William Busse, Steven M Koenig, John Oppenheimer, Steven A Sahn, Steven W Yancey, Donna Reilly, Lisa D Edwards, Paul M Dorinsky
Steroid-sparing effects of fluticasone propionate 100 microg and salmeterol 50 microg administered twice daily in a single product in patients previously controlled with fluticasone propionate 250 microg administered twice daily.
J Allergy Clin Immunol. 2003 Jan;111(1):57-65.
Abstract/Text BACKGROUND: Concurrent use of an inhaled corticosteroid (ICS) and an inhaled long-acting beta2-agonist provides better overall asthma control than the use of higher doses of ICS alone.
OBJECTIVE: The purpose of this investigation was to determine whether fluticasone propionate (FP) combined with salmeterol in the Diskus device can be used to reduce the dose of ICS in patients currently stable on medium-dose ICS while maintaining asthma control.
METHODS: This was a randomized, double-blind, parallel-group, 12- to 24-week trial consisting of a 3-part run-in period. The run-in period was designed to first establish FP 250 microg administered twice a day (bid) via Diskus as the minimum effective dose. During run-in period 1, patients received FP 220 microg bid or the equivalent for 10 to 14 days. Controlled patients moved to run-in period 2 (5-28 days), which assessed asthma stability on FP 100 microg bid administered via Diskus. Only patients who became unstable on FP 100 microg bid were eligible to enter run-in period 3 (26-30 days), during which they were placed on FP 250 microg bid and those regaining asthma control were eligible for randomization. The primary efficacy endpoint was the proportion of patients who remained in the study with no evidence of worsening asthma. Secondary efficacy measures included FEV1, morning peak expiratory flow, percent of symptom-free days, and daily albuterol use.
RESULTS: Only 5% of patients treated with FP100/salmeterol withdrew because of worsening asthma in the first 12 weeks; this compared with 7% in the FP250 group. All patients from a subset of sites continued in the study for an additional 12 weeks; only an additional 1% of patients treated with either FP100/salmeterol or FP250 withdrew because of worsening asthma. Secondary efficacy measures confirmed primary efficacy results.
CONCLUSION: In patients requiring FP250 bid for asthma stability, FP100/salmeterol bid was steroid-sparing, allowing a 60% reduction in the FP dose while maintaining overall asthma control.

PMID 12532097
R A Pauwels, M R Sears, M Campbell, C Villasante, S Huang, A Lindh, W Petermann, M Aubier, G Schwabe, T Bengtsson, RELIEF Study investigators
Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial.
Eur Respir J. 2003 Nov;22(5):787-94.
Abstract/Text The aim of the study was to compare the safety and effectiveness of as-needed formoterol with salbutamol in a large international real-life asthma study. Children and adults (n=18,124) were randomised to 6 months as-needed treatment with open-label formoterol 4.5 microg Turbuhaler or salbutamol 200 microg pressurised metered dose inhaler or equivalent. Primary safety variables were asthma-related and nonasthma-related serious adverse events (SAE)s and adverse events (AE)s resulting in discontinuation (DAE)s. The primary efficacy variable was time to first asthma exacerbation. The incidences of AEs, SAEs and DAEs arising from SAEs were not significantly different between treatments. DAEs for nonserious AEs were higher with formoterol. Asthma-related AEs decreased with formoterol (1,098 (12.3%) versus 1,206 (13.5%)), asthma-related SAEs were similar (108 (1.2%) versus 121 (1.4%)) but more asthma-related DAEs occurred in the formoterol group (89 (1.0%) versus 48 (0.5%)). Time to first exacerbation was prolonged (hazard ratio 0.86) and less as-needed and maintenance medication was used with formoterol. Reductions of exacerbations with as-needed formoterol versus salbutamol increased with increasing age and asthma medication level. This real-life study demonstrates that formoterol as-needed has a similar safety profile to salbutamol, and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations.

