Revisiting asthma control: How should it best be defined?

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Pulmonary Pharmacology & Therapeutics 20 (2007) 483–492 www.elsevier.com/locate/ypupt

Revisiting asthma control: How should it best be defined? Nicola A. Hanania Pulmonary and Critical Care Medicine, Asthma Clinical Research Center, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030, USA Received 14 February 2006; received in revised form 27 April 2006; accepted 29 April 2006

Abstract Management guidelines for asthma emphasize a stepwise approach in treating this disease based on daytime symptoms, nighttime symptoms, and lung function assessed by peak expiratory flow or forced expiratory volume at 1 s (FEV1). Although improvement of lung function is a key goal in managing asthma, clinicians often see patients who may have achieved a normal FEV1 with guidelinerecommended treatment but continue to experience limitations in their daily activities. In such situations, focusing the assessment solely on pulmonary function (e.g. FEV1) is often inadequate and may lead to undertreatment. Alternate assessment measures are therefore often needed to assess asthma control and achieve a successful treatment outcome. This review will provide practical guidance relevant to the clinical assessment of asthma control. r 2006 Elsevier Ltd. All rights reserved. Keywords: Asthma control; Control assessment; Persistent asthma; Symptoms; Severity; IgE

1. Introduction: impact of asthma Asthma is a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness (BHR) and airflow obstruction. It is a significant and growing health burden in the United States and around the world. In the US, recent data revealed that approximately 20 million persons (6.2 million children o18 years of age) reported current asthma symptoms in 2003; in addition, 30 million persons (9.1 million o18 years of age) reported being told by a health care professional at some point in their lifetime that they had asthma (lifetime prevalence) [1]. High mortality and health care utilization rates in the United States clearly indicate that there are a significant number of persons with poorly controlled asthma: in 2002, 4261 people died from asthma and there were 484,000 hospital discharges, 1.2 million hospital outpatient visits and 12.7 million office-based physician visits due to asthma [1]. Most of asthma costs may be attributed to uncontrolled asthma symptoms [2], with more than 80% of asthma costs attributed to 20% of patients with asthma [3]. Vollmer and colleagues demonstrated this concept when they reported Tel.: +1 713 873 3454; fax: +1 713 873 3346.

E-mail address: [email protected]. 1094-5539/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pupt.2006.04.005

that the rate of acute asthma episodes was proportional to the number of control problems as indicated by the Asthma Therapy Assessment Questionnaire (ATAQ). Patients with 3 to 4 control problems had 3.5 times more acute care episodes than those with no control problems [4]. 2. Goals of management Guidelines from the National Asthma Education and Prevention Program (NAEPP) [5] and the Global Initiative for Asthma (GINA) [6] were created to assist physicians in evaluating patients’ asthma severity status and suggest appropriate pharmacologic therapy. The NAEPP and GINA guidelines have established a number of asthma therapy goals which focus on the maintenance of normal activity levels (Table 1) [5,6]. The patient’s clinical management should be reassessed when any of these goals are not met. As evidenced by the results from the national Asthma in America survey of 2509 adults with asthma or parents of children with asthma, it is obvious that these goals are not being met [7]. Data, from that study, showed that in the year prior to the survey 41% of patients were hospitalized, treated in the emergency department (ED) or required other acute care for asthma, 48% limited their

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Table 1 Goals of asthma therapy [5,6] National Asthma Education and Prevention Program (NAEPP) guidelines.

Global Initiative for Asthma (GINA) guidelines.

Prevent chronic and troublesome symptoms Maintain (near) ‘‘normal’’ pulmonary function Maintain normal activity levels (including exercise and other physical activities) Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits and hospitalizations Provide optimal pharmacotherapy with minimal or no adverse effects Meet patients’ and families’ expectations of and satisfaction with asthma care

Achieve and maintain control of symptoms Maintain pulmonary function as close to normal levels as possible Maintain normal activity levels, including exercise Prevent asthma exacerbations Avoid adverse effects from asthma medications Prevent development of irreversible airflow limitation Prevent asthma mortality

