Diagnosis and Management of Asthma in Older Adults Sanjay Haresh Chotirmall, MD, Michael Watts, MD, Peter Branagan, MD, Ciaran F

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 Euro- from 6.5% to 17.0%.5 Death rates associated with asthma pean Global Initiative for Asthma and the U.S. National depend on patient age; in a group of patients aged 55 to 59, Asthma Education and Prevention Program on the diagno- the death rate was 2.8 per 100,000 people, whereas in sis and management of asthma, its mortality in older adults people aged 60 to 64, it was 4.2 per 100, 000.6 Diagnostic continues to rise. Diagnostic and therapeutic problems and therapeutic problems contribute to many patients being contribute to older patients being inadequately treated. The inadequately treated. Despite its importance in older pa- diagnosis of asthma rests on the history and characteristic tients, asthma is particularly difficult to diagnose in this age pulmonary function testing (PFT) with the demonstration group. Symptoms typical of asthma such as intermittent of reversible airway obstruction, but there are unique prob- wheezing, breathlessness, and cough can also indicate other lems in performing this test in older patients and in its in- respiratory problems in older patients, particularly chronic terpretation. This review aims to address the difficulties in obstructive pulmonary disease (COPD). Similarly, other performing and interpreting PFT in older patients because symptoms of asthma such as chest pain or tightness may of the effects of age-related changes in lung function on be due to nonpulmonary disease such as ischemic heart respiratory physiology. The concept of ‘‘airway remodel- disease,7 congestive cardiac failure, anemia, or pulmonary ing’’ resulting in ‘‘fixed obstructive’’ PFT and the relevance embolism. Furthermore, many older patients regard breath- of atopy in older people with asthma are assessed. There are lessness and cough as simply ‘‘signs of old age’’ and do not certain therapeutic issues unique to older patients with present to their general practitioner. Although age is asso- asthma, including the increased probability of adverse ciated with a progressive decrease in lung performance, the effects in the setting of multiple comorbidities and issues respiratory system remains capable of maintaining ade- surrounding effective drug delivery. The use of beta 2- quate gas exchange throughout life.8 Thus, an underlying agonist, anticholinergic, corticosteroid, and anti-immuno- diagnosis should always be sought when these symptoms globulin E treatments are discussed in the context of these are present. Treatment in older patients should be based on therapeutic issues. J Am Geriatr Soc 57:901–909, 2009. symptoms and the demonstration of airway obstruction. This is most commonly done by performing pulmonary Key words: asthma; diagnosis; treatment 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 he number of cases of asthma in all age groups is delivery methods and several classes of medications used in Tincreasing.1–3 Although awareness of many aspects of treatment, including their associated adverse effects. diagnosis and management of asthma has become well established, its mortality in older adults continues to rise.4 DESCRIPTION OF AGE EFFECTS ON ASTHMA Ireland, with the fourth highest prevalence rate of asthma worldwide, provides a case in point. As the population ages, Long-Standing Versus Late-Onset Asthma this problem has gained greater prominence, with current Older patients with asthma are divided into two major cat- estimated frequencies of asthma in elderly people ranging egories: those diagnosed as children who subsequently carry the diagnosis throughout life (long-standing asthma) and From the Department of Medicine, Beaumont Hospital, Dublin, Ireland, and those who develop new symptoms in their sixth decade Department of Medicine, Mid-Western Regional Hospital, Limerick, Ireland. of life (aged 65). Understandably, this latter group is Address correspondence to Dr. Sanjay Haresh Chotirmall, Respiratory challenging to recognize and accounts for the majority of Research Division, Education & Research Centre, Beaumont Hospital, undiagnosed cases. A number of studies have suggested that Dublin 9, Republic of Ireland. E-mail: [email protected] people with long-standing asthma have shorter symptom- DOI: 10.1111/j.1532-5415.2009.02216.x free periods, more hospitalizations, more emergency inter-

JAGS 57:901–909, 2009 r 2009, Copyright the Authors Journal compilation r 2009, The American Geriatrics Society 0002-8614/09/$15.00 902 CHOTIRMALL ET AL. MAY 2009–VOL. 57, NO. 5 JAGS ventions, and worse lung function than those developing a mechanical disadvantage. Because the diaphragm is flat- symptoms at age 65 and older.9 In contrast, another study tened, its ability to generate negative intrathoracic pressure found no relationship between disease duration and sever- is reduced. In addition, a significant decrease in the strength ityFa finding now gaining broad acceptance,10 although some of the diaphragm in older patients has been shown.22 This definitions of ‘‘late-onset asthma’’ consider symptom onset at in combination with the anatomical changes in the chest ages as young as 30 as ‘‘late onset.’’11 The course of late-onset wall and its greater stiffness reduces the force-generating elderly asthma appears similar to that of long-standing asthma capacity of the diaphragm. In addition, nutritional status, in terms of respiratory dysfunction, with neither showing acute which is often deficient in older patients, frequently con- deterioration but gradual loss of ventilatory capacity instead. tributes to altered respiratory muscle strength.23 Normal aging is associated with a reduction in elastic Atopy in the Older Adult with Asthma recoil of the lung parenchyma. The exact underlying mech- anism for this remains unclear. It has been postulated that it Atopic (extrinsic) asthma is associated with disease pre- may be related to the spatial arrangement of the elastic fiber dominantly diagnosed in childhood. Its role in older adults network,20 rather than an actual reduction in the total con- with asthma is less well established. From the Greek atopos, tent of collagen and elastin. Thus, during expiration, there meaning ‘‘out of place,’’ it is defined as the genetic tendency is a greater tendency for small airways to collapse, with to develop classical allergic disease. It involves a capacity resultant air trapping and an increase in residual volume. to produce abnormal amounts of immunoglobulin E (IgE) The stiff, poorly compliant chest wall of older patients to environmental allergens such as grass or pollen. The causes less outward recoil, particularly marked at high lung ‘‘well documented’’ triad (asthma, eczema, and hay fever) volumes. This reduction in recoil pressure causes a reduc- causes a number of cases, although an isolated high IgE tion in vital capacity (VC); this is balanced by the increase in level against an allergen does not necessarily result in this residual volume (RV). Thus, older patients have greater ‘‘triad.’’ The role of atopy in the pathogenesis of asthma functional residual capacity (FRC). The net effect is that is undisputed, and a high serum IgE level has in previous older patients breathe at higher lung volumes than younger studies been found to be a risk factor for the development patients. This places increased elastic load on the chest wall of obstructive airway disease.12 Such a relationship is and an additional burden on the respiratory muscles, lead- independent of smoking, but synergism exists.13 Atopy ing to an increase in metabolic demand. is age-related: high in childhood, moderate in mid-life, and 14 low in older age groups. Consequently, high IgE levels at The Concept of ‘‘Airway Remodeling’’ Resulting in any age increase the probability of a diagnosis of asthma ‘‘Fixed Obstructive’’ PFTs during later life,15 although a past history of atopy repre- ‘‘Fixed obstruction’’ may be observed in the interpretation sents one of the predictors of asthma at an older age; if one of PFTs of people with long-standing asthma versus late- was at risk of being sensitized, this has probably already onset counterparts. A proposed mechanistic model is the occurred once entering the latter decades of life.16 Con- concept of ‘‘airway remodeling.’’ Years of airway inflam- versely, the Normative Aging Study showed that late-onset mation activate this process, which combines fibrinolytic cat hypersensitivity predicted asthma onset in older patients.17 mediators (including growth factors and interleukins) with Allergen sensitization in later life does therefore occur and an intricate interaction between cell membranes, airway may act as a predictor of asthma; a past history of atopy has epithelium, and glandular and vascular structures.24,25 The not consistently been shown to be the ‘‘strongest’’ predictor, resultant outcome is the development of permanent airway but is a predictor, of late-onset asthma. It is safe to state that narrowing, resulting in ‘‘fixed bronchial obstruction,’’ as atopy is important in some but not all cases of older age reflected in pulmonary function findings.26 The same asthma, and rarely does an environmental source provoke an inflammatory notion demonstrated is not restricted to asthma attack in an older patient. asthma but is also seen in COPD.27 More-severe or recur- Nonatopic (intrinsic) asthma is far more common in rent infections may accelerate the ‘‘remodeling’’ process, a older people with asthma, particularly those with late-onset particularly important factor in the older population pre- disease. In a study comparing bronchial biopsies from the two dominantly due to a reduced immune response to infection groups, a more-pronounced inflammatory response was seen with advancing age.28 In terms of the ‘‘fixed obstruction’’ in nonatopic asthma.18 A potential reason for this includes resulting from airway remodeling reflected in PFTs, long- airway activation in response to viral or in vivo antigens standing asthma can be indistinguishable from COPD, yet undescribed. People with late-onset asthma usually have presenting a challenge for clinicians.29–31 Age-dependant initial symptoms leading to a subsequent diagnosis during or physiological changes in pulmonary function, particularly after an upper respiratory tract infection.19 age-related decreased elastic recoil, contribute additionally to clinical difficulty in differentiating asthma from COPD Age-Related Changes in Lung Function from PFTs. Consequently, approximately 20% of people With older age, the chest wall becomes stiffer and less with asthma are misdiagnosed.32 Thinking of these two compliant. This is usually felt to be related to calcification diagnoses in terms of an overlap syndrome may be more of costal cartilage and rib–vertebral articulations and appropriate, especially because both diseases can coexist as narrowing of intervertebral disc spaces.20 As a result of one ages.33 Reduced diffusion capacity and significant age-related osteoporosis and subsequent vertebral collapse, smoking history may tilt the diagnosis toward COPD, the shape of the thorax changes. This leads to greater dorsal whereas a history of atopy or a high concentration of kyphosis and anteroposterior diameter.21 Thus, not only is eosinophils in blood, sputum, or bronchoalveolar lavage the chest wall more fixed, but the contained lungs are left at specimens may support asthma as being predominant.34 JAGS MAY 2009–VOL. 57, NO. 5 DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS 903

DIAGNOSTIC DIFFICULTIES AND OPTIONS although it must be appreciated that an obstructive pattern WITH PFT alone on spirometry in the absence of symptoms may reflect Pulmonary Function Testing age-related pulmonary change and not necessarily asthma. When comparing long-standing and late-onset asthma, The diagnosis of asthma rests on history (Table 1) and an element of ‘‘fixed obstruction’’ may be encountered. This characteristic PFTs, with the demonstration of reversible is evidenced by unchanged FEV1 and FEV1/FVC values airway obstruction. pre- and postbronchodilator administration37 and must be a clinical consideration when interpreting PFT results in this Spirometry group. Changes in Forced Expiratory Volume in 1 Second and Forced Vital Capacity Beta-Agonist Versus Anticholinergic Reversibility 38–41 Lung growth occurs up until early adult life (age 15–25), Definitions of reversibility, controversial in COPD, are whereas lung function changes little.22 Forced expiratory more clear cut for asthma. An improvement in FEV1 of at volume in 1 second (FEV1) begins to decline from approx- least 12% after administration of bronchodilators is ac- 42 imately the middle of the third decade at the rate approx- cepted. It must be appreciated that a diagnosis of asthma imately 30 mL/year for men and 25 mL/year for women. remains clinical and that PFT not demonstrating reversibil- Most longitudinal studies suggest an accelerated decline in ity does not preclude the diagnosis, although demonstrable FEV1 (to 38 mL/year) and forced vital capacity (FVC) with reversibility according to PFT is useful in aiding a diagnosis age, the loss being greater in men and more rapid in people of asthma. Although reversibility may be useful in distin- with high airway reactivity.20 Predicted values of FEV1 and guishing between asthma and COPD, these two conditions FVC in normal older patients are based on extrapolated can also be differentiated according to diffusion capacity of data from younger patients and tend to overpredict carbon monoxide (DLCO) on formal PFTs. Low DLCO is values.35 The accelerated decline in VC in older patients observed in some cases of COPD due to emphysema causing should be taken into account when making a diagnosis of terminal alveolar destruction, which is absent by definition airflow obstruction. in asthma. However, in older patients with and without asthma, beta (b)-adrenergic dysfunction is observed.43 Change in FEV1/FVC Ratio Cholinergic receptor function is less well studied, but it is A study examining flow volume changes with aging dem- thought that cholinergic changes are less pronounced than 44,45 onstrated an obstructive pattern in lifetime nonsmokers, in the b-adrenergic counterpart. As a result, when implying that this