PMID 14621086
Abstract/Text Guidelines on asthma management recommend that in patients who still have symptoms on treatment with low-dose inhaled corticosteroids the first step should be an increase in inhaled corticosteroid dose. The addition of long-acting inhaled beta 2-adrenoceptor agonists is another option. We have compared these two strategies in a randomised, double-blind, parallel-group trial. We studied 429 adult asthmatic patients who still had symptoms despite maintenance treatment with 200 micrograms twice daily inhaled beclomethasone dipropionate (BDP). 3 did not provide verifiable data. Of the others, 220 were assigned salmeterol xinafoate (50 micrograms twice daily) plus BDP and 206 were assigned higher-dose BDP (500 micrograms twice daily) for 6 months. The mean morning peak expiratory flow increased from baseline in both groups, but the increase was greater in the salmeterol/BDP group than in the higher-dose BDP group at all time points (differences 16-21 L/min, p < 0.05). Mean evening PEF also increased with salmeterol/BDP but not with higher-dose BDP. There were significant differences in favour of salmeterol/BDP in diurnal variation of PEF (all time points) and in use of rescue bronchodilator (salbutamol) and daytime and night-time symptoms (some time points). There was no significant difference between the groups in adverse effects or exacerbations of asthma, indicating that in this group of patients regular beta 2-agonist therapy was not associated with any risk of deteriorating asthma control over 6 months. This study suggests a need for a flexible approach to asthma management.

PMID 7913155
A Woolcock, B Lundback, N Ringdal, L A Jacques
Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids.
Am J Respir Crit Care Med. 1996 May;153(5):1481-8. doi: 10.1164/ajrccm.153.5.8630590.
Abstract/Text A study was done to compare the efficacy and safety of the coprescription of salmeterol 50 microgram twice daily or 100 microgram twice daily with beclomethasone dipropionate (BDP) 500 micrograms twice daily (SALM 50 and SALM 100) with BDP 1,000 microgram twice daily (BDP 1,000) in patients with asthma not controlled by BDP 500 microgram twice daily (or the equivalent). Following a run-in period, 738 patients at 72 centers were randomized to treatment for 24 wk in a double-blind, parallel-group study during which they maintained a daily record of peak expiratory flow rates (PEFRs) and symptom scores. At about 40 of the centers, bronchial hyperresponsiveness (BHR) to histamine was measured during and at 3 and 14 d after stopping treatment. Both groups taking salmeterol showed an improvement of more than 45 L/min in their morning PEFR and 30 L/min in their evening PEFR, compared with respective improvements of 16 L/min and 6 L/min in the group taking BDP 1,000. Both the SALM 50 and SALM 100 groups had a significantly increased percentage of symptom-free and rescue-free days and nights compared with the BDP 1,000 group, and there was no difference between the two salmeterol groups. None of the treatments altered BHR. Exacerbation rates did not differ among the three groups. We conclude that in this selected group of symptomatic patients taking BDP 500 micrograms twice daily, the addition of salmeterol provides better improvement in lung function and symptom control, without altering BHR or increasing exacerbation rates, than does doubling the dose of BDP.

PMID 8630590
Klaus F Rabe, Tito Atienza, Pál Magyar, Per Larsson, Carin Jorup, Umesh G Lalloo
Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study.
Lancet. 2006 Aug 26;368(9537):744-53. doi: 10.1016/S0140-6736(06)69284-2.
Abstract/Text BACKGROUND: The contributions of as-needed inhaled corticosteroids and long-acting beta2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting beta2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy.
METHODS: We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 microg and 4.5 microg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications-terbutaline (0.4 mg), formoterol (4.5 microg), or budesonide-formoterol (160 microg and 4.5 microg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more.
FINDINGS: Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0.0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0.0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0.67 [95% CI 0.56-0.80; p<0.0001]; budesonide-formoterol versus terbutaline 0.52 [0.44-0.62; p<0.0001]; formoterol versus terbutaline 0.78 [0.67-0.91; p=0.0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated.
INTERPRETATION: Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.

PMID 16935685
Eric D Bateman, Helen K Reddel, Göran Eriksson, Stefan Peterson, Ollie Ostlund, Malcolm R Sears, Christine Jenkins, Marc Humbert, Roland Buhl, Tim W Harrison, Santiago Quirce, Paul M O'Byrne
Overall asthma control: the relationship between current control and future risk.
J Allergy Clin Immunol. 2010 Mar;125(3):600-8, 608.e1-608.e6. doi: 10.1016/j.jaci.2009.11.033. Epub 2010 Feb 11.
Abstract/Text BACKGROUND: Asthma guidelines emphasize both maintaining current control and reducing future risk, but the relationship between these 2 targets is not well understood.
OBJECTIVE: This retrospective analysis of 5 budesonide/formoterol maintenance and reliever therapy (Symbicort SMART Turbuhaler(*)) studies assessed the relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations.
METHODS: The percentage of patients with Global Initiative for Asthma-defined controlled asthma over time was assessed for budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies; higher dose inhaled corticosteroid (ICS), same dose ICS/long-acting beta(2)-agonist (LABA), and higher dose ICS/LABA plus short-acting beta(2)-agonist. The relationship between baseline ACQ-5 and exacerbations was investigated. A Markov analysis examined the transitional probability of change in control status throughout the studies.
RESULTS: The percentage of patients achieving asthma control increased with time, irrespective of treatment; the percentage Controlled/Partly Controlled at study end was at least similar to budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies: higher dose ICS (56% vs 45%), same dose ICS/LABA (56% vs 53%), and higher dose ICS/LABA (54% vs 54%). Baseline ACQ-5 score correlated positively with exacerbation rates. A Controlled or Partly Controlled week predicted at least Partly Controlled asthma the following week (>or=80% probability). The better the control, the lower the risk of an Uncontrolled week. The probability of an exacerbation was related to current state and was lower with budesonide/formoterol maintenance and reliever therapy.
CONCLUSIONS: Current control predicts future risk of instability and exacerbations. Budesonide/formoterol maintenance and reliever therapy reduces exacerbations versus comparators and achieves at least similar control.

