Diagnosis and Management of Asthma in Older Adults

PROGRESS IN GERIATRICS Diagnosis and Management of Asthma in Older Adults Sanjay Haresh Chotirmall, MD, Michael Watts, MD, Peter Branagan, MD, Ciaran...
Author: Charleen King
12 downloads 0 Views 183KB Size
PROGRESS IN GERIATRICS

Diagnosis and Management of Asthma in Older Adults Sanjay Haresh Chotirmall, MD, Michael Watts, MD, Peter Branagan, MD, Ciaran F. Donegan, MD, Allan Moore, MD, and Noel Gerard McElvaney, MD

Despite comprehensive guidelines established by the European Global Initiative for Asthma and the U.S. National Asthma Education and Prevention Program on the diagnosis and management of asthma, its mortality in older adults continues to rise. Diagnostic and therapeutic problems contribute to older patients being inadequately treated. The diagnosis of asthma rests on the history and characteristic pulmonary function testing (PFT) with the demonstration of reversible airway obstruction, but there are unique problems in performing this test in older patients and in its interpretation. This review aims to address the difficulties in performing and interpreting PFT in older patients because of the effects of age-related changes in lung function on respiratory physiology. The concept of ‘‘airway remodeling’’ resulting in ‘‘fixed obstructive’’ PFT and the relevance of atopy in older people with asthma are assessed. There are certain therapeutic issues unique to older patients with asthma, including the increased probability of adverse effects in the setting of multiple comorbidities and issues surrounding effective drug delivery. The use of beta 2agonist, anticholinergic, corticosteroid, and anti-immunoglobulin E treatments are discussed in the context of these therapeutic issues. J Am Geriatr Soc 57:901–909, 2009.

Key words: asthma; diagnosis; treatment

T

he number of cases of asthma in all age groups is increasing.1–3 Although awareness of many aspects of diagnosis and management of asthma has become well established, its mortality in older adults continues to rise.4 Ireland, with the fourth highest prevalence rate of asthma worldwide, provides a case in point. As the population ages, this problem has gained greater prominence, with current estimated frequencies of asthma in elderly people ranging From the Department of Medicine, Beaumont Hospital, Dublin, Ireland, and Department of Medicine, Mid-Western Regional Hospital, Limerick, Ireland. Address correspondence to Dr. Sanjay Haresh Chotirmall, Respiratory Research Division, Education & Research Centre, Beaumont Hospital, Dublin 9, Republic of Ireland. E-mail: [email protected] DOI: 10.1111/j.1532-5415.2009.02216.x

JAGS 57:901–909, 2009 r 2009, Copyright the Authors Journal compilation r 2009, The American Geriatrics Society

from 6.5% to 17.0%.5 Death rates associated with asthma depend on patient age; in a group of patients aged 55 to 59, the death rate was 2.8 per 100,000 people, whereas in people aged 60 to 64, it was 4.2 per 100, 000.6 Diagnostic and therapeutic problems contribute to many patients being inadequately treated. Despite its importance in older patients, asthma is particularly difficult to diagnose in this age group. Symptoms typical of asthma such as intermittent wheezing, breathlessness, and cough can also indicate other respiratory problems in older patients, particularly chronic obstructive pulmonary disease (COPD). Similarly, other symptoms of asthma such as chest pain or tightness may be due to nonpulmonary disease such as ischemic heart disease,7 congestive cardiac failure, anemia, or pulmonary embolism. Furthermore, many older patients regard breathlessness and cough as simply ‘‘signs of old age’’ and do not present to their general practitioner. Although age is associated with a progressive decrease in lung performance, the respiratory system remains capable of maintaining adequate gas exchange throughout life.8 Thus, an underlying diagnosis should always be sought when these symptoms are present. Treatment in older patients should be based on symptoms and the demonstration of airway obstruction. This is most commonly done by performing pulmonary function testing (PFT), which can be difficult to interpret in older patients. This article aims to address difficulties in performing and interpreting PFT in older patients. Other issues related to diagnosis such as atopy will be discussed and several therapeutic aspects of asthma in older patients considered. This latter subject will focus on available drug delivery methods and several classes of medications used in treatment, including their associated adverse effects.

DESCRIPTION OF AGE EFFECTS ON ASTHMA Long-Standing Versus Late-Onset Asthma Older patients with asthma are divided into two major categories: those diagnosed as children who subsequently carry the diagnosis throughout life (long-standing asthma) and those who develop new symptoms in their sixth decade of life (aged 65). Understandably, this latter group is challenging to recognize and accounts for the majority of undiagnosed cases. A number of studies have suggested that people with long-standing asthma have shorter symptomfree periods, more hospitalizations, more emergency inter-

0002-8614/09/$15.00

902

CHOTIRMALL ET AL.

ventions, and worse lung function than those developing symptoms at age 65 and older.9 In contrast, another study found no relationship between disease duration and severityFa finding now gaining broad acceptance,10 although some definitions of ‘‘late-onset asthma’’ consider symptom onset at ages as young as 30 as ‘‘late onset.’’11 The course of late-onset elderly asthma appears similar to that of long-standing asthma in terms of respiratory dysfunction, with neither showing acute deterioration but gradual loss of ventilatory capacity instead.

Atopy in the Older Adult with Asthma Atopic (extrinsic) asthma is associated with disease predominantly diagnosed in childhood. Its role in older adults with asthma is less well established. From the Greek atopos, meaning ‘‘out of place,’’ it is defined as the genetic tendency to develop classical allergic disease. It involves a capacity to produce abnormal amounts of immunoglobulin E (IgE) to environmental allergens such as grass or pollen. The ‘‘well documented’’ triad (asthma, eczema, and hay fever) causes a number of cases, although an isolated high IgE level against an allergen does not necessarily result in this ‘‘triad.’’ The role of atopy in the pathogenesis of asthma is undisputed, and a high serum IgE level has in previous studies been found to be a risk factor for the development of obstructive airway disease.12 Such a relationship is independent of smoking, but synergism exists.13 Atopy is age-related: high in childhood, moderate in mid-life, and low in older age groups.14 Consequently, high IgE levels at any age increase the probability of a diagnosis of asthma during later life,15 although a past history of atopy represents one of the predictors of asthma at an older age; if one was at risk of being sensitized, this has probably already occurred once entering the latter decades of life.16 Conversely, the Normative Aging Study showed that late-onset cat hypersensitivity predicted asthma onset in older patients.17 Allergen sensitization in later life does therefore occur and may act as a predictor of asthma; a past history of atopy has not consistently been shown to be the ‘‘strongest’’ predictor, but is a predictor, of late-onset asthma. It is safe to state that atopy is important in some but not all cases of older age asthma, and rarely does an environmental source provoke an asthma attack in an older patient. Nonatopic (intrinsic) asthma is far more common in older people with asthma, particularly those with late-onset disease. In a study comparing bronchial biopsies from the two groups, a more-pronounced inflammatory response was seen in nonatopic asthma.18 A potential reason for this includes airway activation in response to viral or in vivo antigens yet undescribed. People with late-onset asthma usually have initial symptoms leading to a subsequent diagnosis during or after an upper respiratory tract infection.19 Age-Related Changes in Lung Function With older age, the chest wall becomes stiffer and less compliant. This is usually felt to be related to calcification of costal cartilage and rib–vertebral articulations and narrowing of intervertebral disc spaces.20 As a result of age-related osteoporosis and subsequent vertebral collapse, the shape of the thorax changes. This leads to greater dorsal kyphosis and anteroposterior diameter.21 Thus, not only is the chest wall more fixed, but the contained lungs are left at