pattern may be normal in old age.36 The assessing PFT reversibility in older patients, it is recom- Global Initiative for Chronic Obstructive Lung Disease mended that testing be performed initially using a short- criteria state that a 70% ratio of FEV1/FVC as the cutoff for acting b2-mimetic. With the absence of detectable change, airflow obstruction may not necessarily be true in older repeat testing with an anticholinergic agent should be con- people and can result in overdiagnosis of obstructive lung sidered. The benefit of performing this second test is to disease in older patients. Severity of pulmonary function overcome the apparent decline in adrenergic response with decline in elderly people with asthma is multifactorial; age. This consequently prevents ‘‘missing’’ diagnoses of severity of clinical course, age, time before diagnosis, his- asthma when testing with a single agent alone. tory of cigarette smoking, and clinical phenotype all can In some individuals, PFT does not demonstrate revers- contribute to disease severity. Abnormal spirometry at ibility, although an improvement in pulmonary function is diagnosis of asthma in older patients is a common phe- noted when a systemic corticosteroid is administered. The nomenon, and its relationship to delay in diagnosis and explanation of this phenomenon lies mainly in the antiin- commencement of appropriate therapy is likely because of flammatory effect of systemic corticosteroids, although nonspecific presentation of symptoms and the diagnostic there is accumulating evidence that steroid therapy may difficulties highlighted above. The delay, in an elderly affect the b2-adrenergic receptor response when combined patient may represent months to years.15 A study showed with b-agonists. Long-standing airway inflammation causes that, in more than 27% of elderly patients newly diagnosed less expression of adrenergic receptors, predominantly b2in with asthma, no other respiratory diagnosis was previously origin, and consequently a reduced affinity for agonist- reached.32 In essence, patients presenting with minor symp- based therapy. Corticosteroids limit these processes by re- toms who subsequently demonstrate an obstructive pattern ducing inflammation and therefore may provide notable 46,47 on spirometry warrant further examination for asthma, lung function changes when administered. A 2-week course of oral corticosteroids should be considered before repeat spirometry to detect improvement from the above- Table 1. Elements in a Medical History Supporting a stated phenomenon and aid in making a diagnosis of Diagnosis of Asthma asthma in difficult cases. Shortness of breath Chest tightness Barriers to Performing PFTs in Older Patients Cough (usually ‘‘dry’’) There are unique problems in performing these tests in older Recurrent wheezing patients and in their interpretation (Table 2). Nocturnal symptomatology Many older patients will have difficulty performing Nocturnal worsening of disease PFTs because of an inability to perform forced expiratory Symptom triggers (cold air, exercise or allergen exposure) 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. MAY 2009–VOL. 57, NO. 5 JAGS

Table 2. Potential Barriers to Performing Effective Pul- more discriminatory in older patients. This relaxed VC monary Function Testing (PFT) in Older Adults and Main volume can be used as the denominator to determine Difficulties Clinicians Face During Interpretation of PFT whether obstructive disease is present by using FEV1 as the in Older Adults numerator determined using PFT. This overcomes problems associated with underestimation of VC using forced Potential barriers to effective PFT in older adults expiratory maneuvers, but assessing relaxed VC accurately Inability performing forced expiratory maneuvers efficiently is more time consuming and requires technical expertise Cognitive impairment (unable to follow technician instructions) to perform correctly. Lack of appreciable reversibility with beta-agonism Fatigue and comorbid medical conditions (e.g., cardiovascular, thyroid Airway Resistance disease) The measurement of airway resistance or impedance has Sensory deficits (e.g., cataracts, deafness) been proposed or examined as a measure of airway Impaired coordination (e.g., Parkinson’s disease, stroke) obstruction in older patients.52 Using impulse oscillometry Mouth or dental problems (e.g., dentures, ulceration) as a measure of resistance in a group of patients with mod- Main difficulties for clinicians in interpreting PFT in older adults erate to severe dementia, it has been shown that airway Age-related physiological changes ( # vital capacity, " residual volume, obstruction could be not only identified, but also quantified. and " functional residual capacity) Airway resistance can also be measured using constant Overpredicted ‘‘extrapolated’’ reference FEV1 and FVC values volume plethysmography, a method used to estimate tho- Standard FEV1/FVC cutoff of 70% for airflow obstruction leading to racic gas volume and airway resistance. It is performed by overdiagnosis of obstruction in older patients placing a subject into a chamber equipped to measure pres- Airway remodeling contributing to ‘‘fixed obstruction’’ easily mistaken sure, flow, or volume changes. It does not rely on maximal for COPD expiratory effort and may thus be particularly suitable for Coexistence of ‘‘overlap syndrome’’ of concurrent asthma and COPD older patients. Its value in the assessment of asthma in children has long been established,53 but no studies exam- FEV1 5 forced expiratory volume in 1 second; FVC 5 forced vital capacity; ining the feasibility of this technique in older patients have COPD 5 chronic obstructive pulmonary disease. been performed, so it is not routinely encountered in clinical practice. This represents an area for future studies although not in all hospitalized or institutionalized older to address validity and practicality of these techniques to patients. There are many potential reasons for this, includ- assess airway obstruction in older patients. ing significant comorbidity, sensory deficits, coordination impairment, mouth or dental problems, and general fa- Exhaled Nitric Oxide tigue. However, cognitive impairment is one of the Nitric oxide (NO) acts as a neurotransmitter in addition to most significant limiting factors in performing PFT.48 The having dilatatory effects on the airway and its associated prevalence of delirium, another prohibitory factor in per- vasculature.54,55 Measurement of exhaled NO (eNO) is forming PFT, varies from 10% to 24% on admission, employed to aid diagnosis and treatment of asthma in whereas delirium develops in 5% to 32% of older certain groups.56–58 People with asthma have higher eNO patients after admission.49 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 Alternative Lung Function Measures airway effects of NO support its role in the pathophysiology Peak Flow of asthma, it has been suggested that high eNO is simply a Unlike in younger patients, in whom peak flow variations marker of airway inflammation, and links between asthma, have been shown to correlate well with the diagnosis of airway inflammation, and eNO