PMID 20153029
D B Price, D Hernandez, P Magyar, J Fiterman, K M Beeh, I G James, S Konstantopoulos, R Rojas, J A van Noord, M Pons, L Gilles, J A Leff, Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group
Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma.
Thorax. 2003 Mar;58(3):211-6.
Abstract/Text BACKGROUND: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes. This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients. This double blind, randomised, parallel group, non-inferiority, multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma.
METHODS: After a 1 month single blind run in period, patients inadequately controlled on inhaled budesonide (800 microg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 microg/day (n=448) or budesonide 1600 microg/day (n=441) for 12 weeks.
RESULTS: Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min). During days 1-3 after start of treatment, the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group. Both groups showed similar improvements with respect to "as needed" beta agonist use, mean daytime symptom score, nocturnal awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and asthma specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well tolerated.
CONCLUSION: The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone.

PMID 12612295
Leif Bjermer, Hans Bisgaard, Jean Bousquet, Leonardo M Fabbri, Andrew P Greening, Tari Haahtela, Stephen T Holgate, Cesar Picado, Joris Menten, S Balachandra Dass, Jonathan A Leff, Peter G Polos
Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial.
BMJ. 2003 Oct 18;327(7420):891. doi: 10.1136/bmj.327.7420.891.
Abstract/Text OBJECTIVES: To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol.
PARTICIPANTS: Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of > or = 12% in FEV1.
MAIN OUTCOME MEASURES: The primary end point was the percentage of patients with at least one asthma exacerbation.
RESULTS: 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereas FEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated.
CONCLUSION: The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.

PMID 14563743
Sven-Erik Dahlén, Kerstin Malmström, Ewa Nizankowska, Barbro Dahlén, Piotr Kuna, Marek Kowalski, William R Lumry, César Picado, Donald D Stevenson, Jean Bousquet, Romain Pauwels, Stephen T Holgate, Aditi Shahane, Ji Zhang, Theodore F Reiss, Andrew Szczeklik
Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial.
Am J Respir Crit Care Med. 2002 Jan 1;165(1):9-14. doi: 10.1164/ajrccm.165.1.2010080.
Abstract/Text Leukotriene antagonists block the proinflammatory actions of leukotrienes (LT) and have been introduced as new treatments for asthma. Conventional therapy with glucocorticosteroids does not inhibit the biosynthesis of leukotrienes. We therefore tested whether addition of the leukotriene receptor antagonist montelukast was of therapeutic benefit in a group of aspirin-intolerant patients with asthma of whom 90% already were treated with moderate to high doses of glucocorticosteroids. Under double-blind conditions, 80 aspirin-intolerant patients with asthma were randomized to receive 4 wk oral treatment of either 10 mg of montelukast or placebo once daily at bedtime. Pulmonary function was measured as forced expiratory volume in 1 s (FEV(1)) once a week in the clinic and daily as morning and evening peak expiratory flow rate (PEFR). Asthma symptoms and use of rescue bronchodilator were also recorded daily. Asthma specific quality of life (QoL) was assessed before and after the treatments. The group receiving montelukast showed a remarkable improvement of their asthma, whereas the group given placebo showed no change. Thus, from equal baseline values, the mean difference between the groups over the 4-wk treatment period was 10.2% for FEV(1) and 28.0 L for morning PEFR (p for both < 0.001). The improved pulmonary function in the group receiving montelukast occurred at the same time as 27% less bronchodilator was used (p < 0.05), and it was associated with fewer asthma symptoms than in the group given placebo, including 1.3 nights more of sleep per week and 54% fewer asthma exacerbations (p < 0.05). There was also an improvement in asthma-specific QoL (p < 0.05). The therapeutic response to montelukast was consistent across patients with different baseline characteristics and did not correlate with baseline urinary LTE(4). Addition of a leukotriene receptor antagonist such as montelukast improves asthma in aspirin-intolerant patients over and above what can be achieved by glucocorticosteroids.

