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DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
TREATMENT OF ASTHMA AND ALLERGIC DISEASE IN THE ELDERLY
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DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY Molly Lee Osborne, MD, PhD
Bronchial asthma in the elderly is receiving increasing attention for several reasons. First, the elderly population is increasing. Although we have increased the maximum age by only 1 month in the last few decades, we have increased the average maximum age to 75 years. Projections suggest that the number of Americans more than 65 years of age will increase from 30 million to 50 million over the next 30 years.I9 Second, the elderly continue to consume about one third of the total health care resources available, primarily in the area of cardiopulmonary disease. Third, chronic airflow obstruction is very common and will likely increase in the next few decades as a consequence of longer exposure to tobacco smoke and other environmental indoor and outdoor pollutants, as well as to inhaled antigens. This article addresses the differential diagnosis of bronchial asthma in the elderly. First, a definition of asthma is given and the epidemiology and natural history are discussed, emphasizing the underdiagnosis of asthma in the elderly. Next, the differential diagnosis of asthma in the elderly is discussed, contrasting it with similar conditions such as chronic obstructive pulmonary disease (COPD), cardiac disease, upper airflow obstruction, gastroesophageal reflux, and bronchogenic carcinoma. Chronic airflow obstruction includes asthma as well as COPD, and COPD includes both chronic bronchitis and emphysema. Finally, the interactions of aging, asthma, and coexisting diseases are discussed,
From the Veterans Affairs Medical Center, Portland, Oregon
IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA
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VOLUME 17 NUMBER 4 NOVEMBER 1997
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pointing out how normal aging-associated changes in lung structure may exaggerate asthma symptoms. Key points from the National Asthma Education and Prevention Program (NAEPI’) working group report are as follows: Asthma in all ages is a lung disease characterized by the following aspects: (1) airflow obstruction that is reversibIe (but not completely so in some patients), either spontaneously or with treatment; (2) airway inflammation; and (3) increased airway responsiveness to a variety of stimuli. Incomplete reversibility becomes increasingly common among elderly patients, however, especially when asthma is longstanding or severe; the lack of reversibility probably results from smooth muscle hypertrophy and fibrosis. Available data and clinical observations suggest that asthma does occur frequently among the elderly. Normal changes in the lung that occur with aging may interact with asthma-related pathophysiologic events. Irreversible airflow obstruction is more likely to develop if asthma is severe and longstanding. Events that trigger acute exacerbations of asthma are the same for all ages, but sensitivity to inhaled allergens is less prevalent in elderly patients, especially if the asthma is of recent onset. DEFINITION, EPIDEMIOLOGY, AND NATURAL HISTORY OF ASTHMA IN THE ELDERLY Definition
Asthma is a lung disease generally characterized by airway obstruction that is reversible, airway inflammation, and increased airway responsiveness to a variety of stimuli.23This definition is very useful in young adults, but may be problematic in the elderly. For example, asthma, chronic bronchitis, or emphysema may present with symptoms of chest tightness, wheezing, dyspnea, or cough, despite the markedly zy different pathophysiologies and natural histories of these Still, at least some degree of reversibility of airflow obstruction is defined as asthma, even though it may be seen in conjunction with any one of these disorders; airway hyperresponsiveness as measured in the laboratory setting is characteristic of asthma. Epidemiology
The prevalence of asthma is relatively high, about 5% to 7% in the United States, and is on the rise.I2 Although the exact prevalence is difficult to determine in the elderly, studies from Tecumseh, Michigan and Tucson, Arizona suggest a prevalence of 7% to 9”/0in patients more than 70 years of age. These data suggest that asthma is more prevalent
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in the elderly than in a younger population. Because it may be difficult to distinguish between asthma and COPD, the term asthmatic bronchitis has been used for patients with characteristics of both asthma and COPD.3 Perhaps a better term is mixed disease, referring to the presence of both a reduced forced expiratory volume in 1 second (FEV,) (fixed disease) and a response to an inhaled bronchodilator (reversible disease). Newly diagnosed asthma is also common in the elderly. Up to 40% of patients with asthma are at least 40 years of age when they suffer their first attack. In fact, although many asthmatics are diagnosed before 40 years of age, an equal number have their first episode after 70 years of age.27Health care providers, however, are often unaware that asthma can first present in the elderly. Indeed, asthma frequently goes unrecognized. Enright et all1demonstrated that chronic airways obstruction (CAO) is very common in patients more than 65 years of age in the United States. In their study of 5201 patients, symptoms, medication use, and lung function were assessed. Undiagnosed airways obstruction was defined as airflow limitation demonstrated by spirometric methods in participants who did not have a physician diagnosis of obstructive lung disease (asthma, chronic bronchitis, or emphysema). Undiagnosed airways obstruction was twice as likely in women and in patients with lower income, and was associated with current and former smoking, and chronic cough. A second study described in a recent article by Renwick and ConnollyZ6demonstrated that although CAO is very common in adults more than 45 years of age in the United Kingdom, it is frequently overlooked. In the postal questionnaire survey of 783 men and women (92% response rate), respiratory symptoms and smoking history were ascertained. Almost 30% were current smokers and 37% were ex-smokers. About 76% of the subjects had CAO symptoms, and 55% had features suggesting improvement with treatment (increased nonspecific bronchial responsiveness or significant bronchodilator reversibility).Spirometric evidence of airways obstruction was demonstrated in 26% of 247 participants clinically evaluated for evidence of airways obstruction. Only 55% of subjects with demonstrated CAO had received a diagnosis of airways obstruction of any kind, and only 37% were using inhaled bronchodilators or steroids. The reasons for this underdiagnosis are not fully known. Patients may self-limit their regular activities without realizing it to minimize symptoms. Patients may not recognize breathlessness, cough, or wheezing as evidence of treatable airflow obstruction, thinking that these symptoms may be consequences of aging. It is also possible that elderly subjects actually have reduced perceptions of bronchoconstriction.3 Natural History The natural history of asthma is variable. Some patients have asthma throughout life. Others deny symptoms until quite late in life,
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although recall bias cannot be excluded in these patients. Still others may have symptoms misclassified as chronic bronchitis. The rate of decline of pulmonary function in elderly patients with asthma is controversial. Some studies demonstrate worsening of airflow obstruction over time,25whereas others do not.6 The long-term survival of patients with asthma alone does not appear to be significantly different from expected survival over a broad age range. In a recent study, however, patients 35 years of age or older who had asthma associated with COPD had worse than expected survival, in contrast to asthmatics without COPD (Fig. 1).28 This survival rate may partially reflect the presence of fixed airflow obstruction. In fact, one interesting interpretation of these findings is that patients with fixed airflow obstruction may have worse than expected survival. For example, results from the Normative Aging Study33demonstrate that FEV, and peripheral blood leukocyte count are predictors of mortality. EVALUATION OF ASTHMA IN THE ELDERLY
Symptoms
The intermittent symptoms of cough, dyspnea, wheezing, and chest tightness are classic for asthma. In the elderly with asthma, symptoms are similar. Cough is virtually universal, and almost half the patients 100
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Asthma only .. . . Observed - Expected Asthma and another lung disease -Observed
- Expected 5
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Years after Onset Figure 1. Kaplan-Meier curves of observed and expected survival for 2406 residents of Rochester, Minnesota, with asthma alone (mean age at onset 13 years) and 93 residents with asthma and another lung disease (mean age atmset of asthma, 52 years). Expected survival was calculated from Olmsted County mortality rates. Dotted line = observed asthma; gray line = expected asthma; solid line = observed asthma and another lung disease; and dashed line = expected asthma and another lung disease. (From Silverstein MD, Reed CE, OConnell EJ, et at: Long-term survival of a cohort of community residents with asthma. N Engl J Med 331:1537-1541, 1994; with permission.)
