Siddiqui A, Lisa Kopas L. Nucleic Acid Delivery for Endothelial Dysfunction in Cardiovascular Diseases. Methodist DeBakey Cardiovascular Journal. 2017;13(2):47-89.doi: https://doi.org/10.14797/mdcj-13-2-82
The column in this issue is supplied by Atif Siddiqui, M.D., and Lisa Kopas, M.D. Dr. Siddiqui is a pulmonary and critical care fellow at Houston Methodist Hospital in Houston, Texas. He obtained his medical degree from Dow Medical College in Pakistan and completed his internal medicine residency at Texas Tech University Health Sciences Center. Dr. Kopas is a pulmonologist at Houston Methodist Hospital. Upon earning her medical degree from Baylor College of Medicine in Houston, Dr. Kopas stayed at Baylor to complete an internal medicine residency followed by a fellowship in pulmonary and critical care medicine.
Asthma is a common chronic respiratory disease that affects 1% to 18% of the population worldwide. From 2001 to 2010, the age-adjusted prevalence of asthma in the United States alone increased from 7.3% to 8.4%. Asthma is responsible for nearly 4,000 U.S. deaths each year and is associated with an increase in cardiovascular disease risk; it is also an independent predictor of increased risk for coronary heart disease. In addition, chronic airway inflammation may contribute to systemic inflammation and can increase the risk of vascular disease. Conversely, prevention of asthma exacerbations can decrease cardiovascular morbidity.
Cough, shortness of breath, and wheezing can be present in pulmonary edema, chronic obstructive pulmonary disease, vocal cord dysfunction, gastroesophageal reflux disease, bronchiectasis, hypersensitivity pneumonitis, and central airway obstruction. Always consider these conditions in the differential diagnosis of asthma (Table 1).
A small subset of asthmatic patients (5%–10%) continue to have symptoms despite maximal therapy. For these patients, limited treatment options result in uncontrolled disease and a significant increase in morbidity.1,2 Until recent therapeutic developments and advances, these patients experienced a severe decline in quality of life.
- According to American Thoracic Society guidelines, “severe” asthma requires management with high-dose inhaled corticosteroids as well as a second asthma controller that potentially includes a systemic corticosteroid.2 It is important to note that the definition of severe asthma does not include pulmonary function values (Table 2).
- The goal of treatment is to use disease prevention strategies that help patients avoid serious exacerbations of acute asthma, improve daily symptoms, and improve quality of life.3
- Allergen immunotherapy should be considered when maximum treatment with inhaled bronchodilators and corticosteroids is not effective in patients with significant environmental allergies.4
- Patients with asthma can have elevated levels of immunoglobulin E (IgE); therefore, treatments that target IgE-mediated pathways are beneficial.5 Omalizumab is a recombinant monoclonal antibody that binds with free IgE to block its interaction with receptors on mast cells, basophils, and other cells.6 Omalizumab is approved for use in patients with moderate to severe persistent asthma whose symptoms are uncontrolled with inhaled corticosteroids, who have positive allergen testing, and whose total serum IgE concentration is between 30 to 700 IU/mL. A minimum of 12 weeks of therapy is required before determining therapeutic efficacy. In patients with uncontrolled asthma despite treatment with long-acting β2-agonists and high-dose inhaled corticosteroids, omalizumab was found to significantly reduce asthma exacerbations and decrease the need for corticosteroids.7
- Interleukin-5 (IL-5) inhibitors reduce blood and airway eosinophil counts, improve asthma control, and decrease the rate of exacerbations.8 Randomized controlled trials showed that mepolizumab, an IL-5 inhibitor, improved asthma control and reduced the rate of exacerbations in patients with uncontrolled eosinophilic asthma (blood eosinophils > 150 cells per μL).9–12 Mepolizumab should be considered in patients with elevated eosinophils and frequent asthma exacerbations even with chronic oral corticosteroid use. Another IL-5 inhibitor, reslizumab, was shown to improve lung function, asthma control, and quality of life in patients who had inadequately controlled asthma on inhaled corticosteroids and a blood eosinophil count ≥ 400 cells/μL. Reslizumab (3 mg/kg/mo intravenously) should be considered in patients with uncontrolled eosinophilic asthma.13,14