PMID 11779723
Andrzej Szczeklik
Hypersensitivity to systemic corticosteroids in aspirin-sensitive patients with asthma.
J Allergy Clin Immunol. 2011 Oct;128(4):904-5. doi: 10.1016/j.jaci.2011.05.026. Epub 2011 Jun 23.
Abstract/Text
PMID 21700324
K Demissie, M B Breckenridge, G G Rhoads
Infant and maternal outcomes in the pregnancies of asthmatic women.
Am J Respir Crit Care Med. 1998 Oct;158(4):1091-5. doi: 10.1164/ajrccm.158.4.9802053.
Abstract/Text We examined the relationship between infant and maternal outcomes and asthma complicating pregnancy, using historical cohort analysis of singleton live deliveries in New Jersey hospitals between 1989 and 1992 (n = 447,963). Subject mother-infant dyads were identified from linked birth certificate and maternal and newborn hospital claims data. Women with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code (493) for asthma (n = 2,289) were compared with a fourfold larger randomly selected control sample (n = 9,156) from the remaining pool of women. After controlling for the effects of important confounding variables, maternal asthma was associated with the following adverse infant outcomes: preterm infant (odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.18 to 1.55), low birth weight (OR = 1. 32; 95% CI, 1.10 to 1.58), small-for-gestational age (OR = 1.26; 95% CI, 1.10 to 1.45), congenital anomalies (OR = 1.37; 95% CI, 1.12 to 1.68), and increased infant hospital length of stay (OR = 1.44; 95% CI, 1.25 to 1.65). The adverse maternal outcomes associated with maternal asthma were: pre-eclampsia (OR = 2.18; 95% CI, 1.68 to 2. 83), placenta previa (OR = 1.71; 95% CI, 1.05 to 2.79), cesarean delivery (OR = 1.62; 95% CI, 1.46 to 1.80), and increased maternal hospital length of stay (OR = 1.86; 95% CI, 1.60 to 2.15). The results emphasize the need for maternal asthma to be added to the list of conditions that increase the risk of adverse pregnancy outcomes.

PMID 9769265
National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group
NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update.
J Allergy Clin Immunol. 2005 Jan;115(1):34-46. doi: 10.1016/j.jaci.2004.10.023.
Abstract/Text
PMID 15637545
Joan B Soriano, Kourtney J Davis, Bobbie Coleman, George Visick, David Mannino, Neil B Pride
The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom.
Chest. 2003 Aug;124(2):474-81.
Abstract/Text STUDY OBJECTIVES: The nonproportional Venn diagram of obstructive lung disease (OLD) produced for the 1995 American Thoracic Society guidelines has not been quantified. We aim to quantify the proportion of the general population with OLD and the intersections of physician-diagnosed asthma, chronic bronchitis, and emphysema in the United States and the United Kingdom, and to examine the relationship to obstructive spirometry.
DESIGN AND PARTICIPANTS: We analyzed data from the US National Health and Nutrition Examination (NHANES) III survey (1988 to 1994) and the UK General Practice Research Database for the year 1998.
RESULTS: The areas of intersection among the three OLD conditions produced seven mutually exclusive disease groups. The asthma-only group was the largest proportion of OLD patients, accounting for 50.3% and 79.4% of all OLD patients in the United States and the United Kingdom, respectively, and decreased with increasing age. Overall, 17% and 19% of OLD patients in the United States and in the United Kingdom, respectively, reported more than one OLD condition, and this percentage increased with age. According to the spirometry data from NHANES III, only 37.4% of emphysema-only patients had objective airflow obstruction. The prevalence of airflow obstruction was significantly higher among participants with combinations of emphysema and chronic bronchitis (57.7%), with emphysema and asthma (51.9%), and with all three OLD diseases concomitantly (52.0%).
CONCLUSION: Concomitant diagnosis of asthma, chronic bronchitis, or emphysema is common among OLD patients from the general population, particularly in adults aged > or = 50 years.

