Nonadherence to therapy is often the culprit Difficult-to-control asthma, part 2: Optimizing therapy key words: Asthma, Allergic rhinitis, GERD, Rhinosinusitis

Patients with difficult-to-control asthma are a challenging group to treat. They require a thoughtful and comprehensive evaluation with selective testing to confirm the diagnosis and to identify the contributors to poor asthma control. Poor control is often a result of multiple factors, and studies have documented that the systematic identification and treatment of these factors can prevent exacerbations and improve asthma control.^1-3

In the August 2007 issue of The Journal of Respiratory Diseases, we reviewed the evaluation of patients with difficult-to-control asthma. In this article, we focus on treatment.

OPTIMIZING THERAPY

In addition to assessing for other respiratory diseases, the clinician should look for the common causes of poor asthma control, including suboptimal medical or environmental therapy or uncontrolled coexisting diseases (Table 1). Several studies have documented that a systematic approach to identifying and treating asthma triggers and coexisting diseases can significantly improve asthma control and decrease corticosteroid dosages.^1,2 Notably, when a systematic approach is taken, most patients are found to have multiple contributors to poorly controlled asthma.⁴

Assessing and managing nonadherence

Nonadherence to long-term inhaler therapy may be the most common reason for poor asthma control. Studies of children and adults with asthma have documented an adherence to twice-daily inhaler regimens of about 50%,^3-5 a strong inclination for patients to overestimate their adherence,^3,4 and a direct correlation between adherence and clinical outcomes.⁴

Nonadherence may be inadvertent because of a poor understanding of asthma action plans or inhaler technique. This should be assessed by witnessing inhaler and spacer technique in the office and questioning patients about the proper adjustment of inhalers for exacerbations and remissions. Translators, family members, and/or pictoral or color-coded action plans should be used, as needed, to improve the patient's understanding. Additional patient information is available through the American Academy of Allergy, Asthma, and Immunology (www.aaaai.org), the Asthma and Allergy Foundation of America (www.aafa.org), and the American Lung Association (www.lungusa.org).

Patients who have a poor perception of their symptoms are at an enormous disadvantage in managing their asthma. Emphasizing the "disconnect" between symptoms and pulmonary function during the office visit can help motivate these patients to monitor themselves with a peak expiratory flow (PEF) me- ter and to adjust their medication accordingly.

Adherence can be limited by many other factors, including medication cost, prior failed treatment trials, poor physician-patient relationship, unrealistic expectations for therapy, forgetfulness, and depression. Asking the patient how many doses of medicine are missed in a week and addressing the cause are both critical.

Identifying offending medications and environmental exposures

Medications should be reviewed to determine whether worsening symptoms correlate with the start of treatment with nonselective ß-blockers, ß-agonists, aspirin, or other NSAIDs. Importantly, history alone may not be enough to detect this effect. For example, 4% to 11% of adults with asthma report an allergy to NSAIDs on surveys, while studies using aspirin challenge show a prevalence of 14% to 29% in all patients with asthma and of 30% to 40% in a subset of patients with nasal polyps and chronic rhinosinusitis.⁶

When it is clinically feasible, the patient should have a therapeutic trial off the offending agent for several weeks, with close monitoring of symptoms and either measurement of PEF or spirometry to establish the relevance of the drug to the patient's asthma. Patients with suspected aspirin-exacerbated respiratory disease should be treated with leukotriene-modifying drugs and referred to a specialist for evaluation, since aspirin desensitization can significantly improve the chronic rhinosinusitis that is typical of this condition. Recreational drugs, particularly cocaine, have also been associated with emergency department (ED) visits for asthma, and their use should be assessed.

Poorly controlled environmental exposures are a common contributing factor in difficult-to-control asthma. Establishing allergies with skin testing or immunological assays for specific IgE in serum and instituting appropriate allergen-specific environmental controls have been shown to improve symptoms and decrease urgent clinic visits, ED visits, and hospitalizations for asthma.⁷ Assessment of workplace exposures and their relationship to symptoms can identify occupational asthma requiring further evaluation.

In addition, active smoking or passive exposure to smoke is associated with an increase in asthma symptoms, a decline in lung function, an increase in the frequency of ED visits, and an attenuated response to inhaled and oral corticosteroids.⁸ Despite this, an estimated 25% of adults with asthma smoke, and 35% of those treated in an ED are active smokers.⁹

TREATING COMORBID DISEASES

Allergic rhinitis

Uncontrolled coexisting medical diseases may significantly worsen airflow obstruction or cause symptoms that are difficult to distinguish from asthma and that obscure assessment of asthma control. Comorbid allergic rhinitis is common and serves as a marker for more severe asthma. A link between upper and lower respiratory tract allergic inflammation is supported by the fact that 30% to 40% of patients who have allergic rhinitis but do not have symptoms of asthma show nonspecific bronchial hyperresponsiveness on methacholine challenge. Furthermore, in patients who have both allergic rhinitis and asthma, treatment with intranasal corticosteroids results in a decrease in asthma symptoms, bronchial hyperresponsiveness, and asthma- related ED visits.^10,11

