Chronic Dyspnea Unexplained by History, Physical Examination, Chest Roentgenogram, and Spirometry

Chronic Dyspnea Unexplained by History, Physical Examination, Chest Roentgenogram, andSpirometry* Analysis of a Seven-year Experience William} DePaso, M.D., F.G.G.R; Richard H. Winter-bauer; M.D., F.G.G.E }ames A. Lusk, M.D.; David F. Dreis, M.D., F.G.G.E; and Steven G. Springmeyer; M.D., F.G.G.E

The purpose of this article is to describe the spectrum and frequency of diseases presenting as unexplained dyspnea and to develop a logical diagnostic approach to such patients. Seventy-two consecutive physician-referred patients had dyspnea greater than one-month duration unexplained by the initial history, physical examination, chest roentgenogram, and spirometry. Patients underwent a standard diagnostic evaluation. A de6nite cause for dyspnea was recognized in 58 patients, and DO answer was found in 14. Twenty-two diseases were recognized in the patient group. Dyspnea was due to pulmonary disease in !6 (36 percent) patients, cardiac disease in ten (14 percent) patients, hyperventilation in 14 (19 percent) patients, and only 3 patients had extrathoracic disease causing dyspnea. Age younger than 40 years, intermittent dyspnea, and normal

alveolar-arterial oxygen pressure difference (P[A-a]OJ at rest breathing room air was strongly predictive of bronchial hyperreactivity or hyperventilation. No patient diagnosed as having disease of the lung parenchyma or vasculature had a P(A-a)O. s20 mm Hg. The differential diagnosis to explain dyspnea in patients with nondirective histories, normal 6ndings from physical examinations, DOrmal chest roentgenograms, and normal spirograms is extensive. The patient's age and measurement of gas exchange at rest help to formulate a diagnostic approach.

patients with chronic dyspnea will have M ostasthma, chronic obstructive lung disease, inter-

nondiagnostic chest roentgenogram; and (3) absence of spirometric evidence for either restrictive (FVC ~80 percent predicted normal) or obstructive (FEV/FVC 2:70 percent) lung disease. The chest roentgenogram was usually normal. In some instances there were minor roentgenographic abnormalities (focal parenchymal or pleural scarring, prominence ofpulmonary arteries, or plate-like atelectasiS) that were judged clinically insignificant because they were not an adequate explanation for the dyspnea and/or stable prior to and during the dyspnea. A flow-volume curve was performed with a spirometer (Ohio 840 or Wedge Med-Science 570) with a forced expiratory maneuver from maximal inhalation and analyzed according to the predicted normal values of Schoenberg et al. l

stitiallung disease, or cardiomyopathy diagnosed on objective findings from the histol"}; physical examination, chest roentgenogram, and spirometry.l Dyspnea that remains unexplained after this diagnostic seFor editorial comment see page 1187

quence provides a major diagnostic challenge. This report reviews our experience with 72 such patients seen over a seven-year period in a referral pulmonary practice. Our goals were to describe the spectrum and frequency of diseases presenting as unexplained dyspnea and to determine if a logical diagnostic approach could be formulated. METHODS

lbtient Population All physician-referred patients who presented to the section of Pulmonary and Critical Care Medicine of the Virginia Mason Clinic (Seattle, WA) between 1981 and 1988 with unexplained dyspnea of greater than one-month duration were prospectively enrolled in the stud~ Entry criteria included the following: (1) an unrevealing history and physical exmaination by the referring physician; (2) a ·From the Section of Pulmonary and Critical Care Medicine, the Virginia Mason Medical Center, Seattle, Washington. Manuscript received August 27; revision acceptea March 8. Reprint requests: Dr. Winterbauer, 1100 Ninth Avenue, Seattle, 98101

(Cheat 1991; 100:1293-99)

nco. =single breath carbon monoxide difFusion capacity; MlPI =maximal inspiratory and expiratory pressure; VIQ scan =ventilation-pelfusion lung scan

