High-Dose Inhaled Corticosteroids for Asthma Exacerbations: Helpful in Adults and Adolescents, But Not in Children

Asthma is a chronic disease characterized by inflammation and reversible narrowing of airways in the lungs, resulting in difficulty breathing. The disease is very common, afflicting more than 18 million adults and 6 million children in the U.S.[1]

Among the mainstays of asthma treatment are inhaled corticosteroids (ICSs) — also called glucocorticosteroids or glucocorticoids — which are used daily by patients who have persistent asthma to suppress the inflammation that contributes to airway narrowing. The commonly followed treatment guidelines for asthma issued by the Global Initiative for Asthma recommend that patients who use ICSs daily for asthma control should increase their dose of these medications in the short term when they experience early signs of worsening asthma control (asthma exacerbation).[2] However, there has been limited evidence to support this home management strategy, particularly in children.[3]

Results of two randomized clinical trials published in the New England Journal of Medicine (NEJM) on March 8, 2018, provide important new evidence regarding the benefits and risks of having patients increase their ICS dose whenever they develop early signs of worsening asthma control. One trial suggests that a short-term fourfold increase in ICS dose in such circumstances may provide some limited benefit to adults and adolescents with asthma,[4] whereas the other trial found that a shortterm fivefold increase in ICS dose is not beneficial in asthmatic children and may impair their growth.[5]

Asthma overview

Symptoms of asthma include wheezing, shortness of breath, chest tightness and coughing.[6] These symptoms tend to vary over time, are often worse at night or when waking up, and can increase in response to various triggers, such as allergens, viral infections, cold air or exercise. Diagnosing asthma involves assessing the presence of these symptoms and conducting a simple breathing test that measures how much air a person can inhale and exhale, as well as how quickly air can be exhaled.

Although many people with asthma have mild and infrequent symptoms, the disease can be deadly. Asthma kills more than 3,600 Americans every year,[7] highlighting the importance of continuous treatment in patients with persistent asthma.

Asthma is classified into two major types: allergic asthma and nonallergic asthma.[8] Allergic asthma often begins in childhood and, as its name suggests, is triggered by exposure to allergens, such as tree or grass pollen and pet dander, and is associated with a personal or family history of allergic diseases, such as eczema, nasal allergies or allergies to certain foods or drugs. Non-allergic asthma usually occurs in adults, with some cases that start in adulthood known as lateonset asthma.

The goals of persistent asthma treatment are to control daily symptoms and to reduce the risk of future asthma attacks, hospitalizations and death. Regular daily treatment with ICSs generally is highly effective in achieving these goals[9] (see table below, for a list of ICSs approved by the Food and Drug Administration for treating asthma). However, patients with non-allergic asthma often do not respond as well to ICSs as do those with allergic asthma.[10]

Asthma patients also are treated routinely with beta-2 agonists (for example, albuterol [ACCUNEB, PROAIR HFA, PROAIR RESPICLICK, PROVENTIL-HFA, VENTOLIN HFA, VOSPIRE ER]) — also called bronchodilators — which work by opening the airways in the lungs, helping patients breathe easier.

Inhaled Corticosteroids Approved in the U.S. for Treating Asthma

*Brand-name combination products that contain an inhaled corticosteroid with a long-acting beta agonist drug are not listed.
**Do Not Use for Seven Years (until September 2021)

Prior research

A 2016 study published in the Cochrane Database of Systematic Reviews (CDSR) analyzed the results of eight randomized clinical trials that compared a short-term increase in ICS dose with maintaining a stable ICS dose for home management of asthma exacerbations.[11] The trials enrolled patients with mild-tomoderate persistent asthma who were already using ICSs daily. Three of the trials involved a total of 422 children, and the other five involved a total of 1,247 adults. If an exacerbation occurred, subjects increased their ICS dose fivefold in one adult trial, fourfold in one adult trial and twofold in the remaining six trials.

The authors of the CDSR study found that, based on the results of these eight trials, a short-term increase in ICS dose when an asthma exacerbation occurred overall did not result in better outcomes in patients with mild-to-moderate persistent asthma. They concluded that it was unlikely that increasing the ICS dose at home when asthma exacerbations occur reduces the need for a course of oral corticosteroids to treat an asthma attack, prevents the need for emergency visits to doctors or hospitals, or decreases the time it takes to recover from an asthma exacerbation.

The new NEJM trials

The first of these new trials, which was funded by the U.K.’s National Institute for Health Research, is the largest trial ever conducted that evaluated short-term increases in ICS dosing for home management of worsening asthma control.[12] For this trial, researchers in the U.K. enrolled more than 1,900 subjects age 16 or older who had asthma and were being treated with daily ICSs. To be eligible for the trial, the subjects had to have had at least one severe asthma exacerbation in the previous year that led to treatment with systemic corticosteroids (given orally or by injection).