Chronic rhinosinusitis and GERD

Patients with asthma and chronic rhinosinusitis also have a more severe clinical course, but adequate reproducible randomized controlled clinical trials have not been performed to distinguish whether the association between chronic rhinosinusitis and asthma is causal or coincidental.¹⁰

Gastroesophageal reflux disease (GERD) can incite cough and chest discomfort, but it does not clearly worsen pulmonary function, as measured by forced expiratory volume in 1 second (FEV₁) or PC₂₀ (the concentration of methacholine at which FEV₁ falls by 20%). Several studies have demonstrated that treatment of GERD improves asthma symptoms without producing significant changes in resting lung function or airway hyperresponsiveness.^12,13 In one of the largest clinical trials to address this issue, 770 persons who had asthma were randomly assigned to receive high-dose proton pump inhibitor (PPI) therapy or placebo for 16 weeks, and they were stratified according to the presence or absence of GERD symptoms and nocturnal respiratory symptoms. Patients who had both symptomatic GERD and nocturnal symptoms had a very modest improvement in PEF with PPI therapy, while the remainder of the population had no improvement.¹⁴

Despite the paucity of clear physiological evidence that chronic rhinosinusitis or GERD worsens bronchial airflow obstruction or airway hyperreactivity, both can contribute to cough, production of phlegm, and chest discomfort that is indistinguishable from asthma symptoms. Furthermore, they are consistently identified as problems in difficult-to-control asthma, and strategies to treat them have also decreased patients' asthma symptoms and allowed asthma controller therapy to be decreased.^1,15

Stress, premenstrual asthma, and obesity

The neuroendocrine axis may have a significant effect on asthma control, although the physiology of this interaction is poorly elucidated. A longitudinal epidemiological study has shown that asthma is more likely to develop in patients with panic disorder and vice versa.¹⁶ Also, acute and chronic stress are risk factors for acute asthma attacks.¹⁷

Premenstrual exacerbation of asthma is a well-documented phenomenon and is defined by a decline in FEV₁ or PEF in the week before menses. Although this is thought to result from a luteal-phase increase in airway inflammation, the physiology is poorly understood, and no randomized controlled trials have shown that estradiol or progesterone replacement has a clear benefit. If a patient has a strong history of premenstrual asthma, a trial of increasing dosages of inhaled corticosteroids in the luteal phase is a practical first step.

Finally, obesity is a common comorbid condition in patients who have asthma and is a risk factor for asthma. Although the pathophysiological mechanisms by which this occurs are unclear, studies of obese persons with asthma who lose weight have shown improvement in asthma symptoms, severity, and exacerbations.¹⁸

SEVERE REFRACTORY ASTHMA

Despite optimal medical and environmental control, some patients have persistent severe asthma. In 2000, an American Thoracic Society workshop defined severe asthma (Table 2) to foster a unified approach to future clinical and translational research,¹⁹ and the National Heart, Lung, and Blood Institute sponsored the Severe Asthma Research Program involving 8 clinical centers to identify genetic and clinical risk factors for severe disease and to examine novel pathophysiological hypotheses. Thus far, clinical risk factors associated with severe asthma include lower prebronchodilator FEV₁, less atopy as assessed by skin testing, a history of pneumonia, symptoms with physical activity, and low blood levels of basophils (which may be a marker for corticosteroid use).²⁰

Ongoing investigations will include the role of oxidants and antioxidants, distal lung fibroblasts and myofibroblasts, and aberrant epithelial apoptosis and proliferation. One study center has already identified a deficit in the production of anti-inflammatory lipoxins in patients with severe asthma, which will be a focus of future studies.²¹ Endobronchial biopsies will be used to delineate specific pathological phenotypes (eosinophilic, neutrophilic, and pauci-inflammatory), and genetic association studies will assess the role of polymorphisms in the interleukin (IL)-4, IL-4 receptor a, transforming growth factor-ß₁, and a disintegrin and metalloproteinase (ADAM)-33 gene.²⁰

CONCLUSIONS

Patients who have difficult-to-control asthma require a comprehensive evaluation with selective testing to both confirm the diagnosis and accurately assess the contributors to poor asthma control (Table 3). Poor control is often a result of multiple factors, including poor adherence to medical therapy, persistent environmental exposures, and uncontrolled comorbid disease. Fortunately, the systematic identification and treatment of these factors can prevent exacerbations as well as improve asthma control.^1,2 Further research to delineate clinical, genotypic, pathological, and immunological subtypes of this disease should provide new options for targeted therapy.

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