MEP

Diagnostic Evaluation

Each patient underwent a repeated history and physical examination. The history included age at onset, duration, pattern, and intensity ofdyspnea. The intensity ofdyspnea was graded according to the scale shown in 1llble 1. Patients in whom the repeated history and physical examination yielded previously unrecognized but diagnostically directive 6ndings were subjected to specific testing to confirm the impression reached. Patients with a negative history and normal results of a physical examination had a chemistry battery, including serum thyroxine level, and an arterial blood gas level at rest breathing room air with calculation of the alveolar-arterial oxygen gradient (P[A-a]OJ. The patients were then subjected to noninvasive testing. The tests used included the single-breath carbon monoxide diffusion capacity (Dcos.) analyzed according to Ogilvie et al, 3 repeat spirometry following inhaled bronchodilators, inspiratory flow-volume loop, measurement of maximal inspiratory and expiratory pressures (MIPIMEP), ventilation-perfusion lung scan (VIQ scan), a two-dimensional echocardiogram, cardiac exercise treadmill examination, Holter monitoring, methacholine or exercise bronchoprovocation testing, computed tomographic (Cf) CHEST I 100 I 5 I NOVEMBER, 1991

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Table I-Grade of lJyspnea Grade

Description

1

Dyspnea only with a vigorous exercise program" Dyspnea with walking on a steep hill without a load, walking up more than two flights of stairs, or carrying a moderate load while walking on the level Dyspnea with walking on a gentle hill without a load, walking up less than two flights of stairs, or carrying a light load while walking on the level Dyspnea with any walking on the level Dyspnea at rest Dyspnea of variable intensity

2

3 4 5

Variable

scanning of the thorax, upper gastrointestinal series, 24-hour esophageal pH monitoring, and cardiopulmonary exercise testing with measurement of gas exchange. The sequence and number of tests were performed at the discretion of the managing pulmonologist. The diagnostic sequence was terminated when a disease that offered an adequate explanation for the patient's dyspnea was recognized. No effort was made to perform all tests in all patients. Invasive tests such as fiberoptic bronchoscopy, open lung biopsy, and pulmonary or coronary arteriography were performed only when clinically indicated. Diagnostic Criteria For a disease to be accepted as the explanation for the patient's dyspnea, the follOwing criteria were met. (1) The diagnosis made had to be based on accepted diagnostic criteria. (2) The disease had to be a recognized cause of dyspnea and present in a degree consonant with the severity of the patient's dyspnea. (3) Whenever possible, treatment of the disease had to result in improvement or disappearance ofdyspnea. (4) A minimum one-year period offollowup failed to reveal any additional diseases capable of causing dyspnea. The diagnostic criteria for impaired oxygenation, bronchial hyperreactivity, and hyperventilation are listed in'Thble 2.4-7 Diagnostic criteria for other diseases recognized as causes of dyspnea are detailed and referenced in the CCResults" section. Patients who had no recognizable abnormality were classified as having unexplained dyspnea. Minimum testing in these patients included DcoSB , V/Q scan, and echocardiogram. In most instances, a more extensive evaluation was performed. In addition, a mean two-year follow-up failed to reveal any subsequent diagnoses that explained the dyspnea. At the completion of the study period, aU charts were reviewed by a single investigator (W J. D.) who was not involved in the patient's care, to ensure that diagnostic criteria were met. RESULTS

Seventy-seven patients were entered in the stud~ A repeat history and physical examination revealed previously unrecognized clinical findings that directed the diagnostic sequence in five patients. The presence of stridor led to the diagnosis of upper airway obstruction due to vocal cord paralysis in two patients. A patient with a chronic lower respiratory tract infection was recognized through a history of productive cough. One patient had typical angina pectoris and an endobronchial malignant neoplasm was recognized in one patient who had unilateral diminished breath sounds and palpable supraclavicular adenopath~ The remaining 72 patients with dyspnea unexplained by the 1294

pulmonologist's repeat history and physical examination, chest roentgenogram, and expiratory spirogram make up the final study group. Respiratory tract disease was the explanation for dyspnea in 26 (36 percent) patients, followed by cardiac disease in ten (14 percent), hyperventilation syndrome in 14 (19 percent), gastroesophageal reDux in three (4 percent), thyroid disease in two (3 percent), poor conditioning in two (3 percent), and renal disease in a single patient (Table 3). Fourteen patients (19 percent) had no recognizable cause of dyspnea. Respiratory Tract Disease

