β2AR Polymorphisms and Albuterol Responsiveness in Acute Asthma

The most recently available statistics indicate that approximately 22.2 million people in the United States have asthma. Of these, about 55% experienced at least one attack in the year before the survey resulting in 1.9 million visits to emergency departments and 497,000 hospitalizations. The natural history of acute asthma is one of resolution and 70 to 80% of people rapidly clear their airway obstruction following treatment with 7.5 to 10.0 mg of nebulized albuterol. However, there is a subset of patients with recurrent severe episodes that are poorly responsive to this treatment and require admission to hospital for resolution. Although these patients represent a minority of asthmatics, they have persistent disease that accounts for the vast majority of expenditures for urgent care. Yet virtually nothing is known about them. In the present application, we wish to test the hypothesis that these individuals do poorly with albuterol because of genetic polymorphisms of their beta 2 adrenergic receptors (β2AR) that either influence severity and/or reduce responsiveness to short acting bronchodilators.

One possibility of great clinical significance is that the albuterol non-responders have genetically determined differences in β2AR that down regulate effectiveness. Various polymorphisms have been described in this receptor with the greatest attention being devoted to single nucleotide polymorphisms (SNPs) substitutions at amino acid positions 16 (arginine to glycine, Arg 16 Gly) and 27 (glutamine to glutamic acid, Gln 27 Glu). The Gly 16 receptor exhibits enhanced down regulation in vitro after exposure to agonist while the Arg 16 allele is more resistant. The Gly 16 allele is strongly associated with asthma destabilizations as manifested by nocturnal symptom and an increased risk of severity. In contrast, Arg/Arg homozygosity at position 16 has been associated with poorer outcomes in prospective studies of regular use of short-acting β2 agonists. This phenomenon was not seen in asthmatics that used albuterol on an as needed basis or those who were homozygous for glycine. Since over 90 % of the subjects in our studies, and those of others, on acute asthma take this drug routinely and the vast majority are treated with it emergently, the presence of the Arg/Arg allele could lead to poorer responses. It has also been suggested that this polymorphism may also produce similar effects with long-acting β2 agonists. Again, since a large percentage of asthmatic patients chronically use long acting sympathomimetics, this factor may have a contributory effect. Alternatively, β2AR pharmacogenetics may be totally unimportant. Two studies have implied that neither single genotypes at Codon 16, nor haplotypes in the β2AR have any effect on the acute bronchodilator response to either albuterol or salbutamol. However, since these trials were performed in stable patients, they may not be representative of the non-responsive group described above.

In the current study we propose to build upon previous methods we have used in the care of acute asthma. Clinical assessments and treatment regimens are standardized using a care path as in previous studies. Demographics, height, weight, race, symptoms, signs, past medical histories, and routine medication use for the previous month prior to the index visit are recorded on an intake sheet. We routinely obtain information on disease duration, frequency of attacks, hospitalizations, ICU admissions, intubations, and a list of the general and specific triggers for acute exacerbations. We also record asthma medications including oral and inhaled steroids, short and long-acting beta-adrenergic agonists, antileukotriene drugs, anticholinergics and methylxanthines. We include in our histories all of the concurrent medications including eye drops (beta-blockers and prostaglandins), cardiac and anti-hypertensive drugs, (beta-adrenergic active agents and ACE inhibitors. We ask people how they are taking their asthma drugs, but have no way of knowing if they truly are using them as prescribed. If their medications are obtained at our hospital it may be possible to determine how many prescriptions are filled, but we still will not know use. We also record the use of illicit drugs such as cocaine, heroine, and OxyContin, etc. Body mass index (BMI) is calculated as weight in Kg divided by height in meters squared. Obesity is classified as a BMI ≥ 30 Kg/M2. Arterial oxygen saturation is determined by pulse oximetry on room air and supplemental oxygen is administered as necessary for values less than 90%. Before treatment, the best of three peak expiratory flow rates (PEFR) is taken as representing the patient's initial state of flow limitation. The PEFR data is recorded in absolute terms as well as a percentage of predicted normal. As in previous studies, if a patient's airway obstruction prevented him or her from achieving the minimum level on the peak flow meter, a value of 10 is arbitrarily assigned to avoid dividing by zero when the percentage improvement following albuterol is calculated.

The subjects receive either 2.5 mg of nebulized albuterol every 20 min for three doses or two doses of 5.0 mg of albuterol 20 min apart. Albuterol non-responsiveness is defined as a failure of the PEFR in an acutely ill asthmatic to exceed 40% of predicted following ≥7.5 mg of albuterol (2.5 mg albuterol aerosols q.20 min x3). After completion of each schedule, PEFR is repeated and the patients reexamined. Admission and discharge decisions are made according to published predetermined criteria. Patients are considered ready to be sent home if they are asymptomatic, free of accessory muscle use, have absent or diminished wheezing, and have achieved a peak flow of 60% of predicted. Those not meeting these requirements are given further treatment with adrenergic and anticholinergic bronchodilators and glucocorticoids at the discretion of the ED physician and reassessed hourly. If they subsequently meet the discharge criteria, they are released. If not, they are admitted to hospital. The false-positive admission rate with these algorithms has been found to be less than 1% and the 24-hour relapse rate less than 2%.

Only individuals in whom the index ED visit was for the treatment of an acute asthma attack are studied. Patients with histories suggestive of congestive heart failure, pneumonia, chronic bronchitis, or emphysema are excluded.