Asthma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Philip Marcus, M.D., M.P.H. [2]; Associate Editor(s)-in-Chief:

Overview

Specific therapies available for the management of asthma are broadly classified into three groups: relievers, preventers and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2)[1] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma[2] are the two current guidelines that followed in the management of asthma. Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier, a mast-cell stabilizer, or theophylline may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks. For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks.

Medical Therapy

Quick Relief Medication

There is no cure for asthma; however, medications could help to prevent future attacks and relieve associated symptoms such as, tightness of the chest and troubled breathing. The specific medical treatment recommended depends on the severity and the frequency of exacerbations.

  • LABA are typically provided in pocket-sized, metered-dose inhalers (MDIs).
  • In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits.
  • A nebulizer which provides a larger, continuous dose can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapor, which the patient inhales continuously until the full dosage is administered. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.

Relievers:

  • Short-acting selective beta2-adrenoceptor agonists, such as salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol. Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
  • Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.[3][4] When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.[3] In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.
  • Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β2-adrenoreceptor agonists.

Long-term Control Medications

Long-acting bronchodilators (LABA) are similar in structure to short-acting selective beta2-adrenoceptor agonists, but have much longer side chains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required.

  • In November of 2005, the American FDA released a health advisory alerting the public to findings that show the use of long-acting β2-agonists could lead to a worsening of symptoms, and in some cases death.[6]
  • A recent meta-analysis of the roles of long-acting beta- agonists may indicate a danger to asthmatics. "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a Cornell study. The study goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market".[7] This assertion has drawn criticism from many asthma specialists for being inaccurate. As Dr. Hal Nelson points out in a recent letter to the Annals of Internal Medicine, Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts. Dr. Salpeter has since tempered her comments regarding LABAs.

Glucocorticoids, either inhaled or oral, may help with does up to fluticaonse equivalent of 1600 to 2000 mcg per day.

Macolide antibiotics such as azithromycin[8][9] and clarithromycin[10] may reduce exacerbations.

Biologic therapy

Many monoclonal antibodies have been investigated and reviewed[11].

Anti-IgE therapy such as omalizumab may help.

Monoclonal antibodies against type 2 helper T (Th2) cytokines (interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13)) or their receptors may help eosinophilic asthma:

  • IL-5 or its receptor blockers include mepolizumab, reslizumab, or benralizumab. These drugs may reduce exacerbations of asthma by half in patients with eosinophilic asthma[12].
    • The large ZONDA trial of benralizumab reported benefit[13]
    • A more recent trial of benralizumab was terminated early[14]
  • Dupilumab is active against IL-4 and IL-13
  • Tralokinumab is active against IL-13 but may not be effective at reducing exacerbations of asthma[15].

Monoclonal antibodies against thymic stromal lymphopoietin (TSLP) may be effective:

Therapeutic Regimens

Mild Intermittent Asthma

Step 1 Therapy:

Mild Persistent Asthma

Step 2 Therapy:

Moderate Persistent Asthma

Step 3 Therapy:

  • Preferred treatment:

Severe Persistent Asthma

Step 4 Therapy:

Step 5 Therapy:

Step 6 Therapy:

Guidelines for Diagnosis and Management of Asthma Based On The National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR3) [20]

Severity Components Intermittent Persistent Asthma
Mild Moderate Severe
Symptoms
  • Less than 1 day/week
  • More than 2 days/week
  • Not daily
  • Daily
  • Daily
  • Throughout the day
Nocturnal Symptoms
  • Less than 2 times/month
  • 3 to 4 times/month
  • More than 1 time/week
  • Not every night
  • Every night
Interference w/ Activity
  • Minimal to none
  • Minor limitation of activity
  • Some limitation of activity
  • Severe limitation of activity
Short-Acting Beta-Agonist Use
  • Less than 2 days/week
  • More than 2 days/week but not daily
  • Not more than once/day
  • Daily
  • Several times/day
Pulmonary Function Test
  • Normal FEV1 between exacerbations
  • FEV1 > 80% predicted
  • FEV1/FVC normal
  • FEV1 > 80% predicted
  • FEV1/FVC normal
  • FEV1 > 60% but < 80% predicted
  • FEV1/FVC reduced by 5%
  • FEV1 < 60% predicted
  • FEV1/FVC reduced by > 5%
Recommended Treatment Strategy STEP 1
  • Preferred: Short-acting beta-agonist PRN
STEP 2
  • Preferred: Low-dose inhaled corticosteroids
  • Alternative: Cromolyn, Leukotriene receptor antagonist, Nedocromil, or Theophylline
STEP 3
  • Preferred: Either low-dose inhaled corticosteroids + long-acting beta-agonist OR Medium-dose inhaled corticosteroid
  • Alternative: Low-dose inhaled corticosteroid + either Leukotriene receptor antagonist, Theophylline, or Zileuton
STEP 4
  • Preferred: Medium-dose inhaled corticosteroid + long-acting beta-agonist
  • Alternative: Medium-dose inhaled corticosteroids + either Leukotriene receptor antagonist, Theophylline, or Zileuton