Bronchial Hyperreactivity: There were 12 patients with bronchial hyperreactivity. Inhalational or exercise provocation challenge tests were diagnostic in ten Table 2- DiGgnoBtic CriteritJ Diagnostic Criteria Impaired oxygenation at rest, breathing room air

Bronchial hyperreactivity

Hyperventilation syndrome

Reference PaOt <75 mm Hg P(A-a)OI >20 mm Hg (PaOI calculated using the alveolar gas equation assuming R=0.8 and Patm = 760 mm Hg) 1) ~15% increase in FEV. following inhaled isoproterenol, or 2) ~20% reduction in FEV1 during or within 20 minutes after exercise, or 3) ~20% decrease in FEV. at a methacholine concentration s8 mwml 4) beneficial response to bronchodilators 1) 5 or more of the following must be present: a) Episodic dyspnea; sudden in onset, brief in duration, and unrelated to exercise b) Palpitations c) Circumoral or peripheral paresthesias d) Inability to fill the lungs or take a satisfying breath e) Severe anxiety or fear associated with dyspnea f) Lightheadedness or dizziness g) Frequent sighing or yawning h) Trembling of the hands 2) Normal V/Q, DcoSB , and two-dimensional echocardiogram 3) Complete resolution of symptoms at last follow-up

4

5 6

7

Unexplained Chronic Dyspnea (DePeso et aI)

Table 3- Cause of DyIlpflelJ in 12 Patients Principal Organ System Involved (No. of Patients) Respiratory tract disease (26)

Anatomic Site of Disease (No. of Patients) Airway obstruction (14) Pulmonary parenchyma (5) Pulmonary vasculature (4) Respiratory muscles (2)

Cardiac disease (10)

Central nervous system (14) Thyroid

Chest wall (1) Myocardium (6) Conduction (2) Endocardium (1) Pericardium (1)

Kidney (1) Gastrointestinal tract (3) Poor conditioning (2) Unexplained (14)

patients. 5 ,6 The other two patients had an FEV I >80 percent of predicted normal but had > 15 percent increase in the FEV I after inhaled isoproterenol. All patients had a decrease in dyspnea with bronchodilator therap~

Intrathoracic Focal Large Ainvay Obstruction: One patient had a roentgenographically occult malignant neoplasm. The V/Q scan demonstrated absence of perfusion and ventilation to the affected lung. The diagnosis of endobronchial obstruction was confirmed by fiberoptic bronchoscopy. Surgical resection was successfully performed. Extrathoracic Upper Ainvay Obstruction: One patient had obstructive airflow disease due to bilateral vocal cord paresis. A flow-volume inspiratory loop suggested a variable extrathoracic obstruction and direct visualization demonstrated bilateral vocal cord dysfunction (immobile right cord and abductor paralysis of the left cord) with upper airway occlusion during rapid inspiration. 8 Bullous Disease: Bullous disease without spirometric evidence of airway obstruction was present in two patients. The diagnosis was established by visualization of bullae on both cr scan and pulmonary angiogram. Both patients were heavy smokers with DcosB <40 percent predicted normal and abnormal oxygenation. Interstitial Lung Disease: Roentgenographically occult idiopathic pulmonary fibrosis and hypersensitivity pneumonitis (bird fancier's lung) were diagnosed by open lung biopsy specimens in single patients.9-11 Abnormal oxygenation was present in both.

Diagnosis Asthma Intrathoracic focal obstruction of a large airway Extrathoracic upper airway obstruction Interstitial lung disease Bullous disease Chronic lower respiratory bacterial infection Thromboembolic disease Primary pulmonary hypertension Myasthenia gravis Lower motor neuron disease of unknown cause Pectus deformity Coronary artery disease Cardiomyopathy Arrhythmias Intracardiac shunt Constrictive pericarditis Hyperventilation syndrome Thyrotoxicosis Myxedema Metabolic acidosis Gastroesophageal reRux

