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Editorials: Point and Counterpoint |

POINT: Is Escalation of the Inhaled Corticosteroid Dose Appropriate for Acute Loss of Asthma Control in an Attempt to Reduce Need for Oral Corticosteroids in Children? Yes FREE TO VIEW

Harold J. Farber, MD, MSPH, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: H. J. F. serves as Associate Medical Director for Texas Children’s Health Plan, a not-for-profit Medicaid and CHIP managed care organization owned by Texas Children’s Hospital.

Pulmonary Section, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX

CORRESPONDENCE TO: Harold J. Farber, MD, MSPH, FCCP, Texas Children’s Hospital, Pulmonary Medicine Service, 6701 Fannin, Ste 1040.00, Houston, TX 77030


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(3):488-490. doi:10.1016/j.chest.2016.06.024
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Published online

Guidelines from the National Asthma Education and Prevention Program (2007) recommend managing mild asthma exacerbations with the addition of a short-acting beta agonist to the treatment regimen, and if response is incomplete, adding an oral corticosteroid. Escalating the dose of long-acting controller medication is not recommended as part of management of the acute exacerbation. This approach has several significant problems:

  • Oral corticosteroid medications, although effective, have significant toxicity, even in short bursts.

  • The use of beta agonists relieves asthma symptoms but does not prevent a mild exacerbation from progressing to a severe exacerbation.

  • Nonadherence to the daily use of long-acting controller medication is extremely common.,

A previously published practice parameter from the American Academy of Allergy, Asthma, and Immunology (2014) recommends initiation or escalation of inhaled corticosteroids for acute loss of asthma control.

Short bursts of oral corticosteroid medication have substantial adverse behavioral effects, causing anxiety, mania, irritability, or aggressive behavior, or a combination., It can cause transient hypothalamic-pituitary-adrenal axis suppression, increase blood pressure, and decrease responses to neoantigens., Short courses of oral corticosteroid medication can predispose the patient to infections, with severe varicella infection and tuberculosis reported., Studies in adults have found that frequent short courses of oral steroids decrease bone mineral density. Although quite valuable for the treatment of a moderate to severe asthma flare-up, there can be substantial benefit to decreasing a child’s need for oral corticosteroid medication.

Inhaled corticosteroids are best at stabilizing normal airways and preventing an exacerbation from starting. Initiation or escalation is likely to be most effective at the moment that it starts to get more difficult to keep the airways normal. Studies that waited for symptom duration of 24 to 72 hours or a substantial decrease in peak expiratory flow, or both, before doubling the inhaled corticosteroid dose showed no benefit.,, Through the lens of retrospection, the problem with these studies was that the intervention was too little and too late.

Initiation or substantial escalation of the inhaled corticosteroid dose at the onset of loss of asthma control does show benefit. The challenge is that the escalation needs to be substantial and started early. In adults on a low daily inhaled corticosteroid dose, quadrupling the inhaled corticosteroid dose after the onset of an exacerbation reduced the need for oral corticosteroids. In young children, an extremely high dose of fluticasone, 1,500 μg daily, administered at the first sign of an upper respiratory tract infection substantially decreased the need for oral corticosteroids (OR, 0.49; 95% CI, 0.30-0.83) but at the cost of an unacceptable decrease in growth. Perhaps similar benefits can be obtained at a lower inhaled corticosteroid dose if started sufficiently early in the exacerbation.

A large randomized clinical trial of children 4 to 11 years of age with asthma that was not well controlled on a stable low dose of inhaled corticosteroid compared budesonide/formoterol (80 μg/4.5 μg) as maintenance + reliever to budesonide/formoterol (80 μg/4.5μg) as maintenance + terbutaline as reliever and to high-dose budesonide (320 μg) as maintenance + terbutaline as reliever. The maintenance medications were given once daily. When the maintenance + reliever group was compared with the other two groups, they found a substantial decrease in exacerbations (14% vs 38% and 26%, respectively), exacerbations needing medical attention (8% vs 31% and 20%, respectively), and days of oral corticosteroid use (32 days vs 230 days and 141 days, respectively).