STEP 5

  • Preferred: High-dose inhaled corticosteroids + long-acting beta-agonist
  • Consider adding Omalizumab for patients with allergies

STEP 6

  • Preferred: High-dose inhaled corticosteroids + long-acting beta-agonist + oral corticosteroids
  • Consider adding Omalizumab for patients with allergies
Step down if possible and asthma is controlled for at least 3 months Dualarrow.png Step-up if needed, but first check adherence, environmental control, and comorbidities
  • In each step, patient education, environmental control, and management of comorbidities are important.
  • In STEP 2 - 4, consider subcutaneous allergen immunotherapy for patients with allergic asthma
  • Short-acting beta-agonist as needed for symptoms. Up to 3 treatments at 20 minute intervals as needed.
  • A short course of oral systemic corticosteroids may be needed. Use of a short-acting beta agonist for >2 days a week for symptom control indicates inadequate control and the need to step up therapy.

Monitoring response to treatment

Methods of monitoring response to treatment include:

  • Sputum eosinophils percentage can guide corticosteroid therapy[21]. One approach is[22]:
    • If the sputum eosinophil count is less than 1%, reduce anti-inflammatory treatment irrespective of asthma control.
    • If the eosinophil count is 1–3%, make no changes to anti-inflammatory treatment
    • If the eosinophil count is greater than 3%, increase anti-inflammatory treatment
  • If measuring of sputum eosinophils is not available, a blood eosinophil count of 260 cells per μL or more or a eosinophil percentage of white blood cells of 2.7% or more can indicate eosinophilic inflammation[23]. Alternative cut-offs of 200 cells per μL and 2% and 300 cells per μL in the AZISAST trial[8] and 3%[9] in the AMAZES trial have been used.


The role of monitoring peak expiratory flow rates is limited by variability of measurement[24].

The role of monitoring exhaled nitric oxide levels is not established[25] although an early trial showed benefit[26].

