New Evidence Supporting Controller Therapy Selection in Asthma and Allergic Rhinitis

At a symposium held on November 8, 2003, a panel of experts discussed new guidelines for diagnosing and treating asthma and allergic rhinitis. A key component of these guidelines is the use of corticosteroids, which raises new questions for physicians about their efficacy and safety in special populations.  

This program was supported by an unrestricted educational grant from AstraZeneca.

Approaches for the Management of Allergic Rhinitis: Incorporating Recent Guidelines into Clinical Practice 

“Allergic rhinitis affects 10% to 25% of Americans,” began Stephen Brunton, MD, Vice Chair, Department of Family Medicine, Carolinas Medical Center, Charlotte, NC. The prevalence of seasonal allergic rhinitis is as high as 40% and as high as 18% for perennial allergic rhinitis.

Allergic rhinitis, which affects the upper airways and nasal passages, is induced by IgE-mediated inflammation after allergen exposure. Dr. Brunton emphasized that the upper airway does not end at the lungs, but rather there is continuity. This is important, because issues relating to the upper airway relate to the lower airway as well.

Common symptoms of allergic rhinitis include nasal or pharyngeal pruritus, sneezing, rhinorrhea, nasal congestion, loss of smell (hyposmia and anosmia), snoring, sleep problems, postnasal drip or chronic cough, and sedation.

According to the Allergic Rhinitis in Asthma (ARIA) guidelines developed by the World Health Organization,
allergic rhinitis is classified as intermittent (less than four days per week or less than four weeks per year) or persistent (more than four days per week or more than four weeks per year). These designations are preferred over seasonal and perennial, which are less precise, particularly in areas of the country where pollen can be present all year.

Allergic rhinitis is further classified based on the presence or absence of sleep disturbance, impairment of daily life, school, or work, and troublesome symptoms. In mild allergic rhinitis, none of these are present. In moderate-to-
severe disease, one or more of them are present.

Diagnosis may involve a routine history, ENT exam, allergy tests, endoscopy, nasal secretions/challenge, and radiology. It’s also important to look for comorbidities, such as asthma, conjunctivitis, otitis media, and pharyngitis. “Approximately 17% to 38% of allergic rhinitis patients have asthma,” Dr. Brunton said, and the majority of patients with asthma have allergic rhinitis.

He cited a study by Settipane et al. that followed 690 college freshman, 162 of whom had allergic rhinitis, for 23 years (Allergy Proc 1994;15:21-25). Among those who started with allergic rhinitis, 10.7% later developed asthma, compared to just 3.6% of those who did not have allergic rhinitis. “The incidence of asthma increases by about three times for people with allergic rhinitis,” said Dr. Brunton.

Allergic rhinitis and asthma share common triggers. Dr. Brunton explained one theory about this involves a “nasal bronchial reflex, in which a stimulation of the nose causes some bronchoconstriction.” Because of this, the ARIA guidelines recommend evaluating patients with persistent allergic rhinitis for asthma, evaluating asthmatic patients for rhinitis, and using a combined strategy to treat the upper and lower airways.

In terms of treatment for rhinitis and asthma, the ARIA guidelines make the following recommendations: 1) allergen avoidance; 2) glucocorticosteroids are the most effective treatment when used topically in the nose and lower airway; and 3) leukotriene receptor antagonists have the potential to treat asthma and rhinitis; however, more data are needed to confirm this effect.

“For management of allergic rhinitis, in cases of persistent disease, maintenance treatment with intranasal or oral therapy should be used,” said Dr. Brunton. For patients with serious exacerbations, desensitization with immunotherapy can be used. First line therapy for allergic rhinitis, asserted Dr. Brunton, should be intranasal steroids, particularly for patients with persistent symptoms.

Other options include intranasal or intraocular chromones (e.g., cromolyn, nedocromil), systemic glucocorticoids (which should not be used as first-line therapy, but reserved for more serious situations), oral decongestants (for
intermittent disease, with antihistamines), and intranasal decongestants (used for less than 10 days and not
repeated more than twice a month).