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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have wheezing. In a study of 46 patients (> 65 years of age) with asthma, almost 50°/0 had frequent wheezing attacks and many had severe disease with marked ventilatory impairmenL6 Severity
Asthma severity must be carefully assessed and treated aggressively. Twenty-five consecutive nonsmoking asthmatics over 70 years of age were enrolled in a study that demonstrated that the majority had developed asthma after age 65; all of these patients required continuous bronchodilator therapy to control symptom^.^ Comorbidities
Evaluation of asthma in the elderly requires evaluation for comorbidities. For example, cardiac disease needs to be excluded, particularly in the smoker or ex-smoker. Chest tightness occurs commonly with angina as well as asthma. Also, nocturnal dyspnea and wheezing may reflect angina or congestive heart failure rather than asthma. The timing of the nocturnal symptoms, however, may be helpful in distinguishing between cardiac disease and asthma. For example, symptoms associated with poorly controlled asthma typically occur in the early morning hours (between 4:OO and 6:OO AM), whereas those associated with heart failure typically occur 1 to 2 hours after bedtime. History
The elderly patient may not present with a history of atopy, nor describe allergic triggers. A history of rhinitis, sinusitis, or nasal polyposis, however, is suggestive of atopy, and in combination with sensitivity to aspirin-containing or nonsteroidal antiinflammatory agents would strongly support the diagnosis of asthma. Therefore, it is essential to ask about common precipitants of asthma in the elderly: Viral respiratory infections Irritants (smoke, household aerosols, paints) Metabisulfite ingestions (wine, beer, and food preservatives) Strong odors (perfumes) Aeroallergens Gastroesophageal reflux Aspirin and other nonsteroidal antiinflammatory agents (NSAIDs) Cardiovascular agents, particularly P-blocking agents Ophthalmologic solutions, particularly P-blocking agents It is also essential to ask about medications, because many patients are on multiple medications that may cause adverse reactions in the
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asthmatic. For example, P-adrenergic blocking agents, aspirin, and other nonsteroidal antiinflammatory drugs may worsen bronchospasm. Also, non-potassium sparing diuretics may have additive effects with antiasthma medications that also produce potassium loss. Angiotensin converting enzyme inhibitors can increase the incidence of cough. Cholinergic agents can directly cause bronchospasm and bronchorrhea. Finally, nonsedating antihistamines can worsen cardiac function and cause ventricular arrhythmias. It is also clear that environmental tobacco smoke can exacerbate asthma symptoms: cigarette smoke is a known respiratory irritant. Furthermore, there are data suggesting that environmental tobacco smoke can produce inflammation, because increased bronchial hyperresponsiveness has been demonstrated following experimental exposure to tobacco smoke.l7 Physical Examination
The physical examination should include a thorough inspection of the upper airway. The location of wheezing should be carefully noted. For example, wheezing only at the trachea may suggest an upper airway obstruction, whereas a localized wheeze at midchest level may suggest an endobronchial obstruction such as a bronchogenic carcinoma. Diffuse wheezing can occur with congestive heart failure as well as asthma. Laboratory Studies
Many laboratory studies, particularly pulmonary function testing and allergy testing, are helpful in the diagnosis of asthma. This discussion describes these tests, and also emphasizes imaging studies, specifically high-resolution computed tomography (HRCT), electrocardiography, and the complete blood count. Pulmonary Function Testing
Pulmonary function testing should proceed in a stepwise manner, because each test addresses a specific aspect of pulmonary disease. Tests such as spirometry, bronchoprovocation challenge, lung volumes, and diffusing capacity of carbon monoxide, however, may all be considered, particularly to distinguish asthma from COPD (Table 1). Spirometry is the most commonly performed test for asthma evaluationZ0The diagnosis of asthma is usually confirmed by the following factors: 1. Demonstration of airflow obstruction by a FEV, value less than 80% of predicted and a FEV,/forced vital capacity (FEV) ratio less than 70%.
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DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
Table 1. DIFFERENTIATING ASTHMA AND COPD BY PULMONARY FUNCTION Asthma
Test FEV,
FVC FEVJFVC 2 12% and t FEV,* TLC
2
200 mL
RV
RV/TLC Diffusing capacity of the lung for carbon monoxide
Chronic Obstructive Pulmonary Disease
Decreased Decreased Decreased Usually
Decreased Decreased Decreased Rarely
Normal (or increased during acute episode) Increased Increased Usually normal
Normal or increased Increased Increased Usually decreased
FEV, = forced expiratory volume in 1 second; FVC = forced vital capacity; TLC capacity: RV = residual volume. *Increase after inhaled bronchodilator. Data from references 12a, 16, and 30.
=
total lung
2. Evidence that the airflow obstruction is reversible (more than 12% and 200 mL FEV,) either after bronchodilator administration, with repeated measures over time, or after a course of corticosteroids.
Few elderly asthmatics, however, have completely reversible airflow obstruction. Published data and clinical experience indicate that many elderly patients with asthma have a persistent degree of airflow obstruction, even when optimally treated.5 Furthermore, there is increasing evidence that some nonsmoking patients with chronic asthma develop severe fixed airway obstruction. This may be a function of the duration and severity of previous disease. In a study of elderly nonsmoking asthmatic patients, those with longstanding disease (more than 32 years of symptoms) had a significantly greater degree of airflow obstruction in both prebronchodilator and postbronchodilator pulmonary function testing than those with recently acquired (less than 5 years) disease (postbronchodilator FEV, of 58% predicted versus 75% predicted in the recent-onset asthma g r o ~ p )To . ~ distinguish these patients from COPD patients, a trial of corticosteroid therapy is warranted with repeat spirometry at the end of a 2-week course. If the FEV, has improved more than 500 mL, the patient can be considered to have reversible obstruction. Evidence of irreversible airflow obstruction, even after a corticosteroid trial, is more consistent with COPD (Fig. 2). Several other tests besides spirometry can be very helpful in asthma. Peak expiratory flow (PEF) measurements can be used to confirm the presence of variable airflow obstruction, and a pattern of greater than 20% variation in PEF from morning to evening is suggestive of asthma. Variability is defined by:
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A 0 0
10
20
30 40 50 Age (years)
60
70
80
6 -
5'-
-8 9
4 -
C
J 3 -
2 -
FEV 1.0 sec (L) I t
0
10
20
30
40
50
60
70
80
Age (years)
Figure 2. Decline in ventilatory function with age in men and women. FEF20,_,, = mean forced expiratory flow between 200 and 1200 ml of FVC; FVC = forced vital capacity; FEV,., = forced expiratory volume at 1 second; ,F ,E ,F ,, = mean forced expiratory flow during the middle half of the FVC. (From Weiss EB, Stein M (eds): In Morris JF: Geriatric Considerations in Bronchial Asthma: Mechanisms and Therapeutics. Boston, Little Brown and Company, 1993, pp 1017-1 022; with permission.)
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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PEFPM - PEFAM 1/2 (PEF PM + PEF AM) If spirometry is normal and the diagnosis of asthma is in doubt, a bronchoprovocation challenge ( e g , with methacholine) can be performed to diagnose asthma. This test relies on the principle that asthmatics have hyper-responsive airways; therefore, very low doses of inhaled histamine (or inhaled methacholine) result in bronchoconstriction in asthmatics. Hyperreactivity, however, which is determined by atopy and airway caliber, is not limited to asthma: it can be demonstrated in any respiratory disease and is also found in patients with no evidence of pulmonary disease. Thus hyperreactivity supports, but is not sufficient for, a diagnosis of asthma. Other tests appear to have a more limited role in evaluation of asthma. Lung volume tests, such as total lung capacity (TLC) or thoracic gas volume (TGV), are most helpful to exclude restrictive lung disease. The diffusing capacity for carbon monoxide in the lung (DLCO) is most useful in discriminating between asthma and COPD. The DLCO should be normal or elevated in asthma and decreased in COPD as a consequence of destruction of the alveolar capillary bed. Allergy Testing
The utility of allergy testing in the elderly is still not clear. Atopy decreases with age, particularly after 50 years of age. Therefore, patients who acquire asthma after 60 years of age are less likely to have an atopic history than younger asthmatics5 Elderly patients with asthma are more likely to have negative skin testing results than their younger counterparts, and aeroallergens may not trigger their exacerbations of asthma. Nevertheless allergy testing may identify relevant inhalant allergen triggers of asthma that potentially can be avoided. Even though elderly asthmatics are less atopic than younger asthmatics, elderly patients with asthma have more evidence of atopy than age-matched patients without asthma. For example, elderly patients with asthma have elevated immunoglobulin E levels as compared with agematched patients without asthma. Also, positive skin tests are more frequent in elderly patients with asthma than in those without the d i ~ e a s eThus . ~ atopy is still more common in the elderly with asthma than in age-matched patients without asthma, but the clinical relevance of these findings is unknown. Imaging Studies
Imaging studies have been used for decades to assess airflow obstruction. The chest roentgenogram is likely to be normal in asthma, although hyperinflation can certainly be seen, particularly during acute exacerbations. Patients with COPD, especially emphysema, are likely to have marked hyperinflation, flattened diaphragms, and bullous changes.
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Cardiomegaly and pulmonary vascular changes suggest congestive heart failure. Focal infiltrates and mass lesions are more suggestive of acute infection, inflammation, or malignancy. More recently, sophisticated imaging studies such as CT and HRCT have been used to quantify changes in asthma. CT scanning of the chest may show reversible changes including mucoid impaction, an acinar pattern, and lobar collapse, as well as irreversible changes including bronchiectasis, emphysema, and bronchial thickeningz4 HRCT has been used in an attempt to detect and quantify airway changes in asthmatic volunteers. Abnormalities visible on HRCT include emphysema, lung cysts, and large airways abnormalities, such as bronchiectasis. Also visible are small airways abnormalities, such as bronchiolar dilatation and bronchioles filling with mucus or fluid. Also, HRCT can be used to measure the internal size of the bronchi. In a recent study, Kee et all4 demonstrated that HRCT can quantify changes in the airway internal luminal diameter of asthmatic airways provoked by methacholine and reversed by albuterol inhalation in volunteers with asthma as compared with volunteers without asthma. These changes can be correlated with changes measured by spirometry. As expected, after methacholine inhalation, pulmonary function testing showed significant airflow obstruction, and the median value for the airway internal luminal diameter decreased by 17%. After subsequent albuterol inhalation, pulmonary function returned to baseline levels and the median value for the airway internal luminal diameter increased by 18% above baseline values.14The volunteers without asthma did not show these changes. Electrocardiography An electrocardiogram (ECG) is usually normal in a patient with stable asthma. It is useful in identifying cardiac disease in the patient with asthma, however, and rarely may show changes of hypokalemia in patients on P-adrenergic agonist medication. In the acute setting several abnormalities have been described, including sinus tachycardia, P-pulmonale, right axis deviation, right bundle branch block, and right ventricular strain. Complete Blood Count With Differential Eosinophilia is helpful, because its presence may be used as a predictor of asthma. A level greater than 4% or 300 to 400/mm3 is suggestive of asthma.