Adapted from National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung and Blood Institute, National Institutes of Health; 1997. NIH publication 97-4051; and Adapted from Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Bethesda, MD: National Heart, Lung and Blood Institute, National Institutes of Health; 2004. NIH publication 02-3659.

participation in sports/recreation, 31% limited their lifestyle and 25% of adults missed work because of their asthma. 3. Classification of asthma severity Asthma severity categories were redefined in 1997 as mild intermittent, mild persistent, moderate persistent and severe persistent to guide selection of therapy [5]. Although the choice of therapy depends on severity assessment [5,6,8], correlation between severity assessment and the patient’s true overall health status (e.g. participation in activities and quality of life) is poor [9–16]. Unfortunately, there is considerable inconsistency in asthma severity assessment—and, therefore, in treatment of patients— which can be attributed to many factors. Patient severity status can vary over time, particularly if based on a single variable [5,14]. In addition, definitions are imprecise and often subjective; different evaluators emphasize different measurements [15]. Furthermore, some physicians may underestimate asthma severity when performing assessments and prescribing treatment. One study compared asthma severity assessment by physicians documented in patients’ charts with retroactively applied NAEPP guideline-based severity assessments. Chart review showed that physicians classified 24% of patients as moderate persistent and 1% as severe persistent versus 36% and 10%, respectively, when NAEPP-based assessments were used (Po0:001 for both comparisons) [17]. Patients’ and physicians’ estimates of disease severity may also conflict with each other. In a study where patients self-reported moderate or severe asthma symptoms, most physician estimates were of mild or moderate disease [13]. In the Asthma in America survey, only 22% of patients with severe symptoms, according to the NAEPP guidelines, reported severe disease and only 41% of patients with moderate persistent asthma reported moderate-to-severe disease [5,7]. Furthermore, a recent study demonstrated the considerable lack of agreement between three different methods of asthma severity classification: NAEPP-based,

GINA-based and physician-assessed [18]. Given such a broad disagreement among severity assessments, there is a clear need to develop and use assessment protocols that take into account multiple indicators of the patient’s asthma status, including function in daily activities and quality of life. 4. The global assessment of asthma Although many clinicians use the terms ‘‘asthma control’’ and ‘‘asthma severity’’ interchangeably, they are distinct. Asthma severity strictly refers to the pathological disease state, while asthma control is determined by a collection of objective and subjective factors such as forced expiratory volume at 1 s (FEV1), peak expiratory flow (PEF), daytime symptoms, rescue medication use, nighttime awakenings, exacerbations, ED visits and adverse events, which may necessitate changes in asthma therapy [5,6,8]. Greater precision is needed to avoid ambiguities and variable emphasis on individual factors, and to correlate assessments more accurately with a patient’s quality of life [9]. Patients’ perceptions of their asthma control may not correlate with their true asthma control status and its effect on their daily life. In the Asthma in America survey, 60% of patients with moderatepersistent asthma and 30% with severe-persistent asthma considered their asthma symptoms to be ‘‘well-controlled’’ or ‘‘completely controlled’’ [7]. Physicians’ perceptions may also reflect this discrepancy. In a study where all patients were classified with having uncontrolled asthma according to guidelines-based criteria, clinicians rated 43% of the patients as having adequate to very good asthma control [11]. The common lack of asthma control was documented in the prospective, observational, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study [19]. This was the largest study ever undertaken of patients with severe or difficult-to-treat asthma, with 4756 patients representing children, adolescents and adults of diverse racial and ethnic backgrounds.