Dr. Brunton cited a meta-analysis comparing intranasal corticosteroids to oral antihistamines for allergic rhinitis, which “supports the use of intranasal corticosteroids for first-line treatment because they are more effective at
relieving nasal symptoms and also treat the whole symptom complex” (Welner et al. British Med J. 1998;317:1624-1629).

He went on to cite several studies, all of which favor intranasal corticosteroids over antihistamines. “The medication is applied where it needs to be, so you have a fast onset and less of a chance for side effects,” said Dr. Brunton. Possible disadvantages are that the drug may not reach all target organs, preservatives may irritate or damage nasal
tissues, the drug cannot be administered when the nose is completely blocked, and patient compliance may be a problem.

Dr. Brunton also noted that some drugs have an aftertaste, which patients may find unpleasant. He explained that fluticasone propionate has an odor, which is meant to be pleasant; however, many patients are aware of the smell and don’t like it. In a study comparing fluticasone propionate nasal spray (200 mcg) to budesonide aqueous nasal spray (64 mcg), 80% of patients were aware of the smell of fluticasone, compared to slightly over 30% of those taking budesonide (Shah et al. poster presented at AAAAI 2002).

Patients using fluticasone were also more likely to taste the drug and experience an aftertaste, throat rundown, and nose rundown. “Only a small percentage of patients taking fluticasone were very pleased with the sensory attributes,” said Dr. Brunton.

The ARIA guidelines recommend a stepwise approach to treatment of allergic rhinitis: once symptoms are under control, step down to the minimal dose required to control symptoms. The guidelines also emphasize patient
education and follow up.

Evidence-Based Guidelines for the Diagnosis and Management of Asthma

H. William Kelly, PharmD, Pro-fessor of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, reviewed the recent update to the guidelines of the National Asthma Education Prevention Program (NAEPP).

According to these guidelines, the goals of asthma therapy are to 1) maintain near “normal” pulmonary function; 2) maintain normal daily activity levels, including exercise; 3) prevent chronic and troublesome symptoms; 4) provide optimal pharmacotherapy with minimal or no adverse effects; 5) prevent recurrent exacerbations and minimize the need for ER visits or hospitalization; and 6) meet patients’ and families’ expectations and satisfaction.

Dr. Kelly explained that the classification system for asthma severity has not changed since the 1997 guidelines. Step 1 therapy—for mild intermittent asthma—remains the same. No daily medication is needed for long-term control and a short-acting inhaled beta2-agonist is used, as needed, for symptoms.

Step 2 therapy—for mild persistent asthma—has been changed in the new guidelines. In the old guidelines, nedocromil and cromolyn were preferred therapy for mild persistent asthma in children. The new guidelines state that inhaled corticosteroids should be used in this population. Step 2 therapy for both adults and children over age 5 includes low-dose inhaled corticosteroids as daily medication and short-acting inhaled beta2-agonist, as needed. Alternative daily medications are cromolyn/nedocromil, leukotriene receptor antagonists, and sustained-release theophylline.

Dr. Kelly noted that recommendations for Step 2 therapy in children under age 5 are the same as for adults and children over age 5. However, few studies have been conducted with children this young, and therefore, the data are
limited.

“Inhaled corticosteroids are con- sidered first-line therapy for patients of all ages, partly because epidemiologic studies have shown that they can reduce the risk of dying from asthma,” said Dr. Kelly. He cited a study by Suissa et al., in which patients taking inhaled corticosteroids had a significant reduction in the risk of death from asthma (N Engl J Med. 2000;343:332-336).

Dr. Kelly also cited the Childhood Asthma Management Program (CAMP) Study, in which 1,000 children were studied for 4.5 to 5 years (N Engl J Med. 2000;343:1054-1063). Placebo and nedocromil had very little effect on hyperresponsiveness, whereas a medium-dose (400 mcg) inhaled corticosteroid (budesonide) per day had a significant effect. Compared to placebo, among subjects taking budesonide, there were 43% fewer hospitalizations, 45% fewer urgent care visits, 43% less prednisone use, less rescue albuterol use, fewer symptoms, and more episode-free days.