remain far from under- asthma, older age has been shown to be an independent stood.64 Consequently, routine use of eNO for the diagnosis factor for variability in longitudinal monitoring of peak and management of asthma requires standardization and flow.50 In addition, because peak flow tends to decrease agreed reference ranges, which vary as a function of age and with age, the variability in predicted values become less height.65 This, coupled with a lack of solid literature (most reliable.51 In a study of 1,223 patients with a mean age of studies involve children and young adults), precludes rou- 66 (range 43–80), peak flow variability of 9.2 5.5% was tine recommendation of its use in older people with asthma. reported in men and 8.3 4.6% in women. Peak flow variability was considered to be reliable in 87% of these ISSUES WITH TREATMENT patients, although the percentage declined with older age.51 Peak flow is not used for making a diagnosis of asthma; Treatment of Asthma in Older Patients instead, it is useful in detecting poorly controlled or wors- Main cornerstones of the treatment of asthma remain con- ening disease, although there are instances in which it is not sistent across all age groups. Therapy such as corticoste- fully reliable even in these circumstances. roids are used for ‘‘maintenance’’ and exacerbation, whereas inhaled b-agonists or anticholinergics remain the Relaxed Vital Capacity mainstay of ‘‘rescue.’’ There are certain therapeutic con- Because older patients have difficulty performing forced cerns unique to older patients that need to be addressed expiratory maneuvers during full PFT, a suitable alternative (Table 3). The most important of these are the greater test is a relaxed VC, because it will produce a higher volume probability of adverse effects in the setting of multiple than the more commonly performed FVC and thus be comorbidities and problems with effective drug delivery. JAGS MAY 2009–VOL. 57, NO. 5 DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS 905

70 Table 3. Concerns for Clinicians to Consider When Se- this rises rapidly to 5.6% after 75 and 22.0% after 80. lecting Asthma Therapy in Older Adults Thus, assessment of cognitive function is essential in older patients in whom inhaled therapy is being contemplated. Possible adverse effects The choice of delivery system in cognitively impaired pa- Effects of polypharmacy and drug interactions tients may thus seem limited, and nebulized therapy is the Patient coordination and strength logical and perhaps only choice,71 but there have been no Degree of cognitive impairment trials comparing the use of nebulizers in such patients with a Availability of caregiver to administer medications 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-2- Drug Delivery Systems agonists, anticholinergics, and corticosteroids to the lungs. After the diagnosis of reversible airflow obstruction has A further consideration in prescribing nebulizers to patients been made, an even more challenging problem is the deliv- with coexistent COPD is that they should have an air rather ery of drugs to the lungs. There are three main methods of than oxygen cylinder driving the nebulizer unless specific dispersing medication into an aerosol for inhalation: pres- blood gas analysis has been performed indicating a benefit surized metered dose inhaler (MDI), dry powder inhaler from continuous oxygen therapy. In addition, there is a lack (DPI), or a nebulizer (Table 4). Manually actuated pressur- of evidence showing that nebulizers are better than MDIs in ized MDIs require good coordination and psychomotor asthma, particularly when used in combination with a spacer skills to ensure that actuation, inhalation, and breath hold- and the doses given are in excess of those normally admin- ing occur in precise sequence.66 It is generally accepted that istered by MDI. Further studies are warranted in this area. a pressurized MDI without a spacer is not a suitable choice The only device that has been shown to give a signifi- for many physically or cognitively impaired older cant benefit to older patients and patients with poor inhaler adults.67,68 Breath-actuated MDIs reduce the need to coor- technique is the Autohaler,71,72 but this device is spring dinate actuation and inhalation precisely and so make these loaded, and although patients inhale well, they have diffi- devices easier for elderly people. Extension devices used culty activating it. There are other devices available, par- with pressurized MDIs require good coordination, but ticularly DPIs, with which no activation other than the holding chambers reduce the need for coordination between ability to inhale is required to release the drug, but many MDI actuation and inhalation and are generally easier for patients complain that they cannot tell whether they are older, frailer patients.67 DPIs do not require propellants, receiving the drug or not. As with any drug treatment in and there is evidence that patients unable to use an MDI older patients, because of the inherent increase in suscep- alone find it easier to use a DPI, because it avoids the prob- tibility to adverse drug reactions, choices and doses of drugs lems of coordination of actuation and inspiration.68 Incor- should be carefully considered when prescribing. Individ- rect drug use remains a significant concern in elderly people ualized patient assessment drives appropriate prescribing in with asthma, particularly with inhaled preparations. older people with asthma. A number of factors complicate successful treatment of reversible airway obstruction in older patients. One study Efficacy of Classes of Medication showed that age is a factor in predicting ability to use a MDI correctly, with patients younger than 65 doing significantly b2-Agonists Versus Anticholinergic Agents better than older patients.69 This study also demonstrated The efficacy of b2-agonists in older patients with stable that the force required to activate many MDIs exceeded COPD73 and asthma is well established, although there that of a significant number of older patients, although age have been studies suggesting that responsiveness declines and strength are much less important predictors of good with age.43,74 In addition, the return of baseline FEV1 after inhaler technique than cognitive function. It has been dem- methacholine challenge and subsequent b-agonist adminis- onstrated that cognitive function is the best predictor of tration is more impaired in older patients than in younger ability to use a MDI in people aged 75 and older.68 The patients.74,75 Common side effects of nebulized b-agonists prevalence of dementia before the age of 75 is 2.9%, but 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 Table 4. Available Inhalation Drug Delivery Methods for many patients with chronic lung disease are smokers. The the Treatment of Older People with Asthma incidence of silent ischemia or asymptomatic ischemic heart MDI DPI Nebulizer disease also increases with age. The incidence of dysrhyth- mias after the administration of nebulized b2-agonists is Require good coordination Do not require Best choice for the well recognized and reported to be as high as 