MAY 2009–VOL. 57, NO. 5

JAGS

a mechanical disadvantage. Because the diaphragm is flattened, its ability to generate negative intrathoracic pressure is reduced. In addition, a significant decrease in the strength of the diaphragm in older patients has been shown.22 This in combination with the anatomical changes in the chest wall and its greater stiffness reduces the force-generating capacity of the diaphragm. In addition, nutritional status, which is often deficient in older patients, frequently contributes to altered respiratory muscle strength.23 Normal aging is associated with a reduction in elastic recoil of the lung parenchyma. The exact underlying mechanism for this remains unclear. It has been postulated that it may be related to the spatial arrangement of the elastic fiber network,20 rather than an actual reduction in the total content of collagen and elastin. Thus, during expiration, there is a greater tendency for small airways to collapse, with resultant air trapping and an increase in residual volume. The stiff, poorly compliant chest wall of older patients causes less outward recoil, particularly marked at high lung volumes. This reduction in recoil pressure causes a reduction in vital capacity (VC); this is balanced by the increase in residual volume (RV). Thus, older patients have greater functional residual capacity (FRC). The net effect is that older patients breathe at higher lung volumes than younger patients. This places increased elastic load on the chest wall and an additional burden on the respiratory muscles, leading to an increase in metabolic demand.

The Concept of ‘‘Airway Remodeling’’ Resulting in ‘‘Fixed Obstructive’’ PFTs ‘‘Fixed obstruction’’ may be observed in the interpretation of PFTs of people with long-standing asthma versus lateonset counterparts. A proposed mechanistic model is the concept of ‘‘airway remodeling.’’ Years of airway inflammation activate this process, which combines fibrinolytic mediators (including growth factors and interleukins) with an intricate interaction between cell membranes, airway epithelium, and glandular and vascular structures.24,25 The resultant outcome is the development of permanent airway narrowing, resulting in ‘‘fixed bronchial obstruction,’’ as reflected in pulmonary function findings.26 The same inflammatory notion demonstrated is not restricted to asthma but is also seen in COPD.27 More-severe or recurrent infections may accelerate the ‘‘remodeling’’ process, a particularly important factor in the older population predominantly due to a reduced immune response to infection with advancing age.28 In terms of the ‘‘fixed obstruction’’ resulting from airway remodeling reflected in PFTs, longstanding asthma can be indistinguishable from COPD, presenting a challenge for clinicians.29–31 Age-dependant physiological changes in pulmonary function, particularly age-related decreased elastic recoil, contribute additionally to clinical difficulty in differentiating asthma from COPD from PFTs. Consequently, approximately 20% of people with asthma are misdiagnosed.32 Thinking of these two diagnoses in terms of an overlap syndrome may be more appropriate, especially because both diseases can coexist as one ages.33 Reduced diffusion capacity and significant smoking history may tilt the diagnosis toward COPD, whereas a history of atopy or a high concentration of eosinophils in blood, sputum, or bronchoalveolar lavage specimens may support asthma as being predominant.34

JAGS

MAY 2009–VOL. 57, NO. 5

DIAGNOSTIC DIFFICULTIES AND OPTIONS WITH PFT Pulmonary Function Testing The diagnosis of asthma rests on history (Table 1) and characteristic PFTs, with the demonstration of reversible airway obstruction. Spirometry Changes in Forced Expiratory Volume in 1 Second and Forced Vital Capacity Lung growth occurs up until early adult life (age 15–25), whereas lung function changes little.22 Forced expiratory volume in 1 second (FEV1) begins to decline from approximately the middle of the third decade at the rate approximately 30 mL/year for men and 25 mL/year for women. Most longitudinal studies suggest an accelerated decline in FEV1 (to 38 mL/year) and forced vital capacity (FVC) with age, the loss being greater in men and more rapid in people with high airway reactivity.20 Predicted values of FEV1 and FVC in normal older patients are based on extrapolated data from younger patients and tend to overpredict values.35 The accelerated decline in VC in older patients should be taken into account when making a diagnosis of airflow obstruction. Change in FEV1/FVC Ratio A study examining flow volume changes with aging demonstrated an obstructive pattern in lifetime nonsmokers, implying that this pattern may be normal in old age.36 The Global Initiative for Chronic Obstructive Lung Disease criteria state that a 70% ratio of FEV1/FVC as the cutoff for airflow obstruction may not necessarily be true in older people and can result in overdiagnosis of obstructive lung disease in older patients. Severity of pulmonary function decline in elderly people with asthma is multifactorial; severity of clinical course, age, time before diagnosis, history of cigarette smoking, and clinical phenotype all can contribute to disease severity. Abnormal spirometry at diagnosis of asthma in older patients is a common phenomenon, and its relationship to delay in diagnosis and commencement of appropriate therapy is likely because of nonspecific presentation of symptoms and the diagnostic difficulties highlighted above. The delay, in an elderly patient may represent months to years.15 A study showed that, in more than 27% of elderly patients newly diagnosed with asthma, no other respiratory diagnosis was previously reached.32 In essence, patients presenting with minor symptoms who subsequently demonstrate an obstructive pattern on spirometry warrant further examination for asthma, Table 1. Elements in a Medical History Supporting a Diagnosis of Asthma Shortness of breath Chest tightness Cough (usually ‘‘dry’’) Recurrent wheezing Nocturnal symptomatology Nocturnal worsening of disease Symptom triggers (cold air, exercise or allergen exposure)

DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS

903

although it must be appreciated that an obstructive pattern alone on spirometry in the absence of symptoms may reflect age-related pulmonary change and not necessarily asthma. When comparing long-standing and late-onset asthma, an element of ‘‘fixed obstruction’’ may be encountered. This is evidenced by unchanged FEV1 and FEV1/FVC values pre- and postbronchodilator administration37 and must be a clinical consideration when interpreting PFT results in this group.

