What could be the cause of shortness of breath (dyspnea) on exertion over short distances, feeling of weakness, in an adult with a negative stress test, and what further evaluation and management would be recommended?

Evaluation of Exertional Dyspnea with Negative Stress Test

In an adult with shortness of breath on exertion over short distances, weakness, and a negative stress test, perform spirometry before and after bronchodilator followed by cardiopulmonary exercise testing (CPET) to differentiate between exercise-induced bronchoconstriction, dysfunctional breathing, deconditioning, and non-ischemic cardiac causes—as the negative stress test excludes ischemic heart disease but does not rule out other important cardiopulmonary pathologies. 1, 2

Initial Diagnostic Workup

Spirometry and Pulmonary Function Testing

• Obtain baseline spirometry with pre- and post-bronchodilator measurements to identify underlying asthma, COPD, or restrictive lung disease that may not be apparent on history alone. 3, 2
• Perform a focused physical examination specifically looking for signs of restrictive conditions including obesity, skeletal defects (pectus excavatum), evidence of diaphragmatic dysfunction, or interstitial disease. 3
• Normal spirometry does not exclude exercise-induced bronchoconstriction (EIB), which is the most common pathologic cause of exercise-related dyspnea in adults. 2

Exercise Challenge Testing

• If spirometry is normal or near-normal, proceed with formal exercise challenge testing using treadmill or cycle ergometry, as indirect challenges are more sensitive than methacholine for diagnosing EIB. 1, 2
• The patient must achieve and sustain heart rate ≥85% of maximum for 6 minutes after a 2-4 minute warm-up period. 3, 1, 2
• Measure spirometry at baseline, immediately post-exercise, and at 5,10, and 15-minute intervals to detect delayed bronchoconstriction—a fall in FEV1 ≥10% from baseline confirms EIB. 1, 2

Differential Diagnosis Considerations

Exercise-Induced Bronchoconstriction

• EIB commonly presents with chest tightness and dyspnea triggered by exertion that resolves at rest, particularly in cold air. 1
• Do not diagnose based on self-reported symptoms alone—objective bronchoprovocation testing is mandatory. 3, 1, 2
• Do not initiate therapeutic trials without establishing a diagnosis, as this leads to unnecessary medication use and missed alternative diagnoses. 1, 2

Dysfunctional Breathing and Deconditioning

• If exercise challenge is negative but symptoms persist, perform comprehensive cardiopulmonary exercise testing (CPET) to differentiate between true pathologic dyspnea, hyperventilation, dysfunctional breathing patterns, or simple deconditioning. 3, 2
• Deconditioning is perhaps the most common reason for exercise-induced dyspnea without underlying disease, particularly in poorly conditioned individuals. 3
• Idiopathic hyperventilation presents with sustained hyperventilation, hypocapnia, and dyspneic drive during exercise. 3

Exercise-Induced Laryngeal Dysfunction (EILD)

• Consider EILD if inspiratory stridor is present or suspected—this requires flexible laryngoscopy during exercise for diagnosis. 3, 2
• EILD can coexist with EIB and may require a multidisciplinary approach including speech therapy. 3

Non-Ischemic Cardiac Causes

• Although the stress test is negative for ischemia, consider stress echocardiography with expanded protocol to evaluate for elevated left ventricular end-diastolic pressure (E/e' ratio), diastolic dysfunction, or exercise-induced mitral regurgitation. 4
• Look for chronotropic insufficiency during exercise, particularly if the patient is on beta-blockers—this can cause exertional dyspnea and weakness independent of ischemia. 4
• Beta-blockers themselves can cause dyspnea and shortness of breath as adverse effects in approximately 3% of patients. 5

Other Considerations

• Evaluate for gastroesophageal reflux disease (GERD), which can cause exercise-related respiratory symptoms that mimic asthma. 3
• Consider exercise-induced anaphylaxis if systemic symptoms like pruritus, urticaria, or hypotension accompany respiratory symptoms. 3, 1
• Obtain complete blood count to exclude anemia as a contributor to exertional dyspnea and weakness. 6

Critical Pitfalls to Avoid

• Do not assume a pulmonary cause without excluding cardiac pathology beyond ischemia—diastolic dysfunction, valvular disease, and chronotropic insufficiency can all present with exertional dyspnea despite negative stress testing. 1, 4
• Do not overlook medication side effects, particularly if the patient is on beta-blockers, which commonly cause dyspnea and fatigue. 5
• Recognize that in approximately one-third of patients, dyspnea has multifactorial etiology—more than one condition may be contributing simultaneously. 6
• If psychological factors are suspected (particularly in young women with breathlessness without objective findings), consider referral for psychological evaluation, but only after thorough objective testing excludes organic pathology. 3