PMID 12907531
K Ohta, P-J Bousquet, H Aizawa, K Akiyama, M Adachi, M Ichinose, M Ebisawa, G Tamura, A Nagai, S Nishima, T Fukuda, A Morikawa, Y Okamoto, Y Kohno, H Saito, H Takenaka, L Grouse, J Bousquet
Prevalence and impact of rhinitis in asthma. SACRA, a cross-sectional nation-wide study in Japan.
Allergy. 2011 Oct;66(10):1287-95. doi: 10.1111/j.1398-9995.2011.02676.x. Epub 2011 Jul 22.
Abstract/Text BACKGROUND: Asthma and rhinitis are common co-morbidities everywhere in the world but nation-wide studies assessing rhinitis in asthmatics using questionnaires based on guidelines are not available.
OBJECTIVE: To assess the prevalence, classification, and severity of rhinitis using the Allergic Rhinitis and its Impact on Asthma (ARIA) criteria in Japanese patients with diagnosed and treated asthma.
METHODS: The study was performed from March to August 2009. Patients in physicians' waiting rooms, or physicians themselves, filled out questionnaires on rhinitis and asthma based on ARIA and Global Initiative for Asthma (GINA) diagnostic guides. The patients answered questions on the severity of the diseases and a Visual Analog Scale. Their physicians made the diagnosis of rhinitis.
RESULTS: In this study, 1910 physicians enrolled 29,518 asthmatics; 15,051 (51.0%) questionnaires were administered by physician, and 26,680 (90.4%) patients were evaluable. Self- and physician-administered questionnaires gave similar results. Rhinitis was diagnosed in 68.5% of patients with self-administered questionnaires and 66.2% with physician-administered questionnaires. In this study, 994 (7.6%) patients with self-administered and 561 (5.2%) patients with physician-administered questionnaires indicated rhinitis symptoms on the questionnaires without a physician's diagnosis of rhinitis. Most patients with the physician's diagnosis of rhinitis had moderate/severe rhinitis. Asthma control was significantly impaired in patients with a physician's diagnosis of rhinitis for all GINA clinical criteria except exacerbations. There were significantly more patients with uncontrolled asthma as defined by GINA in those with a physician's diagnosis of rhinitis (25.4% and 29.7%) by comparison with those without rhinitis (18.0% and 22.8%).
CONCLUSION: Rhinitis is common in asthma and impairs asthma control.

© 2011 John Wiley & Sons A/S.
PMID 21781135
H Sotomayor, M Badier, D Vervloet, J Orehek
Seasonal increase of carbachol airway responsiveness in patients allergic to grass pollen. Reversal by corticosteroids.
Am Rev Respir Dis. 1984 Jul;130(1):56-8.
Abstract/Text By measuring airway resistance (Raw) as an index of response, dose-response curves to aerosolized carbachol were constructed in 10 patients suffering from grass pollen allergy. The subjects were first tested before the pollen season (March). During the pollen season (May and June), another control test was performed; the patients were then treated (double blind and at random) with placebo or methylprednisolone (16 mg/day given orally) for 7 days and then retested. After a 10-day interval devoid of treatment, the 2 treatments were crossed over and a fourth carbachol test was performed. Baseline function values were comparable for all 4 tests. In all but one subject (who was a smoker), carbachol increased Raw by more than 150% over baseline for each of the 4 tests. In these 9 patients, carbachol responsiveness significantly increased during the pollen season and returned to its preseason level after corticosteroid treatment. The data suggest that airway inflammation was responsible for the seasonal increase in airway reactivity.

PMID 6742612
George Philip, Anjuli S Nayak, William E Berger, Francisque Leynadier, France Vrijens, S Balachandra Dass, Theodore F Reiss
The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis.
Curr Med Res Opin. 2004 Oct;20(10):1549-58. doi: 10.1185/030079904X3348.
Abstract/Text OBJECTIVE: The objective of this study was to evaluate montelukast 10 mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season.
METHODS: This was a multicenter study of 831 patients (ages 15 years-85 years) with seasonal allergen sensitivity, active symptoms of seasonal allergic rhinitis, and active asthma. Following a single-blind, placebo run-in period of 3 days-5 days, patients were randomized to oral montelukast 10 mg (n = 415) or placebo (n = 416) daily during the 2-week, double-blind, active-treatment period.
MAIN OUTCOME MEASURES: The primary endpoint was Daily Rhinitis Symptoms score, average of Daytime Nasal Symptoms and Nighttime Symptoms, as self-rated by patients on a 0-3 scale on daily diaries.
RESULTS: Montelukast reduced the Daily Rhinitis Symptoms score: difference between montelukast and placebo in mean change from baseline was -0.12 [95% CI -0.18, -0.06; p < or = 0.001]. Similar improvements were seen in Daytime Nasal Symptoms (-0.14 [-0.21, -0.07; p < or = 0.001]) and Nighttime Symptoms (-0.10 [-0.16, -0.04; p < or = 0.001]). Improvements (p < 0.05) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician, and Rhinoconjunctivitis Quality of Life. In exploratory analyses, improvement in rhinitis symptoms was numerically (though not statistically) larger in patients with greater levels of asthma at study start. Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician: mean differences were -0.24 [-0.41, -0.06; p = 0.008] and -0.17 [-0.33, -0.01; p = 0.037]. Similarly, as-needed beta-agonist use (puffs/day) was reduced with montelukast (p < or = 0.005).
CONCLUSION: Montelukast provides significant relief from symptoms of seasonal allergic rhinitis, while also conferring a benefit for asthma, in patients with both allergic rhinitis and asthma.