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All age groups exhibited substantial health care utilization, reflected in unscheduled office visits (46%), ED visits (15%) and hospitalizations (5%). TENOR also demonstrated the impact of asthma on activity limitations, with 14%, 19% and 18% of adults, adolescents, and children, respectively, missing work or school days. The lack of asthma control persisted despite prescribed treatments with 56–58% of patients taking three or more asthma control medications. In general, at least 40% of adult patients with asthma remain symptomatic [20]. These substantial numbers of patients with uncontrolled asthma pose a challenge and indicate that standard approaches to the assessment and management of asthma control may be inadequate [20]. The absence of clear, objective definitions allows for subjective judgments; individual physicians and patients focus on different assessment components and, therefore, may miss some of the important factors that indicate a lack of control [10,15]. 5. Measures to assess asthma control The evaluation of asthma control is made difficult by a variety of measurements, a lack of rigorous definitions and a consequent inconsistency of assessments by both patients and physicians. Several measurements have been proposed to monitor asthma control. 5.1. Pulmonary function measures Physiologic measurements, which include spirometry, are widely used to measure asthma control. In general, FEV1 predicts prognosis and response to various therapies, and is easy to test and safe with reproducible measurements [21]. However, several significant limitations indicate that spirometry alone is not a sufficient measurement of asthma control. Some marked individual variations in symptoms are independent of FEV1, and symptomatic and functional responses to therapy may also be independent of FEV1. A study of children, by Bacharier and colleagues, found minimal correlation between percent predicted FEV1 and the level of asthma severity. Patients with asthma severity ranging from mild intermittent to severe persistent had comparable patterns of percent predicted FEV1, including very high rates of FEV1480% predicted (Fig. 1a) [22]. Results from a chart review of 67 patients evaluated at an adult asthma clinic showed no significant correlation between asthma symptoms and FEV1 (Fig. 1b) [23]. These data suggest that FEV1 may not accurately track disease progress or reflect changes in asthma control over time which could lead to long-term functional decline or increased frequency of exacerbations. Measurement of PEF can reflect poor asthma control. In general, 420% of day/night fluctuation has classically been considered an indication of poor asthma control, although a recent meta-analysis evaluating asthma self-management programs failed to demonstrate significant advantages of

Fig. 1. Poor relationship between FEV1, asthma severity classification and asthma symptom control. (a) Similar patterns of FEV1 percent predicted in children with different degrees of asthma severity, classified based on symptom frequency or medication use (whichever is worse) [22]. Adapted from: Bacharier LB, Strunk RC, Mauger D, White D, Lemanske RF, Jr., Sorkness CA. Classifying asthma severity in children: mismatch between symptoms, medication use, and lung function. Am J Respir Crit Care Med 2004; 170:426–432. (b) Poor correlation between percent predicted FEV1 and total asthma symptoms [23]. Adapted from: Teeter JG, Bleecker ER. Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Chest 1998; 113:272–277.

PEF-based management programs compared with symptom-based programs [24]. 5.2. Clinical assessment of control Since objective pulmonary measurements such as FEV1 have significant limitations, physicians often supplement their assessments of asthma control with more clinical parameters. The Gaining Optimum Asthma Control (GOAL) study utilized a composite clinical definition of asthma control based on the NAEPP and GINA guidelines treatment goals, which provide a useful starting point for physicians in the clinic (Table 2) [16]. The following factors were used to identify patients with totally controlled and well-controlled asthma, with equal weight given

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Table 2 GOAL definitions of well-controlled and totally controlled asthma based on GINA and NAEPP guideline goals of therapy [16] Goals of GINA/NAEPP

Totally controlled each week (Must have all of the following)

Well controlled each week (Must have X2 of the following)

Daytime symptomsa Rescue beta2-agonist use Morning PEF

Minimal (ideally none) Minimal (ideally none) Near normal

None None 480% predicted every day

Nighttime awakening Exacerbations Emergency visits Treatment-related adverse events

Minimal (ideally none) Minimal (infrequent) No Minimal

None None None None enforcing change in asthma therapy

o2 days with a symptoms score of 41b Use on o2 days and o4 occasions per week 480% predicted every day Must have all of the following None None None None enforcing change in asthma therapy

Totally and well-controlled asthma were defined by achievement of all the specified criteria for that week. Totally controlled asthma was achieved if the patient during the 8 consecutive assessment weeks recorded 7 totally controlled weeks and had no exacerbations, emergency department visits, or treatment-related adverse events criteria. Well-controlled asthma was similarly assessed over the 8 weeks. Adapted from Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836–844. a Exacerbations were defined as deterioration in asthma requiring treatment with an oral corticosteroid or an emergency department visit or hospitalization. b Symptom score: 1 was defined as ‘‘symptoms for one short period during the day.’’ Overall scale: 0 (none)-5 (severe).