No. of Patients 12 1 1 2 2 1 3 1 1 1 1 4 2 2

1 1 14 1 1 1 3 2

14

Chronic Lower Respiratory Bacterial Infection: One patient had dyspnea due to chronic lower respiratory infection. The diagnosis was confirmed with a quantitative culture obtained at bronchoscopy and immunofluorescent demonstration of antibody-coated bacteria. 12 Dyspnea completely resolved following a prolonged course of oral antibiotic therapy. Pulmonary \bscular Disease: Three patients suffered from thromboembolic disease and a fourth had primary pulmonary hypertension. All grades of dyspnea were represented. None of these patients had clinical features of acute pulmonary emboli such as episodic dyspnea, hemoptysis, pleuritic chest pain, or calf tenderness. All had a P(A-a)02 ~50 mm Hg at rest. All patients with pulmonary emboli had high probability V/Q scans. 13 Two had the diagnosis confirmed with pulmonary angiography.14 The patient with primary pulmonary hypertension had an indeterminate V/Q scan, mean pulmonary artery pressure of 55 mm Hg, normal pulmonary angiogram, and a normal pulmonary artery occlusion pressure. 15 Pectus Excavatum Defonnity of the Chest Wall: A 29-yea~old patient with pectus excavatum presented with grade 1 dyspnea and a chest roentgenogram that demonstrated a frontosagittal index of 23.5 percent. 16 Graded cardiopulmonary exercise testing demonstrated a reduced maximum oxygen uptake, normal oxygenation, and an abnormal breathing reserve. Diseases of the Respiratory Muscles: Two patients had dyspnea due to respiratory muscle weakness as the initial manifestation of neurologic disease. One patient had myasthenia gravis (positive Tensilon test CHEST I 100 I 5 I NOVEMBER, 1991

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and elevated antiacetylcholine receptor antibody) and the other had evidence of a motor neuron disease by electromyogram and muscle biopsy specimen, but a specific diagnosis could not be made. Both had low maximum inspiratory and expiratory pressures. 17 Diaphragm dysfunction was demonstrated in both during supine chest fluoroscopy. Heart Disease Coronary Artery Disease: Four patients presented with dyspnea as the primary mmifestation ofcoronary artery insufficiency. Two patients had a history ofprior myocardial infarction, but none had symptoms of angina. All four had diagnostically abnormal results of exercise treadmill examinations and one had an abnormal thallium scan as well. 18-20 Two had their diagnosis confirmed by coronary angiography. All had resolution of dyspnea with antianginal therap~ Cardiomyopathy: Obstructive and nonobstructive hypertrophic cardiomyopathy were each diagnosed by two-dimensional echocardiography in single patients as causes ofdyspnea.21,22 Both had significant improvement in symptoms in response to specific therapy. Arrhythmias: Sick sinus syndrome and paroxysmal atrial fibrillation were each diagnosed in single patients. Holter monitoring demonstrated a correlation between rhythm disturbance and dyspnea in both. Permanent pacemaker implantation in one and cardioversion to normal sinus rhythm in the other resulted in resolution of dyspnea in both. lntracardiac Shunt: An intracardiac shunt through a patent foramen ovale was the cause of dyspnea in one patient. Right heart catheterization with a pulmonary angiogram demonstrated a right-to-Ieft shunt without evidence of pulmonary emboli. She died during the hospitalization, and autopsy demonstrated a large ileal carcinoid tumor with multiple hepatic metastases. A deformed and incompetent tricuspid valve secondary to the carcinoid syndrome had resulted in elevated right atrial pressures and right-toleft shunting through a patent foramen ovale. Constrictive Pericarditis: Constrictive pericarditis was the cause of dyspnea in a patient with a 48-month history of shortness of breath following an episode of ventricular fibrillation and prolonged cardiopulmonary resuscitation. Physical examination demonstrated mild peripheral edema and hepatomegal~ but the neck veins were not distended. An echocardiogram suggested pericardial constriction that was demonstrated at right heart catheterization and confirmed at thoracotomy.23 There was resolution of symptoms following pericardiectomy. Gastroesophageal Reflux Three patients experienced dyspnea in association with gastroesophageal reflux. Correlation between 1296