PMID 15462688
B D Havemann, C A Henderson, H B El-Serag
The association between gastro-oesophageal reflux disease and asthma: a systematic review.
Gut. 2007 Dec;56(12):1654-64. doi: 10.1136/gut.2007.122465. Epub 2007 Aug 6.
Abstract/Text BACKGROUND AND AIMS: Gastro-oesophageal reflux disease (GORD) has been linked to a number of extra-esophageal symptoms and disorders, primarily in the respiratory tract. This systematic review aimed to provide an estimate of the strength and direction of the association between GORD and asthma.
METHODS: Studies that assessed the prevalence or incidence of GORD in individuals with asthma, or of asthma in individuals with GORD, were identified in Medline and EMBASE via a systematic search strategy.
RESULTS: Twenty-eight studies met the selection criteria. The sample size weighted average prevalence of GORD symptoms in asthma patients was 59.2%, whereas in controls it was 38.1%. In patients with asthma, the average prevalence of abnormal oesophageal pH, oesophagitis and hiatal hernia was 50.9%, 37.3% and 51.2%, respectively. The average prevalence of asthma in individuals with GORD was 4.6%, whereas in controls it was 3.9%. Pooling the odds ratios gave an overall ratio of 5.5 (95% CI 1.9-15.8) for studies reporting the prevalence of GORD symptoms in individuals with asthma, and 2.3 (95% CI 1.8-2.8) for those studies measuring the prevalence of asthma in GORD. One longitudinal study showed a significant association between a diagnosis of asthma and a subsequent diagnosis of GORD (relative risk 1.5; 95% CI 1.2-1.8), whereas the two studies that assessed whether GORD precedes asthma gave inconsistent results. The severity-response relationship was examined in only nine studies, with inconsistent findings.
CONCLUSIONS: This systematic review indicates that there is a significant association between GORD and asthma, but a paucity of data on the direction of causality.

PMID 17682001
Emily DiMango, Janet T Holbrook, Erin Simpson, Joan Reibman, Joel Richter, Surinder Narula, Nancy Prusakowski, John G Mastronarde, Robert A Wise, American Lung Association Asthma Clinical Research Centers
Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity.
Am J Respir Crit Care Med. 2009 Nov 1;180(9):809-16. doi: 10.1164/rccm.200904-0625OC. Epub 2009 Aug 6.
Abstract/Text RATIONALE: Silent gastroesophageal reflux (GER) is common in patients with asthma, but it is unclear whether GER is associated with worse asthma symptoms or reduced lung function.
OBJECTIVES: To determine in patients with poorly controlled asthma, whether proximal or distal esophageal reflux is associated with asthma severity, symptoms, physiology, or functional status.
METHODS: Baseline asthma characteristics were measured in patients with asthma enrolled in a multicenter trial assessing the effectiveness of esomeprazole on asthma control. All participants underwent 24-hour esophageal pH probe monitoring. Lung function, methacholine responsiveness, asthma symptoms, and quality-of-life scores were compared in subjects with and without GER.
MEASUREMENTS AND MAIN RESULTS: Of 304 participants with probe recordings, 53% had reflux. Of 242 participants with recordings of proximal pH, 38% had proximal reflux. There was no difference in need for short-acting bronchodilators, nocturnal awakenings, dose of inhaled corticosteroid, use of long-acting beta-agonists, lung function, or methacholine reactivity between individuals with and without proximal or distal GER. Participants with GER reported more use of oral corticosteroids and had worse asthma quality of life and subjects with proximal GER had significantly worse asthma quality of life and health-related quality of life compared with participants without GER.
CONCLUSIONS: Asymptomatic GER is not associated with distinguishing asthma symptoms or lower lung function in individuals with suboptimal asthma control who are using inhaled corticosteroids. Patients with proximal reflux report significantly worse asthma and health-related quality of life despite lack of physiologic impairment or increase in asthma symptoms. Clinical trial registered with www.clinicaltrials.gov (NCT00069823).