DIFFERENTIATING ASTHMA FROM OTHER CONDITIONS IN THE ELDERLY Symptoms of dyspnea, wheezing, cough, and chest tightness should not be considered just part of the normal aging process. Elderly individuals commonly experience breathlessness from identifiable causes:
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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Anatomic Structure 1. Atrophy of respiratory muscles (diaphragm, chest wall) 2. Increased anteroposterior chest distance 3. Calcification of costochondral junction 4. Loss of alveolar wall surface area 5. Loss of bronchial muscle fibers 6. Development of panacinar emphysema Physiologic Function 1. Decreased vital capacity 2. Increased functional residual capacity 3. Increased closing lung volume 4. Decreased expiratory flow 5. Decreased lung diffusing capacity 6. Increased alveolar-arterial Po, gradient 7. Decreased aerobic capacity Because there is no marker for asthma, however, as there is for other diseases (e.g., pancreatitis [amylase] or diabetes [glucose]), it can be difficult to distinguish asthma from other diseases, particularly COPD, in the elderly patient. Yet, because many of the causes of asthma are amenable to treatment, it is appropriate to take a careful history, perform a thorough physical examination, and obtain pulmonary function tests to distinguish between asthma and other respiratory diseases.
Pulmonary Conditions
Chronic Obstructive Pulmonary Disease
Many patients with asthma symptoms either currently smoke cigarettes or have in the past, yet also have a history of childhood asthma or wheezing or allergic rhinitis, suggesting underlying atopy. Therefore, various empiric methods have been developed to distinguish asthma from COPD. Pulmonary function testing, HRCT, and response to corticosteroids were alluded to previously and are described in this section. Because asthma and COPD frequently coexist in many patients, results of these tests often show mixed disease. Pulmonary function testing can be used to distinguish between asthma and COPD (see Table 1).Usually spirometry, including FEV, and FVC and the response to bronchodilators are checked. If there is no response to bronchodilators, asthma often can be excluded.21There are no universally accepted criteria for the degree of reversibility necessary to diagnose asthma, however. Frequently, a 12% to 15% improvement in FEV, expressed as a percent of baseline is employed for this purpose, sometimes with the additional requirement that the improvement be at least 200 mL.22This degree of reversibility, however, is not observed frequently, even in patients with uncomplicated asthma. Perhaps an improvement in FEV, of 10% of the predicted value is sufficient, because
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it exceeds the 96th percentile for bronchodilation in asymptomatic, nonsmoking subjects." Indeed, a recent study demonstrated that a 10% improvement in predicted value was able to identify the asthmatics with 0.92 sensitivity and 0.95 specificity.'s Although the presence of reversibility is helpful in diagnosing asthma, reversibility is not always present. For example, irreversible airflow obstruction can be seen in severe asthma. If patients do not demonstrate significant reversible airflow obstruction following bronchodilator administration, several other parameters can be assessed. For example, elevation of the DLCO above normal can occur in patients with asthma; in contrast, it is decreased in patients with COPD owing to emphysema with destruction of the capillary bed. A normal DLCO is not diagnostic, however, and a mixed picture may be present. Also, although patients with asthma typically have bronchial hyperresponsiveness and those with COPD do not, the response to inhaled methacholine does not always distinguish between the two diseases. For example, if the baseline pulmonary function is decreased, such as in fixed airflow obstruction, bronchial hyperresponsiveness can simply reflect the diminished baseline FEV,, because there is a linear correlation between bronchial hyperresponsiveness and baseline FEV,. Imaging studies do not necessarily distinguish between asthma and COPD due to emphysema. Hyperinflation can be seen on chest roentgenograms in both diseases. As might be expected, even with HRCT, airway abnormalities and air trapping are seen in both diseases, and preliminary data do not show any distinguishing features.31 A response to oral corticosteroids is classically linked to asthma, whereas patients with pure COPD usually do not respond to corticosteroids. Still, as many as 20% of patients with COPD have some airway reversibility and do respond to corticosteroids; these patients likely have mixed disease. Finally, there are patients with longstanding, severe asthma who have developed fixed airflow obstruction and may not respond to corticosteroids. Finally, there have been gender biases in the diagnosis of airflow obstruction by health care providers. Women and patients with a history of allergic disease are much more likely to be diagnosed as having asthma, whereas men and smokers are more likely to be diagnosed as having chronic bronchitis or emphysema.*" In summary, it is difficult to distinguish between asthma and COPD in the elderly with a history of cigarette smoking, probably because many patients have mixed disease, both a reduced FEV, (fixed disease) and a response to an inhaled bronchodilator (reversible disease). Upper Airway Obstruction
After COPD, a likely alternative diagnosis in suspected asthma is upper airway obstruction (UAO), which can be a result of external compression or vocal cord dysfunction. Vocal cord dysfunction can
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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occur as a result of crycoarytenoiditis, particularly in patients with rheumatoid arthritis. It has also been described as a result of a conversion reaction? or, rarely, postnasal drainage.’3 The flow volume loop, from a spirometric maneuver, is very useful in UAO evaluation. Vocal cord dysfunction with fixed obstruction would manifest as a plateau on both the inspiratory and expiratory limbs of the loop. Interstitial Lung Disease Interstitial lung disease (ILD) can usually be distinguished from asthma because the findings on history-taking, physical examination, imaging studies, and pulmonary function testing are quite different from asthma. When describing their symptoms, patients with ILD describe dyspnea, often limiting daily activities, yet rarely describe wheezing. On physical examination they may have clubbing, and usually have fine “velcro” inspiratory crackles heard best at the lung bases. Imaging studies demonstrate interstitial infiltrates, and HRCT is diagnostic. Finally, spirometry demonstrates restrictive rather than obstructive disease (reduction in both FEV, and FVC with the FEV,/FVC ratio normal or elevated), reduced lung volumes (TLC or TGV), and reduced pulmonary diffusing capacity. Bronchiectasis Bronchiectasis can usually be distinguished from asthma, primarily on the bases of history and imaging studies. The two diseases may coexist, however, and longstanding asthmatics may develop bronchiectasis. The patient with bronchiectasis expectorates mucopurulent sputum, occasionally with hemoptysis, often more than several tablespoons daily. Symptoms of cough, wheezing, and dyspnea may be present. The physical examination may be relatively nonspecific. Clubbing may be present, and lung examination may reveal evidence of obstruction with prolonged exhalation and wheezing. Imaging studies are diagnostic of bronchiectasis, however. The abnormal airway architecture is clearly seen on HRCT and can often be seen as tram-track lines on chest CT or even on chest roentgenogram. Pulmonary Embolism Pulmonary embolism (PE) can be associated with dyspnea, wheezing, hypoxemia, and chest pain, and is more prevalent in the elderly than in younger populations? Patients with PE, however, usually don’t have a history of asthma, their symptoms are unlikely to completely reverse with bronchodilator treatment, and pleuritic chest pain is often prominent. Risk factors for PE should be identified, including thrombophilia, and clinical risk factors such as age more than 40 years, obesity, cancer, estrogen treatment, recent surgery, bed rest, congestive heart failure (CHF), myocardial infarction, stroke, fracture, multiple trauma,
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childbirth, and history of venous thrombosis. If clinical suspicion for PE is high, appropriate diagnostic studies should be performed. Diagnostic studies for PE include duplex ultrasonography of the lower extremities, ventilation-perfusion scanning of the lung, and pulmonary angiography. Bronchogenic Carcinoma Lung cancer can usually be distinguished from asthma. Although there may be wheezing due to endobronchial narrowing and turbulent airflow, the wheezing is usually l~calized.~ The chest roentgenogram will usually demonstrate the lesion. CT of the chest can be performed as part of the staging and procedure. Cardiac Disorders
Cardiac asthma can present with symptoms similar to those of asthma. The symptoms of dyspnea, wheezing, and cough are quite nonspecific. The history of weight gain and edema is more suggestive of CHF, however. Physician examination may reveal diffuse wheezing. If the patient is in overt CHF, the cardiovascular examination may reveal an additional heart sound (S3) and vascular congestion with neck vein distention and pedal edema. Pulmonary function testing may not be diagnostic, although CHF usually is associated with a mixed obstructiverestrictive pattern with a predominant restrictive component rather than the pure obstruction seen in asthma. Also, an increased DLCO and increased bronchial hyperresponsiveness can be seen in both diseases.30 In contrast, imaging studies may be quite helpful. If left ventricular failure is present a chest roentgenogram may demonstrate left ventricular enlargement and pulmonary vascular congestion. Also, supine and prone HRCT can be performed, and the vascular congestion will be gravity dependent. Finally, the electrocardiogram may demonstrate left ventricular hypertrophy. If the diagnosis is difficult, it may be necessary to obtain an echocardiogram or directly assess ejection fraction with a gated blood pool scan. Gastrointestinal Disorders