Beta-Agonist Versus Anticholinergic Reversibility Definitions of reversibility, controversial in COPD,38–41 are more clear cut for asthma. An improvement in FEV1 of at least 12% after administration of bronchodilators is accepted.42 It must be appreciated that a diagnosis of asthma remains clinical and that PFT not demonstrating reversibility does not preclude the diagnosis, although demonstrable reversibility according to PFT is useful in aiding a diagnosis of asthma. Although reversibility may be useful in distinguishing between asthma and COPD, these two conditions can also be differentiated according to diffusion capacity of carbon monoxide (DLCO) on formal PFTs. Low DLCO is observed in some cases of COPD due to emphysema causing terminal alveolar destruction, which is absent by definition in asthma. However, in older patients with and without asthma, beta (b)-adrenergic dysfunction is observed.43 Cholinergic receptor function is less well studied, but it is thought that cholinergic changes are less pronounced than in the b-adrenergic counterpart.44,45 As a result, when assessing PFT reversibility in older patients, it is recommended that testing be performed initially using a shortacting b2-mimetic. With the absence of detectable change, repeat testing with an anticholinergic agent should be considered. The benefit of performing this second test is to overcome the apparent decline in adrenergic response with age. This consequently prevents ‘‘missing’’ diagnoses of asthma when testing with a single agent alone. In some individuals, PFT does not demonstrate reversibility, although an improvement in pulmonary function is noted when a systemic corticosteroid is administered. The explanation of this phenomenon lies mainly in the antiinflammatory effect of systemic corticosteroids, although there is accumulating evidence that steroid therapy may affect the b2-adrenergic receptor response when combined with b-agonists. Long-standing airway inflammation causes less expression of adrenergic receptors, predominantly b2 in origin, and consequently a reduced affinity for agonistbased therapy. Corticosteroids limit these processes by reducing inflammation and therefore may provide notable lung function changes when administered.46,47 A 2-week course of oral corticosteroids should be considered before repeat spirometry to detect improvement from the abovestated phenomenon and aid in making a diagnosis of asthma in difficult cases. Barriers to Performing PFTs in Older Patients There are unique problems in performing these tests in older patients and in their interpretation (Table 2). Many older patients will have difficulty performing PFTs because of an inability to perform forced expiratory maneuvers adequately. Performing PFT has been shown to be feasible in up to 90% of outpatients aged 65 and older,48

904

CHOTIRMALL ET AL.

Table 2. Potential Barriers to Performing Effective Pulmonary Function Testing (PFT) in Older Adults and Main Difficulties Clinicians Face During Interpretation of PFT in Older Adults Potential barriers to effective PFT in older adults Inability performing forced expiratory maneuvers efficiently Cognitive impairment (unable to follow technician instructions) Lack of appreciable reversibility with beta-agonism Fatigue and comorbid medical conditions (e.g., cardiovascular, thyroid disease) Sensory deficits (e.g., cataracts, deafness) Impaired coordination (e.g., Parkinson’s disease, stroke) Mouth or dental problems (e.g., dentures, ulceration) Main difficulties for clinicians in interpreting PFT in older adults Age-related physiological changes ( # vital capacity, " residual volume, and " functional residual capacity) Overpredicted ‘‘extrapolated’’ reference FEV1 and FVC values Standard FEV1/FVC cutoff of 70% for airflow obstruction leading to overdiagnosis of obstruction in older patients Airway remodeling contributing to ‘‘fixed obstruction’’ easily mistaken for COPD Coexistence of ‘‘overlap syndrome’’ of concurrent asthma and COPD FEV1 5 forced expiratory volume in 1 second; FVC 5 forced vital capacity; COPD 5 chronic obstructive pulmonary disease.

although not in all hospitalized or institutionalized older patients. There are many potential reasons for this, including significant comorbidity, sensory deficits, coordination impairment, mouth or dental problems, and general fatigue. However, cognitive impairment is one of the most significant limiting factors in performing PFT.48 The prevalence of delirium, another prohibitory factor in performing PFT, varies from 10% to 24% on admission, whereas delirium develops in 5% to 32% of older patients after admission.49

Alternative Lung Function Measures Peak Flow Unlike in younger patients, in whom peak flow variations have been shown to correlate well with the diagnosis of asthma, older age has been shown to be an independent factor for variability in longitudinal monitoring of peak flow.50 In addition, because peak flow tends to decrease with age, the variability in predicted values become less reliable.51 In a study of 1,223 patients with a mean age of 66 (range 43–80), peak flow variability of 9.2  5.5% was reported in men and 8.3  4.6% in women. Peak flow variability was considered to be reliable in 87% of these patients, although the percentage declined with older age.51 Peak flow is not used for making a diagnosis of asthma; instead, it is useful in detecting poorly controlled or worsening disease, although there are instances in which it is not fully reliable even in these circumstances. Relaxed Vital Capacity Because older patients have difficulty performing forced expiratory maneuvers during full PFT, a suitable alternative test is a relaxed VC, because it will produce a higher volume than the more commonly performed FVC and thus be

MAY 2009–VOL. 57, NO. 5

JAGS

more discriminatory in older patients. This relaxed VC volume can be used as the denominator to determine whether obstructive disease is present by using FEV1 as the numerator determined using PFT. This overcomes problems associated with underestimation of VC using forced expiratory maneuvers, but assessing relaxed VC accurately is more time consuming and requires technical expertise to perform correctly.