65%. The risk and psychomotor function propellent cognitively impaired of serious dysrhythmia is greater in patients who have had a With spacer, is better for Suitable for people Lack evidence for previous myocardial infarction.76 b2-agonists cause a net physically or cognitively unable to use MDI superiority over MDI influx of intravascular potassium into cells with subsequent impaired older adults and dry powder inhaler hypokalemia, a recognized complication of nebulized Breath-actuated devices drug.77,78 Older patients taking diuretics or insulin or with easiest for older frailer patients poor nutritional intake also have a greater incidence of hypokalemia and are thus at greater risk of developing this MDI 5 metered dose inhaler; DPI 5 dry powder inhaler. common electrolyte disturbance. In addition, the combina- 906 CHOTIRMALL ET AL. MAY 2009–VOL. 57, NO. 5 JAGS tion of theophylline with b2-agonists has been reported to agonists. Anticholinergics are ideal alternative ‘‘rescue’’ increase myocardial damage in animal studies.79 It has been agents for asthma and should never be used as ‘‘mainte- shown that patients taking oral theophylline at therapeutic nance’’ therapy, similar to b2-agonists. In addition, their levels are at greater risk of the hypokalemic effects of ne- bronchodilating capabilities are less than those observed bulized b2-agonists than those not receiving theophylline with b2-agonists, such that their use is more predominant in therapy in addition to receiving b2-agonists.80 The effects the management of COPD than asthma. of b2-agonists on cardiovascular mortality were initially disputed. Greater mortality has been found,81,82 whereas Oral and Inhaled Corticosteroids more recently the TORCH trial convincingly showed no The assessment of reversible airway obstruction is essential such increase.83 The partial pressure of oxygen in the before the administration of inhaled corticosteroids. The gas driving the nebulizer may also be an important factor use of long-term glucocorticoid therapy has been instru- responsible for greater asthma mortality.84 It has been mental in decreasing morbidity and mortality in asthma, demonstrated a proportion of patients with asthma and and the emerging use of steroids is indicated in all age COPD who were hypercapnic before nebulized salbutamol groups.91 Osteoporosis is common in older patients, affect- developed further rises in carbon dioxide when oxygen was ing up to 40% of women aged 70 and older. Prevalence driving the nebulizer.85 Overall, short-acting b2-agonists studies examining the association between asthma or remain the mainstay of ‘‘rescue’’ treatment in elderly people COPD and osteoporosis have shown that oral steroid us- with asthma (Table 5), although anticholinergic agents are age is associated with up to a 56% vertebral fracture rate, useful alternatives, particularly in cases of partial relaxant with an incidence of up to 42%.92 effects or adverse effects of b2 administration. Clinicians Inhaled glucocorticoids are absorbed into the systemic should limit their prescription of short-acting b2-agonists to circulation, but the extent to which they have adverse that for ‘‘rescue’’ therapy and advise that any patient using effects on bone metabolism is uncertain. Studies assessing them more than twice weekly return to the clinic for re- the effects of inhaled corticosteroids on bone have shown evaluation of asthma control. Use of b2-agonists with any conflicting results. No evidence that inhaled corticosteroid regularity indicates suboptimal asthma control, undertreat- use increases fractures is available. Their use causes de- ment, or worsening disease and should prompt immediate creases in bone mineral density,93,94 although it remains reassessment. unclear whether this translates to a greater fracture rate. It The bronchodilator response to anticholinergics, un- may be that only at higher doses (42,000 mg/day) that in- like b2-agonists, is less age dependent.74,75 The efficacy of haled corticosteroids affect fracture occurrence,95 although inhaled anticholinergics in COPD and stable asthma in like that of oral glucocorticoid administration, the effects older patients, along with their relative lack of side effects, on bone roughly correlate with daily dose, duration, and would suggest that their use should always be considered total cumulative lifetime dose.96 The usual route of admin- when the use of a nebulizer is contemplated. The inhaled istration is MDI or DPI. anticholinergics generally have good safety profiles, al- Notwithstanding anxieties associated with inhaled cor- though they have been shown in older patients to occa- ticosteroids, their considerable role in controlling asthma sionally produce sedative effects86 and functional cognitive should not be undervalued. Recent work from The impairment.87 Because of their somewhat indiscriminate Epidemiology and Natural History of Asthma: Outcomes and often inappropriate use in the treatment of all forms and Treatment Regimes study group97 has shown that high of airway obstruction, particularly in acute asthma, and doses of inhaled corticosteroids significantly benefit older their cost, contraindications for their use were often un- people with asthma and subsequently improve disease out- founded. Two such contraindications specifically directed come. On average, only one-third of people with asthma are toward older patients are the exacerbation of glaucoma and prescribed aerosolized steroids.98 A related study showed the effects on urinary flow in men. Patients with normal- that in up to four of every 10 people with late-onset asthma angle glaucoma, when administered up to four times the admitted to hospital after an exacerbation, inhaled steroids dose recommended for the treatment of airway obstruction, were excluded in their management.99 With respect to have no significant difference in their intraocular pressure, available evidence supporting their use in older people with pupil diameter, or accommodation from patients with nor- asthma,97 the clinician should initiate such therapy at the mal intraocular pressures.88 Prolonged pupillary dilatation earliest opportunity, although monitoring for side effects can occur if the drug is sprayed directly into the eye; thus, if and subsequent morbidity should be heightened because of the drug is to be administered using a nebulizer, care should the greater risk. It is imperative that the clinician weigh the be taken to make sure the facemask creates a good seal risks and benefits of their use in individual patients. Poten- around the face, or an alternative such as a T piece should tial metabolic effects of these medications on bone mineral be used. There is less evidence that inhaled anticholinergics density should always be kept in mind. have any effect on urinary flow in men aged 50 to 70,89 As described earlier, nebulized medications may be although there are no long-term data on the use of nebuli- more efficiently delivered to elderly patients with asthma, zed anticholinergics. Greater adherence has been shown although there remains a paucity of evidence for the use of with tiotropium than any other form of inhaled therapy, nebulized