Aspiration Aspiration is common in the elderly for several reasons. First, the gag reflex is diminished. Second, gastroesophageal reflux is very common. Third, the elderly are frequently on multiple medications that can increase sedation. Fourth, the elderly are prone to neuropsychiatric disorders. About 10% are debilitated; the most common problems are the affective disorders and organic mental disorders, particularly dementia.*O Finally, the elderly have an increased prevalence of alcoholism. Symp-
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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toms of cough and wheeze are common but not always present in patients who aspirate, so clinical suspicion needs to be high. The chest roentgenogram may be helpful, particularly if it demonstrates the lower lobe infiltrates characteristic of aspiration. INTERACTIONS AMONG EFFECTS OF AGING AND ASTHMA Aging causes many changes in the elderly. This section focuses on the well-described anatomic and physiologic changes in the respiratory system as well as the controversial topic of changes in the airway response to pharmacologic therapy. Physiologic Aspects of Aging Both anatomic and physiologic changes occur with aging. The major changes that occur are loss of elastic tissue and elastic recoil. There may be a decrease in the number of fibers, and perhaps a change in the relationship of elastic fibers to each other. Also, the chest wall becomes stiffer, resulting in decreased compliance and an enlarged anteroposterior distance. This results in a small increase in TLC and a larger increase in functional residual capacity (FRC) and residual volume (RV)? The increase in RV is due to premature airway closure. In dependent lung regions, this is exacerbated by increased intrathoracic pressure, which prematurely collapses noncartilaginous airways. This deterioration of ventilatory function is accelerated in smokers by the addition of chronic bronchitis and centrilobular emphysema. Decreased muscle force in the chest wall and diaphragm results in decreased vital capacity and decreased maximum expiratory flows. FEVl declines, although the rate is quite variable (Figure 2). A 15year longitudinal study of healthy nonsmokers in the United States revealed a mean annual decline in FEVl to be 31 mL in men and 26 mL in women. In Australia a similar study demonstrated an annual decline of 35 mL in normal men and 50 mL in nonsmoking asthmatic men. This decline in ventilatory function may not be linear, despite the prediction of linear regression equations. Gas exchange also decreases with aging. This results from loss of surface area, yet the reason for the loss is unclear. Also, there is increased ventilation-perfusion mismatch, perhaps owing to the uneven distribution of ventilation relative to capillary perfusion. Again, the changes are not linear with aging, making evaluation of gas exchange in the elderly more difficult. The decline in maximum oxygen consumption is well established in the elderly.19This decrease in aerobic capacity may not be limiting in patients without lung disease. In patients with airflow obstruction and loss of ventilatory reserve, however, this decreased capacity may be inadequate to maintain physiologically adequate gas exchange, particularly under conditions of stress and infection.
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Changes in Airway Response to Pharmacologic Therapy Pharmacologic therapy with agents such as bronchodilators and antiinflammatory agents has dramatically improved asthma treatment. Antiasthmatic drugs, however, may have significant adverse effects in the elderly and dosage considerations are paramount (Table 2). Furthermore, the effect of the aging process on the airway responses to these agents is not fully understood. There is speculation that airway P-adrenergic receptors change with aging. There are studies suggesting that the response to inhaled Padrenergic agonists decreases with age.32Reasonable hypotheses would be that the airway P-adrenergic receptors decrease in either number or function in the elderly. An intriguing possibility is that there is an agerelated decrease in P-adrenergic receptors out of proportion to a decrease in anticholinergic receptors. This would explain the effectiveness of anticholinergic agents in the elderly with asthma and COPD. Of interest, Barros and Reesla confirmed that increased age was associated with a decline in airway response to albuterol but not to ipratropium bromide. Not all studies, however, show a decrease in response to inhaled Padrenergic agonists with age.I5 CONCLUSION
In conclusion, asthma is very common in the elderly, with a prevalence of about 7% to 9%. Because many patients with asthma either currently smoke cigarettes or have in the past, they frequently have
Table 2. ANTIASTHMATIC DRUGS IN THE ELDERLY Drug
Adverse Effects
Dosage Considerations
p agonist Oral Inhaled Anticholinergic Inhaled Theophylline Oral Corticosteroids Oral Inhaled Cromolyn Inhaled
Tremor, tachycardia Uncommon
Reduce or discontinue No changes necessary
Uncommon
No changes necessary
Nausea, vomiting arrhythmias, seizures
Discontinue or maintain serum level 10-20 kg/mL
Osteoporosis, cataracts, reduces T-cell function, myopathy aggravates hypertension Oropharyngeal candidiasis
Maintenance dosage below 20 mg/AM Use a reservoir spacer
Uncommon
No changes necessary
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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mixed disease with features of both asthma (reversible airflow obstruction) and COPD (fixed airflow obstruction). Patients with COPD often have a reversible component to their condition, such that medications may relieve some symptoms and improve the patient’s quality of life. The differential diagnosis of asthma in the elderly needs to take into account not just COPD, but also other pulmonary conditions such as UAO, ILD, bronchiectasis, PE, and bronchogenic carcinoma. Asthma also needs to be distinguished from nonpulmonary diseases, particularly cardiovascular and gastrointestinal diseases. Finally, it is essential to differentiate the normal, psychologic, and psychosocial changes that accompany aging processes from abnormal changes that accompany age-associated diseases such as asthma.
References 1. Astrand P, Rodahl K Textbook of Work Physiology. New York, McGraw-Hill, 1970, p 171 la. Barros MJ, Rees PJ: Bronchodilator responses to salbutomol followed by ipratropium bromide in partially reversible airflow obstruction. Respir Med 84:371, 1990 2. Billig N: Clinical geropsychiatry. In Reichel W (ed): Clinical Aspects of Aging. Baltimore, Williams and Wilkins, 1989 3. Braman SS: Asthma in the elderly patient. Clin Chest Med 14:413, 1993 4. Braman SS, Davis SM: Wheezing in the elderly. Asthma and other causes. Geriatr Clin North Am 2:269, 1986 5. 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 143:336, 1991 6. Burrows B, Barbee RA, Cline MG, et al: Characteristics of asthma among elderly adults in a sample of the general population. Chest 100:935, 1981 7. Burrows 8, Lebowitz M, Barbee RA, et al: Findings before diagnoses of asthma among elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 88:870, 1991 8. Christopher KL, Wood RPII, Eckert RC, et al: Vocal cord dysfunction presenting as asthma. N Engl J Med 308:1566, 1983 9. Dales RE, Spitzer WO, Tousignant P, et al: Clinical interpretation of airway response to a bronchodilator: Epidemiologic considerations. Am Rev Respir Dis 138:317, 1988 10. Dodge RR, Burrows G: The prevalence and incidence of asthma and asthma-like symptoms in a general population sample. Am Rev Respir Dis 122567, 1980 11. Enright PL, Kronmal RA, Higgins MW, et a 1 Prevalence and correlates of respiratory symptoms and disease in the elderly. Cardiovascular Health Study. Chest 106827, 1994 12. European Community Respiratory Health Survey: Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 9:697, 1996 12a. Evans CC, Ridyard JB, Ogilvie CM: RegionaI lung function in chronic airways obstruction. Scand J Respir Dis Suppl 85:75, 1974 13. Irwin RS, Pratter MR, Holland PS, et al: Postnasal drip causes cough and is associated with reversible upper airway obstruction. Chest 85:346, 1984 14. Kee ST, Fahy JV, Chen DR, et al: High-resolution computed tomography of airway changes after induced bronchoconstriction and bronchodilation in asthmatic volunteers. Acad Radio1 3389, 1996 15. Kendall MJ, Woods KL, Wilkins MR, et al: Responsiveness to beta-adrenergic receptor stimulation: The effects are cardioselective. Br J Clin Pharmacol 142321, 1982
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16. Knudson RJ, Clark DF, Kennedy TC, et al: Effect of age alone on mechanical properties of the lung. J Appl Physiol43:1054, 1977 17. Menon PK, Stankus RP, Rando RJ, et al: Asthmatic responses to passive cigarette smoke: Persistance of reactivity and effect of medication. J Allergy Clin Immunol 88:861, 1991 18. 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 2497, 1989 19. Morris JF: Geriatric considerations. In Weiss EB, Stein M (eds): Bronchial Asthma: Mechanisms and Therapeutics. Boston, Little, Brown, and Company, 1993, p 1017 20. National Heart, Lung and Blood Institutes, NAEPP Working Group Report: Considerations for Diagnosing and Managing Asthma in the Elderly. Bethesda, National Institutes of Health, 1996. National Institutes of Health Publication # 96-3662 21. Nelson HS: Diagnosis and management of severe asthma in the adult. In Szefler SJ, Leung DYM (eds): Severe Asthma Pathogenesis and Clinical Management. New York, Marcel Dekker, 1996, p 391 22. Nicklaus TM, Burgin WW, Taylor J R Spirometric tests to diagnose suspected asthma. Am Rev Respir Dis 100:153, 1969 23. Osborne ML, Deffebach ME: Asthma. In Kelley WN (ed): Textbook of Internal Medicine, 3rd ed. Philadelphia, Lippincott-Raven, 1997, p 1974 24. Paganin F, Trussard V, Seneterre E, et a1 Chest radiography and high resolution computed tomography of the lungs in asthma. Am Rev Respir Dis 146:1084, 1992 25. Peat JK, Woolcock AJ, Cullen K Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 70:171, 1987 26. Renwick DS, Connolly MJ: Prevalence and treatment of chronic airways obstruction in adults over the age of 45. Thorax 51:164, 1996 27. Sherman C B Late-onset asthma: Making the diagnosis, choosing drug therapy. Geriatrics 50:24, 1995 28. Silverstein MD, Reed CE, OConnell EJ, et al: Long-term survival of a cohort of community residents with asthma. N Engl J Med 331:1537-1541, 1994 29. Silvestri GA, Mahler DA. Evaluation of dyspnea in the elderly patient. Clin Chest Med 14:393, 1993 30. Snashall I’D, Chung KT: Airway obstruction and bronchial hyperresponsiveness in left ventricular failure and mitral stenosis (state of the art). Am Rev Respir Dis 144:945, 1991 30a. Stewart RI: Carbon monoxide diffusing capacity in asthmatic patients with mild airflow limitation. Chest 94:332, 1988 31. Sutherland K, Vollmer WM, Salmon C, et al: High resolution computed tomography (HRCT) in asthma and COPD. Presented at Asthma 1995: Theory to Treatment Conference for the Asthma, Allergy, and Immunology/American Thoracic Society Conference, July 15-17, 1995 32. Ullah MI, Newman GB, Saunders K B Influence of age on response to ipratropium and salbutamol in asthma. Thorax 36:523, 1981 33. Weiss ST, Segal MR, Sparrow D, et al: Relation of FEV, and peripheral blood leukocyte count to total mortality: The Normative Aging Study. Am J Epidemiol 142:493, 1995