Airway Resistance The measurement of airway resistance or impedance has been proposed or examined as a measure of airway obstruction in older patients.52 Using impulse oscillometry as a measure of resistance in a group of patients with moderate to severe dementia, it has been shown that airway obstruction could be not only identified, but also quantified. Airway resistance can also be measured using constant volume plethysmography, a method used to estimate thoracic gas volume and airway resistance. It is performed by placing a subject into a chamber equipped to measure pressure, flow, or volume changes. It does not rely on maximal expiratory effort and may thus be particularly suitable for older patients. Its value in the assessment of asthma in children has long been established,53 but no studies examining the feasibility of this technique in older patients have been performed, so it is not routinely encountered in clinical practice. This represents an area for future studies to address validity and practicality of these techniques to assess airway obstruction in older patients. Exhaled Nitric Oxide Nitric oxide (NO) acts as a neurotransmitter in addition to having dilatatory effects on the airway and its associated vasculature.54,55 Measurement of exhaled NO (eNO) is employed to aid diagnosis and treatment of asthma in certain groups.56–58 People with asthma have higher eNO values than people without, and measured changes in eNO may reflect asthmatic control.59 Studies in this area have shown conflicting results to date.60–63 Although the known airway effects of NO support its role in the pathophysiology of asthma, it has been suggested that high eNO is simply a marker of airway inflammation, and links between asthma, airway inflammation, and eNO remain far from understood.64 Consequently, routine use of eNO for the diagnosis and management of asthma requires standardization and agreed reference ranges, which vary as a function of age and height.65 This, coupled with a lack of solid literature (most studies involve children and young adults), precludes routine recommendation of its use in older people with asthma. ISSUES WITH TREATMENT Treatment of Asthma in Older Patients Main cornerstones of the treatment of asthma remain consistent across all age groups. Therapy such as corticosteroids are used for ‘‘maintenance’’ and exacerbation, whereas inhaled b-agonists or anticholinergics remain the mainstay of ‘‘rescue.’’ There are certain therapeutic concerns unique to older patients that need to be addressed (Table 3). The most important of these are the greater probability of adverse effects in the setting of multiple comorbidities and problems with effective drug delivery.

JAGS

MAY 2009–VOL. 57, NO. 5

DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS

Table 3. Concerns for Clinicians to Consider When Selecting Asthma Therapy in Older Adults Possible adverse effects Effects of polypharmacy and drug interactions Patient coordination and strength Degree of cognitive impairment Availability of caregiver to administer medications

Drug Delivery Systems After the diagnosis of reversible airflow obstruction has been made, an even more challenging problem is the delivery of drugs to the lungs. There are three main methods of dispersing medication into an aerosol for inhalation: pressurized metered dose inhaler (MDI), dry powder inhaler (DPI), or a nebulizer (Table 4). Manually actuated pressurized MDIs require good coordination and psychomotor skills to ensure that actuation, inhalation, and breath holding occur in precise sequence.66 It is generally accepted that a pressurized MDI without a spacer is not a suitable choice for many physically or cognitively impaired older adults.67,68 Breath-actuated MDIs reduce the need to coordinate actuation and inhalation precisely and so make these devices easier for elderly people. Extension devices used with pressurized MDIs require good coordination, but holding chambers reduce the need for coordination between MDI actuation and inhalation and are generally easier for older, frailer patients.67 DPIs do not require propellants, and there is evidence that patients unable to use an MDI alone find it easier to use a DPI, because it avoids the problems of coordination of actuation and inspiration.68 Incorrect drug use remains a significant concern in elderly people with asthma, particularly with inhaled preparations. A number of factors complicate successful treatment of reversible airway obstruction in older patients. One study showed that age is a factor in predicting ability to use a MDI correctly, with patients younger than 65 doing significantly better than older patients.69 This study also demonstrated that the force required to activate many MDIs exceeded that of a significant number of older patients, although age and strength are much less important predictors of good inhaler technique than cognitive function. It has been demonstrated that cognitive function is the best predictor of ability to use a MDI in people aged 75 and older.68 The prevalence of dementia before the age of 75 is 2.9%, but

Table 4. Available Inhalation Drug Delivery Methods for the Treatment of Older People with Asthma MDI

Require good coordination and psychomotor function With spacer, is better for physically or cognitively impaired older adults Breath-actuated devices easiest for older frailer patients

DPI

Nebulizer

Do not require propellent Suitable for people unable to use MDI

Best choice for the cognitively impaired Lack evidence for superiority over MDI and dry powder inhaler

MDI 5 metered dose inhaler; DPI 5 dry powder inhaler.

905

this rises rapidly to 5.6% after 75 and 22.0% after 80.70 Thus, assessment of cognitive function is essential in older patients in whom inhaled therapy is being contemplated. The choice of delivery system in cognitively impaired patients may thus seem limited, and nebulized therapy is the logical and perhaps only choice,71 but there have been no trials comparing the use of nebulizers in such patients with a well-trained caregiver with a MDI and spacer or a DPI. Nebulizers do not require patient cooperation or coordination and facilitate the fast delivery of large doses of b-2agonists, anticholinergics, and corticosteroids to the lungs. A further consideration in prescribing nebulizers to patients with coexistent COPD is that they should have an air rather than oxygen cylinder driving the nebulizer unless specific blood gas analysis has been performed indicating a benefit from continuous oxygen therapy. In addition, there is a lack of evidence showing that nebulizers are better than MDIs in asthma, particularly when used in combination with a spacer and the doses given are in excess of those normally administered by MDI. Further studies are warranted in this area. The only device that has been shown to give a significant benefit to older patients and patients with poor inhaler technique is the Autohaler,71,72 but this device is spring loaded, and although patients inhale well, they have difficulty activating it. There are other devices available, particularly DPIs, with which no activation other than the ability to inhale is required to release the drug, but many patients complain that they cannot tell whether they are receiving the drug or not. As with any drug treatment in older patients, because of the inherent increase in susceptibility to adverse drug reactions, choices and doses of drugs should be carefully considered when prescribing. Individualized patient assessment drives appropriate prescribing in older people with asthma.

Efficacy of Classes of Medication b2-Agonists Versus Anticholinergic Agents The efficacy of b2-agonists in older patients with stable COPD73 and asthma is well established, although there have been studies suggesting that responsiveness declines with age.43,74 In addition, the return of baseline FEV1 after methacholine challenge and subsequent b-agonist administration is more impaired in older patients than in younger patients.74,75 Common side effects of nebulized b-agonists are tremor, tachycardia, and palpitations. Nonspecific b-receptor agonism after the systemic absorption of the drug mediates these, and they are dose dependant. The incidence of ischemic heart disease increases with age, and many patients with chronic lung disease are smokers. The incidence of silent ischemia or asymptomatic ischemic heart disease also increases with age. The incidence of dysrhythmias after the administration of nebulized b2-agonists is well recognized and reported to be as high as 65%. The risk of serious dysrhythmia is greater in patients who have had a previous myocardial infarction.76 b2-agonists cause a net influx of intravascular potassium into cells with subsequent hypokalemia, a recognized complication of nebulized drug.77,78 Older patients taking diuretics or insulin or with poor nutritional intake also have a greater incidence of hypokalemia and are thus at greater risk of developing this common electrolyte disturbance. In addition, the combina-

906

CHOTIRMALL ET AL.