to each criterion: PEF, rescue medication use, symptoms, nighttime awakenings, exacerbations, ED visits, and adverse events. In an analysis by Juniper and colleagues, similar components of overall asthma health status were independently identified: airway caliber, asthma-specific quality of life measured by the patient-reported Asthma Quality of Life Questionnaire (AQLQ) (see below), daytime symptoms and daytime beta2-agonist use, and nighttime symptoms and nighttime beta2-agonist use [9]. Juniper’s study concluded that patient well-being must be assessed and treatment prescribed according to these four individual factors. Another important clinical parameter to assess (that was not included in the GOAL or Juniper studies) is the effect of exercise on asthma control. For example, a patient with an acceptable FEV1 or with relatively few symptoms should not be considered ‘‘controlled’’ if he/she is able to maintain normal lung function only by avoiding exercise and usual daily activities. Assessment of exercise tolerance and related use of rescue beta2 agonists is important to include when determining asthma control; both the NAEPP and GINA guidelines emphasize near normal activity, including exercise, as a goal of asthma therapy (Table 1). For example, patients requiring significant rescue bronchodilator medication during exercise or those whose exercise is limited because asthma symptoms are considered poorly controlled even in the presence of normal lung function at rest. A combinatorial assessment of clinical parameters can provide accessible and informative measurements of asthma control. One way to easily and rapidly obtain information on subjective clinical contributors to asthma control is through the use of questionnaires that focus on symptoms, rescue medication use, and activity limitations (i.e. ATAQ) [25].

5.3. Questionnaires Asthma control can be measured by patient surveys. These include the Asthma Treatment Assessment Questionnaire (ATAQ) [25], the Asthma Control Questionnaire (ACQ) [26], the Asthma Control Test (ACT) [27], the AQLQ [28], the Asthma Questionnaire 30 (AQ30) [29], and the Asthma Bother Profile (ABP) [30] (Table 3). These questionnaires often significantly correlate with certain objective measurements of asthma control. For example, the AQLQ correlates with change in symptom score, change in PEF variability [31], and implementation of NAEPP asthma treatment strategies [32]. A potential limitation to using control assessment questionnaires in general is ensuring accurate translation of a numeric score into a corresponding degree of asthma control. A recently published analysis by Juniper and colleagues [33] used data from the GOAL study to determine the optimal ACQ cutpoint score that would differentiate between well-controlled and not well-controlled asthma [16]. The authors determined that the crossover point was close to 1.00 on the ACQ; an ACQ score of p0.75 indicated an 85% chance that the patient was well controlled, while X1.50 indicated an 88% chance of being not well controlled [33]. A specific limitation to the quality of life questionnaires is that they are generally retrospective and assess health status over extended time periods; unfortunately, this precludes an accurate assessment of rapid or fluctuating changes in disease pathology. By using questionnaires in conjunction with conventional measures, such as PEF, individual and overlapping factors are monitored simultaneously to provide a more comprehensive view of asthma control. Evidence supporting the use of the questionnaires in combination with objective measurements came from

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Table 3 Asthma questionnaires to assess asthma control ACQ ACT AQLQ ATAQ AQ30 ABP

Includes 6 questions and the FEV1. Five questions are those rated most important by a survey of 100 clinicians in 18 countries. The sixth question concerns rescue inhaler use [26] Includes 5 questions that most closely correlate patients’ symptoms with their specialists’ evaluations of control [27] Includes 32 questions in 4 domains (symptoms, activity limitations, environmental stimuli and emotional function) that measure the functional problems that are most troublesome to adults with asthma [28] Assesses 4 measures of control over a 4-week period and scores 1 point for each—self-perceived control, missed activities, nighttime waking and use of rescue inhalers [25] Includes 30 questions which determine everyday life health status estimates in patients with asthma. Questions answered ‘‘Yes’’ ¼ 1 and ‘‘No’’ or ‘‘N/A’’ ¼ 0; a total score of 0 ¼ no asthma and 30 ¼ very severe asthma. Correlates with AQLQ and clinical variables [29] Measures asthma distress by bother; patient’s confidence of asthma knowledge, perception of the quality of care, and confidence in managing asthma attacks [30]