rather than inhaled steroids in older patients with particularly for the treatment of COPD.90 It is imperative reversible airflow limitation. This, combined with the large that clinicians be aware that, although anticholinergic ther- doses used and their potential for significant exacerbation apy is a viable treatment alternative in the management of of already-present osteopenia or osteoporosis, means that asthma in older patients, its use should be restricted to their use should be reserved for individuals whose need for people who show no improvement or are intolerant of b2- therapy outweighs the potential for future adverse meta- JAGS MAY 2009–VOL. 57, NO. 5 DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS 907 bolic effects, although the co-prescription of bisphosphon- Table 5. Forms of b2-Adrenergic Receptor Agonist Ther- ates and recombinant parathyroid hormone (teriparatide) apy Available for the Treatment of Asthma may prevent glucocorticoid-dependent bone loss in such patients.100,101 Nevertheless, the use of bisphosphonates in Short Acting Long Acting Ultra-Long Acting preventing bone loss or affecting fracture rates in this context has not been clearly established.102,103 Despite this, Salbutamol/levosalbutamol Salmeterol Indacaterol (limited availability) there is a potentially small number of patients who would be appropriately managed with high-dose nebulized ste- Terbutaline Formoterol roids rather than receiving nebulized b2-agonists and anti- Pirbuterol Bambuterol cholinergics. Metaproterenol

Anti-IgE Therapy Demonstration of reversibility with adrenergic and Omalizumab, a recombinant DNA-derived humanized cholinergic therapy should be performed in older patients. IgG1k monoclonal antibody selectively binding to human Additionally, the concept of airway ‘‘remodeling’’ must be IgE, is used in allergy-related asthma. Delivered subcuta- appreciated in the interpretation of PFT when deciding be- neously every 2 to 4 weeks, its use in older people with tween a diagnosis of COPD, asthma, and an overlap syn- asthma has been recently evaluated in a pooled analysis that drome. DLCO may help distinguish between asthma and showed significant benefit in this age group for suitably se- COPD, as does the presence of atopy. lected patients.104 Side effects of therapy must always be In the acute clinical setting, an older adult with sus- considered, including reduced defences against parasitic in- pected new diagnosis of asthma presenting with shortness fection and adrenal insufficiency. of breath or wheezing not responding to b2-agonist therapy may be considered b-agonist ‘‘resistant’’ because of altered CONCLUSION receptor function. A trial of anticholinergic treatment The diagnosis of asthma is based mainly on history but is should be instituted first to overcome any age-related strengthened by the demonstration of airway reversibility receptor response changes before consideration of alterna- (Figure 1). Given a decline in VC with age, this can be tive diagnoses such as heart failure, chronic aspiration syn- difficult. An understanding of age-related changes in lung dromes, or pulmonary embolic disease. function is required so as not to miss some patients with The treatment of reversible airflow obstruction should treatable airway obstruction. In addition, with a tendency include the assessment of inhaler technique and cognitive for air trapping in expiration due to less elastic recoil function. Nebulizer treatment should be reserved for associated with age, some patients may be incorrectly di- patients who remain symptomatic despite conventional agnosed with airway obstruction. Alternative methods such MDIs, DPIs, or spacer devices. as relaxed VC may be more appropriate than forced ma- The use of nebulizers in the treatment of older patients neuvers in 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 Recommended Dosage Main Side Effect(s)

b-agonist 50 mgor12 mg formoterol Palpitations, tachycardia salmeterol twice daily Anticholinergic 40 mg ipratropium Minimal (possible dry mouth, urinary disorders) Corticosteroid (Inhaled) 168–840 mg (low to Decreased bone mineral medium dose) density 4840 mg (high dose) (Oral) 30–40 mg prednisolone Figure 1. Flowchart summarizing diagnosis and management of (quick taper) asthma in elderly people. PFT 5 pulmonary function testing. 908 CHOTIRMALL ET AL. MAY 2009–VOL. 57, NO. 5 JAGS be considered for nebulized anticholinergics, because aging 23. Enright PL, Kronmal RA, Manolio TA et al. Respiratory muscle strength in is less associated with responsiveness to anticholinergics the elderly correlates and reference values. Am J Respir Crit Care Med than b2-agonists. There is generalized underusage of in- 1994;149:430–438. 24. Chakir J, Shannon J, Molet S et al. Airway remodeling-associated mediators haled corticosteroids in elderly people, but the use of ne- in moderate to severe asthma: Effect of steroids on TGF-beta, IL-11, IL-17, bulized steroids in older patients is poorly researched. Their and type I and type III collagen expression. J Allergy Clin Immunol associated potential side effects mean that their use should 2003;111:1293–1298. be reserved for patients demonstrating a specific need for 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 such treatment. 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. ACKNOWLEDGMENTS J Allergy Clin Immunol 1996;98(Suppl):S3–S6. Conflicts of Interest: The authors have no conflicts of 27. Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J interest to disclose with respect to the manuscript. Respir Crit Care Med 2001;164(Suppl):S28–S38. Author Contributions: All authors participated in the 28. Conolly MJ. Age-related changes in the respiratory system. In: Tallis RC, Fillit HM, eds. Brocklehurst’s Textbook of Geriatric Medicine and Geron- concept and structure of the paper. Chotirmall SH, Watts tology. New York: Churchill Livingstone, 2003, pp 489–493. M, Donegan CF, Moore A, and McElvaney NG: manuscript 29. Cassino C, Berger KI, Goldring RM et al. Duration of asthma and physiologic preparation. Chotirmall SH and McElvaney NG: manu- outcomes in elderly nonsmokers. Am J Respir Crit Care Med 2000;162: script revision. 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 REFERENCES J Med 2002;112:446–452. 31. Ten Hacken NH, Postma DS, Timens W. Airway remodeling and long-term 1. Renwick DS, Connolly MJ. Improving outcomes in elderly patients with decline in lung function in asthma. Curr Opin Pulm Med 2003;9:9–14. asthma. Drugs Ageing 1999;14:1–9. 32. Bellia V, Battaglia S, Catalano F et al. Aging and disability affect misdiagnosis 2. Weiss KB. An overview of recent trends in asthma epidemiology. Eur Respir of COPD in elderly asthmatics: The SARA study. Chest 2003;123:1066– Rev 1996;35:101–104. 1072. 3. Tirimanna PR, Van Schayck CP, Den Otterr JJ et al. Prevalence of asthma and 33. Soriano JB, Davis KJ, Coleman B et al. The proportional Venn diagram of COPD in general practice in 1992: Has it changed since 1977? Br J Gen Pract obstructive lung disease: Two approximations from the United States and the 1996;46:277–281. United Kingdom. Chest 2003;124:474–481. 4. Office of Population and Census Studies. London: HMSO, 1991. 