tion of theophylline with b2-agonists has been reported to increase myocardial damage in animal studies.79 It has been shown that patients taking oral theophylline at therapeutic levels are at greater risk of the hypokalemic effects of nebulized b2-agonists than those not receiving theophylline therapy in addition to receiving b2-agonists.80 The effects of b2-agonists on cardiovascular mortality were initially disputed. Greater mortality has been found,81,82 whereas more recently the TORCH trial convincingly showed no such increase.83 The partial pressure of oxygen in the gas driving the nebulizer may also be an important factor responsible for greater asthma mortality.84 It has been demonstrated a proportion of patients with asthma and COPD who were hypercapnic before nebulized salbutamol developed further rises in carbon dioxide when oxygen was driving the nebulizer.85 Overall, short-acting b2-agonists remain the mainstay of ‘‘rescue’’ treatment in elderly people with asthma (Table 5), although anticholinergic agents are useful alternatives, particularly in cases of partial relaxant effects or adverse effects of b2 administration. Clinicians should limit their prescription of short-acting b2-agonists to that for ‘‘rescue’’ therapy and advise that any patient using them more than twice weekly return to the clinic for reevaluation of asthma control. Use of b2-agonists with any regularity indicates suboptimal asthma control, undertreatment, or worsening disease and should prompt immediate reassessment. The bronchodilator response to anticholinergics, unlike b2-agonists, is less age dependent.74,75 The efficacy of inhaled anticholinergics in COPD and stable asthma in older patients, along with their relative lack of side effects, would suggest that their use should always be considered when the use of a nebulizer is contemplated. The inhaled anticholinergics generally have good safety profiles, although they have been shown in older patients to occasionally produce sedative effects86 and functional cognitive impairment.87 Because of their somewhat indiscriminate and often inappropriate use in the treatment of all forms of airway obstruction, particularly in acute asthma, and their cost, contraindications for their use were often unfounded. Two such contraindications specifically directed toward older patients are the exacerbation of glaucoma and the effects on urinary flow in men. Patients with normalangle glaucoma, when administered up to four times the dose recommended for the treatment of airway obstruction, have no significant difference in their intraocular pressure, pupil diameter, or accommodation from patients with normal intraocular pressures.88 Prolonged pupillary dilatation can occur if the drug is sprayed directly into the eye; thus, if the drug is to be administered using a nebulizer, care should be taken to make sure the facemask creates a good seal around the face, or an alternative such as a T piece should be used. There is less evidence that inhaled anticholinergics have any effect on urinary flow in men aged 50 to 70,89 although there are no long-term data on the use of nebulized anticholinergics. Greater adherence has been shown with tiotropium than any other form of inhaled therapy, particularly for the treatment of COPD.90 It is imperative that clinicians be aware that, although anticholinergic therapy is a viable treatment alternative in the management of asthma in older patients, its use should be restricted to people who show no improvement or are intolerant of b2-

MAY 2009–VOL. 57, NO. 5

JAGS

agonists. Anticholinergics are ideal alternative ‘‘rescue’’ agents for asthma and should never be used as ‘‘maintenance’’ therapy, similar to b2-agonists. In addition, their bronchodilating capabilities are less than those observed with b2-agonists, such that their use is more predominant in the management of COPD than asthma.

Oral and Inhaled Corticosteroids The assessment of reversible airway obstruction is essential before the administration of inhaled corticosteroids. The use of long-term glucocorticoid therapy has been instrumental in decreasing morbidity and mortality in asthma, and the emerging use of steroids is indicated in all age groups.91 Osteoporosis is common in older patients, affecting up to 40% of women aged 70 and older. Prevalence studies examining the association between asthma or COPD and osteoporosis have shown that oral steroid usage is associated with up to a 56% vertebral fracture rate, with an incidence of up to 42%.92 Inhaled glucocorticoids are absorbed into the systemic circulation, but the extent to which they have adverse effects on bone metabolism is uncertain. Studies assessing the effects of inhaled corticosteroids on bone have shown conflicting results. No evidence that inhaled corticosteroid use increases fractures is available. Their use causes decreases in bone mineral density,93,94 although it remains unclear whether this translates to a greater fracture rate. It may be that only at higher doses (42,000 mg/day) that inhaled corticosteroids affect fracture occurrence,95 although like that of oral glucocorticoid administration, the effects on bone roughly correlate with daily dose, duration, and total cumulative lifetime dose.96 The usual route of administration is MDI or DPI. Notwithstanding anxieties associated with inhaled corticosteroids, their considerable role in controlling asthma should not be undervalued. Recent work from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimes study group97 has shown that high doses of inhaled corticosteroids significantly benefit older people with asthma and subsequently improve disease outcome. On average, only one-third of people with asthma are prescribed aerosolized steroids.98 A related study showed that in up to four of every 10 people with late-onset asthma admitted to hospital after an exacerbation, inhaled steroids were excluded in their management.99 With respect to available evidence supporting their use in older people with asthma,97 the clinician should initiate such therapy at the earliest opportunity, although monitoring for side effects and subsequent morbidity should be heightened because of the greater risk. It is imperative that the clinician weigh the risks and benefits of their use in individual patients. Potential metabolic effects of these medications on bone mineral density should always be kept in mind. As described earlier, nebulized medications may be more efficiently delivered to elderly patients with asthma, although there remains a paucity of evidence for the use of nebulized rather than inhaled steroids in older patients with reversible airflow limitation. This, combined with the large doses used and their potential for significant exacerbation of already-present osteopenia or osteoporosis, means that their use should be reserved for individuals whose need for therapy outweighs the potential for future adverse meta-

JAGS

MAY 2009–VOL. 57, NO. 5

bolic effects, although the co-prescription of bisphosphonates and recombinant parathyroid hormone (teriparatide) may prevent glucocorticoid-dependent bone loss in such patients.100,101 Nevertheless, the use of bisphosphonates in preventing bone loss or affecting fracture rates in this context has not been clearly established.102,103 Despite this, there is a potentially small number of patients who would be appropriately managed with high-dose nebulized steroids rather than receiving nebulized b2-agonists and anticholinergics.

Anti-IgE Therapy Omalizumab, a recombinant DNA-derived humanized IgG1k monoclonal antibody selectively binding to human IgE, is used in allergy-related asthma. Delivered subcutaneously every 2 to 4 weeks, its use in older people with asthma has been recently evaluated in a pooled analysis that showed significant benefit in this age group for suitably selected patients.104 Side effects of therapy must always be considered, including reduced defences against parasitic infection and adrenal insufficiency. CONCLUSION The diagnosis of asthma is based mainly on history but is strengthened by the demonstration of airway reversibility (Figure 1). Given a decline in VC with age, this can be difficult. An understanding of age-related changes in lung function is required so as not to miss some patients with treatable airway obstruction. In addition, with a tendency for air trapping in expiration due to less elastic recoil associated with age, some patients may be incorrectly diagnosed with airway obstruction. Alternative methods such as relaxed VC may be more appropriate than forced maneuvers in older patients.

DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS

907

Table 5. Forms of b2-Adrenergic Receptor Agonist Therapy Available for the Treatment of Asthma Short Acting

Long Acting

Ultra-Long Acting

Salbutamol/levosalbutamol

Salmeterol

Indacaterol (limited availability)

Terbutaline Pirbuterol Metaproterenol

Formoterol Bambuterol

Demonstration of reversibility with adrenergic and cholinergic therapy should be performed in older patients. Additionally, the concept of airway ‘‘remodeling’’ must be appreciated in the interpretation of PFT when deciding between a diagnosis of COPD, asthma, and an overlap syndrome. DLCO may help distinguish between asthma and COPD, as does the presence of atopy. In the acute clinical setting, an older adult with suspected new diagnosis of asthma presenting with shortness of breath or wheezing not responding to b2-agonist therapy may be considered b-agonist ‘‘resistant’’ because of altered receptor function. A trial of anticholinergic treatment should be instituted first to overcome any age-related receptor response changes before consideration of alternative diagnoses such as heart failure, chronic aspiration syndromes, or pulmonary embolic disease. The treatment of reversible airflow obstruction should include the assessment of inhaler technique and cognitive function. Nebulizer treatment should be reserved for patients who remain symptomatic despite conventional MDIs, DPIs, or spacer devices. The use of nebulizers in the treatment of older patients with airflow obstruction has not been adequately researched to produce any concrete guidelines for their usage; patient selection for nebulizer treatment should be based on some assessment of reversible airflow obstruction, symptomatic improvement, and an assessment of safety (Table 6). The last should include a screen for underlying ischemic heart disease, such as a history, clinical examination, and electrocardiogram. Measurement of baseline potassium and its monitoring should also occur. The dose of b2-agonist used should be the smallest effective dose that provides symptomatic benefit, given that side effects are dose dependant. Patients receiving nebulizer therapy should

Table 6. Dosage and Side Effects of Treatment Classes Class of Agent

b-agonist Anticholinergic Corticosteroid

Figure 1. Flowchart summarizing diagnosis and management of asthma in elderly people. PFT 5 pulmonary function testing.

Recommended Dosage

Main Side Effect(s)

50 mg or 12 mg formoterol salmeterol twice daily 40 mg ipratropium

Palpitations, tachycardia

(Inhaled) 168–840 mg (low to medium dose) 4840 mg (high dose) (Oral) 30–40 mg prednisolone (quick taper)

Minimal (possible dry mouth, urinary disorders) Decreased bone mineral density

908

CHOTIRMALL ET AL.

be considered for nebulized anticholinergics, because aging is less associated with responsiveness to anticholinergics than b2-agonists. There is generalized underusage of inhaled corticosteroids in elderly people, but the use of nebulized steroids in older patients is poorly researched. Their associated potential side effects mean that their use should be reserved for patients demonstrating a specific need for such treatment.

ACKNOWLEDGMENTS Conflicts of Interest: The authors have no conflicts of interest to disclose with respect to the manuscript. Author Contributions: All authors participated in the concept and structure of the paper. Chotirmall SH, Watts M, Donegan CF, Moore A, and McElvaney NG: manuscript preparation. Chotirmall SH and McElvaney NG: manuscript revision. REFERENCES 1. Renwick DS, Connolly MJ. Improving outcomes in elderly patients with asthma. Drugs Ageing 1999;14:1–9. 2. Weiss KB. An overview of recent trends in asthma epidemiology. Eur Respir Rev 1996;35:101–104. 3. Tirimanna PR, Van Schayck CP, Den Otterr JJ et al. Prevalence of asthma and COPD in general practice in 1992: Has it changed since 1977? Br J Gen Pract 1996;46:277–281. 4. Office of Population and Census Studies. London: HMSO, 1991. 5. Connolly MJ. Asthma and chronic obstructive pulmonary disease. In: Tallis RC, Fillit HM, eds. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. New York: Churchill Livingstone, 2003, pp 489–493. 6. Sly RM. Changing asthma mortality. Ann Allergy 1994;73:259–268. 7. Braman SS. Drug treatment of asthma in the elderly. Drugs 1996;3:415–423. 8. Krumpe PE, Knudson RJ, Parsons G et al. The ageing respiratory system. Clin Geriat Med 1985;1:143–175. 9. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly: A comparison between patients with recently acquired and long standing disease. Am Rev Respir Dis 1991;143:336–340. 10. Burrows B, Barbee RA, Cline MG et al. Characteristics of asthma among elderly adults in a sample of the general population. Chest 1991;100:935– 942. 11. Miranda C, Busacker A, Balzar S et al. Distinguishing severe asthma phenotypes: Role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004;113:101–108. 12. Dow L, Coggon D, Campbell MJ et al. The interaction between immunoglobulin E and smoking in airflow obstruction in the elderly. Am Rev Respir Dis 1992;146:402–407. 13. Burrows B, Halonen M, Barbee RA et al. The relationship of serum immunoglobulin E to cigarette smoking. Am Rev Respir Dis 1981;124:523–525. 14. Barbee RA, Lebowitz MD, Thompson HC et al. Immediate skin-test reactivity in a general population sample. Ann Intern Med 1976;84:129–133. 15. Burrows B, Lebowitz MD, Barbee RA et al. Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 1991;88:870–877. 16. Parameswaran K, Hildreth AJ, Taylor IK et al. Predictors of asthma severity in the elderly: Results of a community survey in northeast England. J Asthma 1999;36:613–618. 17. Litonjua AA, Sparrow D, Weiss ST et al. Sensitization to cat allergen is associated with asthma in older men and predicts new-onset airway hyperresponsiveness. The Normative Aging Study. Am J Respir Crit Care Med 1997;156:23–27. 18. Kay AB. Pathology of mild, severe and fatal asthma. Am J Respir Crit Care Med 1996;154:S66–S69. 19. Bauer BA, Reed CE, Yunginger JW et al. Incidence and outcomes of asthma in the elderly: A population-based study in Rochester, Minnesota. Chest 1997;111:303–310. 20. Crapo RO. The ageing lung. In: Mahler DA, ed. Pulmonary Disease in the Elderly Patient, Vol. 63. New York: Marcel Dekker, 1993, pp 1–21. 21. Edge J, Millard F, Reid L. The radiograph appearance of the chest in persons of advanced age. Br J Radiol 1984;37:769–774. 22. Polkey MI, Harris ML, Hughes PD et al. The contractile properties of the elderly human diaphragm. Am J Respir Crit Care Med 1997;155:1560–1564.