ACQ ¼ Asthma Control Questionnaire; ACT ¼ Asthma Control Test; AQLQ ¼ Asthma Quality of Life Questionnaire; ATAQ ¼ Asthma Therapy Assessment Questionnaire; AQ30 ¼ Asthma Questionnaire 30; ABP ¼ Asthma Bother Profile.

recent data demonstrating that distinct components of severity versus control could not be found using questionnaires alone [34]. The multifaceted nature of asthma and its disease components requires a multifaceted approach to control assessment. 5.4. Measures of BHR and airway inflammation Measurements of airway inflammation and airway hyperresponsiveness can also be utilized as markers of asthma control. These include measures of BHR, exhaled nitric oxide (eNO) and sputum eosinophilia. However, these measures are often hard to perform, are costly and are mainly used as research tools. BHR is a hallmark feature of asthma [35]. Patients with asthma inherently have increased inflammation and airway reactivity, are markedly more sensitive to certain stimuli and respond with more rapid bronchoconstriction, airflow limitation and asthma symptoms than healthy individuals [35,36]. BHR can be assessed either by application of a stimulus (e.g. methacholine) that acts directly on airway smooth muscle or a stimulus (e.g. adenosine monophosphate) that acts indirectly by releasing inflammatory mediators from mast cells [35]. BHR can be utilized as a diagnostic tool for asthma since asthma severity is related to the severity of BHR [5]. Sont and colleagues demonstrated that asthma patients whose treatment regimen was targeted at reducing airway hyperresponsiveness to methacholine (in addition to existing guidelines-based treatment) had a 1.8-fold lower rate of mild exacerbations than patients who were treated according to existing guidelines (P ¼ 0:03) [37]. However, care should be taken when interpreting BHR as results can be abnormal even in the absence of asthma symptoms or when lung function is normal. Furthermore, reduced lung function prior to methacholine challenge testing may be a relative contraindication to perform the test, with cutoff points for challenge initiation ranging from a baseline FEV1 460–o80% predicted [38]. Another disadvantage to the methacholine challenge testing is that the time required to achieve normalization of BHR with treatment can be lengthy.

NO is produced by a variety of cell types including airway epithelial cells, alveolar macrophages and eosinophils [39]. eNO levels are generally increased in asthma [40] and correlate with sputum eosinophilia and BHR [41]. Treatment with inhaled corticosteroids (ICS) reduces eNO in most patients with asthma, either directly through inhibition of inhaled NO synthase or indirectly by suppressing proinflammatory cytokines [39]. Measurements provide a reliable, noninvasive and easy measurement of asthma control—with a positive predictive value for loss of asthma control between 80% and 90% in a study by Jones and colleagues [42]. Results from another study showed that eNO levels decreased and asthma symptoms improved in a dose-dependent manner with inhaled budesonide [43]. A more recent study suggested that measurement of eNO levels may be more helpful in guiding ICS prescription in patients with asthma than the use of clinical/physiologic parameters alone [44]. However, eNO levels are not routinely measured because of the expense involved. In addition, eNO is a nonspecific inflammatory marker that may also be increased in conditions such as bronchiectasis and viral infections, and can be altered by factors such as cigarette smoking, spirometric maneuvers, sputum induction and alcohol, thereby complicating correlations with asthma symptoms [39]. Finally, the range of eNO levels fluctuate from asthma patient-to-patient, with ICS-treated patients often exhibiting the most normal levels [39]. Measurement of sputum eosinophils is another method of assessing airway inflammation and may help in defining asthma control. Sputum induction is safe for the majority of subjects with asthma [45], and sputum eosinophilia has been shown to correlate with FEV1 [46]. In a study by Green and colleagues, asthma patients whose treatment strategy was targeted at normalizing induced sputum eosinophil count and reducing symptoms had significantly fewer severe asthma exacerbations than those patients treated according to standard British Thoracic Society asthma guidelines (35 versus 109; P ¼ 0:01) [47]. One limitation of sputum eosinophil measurement was that some patients were unable to produce an induced sputum