Address reprint requests to Molly Lee Osborne, MD, PhD Pulmonary Section lllD 3710 SW US Veterans Hospital Road Portland, OR 97207
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DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY Molly Lee Osborne, MD, PhD
Bronchial asthma in the elderly is receiving increasing attention for several reasons. First, the elderly population is increasing. Although we have increased the maximum age by only 1 month in the last few decades, we have increased the average maximum age to 75 years. Projections suggest that the number of Americans more than 65 years of age will increase from 30 million to 50 million over the next 30 years.I9 Second, the elderly continue to consume about one third of the total health care resources available, primarily in the area of cardiopulmonary disease. Third, chronic airflow obstruction is very common and will likely increase in the next few decades as a consequence of longer exposure to tobacco smoke and other environmental indoor and outdoor pollutants, as well as to inhaled antigens. This article addresses the differential diagnosis of bronchial asthma in the elderly. First, a definition of asthma is given and the epidemiology and natural history are discussed, emphasizing the underdiagnosis of asthma in the elderly. Next, the differential diagnosis of asthma in the elderly is discussed, contrasting it with similar conditions such as chronic obstructive pulmonary disease (COPD), cardiac disease, upper airflow obstruction, gastroesophageal reflux, and bronchogenic carcinoma. Chronic airflow obstruction includes asthma as well as COPD, and COPD includes both chronic bronchitis and emphysema. Finally, the interactions of aging, asthma, and coexisting diseases are discussed,
From the Veterans Affairs Medical Center, Portland, Oregon
IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA
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pointing out how normal aging-associated changes in lung structure may exaggerate asthma symptoms. Key points from the National Asthma Education and Prevention Program (NAEPI’) working group report are as follows: Asthma in all ages is a lung disease characterized by the following aspects: (1) airflow obstruction that is reversibIe (but not completely so in some patients), either spontaneously or with treatment; (2) airway inflammation; and (3) increased airway responsiveness to a variety of stimuli. Incomplete reversibility becomes increasingly common among elderly patients, however, especially when asthma is longstanding or severe; the lack of reversibility probably results from smooth muscle hypertrophy and fibrosis. Available data and clinical observations suggest that asthma does occur frequently among the elderly. Normal changes in the lung that occur with aging may interact with asthma-related pathophysiologic events. Irreversible airflow obstruction is more likely to develop if asthma is severe and longstanding. Events that trigger acute exacerbations of asthma are the same for all ages, but sensitivity to inhaled allergens is less prevalent in elderly patients, especially if the asthma is of recent onset. DEFINITION, EPIDEMIOLOGY, AND NATURAL HISTORY OF ASTHMA IN THE ELDERLY Definition
Asthma is a lung disease generally characterized by airway obstruction that is reversible, airway inflammation, and increased airway responsiveness to a variety of stimuli.23This definition is very useful in young adults, but may be problematic in the elderly. For example, asthma, chronic bronchitis, or emphysema may present with symptoms of chest tightness, wheezing, dyspnea, or cough, despite the markedly zy different pathophysiologies and natural histories of these Still, at least some degree of reversibility of airflow obstruction is defined as asthma, even though it may be seen in conjunction with any one of these disorders; airway hyperresponsiveness as measured in the laboratory setting is characteristic of asthma. Epidemiology
The prevalence of asthma is relatively high, about 5% to 7% in the United States, and is on the rise.I2 Although the exact prevalence is difficult to determine in the elderly, studies from Tecumseh, Michigan and Tucson, Arizona suggest a prevalence of 7% to 9”/0in patients more than 70 years of age. These data suggest that asthma is more prevalent
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in the elderly than in a younger population. Because it may be difficult to distinguish between asthma and COPD, the term asthmatic bronchitis has been used for patients with characteristics of both asthma and COPD.3 Perhaps a better term is mixed disease, referring to the presence of both a reduced forced expiratory volume in 1 second (FEV,) (fixed disease) and a response to an inhaled bronchodilator (reversible disease). Newly diagnosed asthma is also common in the elderly. Up to 40% of patients with asthma are at least 40 years of age when they suffer their first attack. In fact, although many asthmatics are diagnosed before 40 years of age, an equal number have their first episode after 70 years of age.27Health care providers, however, are often unaware that asthma can first present in the elderly. Indeed, asthma frequently goes unrecognized. Enright et all1demonstrated that chronic airways obstruction (CAO) is very common in patients more than 65 years of age in the United States. In their study of 5201 patients, symptoms, medication use, and lung function were assessed. Undiagnosed airways obstruction was defined as airflow limitation demonstrated by spirometric methods in participants who did not have a physician diagnosis of obstructive lung disease (asthma, chronic bronchitis, or emphysema). Undiagnosed airways obstruction was twice as likely in women and in patients with lower income, and was associated with current and former smoking, and chronic cough. A second study described in a recent article by Renwick and ConnollyZ6demonstrated that although CAO is very common in adults more than 45 years of age in the United Kingdom, it is frequently overlooked. In the postal questionnaire survey of 783 men and women (92% response rate), respiratory symptoms and smoking history were ascertained. Almost 30% were current smokers and 37% were ex-smokers. About 76% of the subjects had CAO symptoms, and 55% had features suggesting improvement with treatment (increased nonspecific bronchial responsiveness or significant bronchodilator reversibility).Spirometric evidence of airways obstruction was demonstrated in 26% of 247 participants clinically evaluated for evidence of airways obstruction. Only 55% of subjects with demonstrated CAO had received a diagnosis of airways obstruction of any kind, and only 37% were using inhaled bronchodilators or steroids. The reasons for this underdiagnosis are not fully known. Patients may self-limit their regular activities without realizing it to minimize symptoms. Patients may not recognize breathlessness, cough, or wheezing as evidence of treatable airflow obstruction, thinking that these symptoms may be consequences of aging. It is also possible that elderly subjects actually have reduced perceptions of bronchoconstriction.3 Natural History The natural history of asthma is variable. Some patients have asthma throughout life. Others deny symptoms until quite late in life,
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although recall bias cannot be excluded in these patients. Still others may have symptoms misclassified as chronic bronchitis. The rate of decline of pulmonary function in elderly patients with asthma is controversial. Some studies demonstrate worsening of airflow obstruction over time,25whereas others do not.6 The long-term survival of patients with asthma alone does not appear to be significantly different from expected survival over a broad age range. In a recent study, however, patients 35 years of age or older who had asthma associated with COPD had worse than expected survival, in contrast to asthmatics without COPD (Fig. 1).28 This survival rate may partially reflect the presence of fixed airflow obstruction. In fact, one interesting interpretation of these findings is that patients with fixed airflow obstruction may have worse than expected survival. For example, results from the Normative Aging Study33demonstrate that FEV, and peripheral blood leukocyte count are predictors of mortality. EVALUATION OF ASTHMA IN THE ELDERLY
Symptoms
The intermittent symptoms of cough, dyspnea, wheezing, and chest tightness are classic for asthma. In the elderly with asthma, symptoms are similar. Cough is virtually universal, and almost half the patients 100
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Asthma only .. . . Observed - Expected Asthma and another lung disease -Observed
- Expected 5
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Years after Onset Figure 1. Kaplan-Meier curves of observed and expected survival for 2406 residents of Rochester, Minnesota, with asthma alone (mean age at onset 13 years) and 93 residents with asthma and another lung disease (mean age atmset of asthma, 52 years). Expected survival was calculated from Olmsted County mortality rates. Dotted line = observed asthma; gray line = expected asthma; solid line = observed asthma and another lung disease; and dashed line = expected asthma and another lung disease. (From Silverstein MD, Reed CE, OConnell EJ, et at: Long-term survival of a cohort of community residents with asthma. N Engl J Med 331:1537-1541, 1994; with permission.)