MAY 2009–VOL. 57, NO. 5

JAGS

23. Enright PL, Kronmal RA, Manolio TA et al. Respiratory muscle strength in the elderly correlates and reference values. Am J Respir Crit Care Med 1994;149:430–438. 24. Chakir J, Shannon J, Molet S et al. Airway remodeling-associated mediators in moderate to severe asthma: Effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol 2003;111:1293–1298. 25. Blackburn MR, Lee CG, Young HW et al. Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway. J Clin Invest 2003;112:332–344. 26. Laitinen LA, Laitinen A, Altraja A et al. Inflammatory determinants of asthma severity- bronchial biopsy findings in intermittent or early asthma. J Allergy Clin Immunol 1996;98(Suppl):S3–S6. 27. Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001;164(Suppl):S28–S38. 28. Conolly MJ. Age-related changes in the respiratory system. In: Tallis RC, Fillit HM, eds. Brocklehurst’s Textbook of Geriatric Medicine and Gerontology. New York: Churchill Livingstone, 2003, pp 489–493. 29. Cassino C, Berger KI, Goldring RM et al. Duration of asthma and physiologic outcomes in elderly nonsmokers. Am J Respir Crit Care Med 2000;162: 1423–1428. 30. Little SA, MacLeod KJ, Chalmers GW et al. Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma. Am J Med 2002;112:446–452. 31. Ten Hacken NH, Postma DS, Timens W. Airway remodeling and long-term decline in lung function in asthma. Curr Opin Pulm Med 2003;9:9–14. 32. Bellia V, Battaglia S, Catalano F et al. Aging and disability affect misdiagnosis of COPD in elderly asthmatics: The SARA study. Chest 2003;123:1066– 1072. 33. Soriano JB, Davis KJ, Coleman B et al. The proportional Venn diagram of obstructive lung disease: Two approximations from the United States and the United Kingdom. Chest 2003;124:474–481. 34. Fabbri L, Romagnoli M, Corbetta L et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:418–424. 35. Milne JS, Williamson J. Respiratory function tests in older people. Clin Sci 1972;42:371–381. 36. Fowler RW, Puck RA, Hertzel MR. Maximal expiratory flow-volume curves in Londoners aged 60 yrs and over. Thorax 1987;42:173–182. 37. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly: A comparison between patients with recently acquired and long-standing disease. Am Rev Respir Dis 1991;143:336–340. 38. Brand PLP, Quanjer PH, Postma DS et al. Interpretation of bronchodilator response in patients with obstructive airways disease. Thorax 1992;47:429– 436. 39. Dompeling E, van Schayck CP, Molema J et al. A comparison of six different ways of expressing the bronchodilating response in asthma and COPD: Reproducibility and dependence of prebronchodilator FEV1. Eur Respir J 1992;5:975–981. 40. Meslier N, Racineux JL, Six P et al. Diagnostic value of reversibility of chronic airway obstruction to separate asthma from chronic bronchitis: A statistical approach. Eur Respir J 1989;2:497–505. 41. Dales RE, Spitzer WO, Tousignant P et al. Clinical interpretation of airway response to a bronchodilator. Am Rev Respir Dis 1986;138:317–320. 42. American Thoracic Society. Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202–1218. 43. Connolly MJ, Crowley JJ, Nielson CP et al. Peripheral mononuclear leukocyte b adrenoceptors and non-specific bronchial responsiveness to metacholine in young and elderly normal subjects and asthmatic patients. Thorax 1994;49:26–32. 44. Davis PB, Bvard PJ. Relationships among airway reactivity, papillary alphaadrenergic and cholinergic responses and age. J Appl Physiol 1988;65:200–204. 45. Van Schayck C, Folgering H, Harbers H et al. Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis. Thorax 1991;46:355–359. 46. Koto H, Mak JC, Haddad EB et al. Mechanisms of impaired beta-adenoreceptor-induced airway relaxation by interleukin-1b in vivo in the rat. J Clin Invest 1996;98:1780–1789. 47. Brodde OE, Howe U, Egeszegi S et al. Effect of prednisolone and ketotifen on b2 adrenoreceptors in asthmatic patients receiving b2-bronchodilatators. Eur J Clin Pharmacol 1988;34:145–150. 48. Dow L, Coggon D, Osmond C et al. A population survey of respiratory symptoms in the elderly. Eur Respir J 1991;4:267–272. 49. Manning H, Mahler D, Harvery A. Dyspnoea in the elderly. In: Mahler D, ed. Pulmonary Disease in the Elderly Patient, Vol. 63. New York: Marcel Dekker, 1993, pp 81–111.