“Thanks to the development of the nebulized solution of budesonide, we now also have data in younger children,” said Dr. Kelly. He cited a study by Baker et al., which showed a significant improvement in nighttime symptoms in children given a minimum of 0.5 mg budesonide inhalation suspension per day (Pediatrics. 1999;103:414-421).

One concern often raised with the use of inhaled corticosteroids in children is whether there is an effect on growth. Dr. Kelly noted that inhaled corticosteroids may cause reduction in growth velocity of about 1 centimeter per year, but this happens only in the first year of therapy, and does not appear to lead to a cumulative effect on final height.

“All of the current data suggest that attainment of final adult height is not affected by low-to-medium-dose inhaled steroids,” said Dr. Kelly. He also stressed that poorly controlled asthma in patients with severe asthma can also retard
linear growth.

Another concern with inhaled corticosteroids is the effect on bone mineral density, which was looked at in the CAMP study. Over the 4.5 years of the study, inhaled corticosteroid use did not affect bone density compared to placebo or nedocromil.

Another major change in the guidelines, continued Dr. Kelly, relates to management of moderate persistent asthma. For long-term control, daily medications should include the combination of a low- to medium-dose inhaled corticosteroid plus a long-acting beta2-agonist. “In the past, we just kept increasing the dose of inhaled corticosteroids,” said Dr. Kelly, noting that it’s difficult to see dose responses with inhaled corticosteroids, and the data now show that combination therapy is the best.

For children under age 5, no data exist on use of combination therapy. Therefore, the guidelines suggest medium-dose inhaled corticosteroids as an acceptable alternative to combination therapy.

“For adults, the most impressive data on combination therapy is not on improvement in lung function, but rather reduction in exacerbations,” noted Dr. Kelly. He explained that adding the long-acting bronchodilator formoterol to a low or high dose of budesonide leads to a significant reduction in exacerbations. He also noted that for patients whose asthma is not adequately controlled with a 200 mcg per day dose of budesonide, reduction in exacerbations can be achieved by quadrupling the dose to 800 mcg per day.

On the other hand, not all patients need this. The OPTIMA trial showed no significant difference between budesonide (200 mcg per day) alone and the combination of budesonide and formoterol for mild persistent asthma (O’Byrne et al. Am J Respir Crit Care Med. 2001;164:1392-1397). “The combination is really only effective for moderate and severe persistent asthma,” said Dr. Kelly.

The OPTIMA trial showed that for moderate asthma, the combination of budesonide plus formoterol was better for reducing exacerbations than simply doubling the dose of budesonide.

Safety and Efficacy of Corticosteroids in Select Patient Populations

Jonathan R. L. Schwartz, MD, Clinical Professor of Medicine, University of Oklahoma Health Sciences Center, discussed safety and efficacy of corticosteroids, particularly in children and pregnant women.

He noted that 28% of asthmatics have mild intermittent disease, meaning that 72% have persistent asthma and, therefore, should be on controller therapy. For patients of all ages with mild, moderate, or severe persistent asthma, first-line therapy is inhaled cortico-steroids.

Dr. Schwartz cited data showing that 30% of children with asthma had the onset before age 1, 20% were age 1 to 2, 20% were age 2 to 3, and 30% were over age 3 (Med J Aust. 1997;167:218-222). “Asthma starts early, and failure to recognize it and start appropriate therapy can lead to a reduction in lung function,” he said.

Diagnosing young children can be difficult because of problems obtaining lung function measurements. For example, it’s not possible to perform spirometry on children younger than age 4 or 5. Treatment and drug delivery can also pose challenges. Currently, the NIH recognizes the nebulizer as an effective delivery method for infants and young children. Inhaled corticosteroids administered by metered dose inhaler remain off-label for children younger than age 6, and these drugs administered via dry-powder inhaler are also not FDA- approved for children younger than age 4.