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have wheezing. In a study of 46 patients (> 65 years of age) with asthma, almost 50°/0 had frequent wheezing attacks and many had severe disease with marked ventilatory impairmenL6 Severity
Asthma severity must be carefully assessed and treated aggressively. Twenty-five consecutive nonsmoking asthmatics over 70 years of age were enrolled in a study that demonstrated that the majority had developed asthma after age 65; all of these patients required continuous bronchodilator therapy to control symptom^.^ Comorbidities
Evaluation of asthma in the elderly requires evaluation for comorbidities. For example, cardiac disease needs to be excluded, particularly in the smoker or ex-smoker. Chest tightness occurs commonly with angina as well as asthma. Also, nocturnal dyspnea and wheezing may reflect angina or congestive heart failure rather than asthma. The timing of the nocturnal symptoms, however, may be helpful in distinguishing between cardiac disease and asthma. For example, symptoms associated with poorly controlled asthma typically occur in the early morning hours (between 4:OO and 6:OO AM), whereas those associated with heart failure typically occur 1 to 2 hours after bedtime. History
The elderly patient may not present with a history of atopy, nor describe allergic triggers. A history of rhinitis, sinusitis, or nasal polyposis, however, is suggestive of atopy, and in combination with sensitivity to aspirin-containing or nonsteroidal antiinflammatory agents would strongly support the diagnosis of asthma. Therefore, it is essential to ask about common precipitants of asthma in the elderly: Viral respiratory infections Irritants (smoke, household aerosols, paints) Metabisulfite ingestions (wine, beer, and food preservatives) Strong odors (perfumes) Aeroallergens Gastroesophageal reflux Aspirin and other nonsteroidal antiinflammatory agents (NSAIDs) Cardiovascular agents, particularly P-blocking agents Ophthalmologic solutions, particularly P-blocking agents It is also essential to ask about medications, because many patients are on multiple medications that may cause adverse reactions in the
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asthmatic. For example, P-adrenergic blocking agents, aspirin, and other nonsteroidal antiinflammatory drugs may worsen bronchospasm. Also, non-potassium sparing diuretics may have additive effects with antiasthma medications that also produce potassium loss. Angiotensin converting enzyme inhibitors can increase the incidence of cough. Cholinergic agents can directly cause bronchospasm and bronchorrhea. Finally, nonsedating antihistamines can worsen cardiac function and cause ventricular arrhythmias. It is also clear that environmental tobacco smoke can exacerbate asthma symptoms: cigarette smoke is a known respiratory irritant. Furthermore, there are data suggesting that environmental tobacco smoke can produce inflammation, because increased bronchial hyperresponsiveness has been demonstrated following experimental exposure to tobacco smoke.l7 Physical Examination
The physical examination should include a thorough inspection of the upper airway. The location of wheezing should be carefully noted. For example, wheezing only at the trachea may suggest an upper airway obstruction, whereas a localized wheeze at midchest level may suggest an endobronchial obstruction such as a bronchogenic carcinoma. Diffuse wheezing can occur with congestive heart failure as well as asthma. Laboratory Studies
Many laboratory studies, particularly pulmonary function testing and allergy testing, are helpful in the diagnosis of asthma. This discussion describes these tests, and also emphasizes imaging studies, specifically high-resolution computed tomography (HRCT), electrocardiography, and the complete blood count. Pulmonary Function Testing
Pulmonary function testing should proceed in a stepwise manner, because each test addresses a specific aspect of pulmonary disease. Tests such as spirometry, bronchoprovocation challenge, lung volumes, and diffusing capacity of carbon monoxide, however, may all be considered, particularly to distinguish asthma from COPD (Table 1). Spirometry is the most commonly performed test for asthma evaluationZ0The diagnosis of asthma is usually confirmed by the following factors: 1. Demonstration of airflow obstruction by a FEV, value less than 80% of predicted and a FEV,/forced vital capacity (FEV) ratio less than 70%.
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DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
Table 1. DIFFERENTIATING ASTHMA AND COPD BY PULMONARY FUNCTION Asthma
Test FEV,
FVC FEVJFVC 2 12% and t FEV,* TLC
2
200 mL
RV
RV/TLC Diffusing capacity of the lung for carbon monoxide
Chronic Obstructive Pulmonary Disease
Decreased Decreased Decreased Usually
Decreased Decreased Decreased Rarely
Normal (or increased during acute episode) Increased Increased Usually normal
Normal or increased Increased Increased Usually decreased
FEV, = forced expiratory volume in 1 second; FVC = forced vital capacity; TLC capacity: RV = residual volume. *Increase after inhaled bronchodilator. Data from references 12a, 16, and 30.
=
total lung
2. Evidence that the airflow obstruction is reversible (more than 12% and 200 mL FEV,) either after bronchodilator administration, with repeated measures over time, or after a course of corticosteroids.
Few elderly asthmatics, however, have completely reversible airflow obstruction. Published data and clinical experience indicate that many elderly patients with asthma have a persistent degree of airflow obstruction, even when optimally treated.5 Furthermore, there is increasing evidence that some nonsmoking patients with chronic asthma develop severe fixed airway obstruction. This may be a function of the duration and severity of previous disease. In a study of elderly nonsmoking asthmatic patients, those with longstanding disease (more than 32 years of symptoms) had a significantly greater degree of airflow obstruction in both prebronchodilator and postbronchodilator pulmonary function testing than those with recently acquired (less than 5 years) disease (postbronchodilator FEV, of 58% predicted versus 75% predicted in the recent-onset asthma g r o ~ p )To . ~ distinguish these patients from COPD patients, a trial of corticosteroid therapy is warranted with repeat spirometry at the end of a 2-week course. If the FEV, has improved more than 500 mL, the patient can be considered to have reversible obstruction. Evidence of irreversible airflow obstruction, even after a corticosteroid trial, is more consistent with COPD (Fig. 2). Several other tests besides spirometry can be very helpful in asthma. Peak expiratory flow (PEF) measurements can be used to confirm the presence of variable airflow obstruction, and a pattern of greater than 20% variation in PEF from morning to evening is suggestive of asthma. Variability is defined by:
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A 0 0
10
20
30 40 50 Age (years)
60
70
80
6 -
5'-
-8 9
4 -
C
J 3 -
2 -
FEV 1.0 sec (L) I t
0
10
20
30
40
50
60
70
80
Age (years)
Figure 2. Decline in ventilatory function with age in men and women. FEF20,_,, = mean forced expiratory flow between 200 and 1200 ml of FVC; FVC = forced vital capacity; FEV,., = forced expiratory volume at 1 second; ,F ,E ,F ,, = mean forced expiratory flow during the middle half of the FVC. (From Weiss EB, Stein M (eds): In Morris JF: Geriatric Considerations in Bronchial Asthma: Mechanisms and Therapeutics. Boston, Little Brown and Company, 1993, pp 1017-1 022; with permission.)