A more recently published open-label randomized clinical trial in 16- to 65-year-old nonsmokers provided budesonide/formoterol twice daily as maintenance and compared additional doses as needed of budesonide/formoteral for symptom relief vs the addition of albuterol for symptom relief. The patients who escalated their budesonide/formoterol for symptoms had a lower risk for severe exacerbations than did those who escalated their dose with albuterol only (19% vs 33%; P = .004) as well as fewer courses of oral corticosteroids per year of follow-up (0.80 vs 1.1; P = .004).

A randomized controlled clinical trial in nonsmoking adults with mild persistent asthma that was controlled on low-dose beclomethasone randomized patients to placebo maintenance + beclomethasone/albuterol (250 μg/100 μg in a single inhaler) as reliever vs beclomethasone/albuterol (250 μg/100 μg in a single inhaler) maintenance + albuterol 100 μg as reliever, beclomethasone (250 μg twice daily) as maintenance + albuterol 100 μg as reliever, and placebo as maintenance + albuterol (100 μg) as reliever. Subjects were instructed to use the reliever medication as needed for symptom relief. They found that the rate of having one or more exacerbations was similar with the as-needed combination and the regular beclomethasone and was lower than the as-needed albuterol-only group (4.92% and 5.66% vs 17.8%; P < .01).

The Treatment for Children With Mild Persistent Asthma (TREXA) study recruited children 6 to 18 years of age with well-controlled mild persistent asthma. Subjects were randomized to one of four treatment groups, including beclomethasone (40 μg) twice daily with beclomethasone + albuterol as rescue, twice daily beclomethasone + albuterol as rescue, twice daily placebo with albuterol + beclomethasone as rescue, and twice daily placebo with albuterol as rescue. Rescue medication was used as needed for symptom relief or a drop in peak expiratory flow, with the individual patient determining how many rescue puffs to take. The exacerbation rate requiring prednisone was lower in the rescue beclomethasone + albuterol group than in the albuterol-only group, but criteria for statistical significance (P < .05) were not met (35% vs 49%; P = .07). In looking at treatment failures (requiring a second course of prednisone), the difference (8.5% vs 23%) was statistically significant (P = .02) and clinically important.

The Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST) trial in toddlers 12 to 53 months with recurrent wheezing compared daily nebulized budesonide (0.5 mg once daily) to 7 days of higher-dose budesonide (1.0 mg twice daily for 7 days) at the start of a respiratory illness and found very similar rates of both episode-free days and asthma exacerbation between the groups. The cumulative inhaled corticosteroid dose was lower in the intermittent-therapy group.

Repeated well-designed clinical trials in both children and adults show that when initiated at the very onset of loss of control, as-needed initiation or escalation of inhaled corticosteroid medication in combination with a bronchodilator is more effective in reducing the risk of severe exacerbations and reducing the need for oral corticosteroids compared with as-needed bronchodilator use alone. Several studies found that in patients on a daily low dose of inhaled corticosteroid/beta agonist combination, escalation of the inhaled corticosteroid in parallel with the beta agonist is superior to escalation of a beta agonist alone. Studies that focused on doubling the inhaled corticosteroid dose after the asthma flare was established did not show benefit. The key factor in the studies showing benefit of as-needed inhaled corticosteroid escalation is early initiation and substantial escalation. Extremely high inhaled corticosteroid doses, however, should be avoided because of the concern about adverse effects on growth.

As-needed escalation of the inhaled corticosteroid dose in addition to bronchodilator use is appropriate for the onset of loss of asthma control. This strategy is superior to the initiation or escalation of an as-needed bronchodilator alone. As adherence to recommendations for daily use of inhaled corticosteroid medication is poor, as-needed initiation or escalation is an important option to reduce the need for oral corticosteroids. Decreasing the need for oral corticosteroid medication is important, as it has substantial adverse effects for children, some of which may have long-lasting consequences.

National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report-3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health, 2007. NIH Publication No. 08-4051.http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed December 15, 2007.
 