Nebulized budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as
prophylactic therapy in children ages 12 months to 8 years. It’s administered by oral inhalation via compressed air-driven jet nebulizers. It’s not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Approval of nebulized budesonide for this patient population was based on three randomized, double-blind, placebo-controlled trials, involving over 1,000 children ages 6 months to 8 years. All children were using one or more chronic asthma medications daily and a bronchodilator as needed during the three months prior to study entry.

The first trial looked at 359 children ages 6 months to 8 years with mild persistent asthma, who received 0.25, 0.5, or 1 mg budesonide per day or placebo (Ann Allergy Asthma Immunol. 1999; 83:231-239). The second trial included 178 children ages 4 to 8 with inhaled steroid dependent persistent asthma (randomized to 0.25, 0.5, or 1 mg budesonide twice a day vs. placebo) (J Allergy Clin Immunol. 1998;102:789-796). The third study was in 480 children aged 6 months to 8 years with moderate persistent asthma (randomized to 0.25 or 1 mg budesonide per day or 0.25 or 0.5 mg twice a day vs. placebo) (Pediatrics. 1999;103:414-421).

All three studies showed that budesonide was significantly more effective than placebo in improving symptoms and decreasing p.r.n. bronchodilator usage. The second study, which was done in older children so that pulmonary function could be measured, also showed significant improvement in lung function in the budesonide-treated groups. In the first study, all three active treatments were significantly better than placebo in relieving daytime and nighttime symptoms. The second trial demonstrated significant improvement in morning PEF with 0.25 or 0.5 mg budesonide twice daily. The third trial also found that all treatment groups had a significant decline in bronchodilator use.

Dr. Schwartz next addressed older children and adolescents, who can be challenging to treat because they may resist taking their medication. “One way to improve compliance is by using a once daily regimen,” he said. He cited a placebo-controlled study of once-daily budesonide Turbuhaler (200 mcg or 400 mcg per day) in children previously receiving inhaled corticosteroids (Ann Allergy Asthma Immunol. 2001;86:633-640).

Both active treatment groups had an improvement in FEV1 and evening PEF and a reduction in bronchodilator use compared to placebo.

Dr. Schwartz continued with a discussion of drug safety, which he said is particularly important in children and pregnant women. He noted that asthma is common in women, and that, compared to men, they have more emergency department visits for acute asthma and more hospitalizations. Asthma mortality is also slightly higher in women.

Dr. Schwartz also explained that in pregnant women, asthma is often not recognized and is suboptimally treated. In addition, pregnant asthmatic women have an increased likelihood of perinatal mortality, preeclampsia, premature delivery, and intrauterine growth retardation. Poor asthma control can lead to complications for both the woman and the fetus.

The NAEPP guidelines recommend aggressive asthma treatment in pregnancy with a daily controller medication and inhaled corticosteroids. Dr. Schwartz reviewed several studies examining the safety of budesonide in pregnant women. No difference was found in these studies between women using inhaled budesonide and the population at large for congenital malformations, premature birth, birth weight/length, C-section, stillbirth, or multiple births.

In December 2001, budesonide Turbuhaler was upgraded to a pregnancy category B based on data from over 2,500 infants whose mothers used inhaled budesonide in early pregnancy. All other inhaled corticosteroids are
designated category C.

Dr. Schwartz next discussed safety data in children. A study by Agertoft and Pedersen of long-term treatment with inhaled budesonide in children (ages 3 to 13) included 142 asthmatic children using budesonide, 18 control patients with asthma who never received inhaled steroids, and 51 healthy siblings of the budesonide group (N Engl J Med 2000; 343:1064-1069). After 9.2 years, there was no difference in achieved growth between the groups. Children with asthma who received long-term treatment with inhaled budesonide achieved normal adult height.

In closing, Dr. Schwartz stressed the importance of patient compliance and education. “It’s important to talk to patients, simplify the regimen, and use a once-a-day regimen whenever possible to improve compliance, particularly for adolescents. Improved compliance will lead to increased quality of life and survival,” he concluded.

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