PMID 19661245
Ting Kin Cheung, Bing Lam, Kam Fai Lam, Mary Ip, Connie Ng, Roger Kung, Benjamin C Y Wong
Gastroesophageal reflux disease is associated with poor asthma control, quality of life, and psychological status in Chinese asthma patients.
Chest. 2009 May;135(5):1181-5. doi: 10.1378/chest.08-1702. Epub 2008 Dec 31.
Abstract/Text BACKGROUND: Both asthma and gastroesophageal reflux disease (GERD) are common, often coexist, and have significant impact on a patient's quality of life. Our aim was to determine the prevalence of GERD in asthmatic patients at a major hospital in Hong Kong, and to examine the impact of GERD and its association with asthma control.
METHODS: Patients with asthma who attended the respiratory clinic at Queen Mary Hospital, Hong Kong, were recruited. Demographic data were collected, and a validated Chinese GERD questionnaire was used. The Medical Outcomes Study 36-item short form (SF-36) was used to assess quality of life, and the Hospital Anxiety and Depression Scale (HADS) was used to assess psychological status. Asthma control was assessed by the asthma control test.
RESULTS: A total of 218 patients were recruited; 40.4% of asthmatic patients (88 patients) had GERD, as defined by the GERD questionnaire. Compared with those patients without GERD, those with GERD had significantly worse asthma control (p = 0.022), worse quality of life in all domains of the SF-36 (all p < 0.01), and more anxiety (6.82 vs 4.90, respectively; p < 0.001) and depression (6.09 vs 4.05, respectively; p < 0.001) as reflected by HADSs.
CONCLUSIONS: A significant proportion of asthmatic patients in Hong Kong have GERD, and this is associated with poorer asthmatic control, quality of life, and psychological status.

PMID 19118263
Toni O Kiljander, Ola Junghard, Ola Beckman, Tore Lind
Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study.
Am J Respir Crit Care Med. 2010 May 15;181(10):1042-8. doi: 10.1164/rccm.200910-1537OC. Epub 2010 Jan 28.
Abstract/Text RATIONALE: Gastroesophageal reflux disease (GERD) is common among patients with asthma; however, studies investigating the effect of proton pump inhibitors on asthma outcomes report conflicting results.
OBJECTIVES: To investigate the effect of esomeprazole 40 mg once or twice daily on asthma outcomes in patients with concomitant symptoms of GERD.
METHODS: This 26-week, randomized, double-blind, placebo-controlled study (NCT00317044) included adult patients (18-70 yr) with moderate-to-severe asthma and symptomatic GERD. The change in morning peak expiratory flow (primary variable), evening peak expiratory flow, FEV(1), asthma symptoms, Asthma Quality of Life Questionnaire, Reflux Disease Questionnaire, and tolerability were assessed.
MEASUREMENTS AND MAIN RESULTS: A total of 961 patients were randomized and 828 completed the study. Relative to baseline, improvement in morning peak expiratory flow was observed for both esomeprazole 40 mg once daily (+3.5 L/min; 95% CI, -3.2 to 10.2) and 40 mg twice daily (+5.5 L/min; 95% CI, -1.2 to 12.2), although no statistically significant between-treatment differences were apparent. At treatment end, both doses of esomeprazole significantly improved FEV(1) versus placebo (+0.09 L and +0.12 L; P = 0.0039 and P < 0.0001, respectively). However, only esomeprazole 40 mg twice daily demonstrated a significant improvement when FEV(1) was calculated over the entire 26-week period (+0.07 L; P = 0.0042). Significant improvements in Asthma Quality of Life Questionnaire total score were demonstrated for both esomeprazole doses compared with placebo (+0.28 and +0.41; P = 0.0006 and P < 0.0001, respectively).
CONCLUSIONS: Esomeprazole may improve pulmonary function and asthma-related quality of life. However, the improvements were minor and of small clinical significance.