JAGS

MAY 2009–VOL. 57, NO. 5

50. DuWayne Schmidt C, Dickman ML, Gardner RM et al. Spirometric standards for healthy elderly men and women: 532 subjects, ages 55 through 94 years. Am Rev Respir Dis 1973;108:933–939. 51. Enright P, Burchette R, Peters J et al. Peak flow lability: Association with asthma and spirometry in an older cohort. Chest 1997;42:371–381. 52. Carvalhales-Neto N, Lorino H, Gallinari C et al. Cognitive assessment of lung function in the elderly. Am J Respir Crit Care Med 1995;152:1611–1615. 53. Leben M, Von Der Hardt H. Airway resistance, airway conductance, specific airway resistance, and specific airway conductance in children. Pediatr Res 1983;17:508–513. 54. Blitzer ML, Loh E, Roddy MA et al. Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans. J Am Coll Cardiol 1996;28:591–596. 55. Belvisi MG, Stretton CD, Yacoub M et al. Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. Eur J Pharmacol 1992;210:221–222. 56. Berkman N, Avital A, Breuer R et al. Exhaled nitric oxide in the diagnosis of asthma: Comparison with bronchial provocation tests. Thorax 2005;60:383. 57. Pijnenburg MW, Hofhuis W, Hop WC et al. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax 2005;60:215. 58. Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: A longitudinal study in unselected patients. Eur Respir J 2008; 31:539. 59. Massaro AF, Gaston B, Kita D et al. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995;152:800. 60. Jones SL, Kittelson J, Cowan JO et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001;164:738. 61. Smith AD, Cowan JO, Filsell S et al. Diagnosing asthma: Comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 2004;169:473. 62. Pijnenburg MW, Bakker EM, Hop WC et al. Titrating steroids on exhaled nitric oxide in children with asthma: A randomized controlled trial. Am J Respir Crit Care Med 2005;172:831. 63. Smith AD, Cowan JO, Brassett KP et al. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352:2163. 64. Franklin PJ, Stick SM, Le Souef PN et al. Measuring exhaled nitric oxide levels in adults: The importance of atopy and airway responsiveness. Chest 2004;126:1540. 65. Smith AD, Taylor DR. Is exhaled nitric oxide measurement a useful clinical test in asthma? Curr Opin Allergy Clin Immunol 2005;5:49. 66. Drug and Therapeutics Bulletin, Vol 38 No 2, February 2000 [on-line]. Available at http://dtb.bmj.com/content/vol38/issue2/index.dtl Accessed May 26, 2008. 67. Hendry A, Coote J, Black H et al. Comparison of conventional metered dose inhaler and breath actuated inhaler in elderly patients. Int J Pharm Pract 1995;3:115–118. 68. Allen SC. Competence thresholds for use of inhalers in people with dementia. Age Ageing 1997;26:83–86. 69. Hindle M, Newton DAG, Chrystyn H. Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary salbutamol assay technique. Chest 1995;107:629–633. 70. Armitage JM. Inhaler technique in the elderly. Age Ageing 1988;17:275–278. 71. Diggory P, Bailey R, Vallon A. Effectiveness of inhaled bronchodilator delivery systems for elderly patients. Age Ageing 1991;20:379–382. 72. Newman SP, Weiz AWB, Talace N et al. Improvement of drug delivery with a breath-activated pressurised aerosol for patients with poor inhaler technique. Thorax 1991;46:712–716. 73. Geraghty R, Foster C, Black D et al. Bronchodilator response to nebulised salbutamol in elderly patients with stable chronic airflow limitation. Respir Med 1993;87:375–378. 74. Ullah MI, Newman GB, Saunders KB. Influence of ageing on response to ipratropium and salbutamol in asthma. Thorax 1981;36:523–529. 75. Connolly MJ, Crowley JJ, Charan N et al. Impaired bronchodilator response to albuterol in healthy elderly men and women. Chest 1995;108:401–406. 76. Brashear RE. Arrhythmias in patients with chronic obstructive pulmonary disease. Med Clin North Am 1984;68:969–981. 77. Lim R, Walshaw MJ, Saltissi S et al. Cardiac arrhythmias during acute exacerbations of chronic airflow limitation: Effect of fall in plasma potassium concentration induced by nebulised aˆ agonist therapy. Postgrad Med J 1989;65:449–452. 78. Smith SR, Ryder C, Kendall MJ et al. Cardiovascular and biochemical responses to nebulised salbutamol in normal subjects. Br J Clin Pharmacol 1984;18:641–644.

DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS

909

79. Joseph X, Whitehurst VE, Bloom S et al. Enhancement of cardiac effects of beta-adrenergic bronchodilators by aminophylline in experimental animals. Fundam Appl Toxicol 1981;1:443–447. 80. Lai CKW, Legge JS, Friend JAR. Air-driven nebulised high-dose salbutamol in severe chronic obstructive airways disease: Is it safe? Respiration 1991;18:641–644. 81. Au DH, Curtis JR, Every NR et al. Association between inhaled beta-agonists and the risk of unstable angina and myocardial infarction. Chest 2002;121:846–851. 82. Au DH, Lemaitre RN, Curtis JR et al. The risk of myocardial infarction associated with inhaled beta-adrenoceptor agonists. Am J Respir Crit Care Med 2000;161(3 Pt 1):827–830. 83. Calverley PM, Anderson JA, Celli B et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789. 84. Sears MR, Rea HH, Fenwick J et al. Seventy-five deaths in asthmatics prescribed home nebulisers. BMJ 1987;294:477–480. 85. Gunawardena KA, Patel B, Campbell IA et al. Oxygen as a driving gas for nebulisers: Safe or dangerous? BMJ 1984;288:272–274. 86. Feinberg M. The problems of anticholinergic adverse effects in older patients. Drugs Aging 1993;3:335–348. 87. Ancelin ML, Artero S, Portet F et al. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: Longitudinal cohort study. BMJ 2006;332:455–459. 88. Kalra L, Bone M. The effect of nebulised bronchodilator therapy on intraocular pressure in glaucoma. Chest 1988;93:739–741. 89. Molkenboer JFWM, Lardenoye JG. The effect of Atrovent on micturition function, double blind cross over study. Scand J Respir Dis 1979;103 (suppl):154–158. 90. Cramer JA, Bradley-Kennedy C, Scalera A. Treatment persistence and compliance with medications for chronic obstructive pulmonary disease. Can Respir J 2007;14:25–29. 91. Goldstein MF, Fallon JJ, Harning R. Chronic glucocorticoid therapy induced osteoporosis on patients with obstructive lung disease. Chest 1999;116:1733–1749. 92. Smith BJ, Phillips PJ, Heller RF. Asthma and chronic obstructive airway disease are associated with osteoporosis and fractures. Respirology 1999;4: 101–109. 93. Ip M, Lam K, Yam L et al. Decreased bone mineral density in premenopausal asthma patients receiving long-term inhaled steroids. Chest 1994;105:1722– 1727. 94. Israel E, Banerjee TR, Fitzmaurice GM et al. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 2001; 345:941–947. 95. Suissa S, Ernst P. Inhaled corticosteroids and fracture risk in COPD. Am J Respir Crit Care Med 2004;170:94. 96. Wong CA, Walsh LJ, Smith CJ et al. Inhaled corticosteroid use and bone mineral density in patients with asthma. Lancet 2000;355:1399– 1403. 97. Slavin RG, Haselkorn T, Lee JH et al. Asthma in older adults: Observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. Ann Allergy Asthma Immunol 2006;96: 406–414. 98. Enright PL, Mc Clelland RL, Newman AB et al. Underdiagnosis and under treatment of asthma in the elderly. Chest 1999;116:603–613. 99. Sin DD, Tu JV. Underuse of inhaled steroid therapy in elderly patients with asthma. Chest 2001;119:720–725. 100. Saag KG, Shane E, Boonen S et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028– 2039. 101. Herrala J, Puolijoki H, Lippo K et al. Clodronate is effective in preventing corticosteroid induced bone loss among asthmatic patients. Bone 1998;22: 577–582. 102. Campbell IA, Douglas JG, Francis RM et al. Research Committee of the British Thoracic Society. Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids. Thorax 2004;59:761–768. 103. Kasayama S, Fujita M, Goya K et al. Effects of alendronate on bone mineral density and bone metabolic markers in postmenopausal asthmatic women treated with inhaled corticosteroids. Metabolism 2005; 54:85–90. 104. Maykut RJ, Kianifard F, Geba GP. Response of older patients with IgEmediated asthma to omalizumab: A pooled analysis. J Asthma 2008;45: 173–181.