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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PEFPM - PEFAM 1/2 (PEF PM + PEF AM) If spirometry is normal and the diagnosis of asthma is in doubt, a bronchoprovocation challenge ( e g , with methacholine) can be performed to diagnose asthma. This test relies on the principle that asthmatics have hyper-responsive airways; therefore, very low doses of inhaled histamine (or inhaled methacholine) result in bronchoconstriction in asthmatics. Hyperreactivity, however, which is determined by atopy and airway caliber, is not limited to asthma: it can be demonstrated in any respiratory disease and is also found in patients with no evidence of pulmonary disease. Thus hyperreactivity supports, but is not sufficient for, a diagnosis of asthma. Other tests appear to have a more limited role in evaluation of asthma. Lung volume tests, such as total lung capacity (TLC) or thoracic gas volume (TGV), are most helpful to exclude restrictive lung disease. The diffusing capacity for carbon monoxide in the lung (DLCO) is most useful in discriminating between asthma and COPD. The DLCO should be normal or elevated in asthma and decreased in COPD as a consequence of destruction of the alveolar capillary bed. Allergy Testing
The utility of allergy testing in the elderly is still not clear. Atopy decreases with age, particularly after 50 years of age. Therefore, patients who acquire asthma after 60 years of age are less likely to have an atopic history than younger asthmatics5 Elderly patients with asthma are more likely to have negative skin testing results than their younger counterparts, and aeroallergens may not trigger their exacerbations of asthma. Nevertheless allergy testing may identify relevant inhalant allergen triggers of asthma that potentially can be avoided. Even though elderly asthmatics are less atopic than younger asthmatics, elderly patients with asthma have more evidence of atopy than age-matched patients without asthma. For example, elderly patients with asthma have elevated immunoglobulin E levels as compared with agematched patients without asthma. Also, positive skin tests are more frequent in elderly patients with asthma than in those without the d i ~ e a s eThus . ~ atopy is still more common in the elderly with asthma than in age-matched patients without asthma, but the clinical relevance of these findings is unknown. Imaging Studies
Imaging studies have been used for decades to assess airflow obstruction. The chest roentgenogram is likely to be normal in asthma, although hyperinflation can certainly be seen, particularly during acute exacerbations. Patients with COPD, especially emphysema, are likely to have marked hyperinflation, flattened diaphragms, and bullous changes.
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Cardiomegaly and pulmonary vascular changes suggest congestive heart failure. Focal infiltrates and mass lesions are more suggestive of acute infection, inflammation, or malignancy. More recently, sophisticated imaging studies such as CT and HRCT have been used to quantify changes in asthma. CT scanning of the chest may show reversible changes including mucoid impaction, an acinar pattern, and lobar collapse, as well as irreversible changes including bronchiectasis, emphysema, and bronchial thickeningz4 HRCT has been used in an attempt to detect and quantify airway changes in asthmatic volunteers. Abnormalities visible on HRCT include emphysema, lung cysts, and large airways abnormalities, such as bronchiectasis. Also visible are small airways abnormalities, such as bronchiolar dilatation and bronchioles filling with mucus or fluid. Also, HRCT can be used to measure the internal size of the bronchi. In a recent study, Kee et all4 demonstrated that HRCT can quantify changes in the airway internal luminal diameter of asthmatic airways provoked by methacholine and reversed by albuterol inhalation in volunteers with asthma as compared with volunteers without asthma. These changes can be correlated with changes measured by spirometry. As expected, after methacholine inhalation, pulmonary function testing showed significant airflow obstruction, and the median value for the airway internal luminal diameter decreased by 17%. After subsequent albuterol inhalation, pulmonary function returned to baseline levels and the median value for the airway internal luminal diameter increased by 18% above baseline values.14The volunteers without asthma did not show these changes. Electrocardiography An electrocardiogram (ECG) is usually normal in a patient with stable asthma. It is useful in identifying cardiac disease in the patient with asthma, however, and rarely may show changes of hypokalemia in patients on P-adrenergic agonist medication. In the acute setting several abnormalities have been described, including sinus tachycardia, P-pulmonale, right axis deviation, right bundle branch block, and right ventricular strain. Complete Blood Count With Differential Eosinophilia is helpful, because its presence may be used as a predictor of asthma. A level greater than 4% or 300 to 400/mm3 is suggestive of asthma.
DIFFERENTIATING ASTHMA FROM OTHER CONDITIONS IN THE ELDERLY Symptoms of dyspnea, wheezing, cough, and chest tightness should not be considered just part of the normal aging process. Elderly individuals commonly experience breathlessness from identifiable causes:
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Anatomic Structure 1. Atrophy of respiratory muscles (diaphragm, chest wall) 2. Increased anteroposterior chest distance 3. Calcification of costochondral junction 4. Loss of alveolar wall surface area 5. Loss of bronchial muscle fibers 6. Development of panacinar emphysema Physiologic Function 1. Decreased vital capacity 2. Increased functional residual capacity 3. Increased closing lung volume 4. Decreased expiratory flow 5. Decreased lung diffusing capacity 6. Increased alveolar-arterial Po, gradient 7. Decreased aerobic capacity Because there is no marker for asthma, however, as there is for other diseases (e.g., pancreatitis [amylase] or diabetes [glucose]), it can be difficult to distinguish asthma from other diseases, particularly COPD, in the elderly patient. Yet, because many of the causes of asthma are amenable to treatment, it is appropriate to take a careful history, perform a thorough physical examination, and obtain pulmonary function tests to distinguish between asthma and other respiratory diseases.
Pulmonary Conditions
Chronic Obstructive Pulmonary Disease
Many patients with asthma symptoms either currently smoke cigarettes or have in the past, yet also have a history of childhood asthma or wheezing or allergic rhinitis, suggesting underlying atopy. Therefore, various empiric methods have been developed to distinguish asthma from COPD. Pulmonary function testing, HRCT, and response to corticosteroids were alluded to previously and are described in this section. Because asthma and COPD frequently coexist in many patients, results of these tests often show mixed disease. Pulmonary function testing can be used to distinguish between asthma and COPD (see Table 1).Usually spirometry, including FEV, and FVC and the response to bronchodilators are checked. If there is no response to bronchodilators, asthma often can be excluded.21There are no universally accepted criteria for the degree of reversibility necessary to diagnose asthma, however. Frequently, a 12% to 15% improvement in FEV, expressed as a percent of baseline is employed for this purpose, sometimes with the additional requirement that the improvement be at least 200 mL.22This degree of reversibility, however, is not observed frequently, even in patients with uncomplicated asthma. Perhaps an improvement in FEV, of 10% of the predicted value is sufficient, because
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it exceeds the 96th percentile for bronchodilation in asymptomatic, nonsmoking subjects." Indeed, a recent study demonstrated that a 10% improvement in predicted value was able to identify the asthmatics with 0.92 sensitivity and 0.95 specificity.'s Although the presence of reversibility is helpful in diagnosing asthma, reversibility is not always present. For example, irreversible airflow obstruction can be seen in severe asthma. If patients do not demonstrate significant reversible airflow obstruction following bronchodilator administration, several other parameters can be assessed. For example, elevation of the DLCO above normal can occur in patients with asthma; in contrast, it is decreased in patients with COPD owing to emphysema with destruction of the capillary bed. A normal DLCO is not diagnostic, however, and a mixed picture may be present. Also, although patients with asthma typically have bronchial hyperresponsiveness and those with COPD do not, the response to inhaled methacholine does not always distinguish between the two diseases. For example, if the baseline pulmonary function is decreased, such as in fixed airflow obstruction, bronchial hyperresponsiveness can simply reflect the diminished baseline FEV,, because there is a linear correlation between bronchial hyperresponsiveness and baseline FEV,. Imaging studies do not necessarily distinguish between asthma and COPD due to emphysema. Hyperinflation can be seen on chest roentgenograms in both diseases. As might be expected, even with HRCT, airway abnormalities and air trapping are seen in both diseases, and preliminary data do not show any distinguishing features.31 A response to oral corticosteroids is classically linked to asthma, whereas patients with pure COPD usually do not respond to corticosteroids. Still, as many as 20% of patients with COPD have some airway reversibility and do respond to corticosteroids; these patients likely have mixed disease. Finally, there are patients with longstanding, severe asthma who have developed fixed airflow obstruction and may not respond to corticosteroids. Finally, there have been gender biases in the diagnosis of airflow obstruction by health care providers. Women and patients with a history of allergic disease are much more likely to be diagnosed as having asthma, whereas men and smokers are more likely to be diagnosed as having chronic bronchitis or emphysema.*" In summary, it is difficult to distinguish between asthma and COPD in the elderly with a history of cigarette smoking, probably because many patients have mixed disease, both a reduced FEV, (fixed disease) and a response to an inhaled bronchodilator (reversible disease). Upper Airway Obstruction
After COPD, a likely alternative diagnosis in suspected asthma is upper airway obstruction (UAO), which can be a result of external compression or vocal cord dysfunction. Vocal cord dysfunction can