34. Fabbri L, Romagnoli M, Corbetta L et al. Differences in airway inflammation 5. Connolly MJ. Asthma and chronic obstructive pulmonary disease. In: Tallis in patients with fixed airflow obstruction due to asthma or chronic obstruc- RC, Fillit HM, eds. Brocklehurst’s Textbook of Geriatric Medicine and Ger- tive pulmonary disease. Am J Respir Crit Care Med 2003;167:418–424. ontology. New York: Churchill Livingstone, 2003, pp 489–493. 35. Milne JS, Williamson J. Respiratory function tests in older people. Clin Sci 6. Sly RM. Changing asthma mortality. Ann Allergy 1994;73:259–268. 1972;42:371–381. 7. Braman SS. Drug treatment of asthma in the elderly. Drugs 1996;3:415–423. 36. Fowler RW, Puck RA, Hertzel MR. Maximal expiratory flow-volume curves 8. Krumpe PE, Knudson RJ, Parsons G et al. The ageing respiratory system. Clin in Londoners aged 60 yrs and over. Thorax 1987;42:173–182. Geriat Med 1985;1:143–175. 37. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly: A comparison 9. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly: A comparison between patients with recently acquired and long-standing disease. Am Rev between patients with recently acquired and long standing disease. Am Rev Respir Dis 1991;143:336–340. Respir Dis 1991;143:336–340. 38. Brand PLP, Quanjer PH, Postma DS et al. Interpretation of bronchodilator 10. Burrows B, Barbee RA, Cline MG et al. Characteristics of asthma among response in patients with obstructive airways disease. Thorax 1992;47:429– elderly adults in a sample of the general population. Chest 1991;100:935– 436. 942. 39. Dompeling E, van Schayck CP, Molema J et al. A comparison of six different 11. Miranda C, Busacker A, Balzar S et al. Distinguishing severe asthma phe- ways of expressing the bronchodilating response in asthma and COPD: Re- notypes: Role of age at onset and eosinophilic inflammation. J Allergy Clin producibility and dependence of prebronchodilator FEV1. Eur Respir J Immunol 2004;113:101–108. 1992;5:975–981. 12. Dow L, Coggon D, Campbell MJ et al. The interaction between immuno- 40. Meslier N, Racineux JL, Six P et al. Diagnostic value of reversibility of globulin E and smoking in airflow obstruction in the elderly. Am Rev Respir chronic airway obstruction to separate asthma from chronic bronchitis: Dis 1992;146:402–407. 13. Burrows B, Halonen M, Barbee RA et al. The relationship of serum immuno- A statistical approach. Eur Respir J 1989;2:497–505. globulin E to cigarette smoking. Am Rev Respir Dis 1981;124:523–525. 41. Dales RE, Spitzer WO, Tousignant P et al. Clinical interpretation of airway 14. Barbee RA, Lebowitz MD, Thompson HC et al. Immediate skin-test reac- response to a bronchodilator. Am Rev Respir Dis 1986;138:317–320. tivity in a general population sample. Ann Intern Med 1976;84:129–133. 42. American Thoracic Society. Lung function testing: Selection of reference val- 15. Burrows B, Lebowitz MD, Barbee RA et al. Findings before diagnoses of ues and interpretative strategies. Am Rev Respir Dis 1991;144:1202–1218. asthma among the elderly in a longitudinal study of a general population 43. Connolly MJ, Crowley JJ, Nielson CP et al. Peripheral mononuclear leuko- sample. J Allergy Clin Immunol 1991;88:870–877. cyte b adrenoceptors and non-specific bronchial responsiveness to metacho- 16. Parameswaran K, Hildreth AJ, Taylor IK et al. Predictors of asthma severity line in young and elderly normal subjects and asthmatic patients. Thorax in the elderly: Results of a community survey in northeast England. J Asthma 1994;49:26–32. 1999;36:613–618. 44. Davis PB, Bvard PJ. Relationships among airway reactivity, papillary alpha- 17. Litonjua AA, Sparrow D, Weiss ST et al. Sensitization to cat allergen is as- adrenergic and cholinergic responses and age. J Appl Physiol 1988;65:200–204. sociated with asthma in older men and predicts new-onset airway hyperre- 45. Van Schayck C, Folgering H, Harbers H et al. Effects of allergy and age on sponsiveness. The Normative Aging Study. Am J Respir Crit Care Med responses to salbutamol and ipratropium bromide in moderate asthma and 1997;156:23–27. chronic bronchitis. Thorax 1991;46:355–359. 18. Kay AB. Pathology of mild, severe and fatal asthma. Am J Respir Crit Care 46. Koto H, Mak JC, Haddad EB et al. Mechanisms of impaired beta-adeno- Med 1996;154:S66–S69. receptor-induced airway relaxation by interleukin-1b in vivo in the rat. J Clin 19. Bauer BA, Reed CE, Yunginger JW et al. Incidence and outcomes of asthma in Invest 1996;98:1780–1789. the elderly: A population-based study in Rochester, Minnesota. Chest 47. Brodde OE, Howe U, Egeszegi S et al. Effect of prednisolone and ketotifen on 1997;111:303–310. b2 adrenoreceptors in asthmatic patients receiving b2-bronchodilatators. Eur 20. Crapo RO. The ageing lung. In: Mahler DA, ed. Pulmonary Disease in the J Clin Pharmacol 1988;34:145–150. Elderly Patient, Vol. 63. New York: Marcel Dekker, 1993, pp 1–21. 48. Dow L, Coggon D, Osmond C et al. A population survey of respiratory 21. Edge J, Millard F, Reid L. The radiograph appearance of the chest in persons symptoms in the elderly. Eur Respir J 1991;4:267–272. of advanced age. Br J Radiol 1984;37:769–774. 49. Manning H, Mahler D, Harvery A. Dyspnoea in the elderly. In: Mahler D, ed. 22. Polkey MI, Harris ML, Hughes PD et al. The contractile properties of the Pulmonary Disease in the Elderly Patient, Vol. 63. New York: Marcel Dekker, elderly human diaphragm. Am J Respir Crit Care Med 1997;155:1560–1564. 1993, pp 81–111. JAGS MAY 2009–VOL. 57, NO. 5 DIAGNOSIS AND MANAGEMENT OF ASTHMA IN OLDER ADULTS 909

50. DuWayne Schmidt C, Dickman ML, Gardner RM et al. Spirometric stan- 79. Joseph X, Whitehurst VE, Bloom S et al. Enhancement of cardiac effects of dards for healthy elderly men and women: 532 subjects, ages 55 through 94 beta-adrenergic bronchodilators by aminophylline in experimental animals. years. Am Rev Respir Dis 1973;108:933–939. Fundam Appl Toxicol 1981;1:443–447. 51. Enright P, Burchette R, Peters J et al. Peak flow lability: Association with 80. Lai CKW, Legge JS, Friend JAR. Air-driven nebulised high-dose salbutamol in asthma and spirometry in an older cohort. Chest 1997;42:371–381. severe chronic obstructive airways disease: Is it safe? Respiration 52. Carvalhales-Neto N, Lorino H, Gallinari C et al. Cognitive assessment of lung 1991;18:641–644. function in the elderly. Am J Respir Crit Care Med 1995;152:1611–1615. 81. Au DH, Curtis JR, Every NR et al. Association between inhaled beta-agonists 53. Leben M, Von Der Hardt H. Airway resistance, airway conductance, specific and the risk of unstable angina and myocardial infarction. Chest airway resistance, and specific airway conductance in children. Pediatr Res 2002;121:846–851. 1983;17:508–513. 82. Au DH, Lemaitre RN, Curtis JR et al. The risk of myocardial infarction 54. Blitzer ML, Loh E, Roddy MA et al. Endothelium-derived nitric oxide reg- associated with inhaled beta-adrenoceptor agonists. Am J Respir Crit Care ulates systemic and pulmonary vascular resistance during acute hypoxia in Med 2000;161(3 Pt 1):827–830. humans. J Am Coll Cardiol 1996;28:591–596. 