Smith L.A. .Bokhour B. .Hohman K.H. .et al Modifiable risk factors for suboptimal control and controller medication underuse among children with asthma. Pediatrics. 2008;122:760-769 [PubMed]journal. [CrossRef] [PubMed]
 
Finkelstein J.A. .Lozano P. .Farber H.J. .Miroshnik I. .Lieu T.A. . Underuse of controller medications among Medicaid-insured children with asthma. Arch Pediatr Adolesc Med. 2002;156:562-567 [PubMed]journal. [CrossRef] [PubMed]
 
Dinakar C. .Oppenheimer J. .Portnoy J. .et al Management of acute loss of asthma control in the yellow zone: a practice parameter. Ann Allergy Asthma Immunol. 2014;113:143-159 [PubMed]journal. [CrossRef] [PubMed]
 
Brown E.S. .Suppes T. .Khan D.A. .Carmody T.J. 3rd. Mood changes during prednisone bursts in outpatients with asthma. J Clin Psychopharmacol. 2002;22:55-61 [PubMed]journal. [CrossRef] [PubMed]
 
Kayani S. .Shannon D.C. . Adverse behavioral effects of treatment for acute exacerbation of asthma in children: a comparison of two doses of oral steroids. Chest. 2002;122:624-628 [PubMed]journal. [CrossRef] [PubMed]
 
Aljebab F. .Choonara I. .Conroy S. . Systematic review of the toxicity of short-course oral corticosteroids in children. Arch Dis Child. 2016;101:365-370 [PubMed]journal. [CrossRef] [PubMed]
 
Ducharme F.M. .Ochs H.D. .Resendes S. .Zhang X. .Mazer B.D. . A short burst of oral corticosteroid for children with acute asthma: is there an impact on immunity? Pediatr Allergy Immunol Pulmonol. 2010;23:243-252 [PubMed]journal. [CrossRef]
 
Dowell S.F. .Bresee J.S. . Severe varicella associated with steroid use. Pediatrics. 1993;92:223-228 [PubMed]journal. [PubMed]
 
Jick S.S. .Lieberman E.S. .Rahman M.U. .Choi H.K. . Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum. 2006;55:19-26 [PubMed]journal. [CrossRef] [PubMed]
 
Matsumoto H. .Ishihara K. .Hasegawa T. .Umeda B. .Niimi A. .Hino M. . Effects of inhaled corticosteroid and short courses of oral corticosteroids on bone mineral density in asthmatic patients. Chest. 2001;120:1468-1473 [PubMed]journal. [CrossRef] [PubMed]
 
FitzGerald J.M. .Becker A. .Sears M.R. . Canadian Asthma Exacerbation Study Groupet al Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax. 2004;59:550-556 [PubMed]journal. [CrossRef] [PubMed]
 
Garrett J. .Williams S. .Wong C. .Holdaway D. . Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid. Arch Dis Child. 1998;79:12-17 [PubMed]journal. [CrossRef] [PubMed]
 
Bisgaard H. .Hermansen M.N. .Loland L. .Halkjaer L.B. .Buchvald F. . Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006;354:1998-2005 [PubMed]journal. [CrossRef] [PubMed]
 
Foresi A. .Morelli M.C. .Catena E. . Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Chest. 2000;117:440-446 [PubMed]journal. [CrossRef] [PubMed]
 
Ducharme F.M. .Lemire C. .Noya F.J. .et al Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med. 2009;360:339-353 [PubMed]journal. [CrossRef] [PubMed]
 
Bisgaard H. .Le Roux P. .Bjåmer D. .Dymek A. .Vermeulen J.H. .Hultquist C. . Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006;130:1733-1743 [PubMed]journal. [CrossRef] [PubMed]
 
Patel M. .Pilcher J. .Pritchard A. .et al Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med. 2013;1:32-42 [PubMed]journal. [CrossRef] [PubMed]
 
Papi A. .Canonica G.W. .Maestrelli P. . BEST Study Groupet al Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356:2040-2052 [PubMed]journal. [CrossRef] [PubMed]
 
Martinez F.D. .Chinchilli V.M. .Morgan W.J. .et al Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377:650-657 [PubMed]journal. [CrossRef] [PubMed]
 
Zeiger R.S. .Mauger D. .Bacharier L.B. .et al Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

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References

National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report-3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health, 2007. NIH Publication No. 08-4051.http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed December 15, 2007.
 