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sample sufficient for analysis [48]. Additionally, a minimal clinically important change in eosinophil cell count has not been identified [49] and methods of sputum induction are not yet standardized. In summary, a multifaceted approach to assess asthma control is needed for most patients. Presently, physicians can use published guidelines and other recognized components of control such as Juniper’s four components mentioned previously [9]. We believe that future treatment regimens should include measures which reflect improvements in quality of life and daily function as important treatment endpoints [5,6,8]. Since specific assessment of asthma control (rather than severity) has recently been shown to alter physician prescribing patterns of controller therapy [50], patients with uncontrolled asthma will benefit most from an evaluation that encompasses not only the severity of their disease state, but also the degree to which the disease is affecting their daily life. 6. Management of poorly controlled asthma In the following section we describe a clinical scenario for a patient with poorly controlled allergic asthma and illustrate an approach to the management of such a patient. 6.1. Clinical scenario Mary is a 45-year-old woman with a history of asthma and allergic rhinitis since childhood. She is currently experiencing worsening symptoms even though she is taking multiple medications that include: fluticasone/salmeterol 500/50, montelukast 10 mg, beclomethasone nasal spray and 4–8 puffs of inhaled albuterol a day. She insists that she is compliant with her asthma treatment regimen. She has had multiple exacerbations from her asthma and had to be hospitalized once during the previous 5 years. She reports significant limitation in her exercise tolerance and her daily activities. During the last year, she has missed at least 2 weeks of work because of her asthma. Her current FEV1 is 33% of predicted (see Table 4 for details). When approaching the management of this patient, it is necessary to determine the degree of asthma control by considering both the NAEPP and GINA guidelines described in Table 1 [5,6] and Juniper’s four components [9]. This patient has poorly controlled asthma despite being on high doses of ICS. When approaching this patient’s case, several factors should be considered in the assessment, management and treatment (Table 5) [51]. An asthma diagnosis should be verified using a number of measurements, including PEF. The NAEPP suggests that a diagnosis of asthma is indicated by a PEF measurement varying X20% from morning (prebronchodilator) to early afternoon (postbronchodilator), and that a prebronchodilator PEF o80% of a patient’s personal best indicates a lack of asthma control and the need for additional medication [5]. Following verification of the diagnosis, identification of factors contributing to the

patient’s worsening asthma may provide a complete picture of the patient’s disease and quality of life. Evaluation of inhaler technique and adherence to therapy regimen will provide information on dosing, compliance and efficacy of treatment. In this case, reasons for her uncontrolled asthma may include poor inhaler technique, unavoidable environmental triggers, irritants such as tobacco smoke [52,53], lack of response to medications, concurrent viral respiratory infection [54], poorly controlled gastroesophageal reflux disease (GERD) [55], or allergic rhinitis. The presence of psychosocial comorbidities plays a major role in complicating the course of asthma and should be addressed very carefully in every patient presenting with poorly controlled asthma. An important factor which may lead to poor asthma control is the lack of adherence to the asthma treatment regimens. Many patients with asthma have difficulty and/ or poor technique when using their inhaler devices, resulting in insufficient dosing. This problem is so common with the use of a metered dose inhaler that alternative delivery devices have been developed to circumvent this issue [56,57]. Spacers have been developed to prevent deposition of the aerosol on the palate and pharynx, although many patients still do not use these devices properly. Additionally, inadequate dosing results when patients do not take their medications as prescribed. They may misplace their medications, not have them when they leave home, be embarrassed to use them in certain social situations, believe they are doing well enough to skip a dose, find them unpleasant to take or simply forget [58]. In addition to poor inhaler technique, poor compliance with asthma medications may be secondary to the prohibitive cost of such medications or the fear of their side effects such as the ‘‘steroid phobia’’ which is quite common. Exposure to inhaled environmental irritants may also result in a lack of asthma control. Custovic and colleagues suggest that in individuals with asthma who are sensitized to a specific allergen, the combination of high allergen levels, respiratory-virus infection, and indoor/outdoor air pollution may contribute to persistent asthma symptoms [59]. However, any of these factors alone may contribute to a lack of asthma control. For example, evidence suggests that more than a quarter of patients with asthma smoke cigarettes [60], which was associated with a significant increase in BHR [52], and current smokers treated with ICS did not achieve asthma control (compared with nonsmokers) [53]. Avoiding known allergens or irritants may assist in achieving asthma control. A study in the New England Journal of Medicine reported a home-based environmental intervention among inner-city children with asthma who were sensitized to specific allergens [61]. Compared with those in the control group, children who received educational intervention had lower allergen levels in the home, as well as fewer days with symptoms during the year the intervention took place (3.39 versus 4.20 days, Po0:001) and the following year (2.62 versus 3.21 days, Po0:001) [61].