83. Calverley PM, Anderson JA, Celli B et al. Salmeterol and fluticasone pro- 55. Belvisi MG, Stretton CD, Yacoub M et al. Nitric oxide is the endogenous pionate and survival in chronic obstructive pulmonary disease. N Engl J Med neurotransmitter of bronchodilator nerves in humans. Eur J Pharmacol 2007;356:775–789. 1992;210:221–222. 84. Sears MR, Rea HH, Fenwick J et al. Seventy-five deaths in asthmatics pre- 56. Berkman N, Avital A, Breuer R et al. Exhaled nitric oxide in the diagnosis of scribed home nebulisers. BMJ 1987;294:477–480. asthma: Comparison with bronchial provocation tests. Thorax 2005;60:383. 85. Gunawardena KA, Patel B, Campbell IA et al. Oxygen as a driving gas for 57. Pijnenburg MW, Hofhuis W, Hop WC et al. Exhaled nitric oxide predicts asthma nebulisers: Safe or dangerous? BMJ 1984;288:272–274. relapse in children with clinical asthma remission. Thorax 2005;60:215. 86. Feinberg M. The problems of anticholinergic adverse effects in older patients. 58. Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma Drugs Aging 1993;3:335–348. control: A longitudinal study in unselected patients. Eur Respir J 2008; 87. Ancelin ML, Artero S, Portet F et al. Non-degenerative mild cognitive im- 31:539. pairment in elderly people and use of anticholinergic drugs: Longitudinal 59. Massaro AF, Gaston B, Kita D et al. Expired nitric oxide levels during treat- cohort study. BMJ 2006;332:455–459. ment of acute asthma. Am J Respir Crit Care Med 1995;152:800. 88. Kalra L, Bone M. The effect of nebulised bronchodilator therapy on intra- 60. Jones SL, Kittelson J, Cowan JO et al. The predictive value of exhaled nitric ocular pressure in glaucoma. Chest 1988;93:739–741. oxide measurements in assessing changes in asthma control. Am J Respir Crit 89. Molkenboer JFWM, Lardenoye JG. The effect of Atrovent on micturition Care Med 2001;164:738. function, double blind cross over study. Scand J Respir Dis 1979;103 61. Smith AD, Cowan JO, Filsell S et al. Diagnosing asthma: Comparisons be- (suppl):154–158. 90. Cramer JA, Bradley-Kennedy C, Scalera A. Treatment persistence and com- tween exhaled nitric oxide measurements and conventional tests. Am J Respir pliance with medications for chronic obstructive pulmonary disease. Can Crit Care Med 2004;169:473. Respir J 2007;14:25–29. 62. Pijnenburg MW, Bakker EM, Hop WC et al. Titrating steroids on exhaled 91. Goldstein MF, Fallon JJ, Harning R. Chronic glucocorticoid therapy induced nitric oxide in children with asthma: A randomized controlled trial. Am osteoporosis on patients with obstructive lung disease. Chest J Respir Crit Care Med 2005;172:831. 1999;116:1733–1749. 63. Smith AD, Cowan JO, Brassett KP et al. Use of exhaled nitric oxide mea- 92. Smith BJ, Phillips PJ, Heller RF. Asthma and chronic obstructive airway dis- surements to guide treatment in chronic asthma. N Engl J Med 2005; ease are associated with osteoporosis and fractures. Respirology 1999;4: 352:2163. 101–109. 64. Franklin PJ, Stick SM, Le Souef PN et al. Measuring exhaled nitric oxide 93. Ip M, Lam K, Yam L et al. Decreased bone mineral density in premenopausal levels in adults: The importance of atopy and airway responsiveness. Chest asthma patients receiving long-term inhaled steroids. Chest 1994;105:1722– 2004;126:1540. 1727. 65. Smith AD, Taylor DR. Is exhaled nitric oxide measurement a useful clinical 94. Israel E, Banerjee TR, Fitzmaurice GM et al. Effects of inhaled glucocor- test in asthma? Curr Opin Allergy Clin Immunol 2005;5:49. ticoids on bone density in premenopausal women. N Engl J Med 2001; 66. Drug and Therapeutics Bulletin, Vol 38 No 2, February 2000 [on-line]. Available 345:941–947. at http://dtb.bmj.com/content/vol38/issue2/index.dtl Accessed May 26, 2008. 95. Suissa S, Ernst P. Inhaled corticosteroids and fracture risk in COPD. Am 67. Hendry A, Coote J, Black H et al. Comparison of conventional metered dose J Respir Crit Care Med 2004;170:94. inhaler and breath actuated inhaler in elderly patients. Int J Pharm Pract 96. Wong CA, Walsh LJ, Smith CJ et al. Inhaled corticosteroid use and 1995;3:115–118. bone mineral density in patients with asthma. Lancet 2000;355:1399– 68. Allen SC. Competence thresholds for use of inhalers in people with dementia. 1403. Age Ageing 1997;26:83–86. 97. Slavin RG, Haselkorn T, Lee JH et al. Asthma in older adults: Observations 69. Hindle M, Newton DAG, Chrystyn H. Dry powder inhalers are bioequiv- from the epidemiology and natural history of asthma: outcomes and treat- alent to metered-dose inhalers. A study using a new urinary salbutamol assay ment regimens (TENOR) study. Ann Allergy Asthma Immunol 2006;96: technique. Chest 1995;107:629–633. 406–414. 70. Armitage JM. Inhaler technique in the elderly. Age Ageing 1988;17:275–278. 98. Enright PL, Mc Clelland RL, Newman AB et al. Underdiagnosis and under 71. Diggory P, Bailey R, Vallon A. Effectiveness of inhaled bronchodilator treatment of asthma in the elderly. Chest 1999;116:603–613. delivery systems for elderly patients. Age Ageing 1991;20:379–382. 99. Sin DD, Tu JV. Underuse of inhaled steroid therapy in elderly patients with 72. Newman SP, Weiz AWB, Talace N et al. Improvement of drug delivery with a asthma. Chest 2001;119:720–725. breath-activated pressurised aerosol for patients with poor inhaler technique. 100. Saag KG, Shane E, Boonen S et al. Teriparatide or alendronate Thorax 1991;46:712–716. in glucocorticoid-induced osteoporosis. N Engl J Med 2007;357:2028– 73. Geraghty R, Foster C, Black D et al. Bronchodilator response to nebulised 2039. salbutamol in elderly patients with stable chronic airflow limitation. Respir 101. Herrala J, Puolijoki H, Lippo K et al. Clodronate is effective in preventing Med 1993;87:375–378. corticosteroid induced bone loss among asthmatic patients. Bone 1998;22: 74. Ullah MI, Newman GB, Saunders KB. Influence of ageing on response to 577–582. ipratropium and salbutamol in asthma. Thorax 1981;36:523–529. 102. Campbell IA, Douglas JG, Francis RM et al. Research Committee of the 75. Connolly MJ, Crowley JJ, Charan N et al. Impaired bronchodilator response British Thoracic Society. Five year study of etidronate and/or calcium as to albuterol in healthy elderly men and women. Chest 1995;108:401–406. prevention and treatment for osteoporosis and fractures in patients with 76. Brashear RE. Arrhythmias in patients with chronic obstructive pulmonary asthma receiving long term oral and/or inhaled glucocorticoids. Thorax disease. Med Clin North Am 1984;68:969–981. 2004;59:761–768. 77. Lim R, Walshaw MJ, Saltissi S et al. Cardiac arrhythmias during acute ex- 103. Kasayama S, Fujita M, Goya K et al. Effects of alendronate on bone acerbations of chronic airflow limitation: Effect of fall in plasma potassium mineral density and bone metabolic markers in postmenopausal concentration induced by nebulised aˆ agonist therapy. Postgrad Med J asthmatic women treated with inhaled corticosteroids. Metabolism 2005; 1989;65:449–452. 54:85–90. 78. Smith SR, Ryder C, Kendall MJ et al. Cardiovascular and biochemical re- 104. Maykut RJ, Kianifard F, Geba GP. Response of older patients with IgE- sponses to nebulised salbutamol in normal subjects. Br J Clin Pharmacol mediated asthma to omalizumab: A pooled analysis. J Asthma 2008;45: 1984;18:641–644. 173–181.