PMID 20110554
L Nannini, C J Cates, T J Lasserson, P Poole
Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease.
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003794. doi: 10.1002/14651858.CD003794.pub3. Epub 2007 Oct 17.
Abstract/Text BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler may facilitate adherence to medication regimens, and improve efficacy.
OBJECTIVES: To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to placebo, in the treatment of adults with chronic obstructive pulmonary disease.
SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007.
SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Studies could compare any combined inhaled corticosteroids and long-acting beta-agonist preparation with placebo.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. One author entered the data.
MAIN RESULTS: Eleven studies met the inclusion criteria (6427 participants randomised). Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were used. Study quality was good. Fluticasone/salmeterol and budesonide/formoterol both reduced the rate of exacerbations. Pooled analysis of both combination therapies indicated that exacerbations were less frequent when compared with placebo, Rate Ratio: 0.74 (95% CI 0.7 to 0.8). The clinical impact of this effect depends on the frequency of exacerbations experienced by patients. The patients included in these trials had on average 1-2 exacerbations per year which means that treatment with combination therapy would lead to a reduction of one exacerbation every two to four years in these individuals. There is an overall reduction in mortality, but this outcome is dominated by the results of TORCH and further studies on budesonide/formoterol are required. The three year number needed to treat to prevent one extra death is 36 (95% CI 21 to 258), using a baseline risk of 15.2% from the placebo arm of TORCH. Both treatments led to statistically significant improvement in health status measurements, although the clinical importance of the differences observed is open to interpretation. Symptoms and lung function assessments favoured combination treatments. There was an increase in the risk of pneumonia with combined inhalers. The three year number needed to treat for one extra case of pneumonia is 13 (95% CI 9 to 20), using a baseline risk of 12.3% from the placebo arm of TORCH. Fewer participants withdrew from studies assessing combined inhalers due to adverse events and lack of efficacy.
AUTHORS' CONCLUSIONS: Compared with placebo, combination therapy led to a significant reduction of a quarter in exacerbation rates. There was a significant reduction in all-cause mortality with the addition of data from the TORCH trial. The increased risk of pneumonia is a concern, and better reporting of this outcome in future studies would be helpful. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, particularly in relation to the profile of adverse events and benefits in relation to different doses of inhaled corticosteroids.

PMID 17943798
Paul M O'Byrne, Soren Pedersen, Lars-Göran Carlsson, Finn Radner, Anders Thorén, Stefan Peterson, Pierre Ernst, Samy Suissa
Risks of pneumonia in patients with asthma taking inhaled corticosteroids.
Am J Respir Crit Care Med. 2011 Mar 1;183(5):589-95. doi: 10.1164/rccm.201005-0694OC. Epub 2010 Oct 1.
Abstract/Text RATIONALE: Inhaled corticosteroids (ICS) are the mainstay of asthma treatment. Studies in chronic obstructive pulmonary disease reported increased rates of pneumonia with ICS. Concerns exist about an increased pneumonia risk in patients with asthma taking ICS.
OBJECTIVES: To evaluate the risks of pneumonia in patients with asthma taking ICS.
METHODS: A retrospective analysis evaluated studies of the ICS budesonide in asthma. The primary data set were all double-blind, placebo-controlled trials lasting at least 3 months, involving budesonide (26 trials, n = 9,067 for budesonide; n = 5,926 for the comparator) sponsored by AstraZeneca. A secondary data set evaluated all double-blind trials lasting at least 3 months but without placebo control (60 trials, n = 33,496 for budesonide, n = 2,773 for fluticasone propionate). Cox proportional hazards regression modeling was used to estimate the relative effect of ICS on pneumonia adverse events (AEs) or serious adverse events (SAEs).
MEASUREMENTS AND MAIN RESULTS: In the primary data set, the occurrence of pneumonia AEs was 0.5% (rate 10.0 events/1,000 patient-years [TPY]) for budesonide and 1.2% (19.3 per TPY) for placebo (hazard ratio, 0.52; 95% confidence interval, 0.36-0.76; P < 0.001); the occurrence of pneumonia SAEs was 0.15% (2.9 per TPY) for budesonide and 0.13% (2.1 per TPY) for placebo (hazard ratio, 1.29; 95% confidence interval, 0.53-3.12; P = 0.58). In the secondary data set, the percentage of patients reporting pneumonia AEs was 0.70% (12.7 per TPY), whereas the percentage of patients reporting pneumonia SAEs was 0.17% (3.1 per TPY). There was no increased risk with higher budesonide doses or any difference between budesonide and fluticasone.
CONCLUSIONS: There is no increased risk of pneumonia in patients with asthma, identified as an AE or SAE, in clinical trials using budesonide.

PMID 20889908

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