Smith L.A. .Bokhour B. .Hohman K.H. .et al Modifiable risk factors for suboptimal control and controller medication underuse among children with asthma. Pediatrics. 2008;122:760-769 [PubMed]journal. [CrossRef] [PubMed]
 
Finkelstein J.A. .Lozano P. .Farber H.J. .Miroshnik I. .Lieu T.A. . Underuse of controller medications among Medicaid-insured children with asthma. Arch Pediatr Adolesc Med. 2002;156:562-567 [PubMed]journal. [CrossRef] [PubMed]
 
Dinakar C. .Oppenheimer J. .Portnoy J. .et al Management of acute loss of asthma control in the yellow zone: a practice parameter. Ann Allergy Asthma Immunol. 2014;113:143-159 [PubMed]journal. [CrossRef] [PubMed]
 
Brown E.S. .Suppes T. .Khan D.A. .Carmody T.J. 3rd. Mood changes during prednisone bursts in outpatients with asthma. J Clin Psychopharmacol. 2002;22:55-61 [PubMed]journal. [CrossRef] [PubMed]
 
Kayani S. .Shannon D.C. . Adverse behavioral effects of treatment for acute exacerbation of asthma in children: a comparison of two doses of oral steroids. Chest. 2002;122:624-628 [PubMed]journal. [CrossRef] [PubMed]
 
Aljebab F. .Choonara I. .Conroy S. . Systematic review of the toxicity of short-course oral corticosteroids in children. Arch Dis Child. 2016;101:365-370 [PubMed]journal. [CrossRef] [PubMed]
 
Ducharme F.M. .Ochs H.D. .Resendes S. .Zhang X. .Mazer B.D. . A short burst of oral corticosteroid for children with acute asthma: is there an impact on immunity? Pediatr Allergy Immunol Pulmonol. 2010;23:243-252 [PubMed]journal. [CrossRef]
 
Dowell S.F. .Bresee J.S. . Severe varicella associated with steroid use. Pediatrics. 1993;92:223-228 [PubMed]journal. [PubMed]
 
Jick S.S. .Lieberman E.S. .Rahman M.U. .Choi H.K. . Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum. 2006;55:19-26 [PubMed]journal. [CrossRef] [PubMed]
 
Matsumoto H. .Ishihara K. .Hasegawa T. .Umeda B. .Niimi A. .Hino M. . Effects of inhaled corticosteroid and short courses of oral corticosteroids on bone mineral density in asthmatic patients. Chest. 2001;120:1468-1473 [PubMed]journal. [CrossRef] [PubMed]
 
FitzGerald J.M. .Becker A. .Sears M.R. . Canadian Asthma Exacerbation Study Groupet al Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax. 2004;59:550-556 [PubMed]journal. [CrossRef] [PubMed]
 
Garrett J. .Williams S. .Wong C. .Holdaway D. . Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid. Arch Dis Child. 1998;79:12-17 [PubMed]journal. [CrossRef] [PubMed]
 
Bisgaard H. .Hermansen M.N. .Loland L. .Halkjaer L.B. .Buchvald F. . Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006;354:1998-2005 [PubMed]journal. [CrossRef] [PubMed]
 
Foresi A. .Morelli M.C. .Catena E. . Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group. Chest. 2000;117:440-446 [PubMed]journal. [CrossRef] [PubMed]
 
Ducharme F.M. .Lemire C. .Noya F.J. .et al Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med. 2009;360:339-353 [PubMed]journal. [CrossRef] [PubMed]
 
Bisgaard H. .Le Roux P. .Bjåmer D. .Dymek A. .Vermeulen J.H. .Hultquist C. . Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006;130:1733-1743 [PubMed]journal. [CrossRef] [PubMed]
 
Patel M. .Pilcher J. .Pritchard A. .et al Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med. 2013;1:32-42 [PubMed]journal. [CrossRef] [PubMed]
 
Papi A. .Canonica G.W. .Maestrelli P. . BEST Study Groupet al Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356:2040-2052 [PubMed]journal. [CrossRef] [PubMed]
 
Martinez F.D. .Chinchilli V.M. .Morgan W.J. .et al Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377:650-657 [PubMed]journal. [CrossRef] [PubMed]
 
Zeiger R.S. .Mauger D. .Bacharier L.B. .et al Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001 [PubMed]journal. [CrossRef] [PubMed]
 
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