What are the differential diagnoses for a patient presenting with dyspnea?

Differential Diagnosis of Breathlessness

Primary Etiologies

The differential diagnosis of dyspnea is dominated by cardiopulmonary disease, with approximately 85% of cases attributable to congestive heart failure, myocardial ischemia, COPD, asthma, and interstitial lung disease, though over 30% of cases involve multiple simultaneous etiologies. 1, 2

Pulmonary Causes

• COPD is the most common pulmonary cause, characterized by progressive dyspnea, chronic cough, sputum production, and smoking or occupational exposure history 2
• Asthma presents with variable dyspnea and chest tightness that fluctuates between days and throughout single days 2
• Interstitial lung disease causes progressive dyspnea with restrictive physiology and sensations of "air hunger" or "inability to get a deep breath" 1
• Pneumonia can present acutely or as chronic dyspnea in certain populations 2
• Small airways disease, including post-COVID-19 air trapping, is detectable on expiratory CT imaging 1, 2
• Bronchiectasis is suspected when large volumes of sputum production are present 2
• Pulmonary embolism typically presents with sudden onset dyspnea 3
• Pneumothorax causes sudden onset dyspnea 3
• Pleural effusion causes compressive atelectasis and stimulation of pulmonary receptors 1

Cardiac Causes

• Congestive heart failure is characterized by orthopnea, paroxysmal nocturnal dyspnea, bendopnea, jugular venous distention, and peripheral edema 2
• Myocardial ischemia accounts for a significant proportion of dyspnea cases 1
• Pulmonary hypertension and other pulmonary vascular diseases cause dyspnea through stimulation of vascular receptors 1, 2
• Right-to-left shunt (PFO/ASD) is particularly suspected when clubbing is present without parenchymal lung disease, especially with concurrent OSA increasing right atrial pressures 2, 4

Neuromuscular Causes

• Myasthenia gravis, Guillain-Barré syndrome, spinal cord injury, myopathy, and post-poliomyelitis syndrome cause dyspnea through muscle weakness and impaired ventilatory mechanics 1
• Diaphragm dysfunction reduces ventilatory capacity 1

Systemic Causes

• Anemia decreases oxygen carrying capacity and stimulates chemoreceptors 1
• Hyperthyroidism increases metabolic demand and respiratory drive 1
• Obesity impairs chest wall compliance 1
• Renal disease causes metabolic acidosis that stimulates respiratory drive 1

Chest Wall and Pleural Causes

• Severe kyphoscoliosis decreases chest wall compliance 1
• Pleural effusion causes compressive atelectasis 1

Psychogenic Causes

• Hyperventilation syndrome, anxiety disorders, and panic attacks cause dyspnea through behavioral factors and altered respiratory drive 1

Critical Diagnostic Approach

Timing Classification

Determining if dyspnea is acute (<4 weeks) or chronic (>4-8 weeks) fundamentally changes the differential diagnosis. 1, 3

• Sudden onset suggests pulmonary embolism or pneumothorax 3
• Gradual progression indicates heart failure, COPD, or interstitial lung disease 3

Key Historical Features to Elicit

• Orthopnea and paroxysmal nocturnal dyspnea are highly specific for heart failure 3
• Bendopnea is highly specific for elevated ventricular filling pressures 2
• Variable daily symptoms suggest asthma, while progressive worsening suggests COPD or ILD 2
• Chest tightness is relatively specific for bronchoconstriction 1
• "Air hunger" and "inability to get a deep breath" are commonly seen with dynamic hyperinflation in COPD or restrictive mechanics in heart failure or pulmonary fibrosis 1

Physical Examination Findings

• Tachypnea (>20 breaths/minute) suggests respiratory distress 3
• Hypoxemia (SaO2 <90%) indicates significant cardiopulmonary pathology 3
• Jugular venous distention indicates elevated right atrial pressure from heart failure or pulmonary hypertension 3
• Clubbing without parenchymal lung disease strongly suggests right-to-left shunt 4

Diagnostic Testing Algorithm

First-Line Testing (Perform in All Patients)

• Chest radiography is the initial imaging study and should be performed in all patients with dyspnea 1, 3, 2
• Spirometry is required to diagnose COPD, with post-bronchodilator FEV1/FVC <0.70 confirming persistent airflow limitation 2
• Electrocardiography identifies arrhythmias, ischemia, and cardiac enlargement 3, 2
• Complete blood count detects anemia and screens for lymphoproliferative disorder 2, 4
• Basic metabolic panel assesses for metabolic causes 2
• BNP/NT-proBNP helps differentiate cardiac from pulmonary causes 3
• Pulse oximetry documents hypoxemia 3

Second-Line Testing (When Initial Testing is Nondiagnostic)

• CT chest without contrast is the most appropriate imaging study for diagnosing suspected pulmonary causes of chronic dyspnea 1, 2
• CT chest with IV contrast is used for suspected pulmonary vascular disease 2, 4
• Inspiratory/expiratory CT evaluates air trapping in small airways disease 1, 2
• Echocardiography assesses cardiac function and structure 3
• Transthoracic echocardiography with bubble study (agitated saline contrast) is appropriate for unexplained dyspnea to detect right-to-left shunt 4
• Pulmonary function tests provide detailed assessment of lung mechanics 3

Definitive Testing (When Diagnosis Remains Elusive)

Cardiopulmonary exercise testing is the definitive test for unexplained dyspnea when initial evaluations are nondiagnostic, as it categorizes abnormalities into oxygen delivery, oxygen utilization, or ventilatory disorders. 3, 5

Common Diagnostic Pitfalls

• Clinical assessment has high specificity (96%) but low sensitivity (59%) for cardiac causes, making objective testing mandatory 3
• Normal chest radiography does not exclude cardiac disease, as early heart failure and diastolic dysfunction may have normal chest X-rays 3
• Assuming single etiology may lead to misdiagnosis, as >30% of chronic dyspnea cases are multifactorial 1, 2
• Normal spirometry does not exclude small airways disease, as air trapping on expiratory CT indicates functional obstruction even when airways appear structurally normal 2
• Using fixed FEV1/FVC ratio <0.70 may overdiagnose COPD in elderly and underdiagnose in adults <45 years 2
• Physical examination is rarely diagnostic, as physical signs of airflow limitation/hyperinflation are usually not identifiable until significantly impaired lung function is present 2