dyspnea and reflux was established with 24-hour pH monitoring. 24 Antireflux therapy resulted in complete resolution of symptoms in two and amelioration in the third. Thyroid Disease Thyrotoxicosis: One patient complained of dyspnea as the sole manifestation of thyrotoxicosis. Normalization of the serum thyroxine level resulted in complete symptom resolution. Myxedema: One patient had hypothyroidism manifested as dyspnea. The T 4 was <0.1 J,LJYdl (normal level, 4.0 to 10.5 J,Lgldl), and thyrotropin was >50 ngldl (normal level, 0 to 12 ngldl). Symptoms resolved with thyroid hormone replacement therapy. Renal Disease (Metabolic Acidosis) One patient had dyspnea secondary to metabolic acidosis associated with mild renal failure due to polycystic kidney disease. Resting arterial blood gas analysis showed a pH of7.36, P02 of 100 mm Hg, and Pco2 of 34 mm Hg with a measured bicarbonate of 19.4 mEq/dl. Symptoms resolved with oral bicarbonate therapy and normalization of the serum bicarbonate level. Poor Conditioning

Two patients developed dyspnea in association with significant weight gain and lack of physical activi~ Their symptoms resolved with an exercise program and weight reduction.

Hyperventilation Syndrome Fourteen patients had dyspnea associated with the hyperventilation syndrome as defined by our diagnostic criteria in Table 2. All had normal Pa02 at rest breathing room air with a mean of92 mm Hg and nine had P(A-a)02 s20 mm Hg. Four of the five with P(A-a)02 >20 mm Hg at rest had improved gas exchange with exercise. All had normal Dcoss , V/Q scan, and echocardiogram. Seven had normal exercise tolerance during a treadmill examination. None of the 14 patients had methacholine challenge tests performed. All had resolution of symptoms after a minimum one-year (mean, two year) follow-up period. Unexplained Dyspnea Fourteen patients complained of dyspnea that remained undiagnosed despite our evaluation. They ranged in age from 47 to 74 years (mean, 62 years). Symptoms were present for a mean of 18 months (range, one to 84 months). All grades and patterns of dyspnea were present. A Dcoss , V/Q scan, and echocardiogram were completed and were either normal or nondiagnostic in all 14 patients. Methacholine challenge testing was performed in only one patient and was normal. Unexplained Chronic Dyspnea (DePaso et aJ)

Two patients had nonnal graded cardiopulmonary exercise tests and four others had nonnal exercise tolerance by cardiac exercise treadmill examination. One patient, who was applying for disability, was suspected of malingering. Hyperventilation syndrome was suspected in two patients, but they failed to meet the diagnostic criteria used in our study. 7 Two patients with associated collagen vascular diseases were suspected of having neuromuscular weakness, but they also failed to meet diagnostic criteria. All patients were followed up one to eight years (mean, five years) with no new diagnoses forthcoming. Two patients had spontaneous resolution ofsymptoms during the followup period. Diagnostic Utility of Specific Tests

The duration and intensity of dyspnea offered no diagnostic insight. A pattern of intermittent dyspnea was seen in 22 patients. Fifteen of the 22 were diagnosed as having hyperventilation or bronchial hyperreactivity. The remaining seven had arrhythmia (two patients), gastroesophageal reflux (two patients), constrictive pericarditis (one patient), and unexplained dyspnea (two patients). An intermittent pattern of dyspnea had a 68 percent positive and 78 percent negative predictability that hyperventilation or bronchial hyperreactivity was present. Seventy-one patients had an arterial blood gas measurement at rest breathing room air. The P(A-a)02 was ~20 mm Hg in 24 patients, 14 of whom had hyperventilation or bronchial hyperreactivity. Arrhythmia, chest wall deformity, constrictive pericarditis, metabolic acidosis, poor conditioning, and upper airway obstruction were each diagnosed in single patients with P(A-a)02 ~20 mm Hg. The remaining four patients had undiagnosed conditions. No patient diagnosed as having disease of the lung parenchyma or vasculature had a P(A-a)02 ~20 mm Hg at rest. There were 16 patients younger than 40 years of age at the time of symptom onset. Thirteen of the 16 were diagnosed as having hyperventilation or bronchial hyperreactivity. The remaining three were diagnosed as having chest wall deformity, malingering, and pulmonary emboli. An age at symptom onset of younger than 40 years was 81 percent positively and 77 percent negatively predictive of hyperventilation or bronchial hyperreactivity. Six of seven patients with the combination of intermittent symptoms and age younger than 40 years had bronchial hyperreactivity or hyperventilation. The combination of onset of dyspnea at age younger than 40 years and a P(A-a)02 ~20 mm Hg was 89 percent positively and 71 percent negatively predictive of the diagnosis of hyperventilation or bronchial hyperreactivity. The addition ofan intermittent pattern of dyspnea increased the positive and negative predictability for these two diagnoses to 100