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occur as a result of crycoarytenoiditis, particularly in patients with rheumatoid arthritis. It has also been described as a result of a conversion reaction? or, rarely, postnasal drainage.’3 The flow volume loop, from a spirometric maneuver, is very useful in UAO evaluation. Vocal cord dysfunction with fixed obstruction would manifest as a plateau on both the inspiratory and expiratory limbs of the loop. Interstitial Lung Disease Interstitial lung disease (ILD) can usually be distinguished from asthma because the findings on history-taking, physical examination, imaging studies, and pulmonary function testing are quite different from asthma. When describing their symptoms, patients with ILD describe dyspnea, often limiting daily activities, yet rarely describe wheezing. On physical examination they may have clubbing, and usually have fine “velcro” inspiratory crackles heard best at the lung bases. Imaging studies demonstrate interstitial infiltrates, and HRCT is diagnostic. Finally, spirometry demonstrates restrictive rather than obstructive disease (reduction in both FEV, and FVC with the FEV,/FVC ratio normal or elevated), reduced lung volumes (TLC or TGV), and reduced pulmonary diffusing capacity. Bronchiectasis Bronchiectasis can usually be distinguished from asthma, primarily on the bases of history and imaging studies. The two diseases may coexist, however, and longstanding asthmatics may develop bronchiectasis. The patient with bronchiectasis expectorates mucopurulent sputum, occasionally with hemoptysis, often more than several tablespoons daily. Symptoms of cough, wheezing, and dyspnea may be present. The physical examination may be relatively nonspecific. Clubbing may be present, and lung examination may reveal evidence of obstruction with prolonged exhalation and wheezing. Imaging studies are diagnostic of bronchiectasis, however. The abnormal airway architecture is clearly seen on HRCT and can often be seen as tram-track lines on chest CT or even on chest roentgenogram. Pulmonary Embolism Pulmonary embolism (PE) can be associated with dyspnea, wheezing, hypoxemia, and chest pain, and is more prevalent in the elderly than in younger populations? Patients with PE, however, usually don’t have a history of asthma, their symptoms are unlikely to completely reverse with bronchodilator treatment, and pleuritic chest pain is often prominent. Risk factors for PE should be identified, including thrombophilia, and clinical risk factors such as age more than 40 years, obesity, cancer, estrogen treatment, recent surgery, bed rest, congestive heart failure (CHF), myocardial infarction, stroke, fracture, multiple trauma,
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childbirth, and history of venous thrombosis. If clinical suspicion for PE is high, appropriate diagnostic studies should be performed. Diagnostic studies for PE include duplex ultrasonography of the lower extremities, ventilation-perfusion scanning of the lung, and pulmonary angiography. Bronchogenic Carcinoma Lung cancer can usually be distinguished from asthma. Although there may be wheezing due to endobronchial narrowing and turbulent airflow, the wheezing is usually l~calized.~ The chest roentgenogram will usually demonstrate the lesion. CT of the chest can be performed as part of the staging and procedure. Cardiac Disorders
Cardiac asthma can present with symptoms similar to those of asthma. The symptoms of dyspnea, wheezing, and cough are quite nonspecific. The history of weight gain and edema is more suggestive of CHF, however. Physician examination may reveal diffuse wheezing. If the patient is in overt CHF, the cardiovascular examination may reveal an additional heart sound (S3) and vascular congestion with neck vein distention and pedal edema. Pulmonary function testing may not be diagnostic, although CHF usually is associated with a mixed obstructiverestrictive pattern with a predominant restrictive component rather than the pure obstruction seen in asthma. Also, an increased DLCO and increased bronchial hyperresponsiveness can be seen in both diseases.30 In contrast, imaging studies may be quite helpful. If left ventricular failure is present a chest roentgenogram may demonstrate left ventricular enlargement and pulmonary vascular congestion. Also, supine and prone HRCT can be performed, and the vascular congestion will be gravity dependent. Finally, the electrocardiogram may demonstrate left ventricular hypertrophy. If the diagnosis is difficult, it may be necessary to obtain an echocardiogram or directly assess ejection fraction with a gated blood pool scan. Gastrointestinal Disorders
Aspiration Aspiration is common in the elderly for several reasons. First, the gag reflex is diminished. Second, gastroesophageal reflux is very common. Third, the elderly are frequently on multiple medications that can increase sedation. Fourth, the elderly are prone to neuropsychiatric disorders. About 10% are debilitated; the most common problems are the affective disorders and organic mental disorders, particularly dementia.*O Finally, the elderly have an increased prevalence of alcoholism. Symp-
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
571
toms of cough and wheeze are common but not always present in patients who aspirate, so clinical suspicion needs to be high. The chest roentgenogram may be helpful, particularly if it demonstrates the lower lobe infiltrates characteristic of aspiration. INTERACTIONS AMONG EFFECTS OF AGING AND ASTHMA Aging causes many changes in the elderly. This section focuses on the well-described anatomic and physiologic changes in the respiratory system as well as the controversial topic of changes in the airway response to pharmacologic therapy. Physiologic Aspects of Aging Both anatomic and physiologic changes occur with aging. The major changes that occur are loss of elastic tissue and elastic recoil. There may be a decrease in the number of fibers, and perhaps a change in the relationship of elastic fibers to each other. Also, the chest wall becomes stiffer, resulting in decreased compliance and an enlarged anteroposterior distance. This results in a small increase in TLC and a larger increase in functional residual capacity (FRC) and residual volume (RV)? The increase in RV is due to premature airway closure. In dependent lung regions, this is exacerbated by increased intrathoracic pressure, which prematurely collapses noncartilaginous airways. This deterioration of ventilatory function is accelerated in smokers by the addition of chronic bronchitis and centrilobular emphysema. Decreased muscle force in the chest wall and diaphragm results in decreased vital capacity and decreased maximum expiratory flows. FEVl declines, although the rate is quite variable (Figure 2). A 15year longitudinal study of healthy nonsmokers in the United States revealed a mean annual decline in FEVl to be 31 mL in men and 26 mL in women. In Australia a similar study demonstrated an annual decline of 35 mL in normal men and 50 mL in nonsmoking asthmatic men. This decline in ventilatory function may not be linear, despite the prediction of linear regression equations. Gas exchange also decreases with aging. This results from loss of surface area, yet the reason for the loss is unclear. Also, there is increased ventilation-perfusion mismatch, perhaps owing to the uneven distribution of ventilation relative to capillary perfusion. Again, the changes are not linear with aging, making evaluation of gas exchange in the elderly more difficult. The decline in maximum oxygen consumption is well established in the elderly.19This decrease in aerobic capacity may not be limiting in patients without lung disease. In patients with airflow obstruction and loss of ventilatory reserve, however, this decreased capacity may be inadequate to maintain physiologically adequate gas exchange, particularly under conditions of stress and infection.
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Changes in Airway Response to Pharmacologic Therapy Pharmacologic therapy with agents such as bronchodilators and antiinflammatory agents has dramatically improved asthma treatment. Antiasthmatic drugs, however, may have significant adverse effects in the elderly and dosage considerations are paramount (Table 2). Furthermore, the effect of the aging process on the airway responses to these agents is not fully understood. There is speculation that airway P-adrenergic receptors change with aging. There are studies suggesting that the response to inhaled Padrenergic agonists decreases with age.32Reasonable hypotheses would be that the airway P-adrenergic receptors decrease in either number or function in the elderly. An intriguing possibility is that there is an agerelated decrease in P-adrenergic receptors out of proportion to a decrease in anticholinergic receptors. This would explain the effectiveness of anticholinergic agents in the elderly with asthma and COPD. Of interest, Barros and Reesla confirmed that increased age was associated with a decline in airway response to albuterol but not to ipratropium bromide. Not all studies, however, show a decrease in response to inhaled Padrenergic agonists with age.I5 CONCLUSION
In conclusion, asthma is very common in the elderly, with a prevalence of about 7% to 9%. Because many patients with asthma either currently smoke cigarettes or have in the past, they frequently have
Table 2. ANTIASTHMATIC DRUGS IN THE ELDERLY Drug
Adverse Effects
Dosage Considerations
p agonist Oral Inhaled Anticholinergic Inhaled Theophylline Oral Corticosteroids Oral Inhaled Cromolyn Inhaled
Tremor, tachycardia Uncommon
Reduce or discontinue No changes necessary
Uncommon
No changes necessary
Nausea, vomiting arrhythmias, seizures
Discontinue or maintain serum level 10-20 kg/mL
Osteoporosis, cataracts, reduces T-cell function, myopathy aggravates hypertension Oropharyngeal candidiasis
Maintenance dosage below 20 mg/AM Use a reservoir spacer
Uncommon
No changes necessary
DIFFERENTIAL DIAGNOSIS OF BRONCHIAL ASTHMA IN THE ELDERLY
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mixed disease with features of both asthma (reversible airflow obstruction) and COPD (fixed airflow obstruction). Patients with COPD often have a reversible component to their condition, such that medications may relieve some symptoms and improve the patient’s quality of life. The differential diagnosis of asthma in the elderly needs to take into account not just COPD, but also other pulmonary conditions such as UAO, ILD, bronchiectasis, PE, and bronchogenic carcinoma. Asthma also needs to be distinguished from nonpulmonary diseases, particularly cardiovascular and gastrointestinal diseases. Finally, it is essential to differentiate the normal, psychologic, and psychosocial changes that accompany aging processes from abnormal changes that accompany age-associated diseases such as asthma.
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Address reprint requests to Molly Lee Osborne, MD, PhD Pulmonary Section lllD 3710 SW US Veterans Hospital Road Portland, OR 97207