References

  1. National Asthma Education and Prevention Program (2002) National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics--2002. J Allergy Clin Immunol 110 (5 Suppl):S141-219. PMID: 12542074
  2. British Thoracic Society & Scottish Intercollegiate Guidelines Network (SIGN). British Guideline on the Management of Asthma. Guideline No. 63. Edinburgh:SIGN; 2004. (HTML, Full PDF, Summary PDF)
  3. 3.0 3.1 Hendeles L, Marshik PL, et al. Response to nonprescription epinephrine inhaler during nocturnal asthma. Ann Allergy Asthma Immunol. 2005 Dec;95(6):530-4. PMID 16400891
  4. Rodrigo GJ, Nannini LJ.Comparison between nebulized adrenaline and beta2 agonists for the treatment of acute asthma. A meta-analysis of randomized trials. Am J Emerg Med. 2006 Mar;24(2):217-22. PMID 16490653
  5. Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, Morelli P, Nicolini G, Fabbri LM; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356:2040-52. PMID 17507703
  6. "Serevent Diskus, Advair Diskus, and Foradil Information (Long Acting Beta Agonists) - Drug information". FDA. 2006-03-03.
  7. Ramanujan, Krishna. "Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert". Cornell Chronicle Online. Cornell News Service.
  8. 8.0 8.1 Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V; et al. (2013). "Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial". Thorax. 68 (4): 322–9. doi:10.1136/thoraxjnl-2012-202698. PMID 23291349.
  9. 9.0 9.1 Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL; et al. (2017). "Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial". Lancet. 390 (10095): 659–668. doi:10.1016/S0140-6736(17)31281-3. PMID 28687413.
  10. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG (2008). "Clarithromycin targets neutrophilic airway inflammation in refractory asthma". Am J Respir Crit Care Med. 177 (2): 148–55. doi:10.1164/rccm.200707-1134OC. PMID 17947611.
  11. Edris A, De Feyter S, Maes T, Joos G, Lahousse L (2019). "Monoclonal antibodies in type 2 asthma: a systematic review and network meta-analysis". Respir Res. 20 (1): 179. doi:10.1186/s12931-019-1138-3. PMC 6688359 Check |pmc= value (help). PMID 31395084.
  12. Farne HA, Wilson A, Powell C, Bax L, Milan SJ (2017). "Anti-IL5 therapies for asthma". Cochrane Database Syst Rev. 9: CD010834. doi:10.1002/14651858.CD010834.pub3. PMC 6483800. PMID 28933516.
  13. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P; et al. (2017). "Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma". N Engl J Med. 376 (25): 2448–2458. doi:10.1056/NEJMoa1703501. PMID 28530840. Review in: Ann Intern Med. 2017 Oct 17;167(8):JC43
  14. https://clinicaltrials.gov/ct2/show/study/NCT01947946
  15. Brightling CE, Chanez P, Leigh R, O'Byrne PM, Korn S, She D; et al. (2015). "Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial". Lancet Respir Med. 3 (9): 692–701. doi:10.1016/S2213-2600(15)00197-6. PMID 26231288.
  16. Shim C, Williams MH (1980) Bronchial response to oral versus aerosol metaproterenol in asthma. Ann Intern Med 93 (3):428-31. PMID: 7436160
  17. Shim C, Williams MH (1981) Comparison of oral aminophylline and aerosol metaproterenol in asthma. Am J Med 71 (3):452-5. PMID: 7282733
  18. Berridge MS, Lee Z, Heald DL (2000) Pulmonary distribution and kinetics of inhaled [11Ctriamcinolone acetonide.] J Nucl Med 41 (10):1603-11. PMID: 11037987
  19. Nelson HS (2001) Advair: combination treatment with fluticasone propionate/salmeterol in the treatment of asthma. J Allergy Clin Immunol 107 (2):398-416. DOI:10.1067/mai.2001.112939 PMID: 11174215
  20. Urbano FL (2008) Review of the NAEPP 2007 Expert Panel Report (EPR-3) on Asthma Diagnosis and Treatment Guidelines. J Manag Care Pharm 14 (1):41-9. PMID: 18240881
  21. Petsky HL, Kynaston JA, Turner C, Li AM, Cates CJ, Lasserson TJ; et al. (2007). "Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults". Cochrane Database Syst Rev (2): CD005603. doi:10.1002/14651858.CD005603.pub2. PMID 17443604.
  22. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P; et al. (2002). "Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial". Lancet. 360 (9347): 1715–21. doi:10.1016/S0140-6736(02)11679-5. PMID 12480423. Review in: ACP J Club. 2003 Jul-Aug;139(1):13 Review in: J Fam Pract. 2003 May;52(5):353-5
  23. Zhang XY, Simpson JL, Powell H, Yang IA, Upham JW, Reynolds PN; et al. (2014). "Full blood count parameters for the detection of asthma inflammatory phenotypes". Clin Exp Allergy. 44 (9): 1137–45. doi:10.1111/cea.12345. PMID 24849076.
  24. Turner RM, Hayen A, Macaskill P, Irwig L, Reddel HK (2012). "Control charts demonstrated limited utility for the monitoring of lung function in asthma". J Clin Epidemiol. 65 (1): 53–61. doi:10.1016/j.jclinepi.2011.04.012. PMID 21803547.
  25. Petsky HL, Kew KM, Turner C, Chang AB (2016). "Exhaled nitric oxide levels to guide treatment for adults with asthma". Cochrane Database Syst Rev. 9: CD011440. doi:10.1002/14651858.CD011440.pub2. PMID 27580628.
  26. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR (2005). "Use of exhaled nitric oxide measurements to guide treatment in chronic asthma". N Engl J Med. 352 (21): 2163–73. doi:10.1056/NEJMoa043596. PMID 15914548. Review in: Evid Based Med. 2006 Feb;11(1):20

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