percent and 67 percent, respectively. The frequency with which a noninvasive test was either diagnostic or directive of further evaluation is listed in Table 4. The DcosB was directive in six patients, methacholine challenge testing was diagnostic in nine patients, and V/Q scanning was directive in seven patients. Cardiac exercise treadmill testing recognized coronary artery disease in four patients and an arrhythmia in another. Cardiopulmonary exercise testing was abnormal and directive in two patients and confirmed normal exercise physiology in another four patients. DISCUSSION

To our knowledge, this is the first reported experience of chronic dyspnea in patients whose conditions remain undiagnosed following a history and physical examination, chest roentgenogram, and spirometry. The present group of72 such patients seen in a referral pulmonary practice over a seven-year period suggests that dyspnea of unknown origin is not uncommon. , However, this is a highly selected group and the true incidence of this clinical presentation is unknown. There is little in the medical literature with which to compare our results. Recently, Pratter and colleagues· reported the causes of dyspnea in 85 patients seen over 14 months in a pulmonary subspecialty clinic. Dyspnea resulted from respiratory disorders in 64 patients (75 percent) with asthma, chronic obstrucTable 4-Diagnoatic 'Yield ofNoninooaive TatB in 72 Potienta No. ofTImes the Abnormal Test Was Either Diagnostic or Directive of No. No. Performed Abnormal Further Evaluation (%) DcoSB * Radionuclide ventilation! perfusion lung scan Echocardiogram Cardiac treadmill examination Methacholine bronchoprovacation Flow volume loop Maximum expiratory pressure! maximum inspiratory pressure Graded cardiopulmonary exercise testing

62 52

6 24

4 (6) 7 (13)

30

37

14 9

4 (11) 5 (11)

12

9

9 (75)

5 6

2 3

1 (20) 2 (33)

15

4

2 (13)

*DrosB = single-breath carbon monoxide diffusion capacity. CHEST I 100 I 5 I NOVEMBER, 1991

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tive pulmonary disease (COPD), and interstitial lung disease seen most commonly. 1 In 66 percent of all patients and in 81 percent of all patients with asthma, COPD, interstitial lung disease, and cardiomyopath), the correct diagnosis was reached following a history and physical examination in combination with a chest roentgenogram. In contrast, our patients had normal chest roentgenograms and we used screening spirometry to specifically exclude COPD and easily recognized asthma. The difference in entry criteria resulted in vastly different patient groups and this is reflected in a comparison of the disease spectrum in the two series. For example, COPD and asthma were the cause of dyspnea in 45 percent of their patients, while no patient in our group had COPD and 17 percent had asthma. Also, pulmonary vascular disease, bullous disease without airway obstruction, vocal cord dysfunction, occult endobronchial neoplasm, disease of the respiratory muscles, and metabolic disease (thyroid dysfunction, metabolic acidosis) collectively explained dyspnea in 18 percent of our patients and were not found in the other series. Despite excluding patients with abnormal forced expirograms, we still found that airflow obstruction in the form of occult bronchial hyperreactivity was a common explanation for dyspnea. When combined with hyperventilation, these diagnoses accounted for 36 percent of patients with unexplained dyspnea. The remaining patients had 1 of 20 different diseases as an explanation for dyspnea. We believe that the relative frequency ofdiagnoses in our patients is representative and thus offers a good basis for formulating a differential diagnosis. Only 3 of 58 patients with an identifiable cause of dyspnea had extrathoracic disease and in each instance it was a metabolic disorder (2 patients with thyroid dysfunction and 1 with metabolic acidosis). Hyperventilation is a diagnosis of exclusion in a compatible clinical setting, and it is difficult to recognize with certaint~ Our seven-year experience with this patient group taught us that bronchial hyperreactivity and hyperventilation are frequently indistinguishable in their clinical presentation. Unfortunatel~ methacholine challenge testing was performed routinely in patients with a clinical diagnosis ofhyperventilation only in the last years ofthe study. This resulted in recognition of five patients with unexpected bronchial hyperreactivit~ A weakness ofour study is found in the 27 patients with hyperventilation or unexplained dyspnea who did not have a methacholine bronchoprovocation test. Despite our use of strict diagnostic criteria for hyperventilation, including spontaneous resolution of symptoms within one year of follow-up, it is very likely that this group contains some patients with unrecognized bronchial hyperreactivity. We reached the following conclusions about the 1298