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Table 4 Patient scenario History of present illness

45-year-old woman with a history of asthma since childhood

 Hospitalization once in the pervious 5 years, several exacerbations requiring emergency department visits  Significant limitation of daily activities, missed 2 weeks of work because of her asthma during the last year Current symptoms

Symptom triggers Family history Social history

Asthma medications

Other medication Physical examination

Spirometry

RAST IgE level

 Worsening of rhinitis and asthma symptoms since moving from Michigan to Texas  Increasing cough and dyspnea with sports, particularly hiking, cycling and occasionally running Exercise, cold air, cigarette smoke, other strong odors, cleaning solutions and perfumes. Mother, sister and both children have asthma. Divorced, mother of 2 children, a boy and a girl, who attend elementary school. Both have asthma. She lives in a 75-year-old house with visible mold growth in all bathrooms. She has carpeting throughout house and central air-conditioning with frequently changed filters. There is a dog in the house. She experienced seasonal increases in symptoms during spring and fall while living in Michigan, but her symptoms have been continuous since she moved to Houston. She works full-time as an administrative assistant, and finds her life relatively stressful.  Fluticasone/salmeterol 500/50, twice daily  Montelukast 10 mg, once daily  Beclomethasone nasal spray, 2 sprays twice daily preceded by nasal washes  Albuterol 2 puffs when needed (uses 6-8 puffs/d) Proton pump inhibitor for GERD.  HEENT: nasal inflammation  Lungs: scant expiratory wheezes

 FVC ¼ 1.35 (48% predicted)  FEV1 ¼ 0.80 (33% predicted)  FEV1/FVC ¼ 59%; PEFR: 150 l/min Tests to perennial antigens: positive. 170 IU/ml

GERD ¼ gastroesophageal reflux disease; HEENT ¼ head, ears, eyes, nose and throat exam; FVC ¼ forced expiratory vital capacity; FEV1 ¼ forced expiratory volume in 1 s.

Alternatively, the lack of response to inhaled steroids may be due to inherent properties of ICS or aberrant molecular responses to the drugs [62]. Although ICS are effective in a large percentage of patients with asthma, some patients may be insensitive to their effect because of defects in glucocorticoid signaling to cells of the airways [62,63]. Normally, ICS bind to the glucocorticoid receptor in the cytoplasm of the cell, which translocates to the nucleus, binds to DNA and other molecules, and modulates inflammatory gene expression [62]. Disruption of this signaling pathway can result in cells that do not respond to corticosteroids. Proposed mechanisms for disrupting a proper response to ICS include aberrant expression or posttranslational modification of the glucocorticoid receptor, and dysfunctional transcription of antiinflammatory genes and subsequent changes in the production of inflammatory mediators such as cytokines [62]. Response to corticosteroids may also be determined by genetic factors; polymorphisms have been observed in a critical gene that mediates the release of corticotropinreleasing hormone receptor-1 (CRHR1). Various alleles of this gene alter the pulmonary response to ICS by a factor of 2–4 [64]. However, the beneficial effect of genetically screening patients for steroid insensitivity remains to be elucidated.

Even though patients may respond to recommended doses of ICS, current evidence suggests that when higher doses of ICS are administered the benefits are no longer proportional to the dose of ICS; this phenomenon is described as the steroid plateau effect [65,66]. A metaanalysis of fluticasone propionate clinical studies showed that treatment with 100–250 mg/d achieved at least 90% of maximum efficacy compared with placebo for endpoints such as exacerbations, lung function, night awakenings and beta-agonist use [65]. Additionally, the risk for potential local and systemic adverse effects is increased when high doses of ICS are used [67–70]. In general, optimization of therapy will initiate with increasing the ICS dose, however, in this case (and many others), higher dose ICS may be less likely to provide incremental clinical benefit. Additional therapies to ICS, such as long-acting beta-agonists (LABAs), should also be considered. In the GOAL study, guideline-defined wellcontrolled asthma was achieved in 71% of patients who received an ICS/LABA combination versus 65% in those treated with ICS alone for 1 year (dose determined based on asthma control during the first phase of the study) [16]. However, guideline-defined total control was only achieved in 41% of these patients during the same treatment period. Once all the steps outlined above have been taken, patients