- Bronchial thermoplasty (BT) is an outpatient procedure that uses fiberoptic bronchoscopy to treat patients with severe asthma.15 Three separate bronchoscopies are performed over a 3-week period with the patient under moderate sedation. During the procedure, segmental and subsegmental bronchi are warmed to 65°C to reduce smooth muscle mass in the airway. This technique works by treating smooth muscle hypertrophy, thus attenuating bronchoconstriction and bronchial hyperreactivity.16,17
- Randomized trials support the use of BT as a treatment for uncontrolled asthma, with efficacy and safety demonstrated for at least 5 years following the procedure.16,18–20 Patients who received BT for moderate-to-severe persistent asthma experienced fewer mild exacerbations, a marked decrease in emergency room visits, and an improvement in symptom-free days, asthma control, and quality of life.16,21 As a result, BT was approved by the FDA for use in adults with severe asthma who have uncontrolled symptoms despite treatment with inhaled corticosteroids and long-acting bronchodilators.
- Clinicians should make shared management decisions and take into account personal preferences when treating patients with severe asthma.
1. Moore WC, Bleecker ER, Curran-Everett D, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol. 2007 Feb; 119( 2): 405– 13.
2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014 Feb; 43( 2): 343– 73.
3. Currie GP, Devereux GS, Lee DK, Ayres JG. Recent developments in asthma management. BMJ. 2005 Mar 12; 330( 7491): 585– 9.
4. Barnes PJ. Severe asthma: advances in current management and future therapy. J Allergy Clin Immunol. 2012 Jan; 129( 1): 48– 59.
5. Licari A, Marseglia G, Castagnoli R, Marseglia A, Ciprandi G. The discovery and development of omalizumab for the treatment of asthma. Expert Opin Drug Discov. 2015; 10( 9): 1033– 42.
6. Milgrom H, Fick RB Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med. 1999 Dec 23; 341( 26): 1966– 73.
7. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011 May 3; 154( 9): 573– 82.
8. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27; 368( 26): 2455– 66.
9. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011 Nov; 128( 5): 989– 95.
10. Ortega H, Liu M, Pavord I, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 25; 371( 13): 1198– 207.
11. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicenter, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18; 380( 9842): 651– 9.
12. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014 Sep 25; 371( 13): 1189– 97.
13. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015 May; 3( 5): 355– 66.
14. Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for Inadequately Controlled Asthma with Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study. Chest. 2016 Oct; 150( 4): 789– 98.
15. Gildea TR, Khatri SB, Castro M. Bronchial thermoplasty: a new treatment for severe refractory asthma. Cleve Clin J Med. 2011 Jul; 78( 7): 477– 85.
16. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007 Mar 29; 356( 13): 1327– 37.
17. Solway J Irvin CG. Airway smooth muscle as a target for asthma therapy. N Engl J Med. 2007 Mar 29; 356( 13): 1367– 9.
18. Pavord ID, Thomson NC, Niven RM, et al.; Research in Severe Asthma Trial Study Group. Safety of bronchial thermoplasty in patients with severe refractory asthma. Ann Allergy Asthma Immunol. 2013 Nov; 111( 5): 402– 7.
19. Castro M, Rubin AS, Laviolette M, et al.; AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010 Jan 15; 181( 2): 116– 24.
20. Castro M, Rubin A, Laviolette M, Hanania NA, Armstrong B, Cox G; AIR2 Trial Study Group. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol. 2011 Jul; 107( 1): 65– 70.
21. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007 Dec 15; 176( 12): 1185– 91.