diagnosis ofdyspnea in patients with a negative history and normal results of a physical examination, normal chest roentgenogram, and normal forced exhalation spirometry. (1) Most but not all patients will have a recognizable disease to explain their dyspnea. (2) The ~isease spectrum is extensive resulting in a very broad differential diagnosis. (3) Neither the duration nor severity of dyspnea provides diagnostic insight. (4) Patients younger than 40 years of age at symptom onset with a P(A-a)02 s20 mm Hg are most likely to have bronchial hyperreactivity or hyperventilation. If all patients younger than 40 years with a P(A-a)02 s20 mm Hg at rest were subjected only to methacholine challenge testing, no patient with an organic cause for dyspnea would have been missed in our patient group. (5) With the exception of methacholine bronchoprovocation, the diagnostic yield of any single noninvasive test was poor because ofthe large number of diagnoses seen in these patients. We have no basis to suggest any specific sequence ofnoninvasive testing. Cost and patient comfort will be the primary considerations. (6) All patients with a clinical diagnosis of hyperventilation should have a methacholine bronchoprovocation test to rule out bronchial hyperreactivity. Also, methacholine bronchoprovocation should be performed on any patient with dyspnea before consigning them to an unexplained categol): (1) Patients with a P(A-a)02 s20 mm Hg are very unlikely to have occult pulmonary parenchymal or pulmonary vascular disease to explain their dyspnea. REFERENCES

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6 Hargreave FE, Ryan G, Thompson NC, Obyrne PM, Latimer K, Juniper EF, et a1. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clio Immunoll981; 68:347-55 7 Magarian GJ. Hyperventilation syndromes: infrequently recognized common expressions ofanxiety and stress. Medicine 1982; 61:219-35 8 Topham JH, Empey DW Practical assessment of obstruction in the larynx and trachea. J Laryngol Oto11974; 88:1185-93 9 Winterbauer RH, Hammar S~ Hallman KO, et a1. Diffuse interstitial pneumonitis: clinicopathologic correlations in 20 patients treated with prednisone and azathioprine. Am J Med 1978; 65:661-72 Unexplained Chronic Dyspnea (DePaso st 8/)

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18 Bruce RA. Exercise testing of patients with coronary artery disease: principles and normal standards for evaluation. Ann Clio Res. 1971; 3:323-32 Beller GA. Should exercise electro-cardiograpbic 19 Gibson testing be replaced byradioisotope methods? In: Rahimtoola SH, ed. Controversies in coronary artery disease. Philadelphia: FA Davis; 1983:1-31 20 Obda RO, Boucher CA, Strauss H~ Pohost GM. Exercise radionuclide imaging: approaches to coronary artery disease. Am J Cardio1198O; 46:1188-203 21 Wayne J, Braunwald E. The cardiomyopathies and myocarditides. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine, 3rd ed. Philadelphia: WB Saunders Co; 1988:1410-60 22 Topol EJ, Traill TA, Fortuin NJ. Hypertensive hypertrophic cardiomyopathy of the elderl~ N Eng) J Med 1985; 312:277-83 23 Fowler NO. Constrictive pericarditis: new aspects. Am J Cardiol 1982; 50:1014-17 24 DeMeester TR, Bonavina L, Iascone C, Courtney ~ Skinner DB. Chronic respiratory symptoms and occult gastroesophageal re8ux. Ann Surg 1980; 211:337-45

its,

North American Society of Pacing and Electrophysiology The NASPE announces call for abstracts for the 13th Annual Scientific Session to be held May 14-16 in Chicago. Deadline for abstracts is December 4, 1991. For information, contact Ms. Barbara K. Krause, Director, Continuing Education, NASPE, 377 Elliot Street, Newton Upper Falls, MA 02164 (617:244-7300).

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