The subjects were randomly assigned to one of two self-management plans. One group was instructed to increase their ICS dose fourfold for up to 14 days if any signs of deteriorating asthma control occurred (the high-dose group), and the other group was instructed to maintain their current ICS dose if such signs occurred (the low-dose group). Subjects in both groups could increase the dose of their bronchodilator medicines for worsening asthma control as needed. The U.K. trial was unblinded, meaning both the researchers and the subjects were aware of a subject’s group assignment. The researchers followed the subjects for one year and assessed whether they suffered a severe asthma exacerbation that required treatment with systemic corticosteroids or an unscheduled visit to a health care professional for asthma.

Significantly fewer subjects in the high-dose group than those in the low-dose group experienced a severe asthma exacerbation during the trial (45 percent versus 52 percent, respectively). Subjects in the highdose group were less likely to receive systemic corticosteroids or have an unscheduled visit to a health care professional for asthma treatment. Of note, hospitalization for asthma occurred only three times in highdose group subjects and 18 times in the low-dose group subjects. Finally, non-serious ICS-related adverse events, including oral candidiasis (fungal infections in the mouth) and hoarseness or speaking difficulty, occurred more frequently in highdose group subjects.

The UK researchers estimated that in order to prevent one severe asthma exacerbation in their trial, 15 patients needed to be treated for one year with self-managed short-term fourfold increases in ICS dose for signs of worsening asthma control. They expressed uncertainty as to whether the magnitude of this benefit was clinically meaningful.

The second NEJM trial was funded by the National Institutes of Health and conducted in the U.S.[13] The researchers enrolled 254 children age 5 to 11 who had mild-to-moderate persistent asthma and who had at least one serious asthma exacerbation that required systemic corticosteroids in the previous year.

All children in this trial were treated for 48 weeks with a low dose of an ICS. Half were randomly assigned to increase the ICS dose fivefold for seven days if early signs of loss of asthma control occurred (highdose group), and the other half were randomly assigned to maintain the low ICS dose if such signs occurred (low-dose group). Unlike the U.K. trial, the U.S. trial was double-blind, meaning neither the researchers nor the subjects were aware of the subjects’ group assignment — a procedure that helps prevent bias. The U.S. researchers measured the rate of severe asthma exacerbations that required treatment with systemic corticosteroids.

The rate of severe asthma exacerbations treated with systemic corticosteroids between the two groups was slightly higher in the high-dose group (0.48 per year) than in the low-dose group (0.37 per year), but this difference was not statistically significant. There were four hospitalizations for asthma in high-dose group subjects and none in low-dose group subjects, though this difference also was not statistically significant.

Of particular concern, children in the high-dose group had a slightly lower rate of growth, as measured by changes in height during the trial, than children in the low-dose group, a difference that almost reached statistical significance.

What You Can Do

If you have persistent asthma, you should be using an ICS daily. If you are 16 or older, you should discuss with your doctor whether your home management plan should include increasing your ICS dose fourfold for up to 14 days whenever you experience signs of worsening asthma control. If you have a child younger than 16 who has persistent asthma, a home-management plan that includes short-term increases in ICS doses for any signs of worsening asthma control generally should be avoided. If your child is currently following such a management plan, talk to your child’s doctor about changing this plan.

References

[1] Centers for Disease Control and Prevention. National current asthma prevalence. February 13, 2018. http://www.cdc.gov/asthma/most_recent_data.htm. Accessed May 3, 2018.

[2] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2018. http://ginasthma.org/download/832/. Accessed May 3, 2018.

[3] Jackson DJ, Bacharier LB, Mauger DT, et al. Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med. 2018;378(10):891-901.

[4] McKeever T, Mortimer K, Wilson A, et al. Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations. N Engl J Med. 2018;378(10):902-910.

[5] Jackson DJ, Bacharier LB, Mauger DT, et al. Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med. 2018;378(10):891-901.

[6] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2018. http://ginasthma.org/download/832/. Accessed May 3, 2018.

[7] Centers for Disease Control and Prevention. National current asthma prevalence. February 13, 2018. http://www.cdc.gov/asthma/most_recent_data.htm. Accessed May 3, 2018.

[8] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2015. http://ginasthma.org/download/832/. Accessed May 3, 2018.

[9] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2015. http://ginasthma.org/download/832/. Accessed May 3, 2018.

[10] Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2015. http://ginasthma.org/download/832/. Accessed May 3, 2018.

[11] Kew KM, Quinn M, Quon BS, Ducharme FM. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev. 2016 Jun 7;(6):CD007524. DOI: 10.1002/14651858.CD007524.pub4.

[12] McKeever T, Mortimer K, Wilson A, et al. Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations. N Engl J Med. 2018;378(10):902-910.

[13] Jackson DJ, Bacharier LB, Mauger DT, et al. Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med. 2018;378(10):891-901.