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Table 5 Steps to approaching a patient with poorly controlled asthma [51] Steps

Actions

Confirm diagnosisa

Confirm reversible airflow limitation and quantify severity. FEV1, PEFR, and flow-volume loop before and after bronchodilators. Bronchoprovocation test if spirometric measures are normal. Consider other tests (see 3 below).  Persistent exposure to allergens  Inhaled irritants, environmental tobacco smoke  GERD  Rhino-sinusitis  Smoking  Medications (aspirin, NSAIDs, beta blockers)  Respiratory tract infections  Psychosocial factors (stress)

Address asthma triggers and other contributing factorsa

Perform other tests

Check inhaler technique and adherence to regimen Optimize therapy

         

Allergen skin testsa CT scan of sinusesa 24 h esophageal pH monitoringa Chest radiographa Blood eosinophil count, skin testing for Aspergillus, IgE levela Alpha-1-anti-trypsin Sleep study Total lung capacity and residual volume to rule out restriction Diffusion capacity in adults (rule out emphysema, pulmonary vascular disease or interstitial lung disease) Psychological consultation

Check MDI and DPI technique every visit. Ask patient to bring his/her medications to clinic every visit. Address questions and concerns about medications.  High dose ICS  LABA/leukotriene modifiers  Second-line–agents J Anti-IgE therapy  Alternative agents for steroid dependent/resistant patients (e.g. methotrexate, gold, others)

FEV1 ¼ forced expiratory volume in 1 s; PEFR ¼ peak expiratory flow rate; GERD ¼ gastroesophageal reflux disease; NSAIDs ¼ non-steroidal antiinflammatory drugs; CT ¼ computed tomography; ICS ¼ inhaled corticosteroids; MDI ¼ metered dose inhaler; DPI ¼ dry powder inhaler; LABA ¼ long-acting beta-agonists; IgE ¼ immunoglobulin-E. a Adapted from American Thoracic Society. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000; 162:2341–2351.

with persistent poorly controlled asthma should be evaluated for alternative or additional novel therapies [71]. The continuation of persistent asthma symptoms despite appropriate ICS therapy, the multiple recent exacerbations and the difficulties with daily activities in our patient clearly indicate that her asthma is not adequately controlled [5,6,8]. As immunoglobulin-E (IgE) participates in both the initiation of acute allergic responses and contributes to chronic allergic bronchial inflammation [72], the IgE-blocking, humanized, monoclonal antibody omalizumab may therefore prove to be a beneficial addition to her treatment regimen [73]. Similar to results observed in phase III clinical trials [74–77], 2 months after initiating this therapy the patient reported a decrease in the use of her rescue medication and a decrease in night awakenings, with corresponding improvement in her quality of life. 7. Conclusions An accurate assessment of asthma control should include multiple aspects of objective measures (i.e. pul-

monary function tests) and subjective measures (i.e. symptoms, quality of life). Measures of airway inflammation and airway hyperresponsiveness may also be helpful although currently less practical to obtain. Patients with normal FEV1 on guideline-recommended treatment, but limitations in daily activities, have uncontrolled asthma that requires further work-up and on occasions additional therapy to meet the treatment goals. Acknowledgment Writing assistance for this manuscript was provided by Genentech, Inc. References [1] American Lung Association: Epidemiology & Statistics Unit. Trends in asthma morbidity and mortality. http://www.lungusa.org/atf/cf/ %7B7A8D42C2-FCCA-4604-8ADE-7F5D5E762256%7D/ASTHMA1. PDF. Accessed March 28, 2006. [2] Barnes PJ, Jonsson B, Klim JB. The costs of asthma. Eur Respir J 1996;9:636–42.

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