What is the differential diagnosis and initial work‑up for a patient presenting with fatigue, tiredness and dyspnea?

Differential Diagnosis and Initial Work-Up for Fatigue, Tiredness, and Dyspnea

Immediate Diagnostic Approach

Obtain a chest X-ray, complete blood count (CBC), electrocardiogram (ECG), and basic metabolic panel (BMP) as the initial diagnostic battery in all patients presenting with fatigue and dyspnea. 1, 2 This foundational testing identifies the most common life-threatening and treatable causes while guiding subsequent evaluation.

Structured Differential Diagnosis by Age

Young Adults (18-44 years)

• Acute asthma exacerbation (most common specified diagnosis in this age group) 3
• Iron deficiency anemia (especially in menstruating women) 1
• Exercise-induced arrhythmias 1
• Early interstitial lung disease 1
• Diastolic heart failure 1

Middle-Aged Adults (45-64 years)

• Obstructive chronic bronchitis/COPD (most common specified diagnosis, 11.1%) 3
• Asthma 3
• Depression (10-25% prevalence in general population, higher with chronic disease) 4
• Anemia 4, 1
• Heart failure with preserved ejection fraction (HFpEF) (especially in women) 1

Older Adults (65-79 years)

• Obstructive chronic bronchitis/COPD (12.4%) 3
• Congestive heart failure 3
• Malignancy (75% of solid tumor patients report fatigue) 4
• Cardiac amyloidosis (consider when increased LV wall thickness plus carpal tunnel or lumbar stenosis) 1

Elderly (≥80 years)

• Congestive heart failure (most common, 15.9%) 3
• Heart failure with reduced ejection fraction (HFrEF) 1
• Pulmonary hypertension 1
• Advanced COPD 3

Critical History Elements

Symptom Characterization

• Onset pattern: Acute versus chronic, progressive versus stable 1
• Dyspnea quality descriptors: "Chest tightness" suggests bronchoconstriction/asthma; "air hunger" suggests cardiac or metabolic causes 1
• Specific triggers: Exertion level required, time of day patterns, environmental exposures, positional changes 1

Red Flag Symptoms

• Constitutional symptoms: Unintentional weight loss, fever, night sweats (suggest malignancy or systemic illness) 1
• Current malignancy status: Assess for recurrence or progression 1
• Prior cancer treatments: Chemotherapy, radiation, targeted therapy (therapy-related fatigue) 1

Comorbidity Assessment

• Document: Hypertension, diabetes, obesity, atrial fibrillation, chronic kidney disease 1
• Medication review: Treatment adverse effects contribute to fatigue 4, 5
• Environmental/occupational exposures: Hypersensitivity pneumonitis risk 1

Targeted Physical Examination

Cardiovascular Signs

• Cannon wave pulsations in neck veins indicate AV dissociation (high-grade heart block) 1
• Cardiac auscultation: Murmurs, gallops, irregular rhythm 1
• Volume status: Jugular venous distension, peripheral edema 1

Pulmonary Findings

• Fine bibasilar crackles ("Velcro rales") suggest interstitial lung disease 1
• Wheezing: Bronchoconstriction/asthma 1

Other Key Findings

• Pallor: Anemia 1
• Digital clubbing: Chronic hypoxemia, interstitial lung disease, malignancy 1
• Severe obesity: Restrictive ventilatory pattern 1

Initial Laboratory Testing

First-Line Tests (All Patients)

• CBC: Anemia is a common treatable cause 1, 2
• Basic metabolic panel: 1, 2
  • Creatinine ≥2 mg/dL indicates renal disease causing dyspnea via metabolic acidosis, fluid overload, and anemia 1
  • Low bicarbonate suggests metabolic acidosis requiring investigation 1
  • Electrolyte abnormalities (hypo/hyperkalemia) cause respiratory muscle weakness 1
• Chest X-ray: Identifies parenchymal disease, cardiomegaly, effusions 1, 2
• ECG: Arrhythmias (atrial fibrillation, heart block) are common causes 1, 2

Second-Line Testing (If Initial Tests Nondiagnostic)

• BNP or NT-proBNP: When cardiac etiology suspected (interpret cautiously if creatinine elevated, as renal dysfunction elevates levels independent of heart failure) 1
• Transthoracic echocardiography: Evaluate systolic/diastolic function, valvular disease, pulmonary artery pressures, right ventricular function 1, 6
• Pulmonary function tests with DLCO: Assess for obstructive/restrictive patterns and gas exchange 1, 6
• High-resolution CT chest: When interstitial lung disease suspected 1
• Six-minute walk test: Objective functional capacity and oxygen desaturation assessment 1, 6

Additional Testing Based on Clinical Suspicion

• Thyroid function panel: Hyperthyroidism causes fatigue, dyspnea, and arrhythmias 6
• Urinalysis for proteinuria: Nephrotic syndrome mimics heart failure with edema 1
• Abdominal ultrasound: When cirrhosis suspected (edema resembles cardiac congestion) 1
• ANA screening: Autoimmune comorbidities with thyroid disease 6

Condition-Specific Considerations

Depression and Anxiety Screening

• Screen systematically: 32% have anxiety, 27% have depression among those with chronic respiratory disease entering rehabilitation 4
• Risk factors: History of mood disorder, lack of social support, poor symptom control, prolonged treatment, advanced malignancy 4
• Impact: Reduces participation in and benefit from treatment 4

Cancer-Related Symptoms

• Screen at initial visit: For newly identified advanced cancer and at chemotherapy visits 4
• Assess for: Depression, insomnia, anemia, treatment adverse effects 4
• Prevalence: 75% of solid tumor patients and 80-99% undergoing chemotherapy/radiotherapy report fatigue 4

Renal Contribution

• Metabolic acidosis from renal failure directly stimulates respiratory drive, causing compensatory hyperventilation and dyspnea 1
• Elevated creatinine affects BNP interpretation and medication dosing 1

Critical Pitfalls to Avoid

• Do not attribute dyspnea to deconditioning without first excluding cardiopulmonary disease or anemia 1
• Do not pursue extensive cardiac evaluation before addressing obvious anemia (e.g., from menorrhagia in young women) 1
• Do not overlook environmental/occupational exposures that may cause hypersensitivity pneumonitis 1
• Do not dismiss "chest tightness" as anxiety without considering asthma 1
• Recognize cardiac amyloidosis can masquerade as HFpEF; look for extracardiac clues (carpal tunnel, lumbar stenosis) 1
• Avoid extensive cardiac workup in young patients without abnormal cardiac findings on exam or ECG, particularly if anemia is present 1
• Note that 44.6% of dyspnea visits result in potentially life-threatening diagnoses, yet respiratory vital signs are frequently normal 3

Referral Indications

Consider specialty referral (cardiology, pulmonology, hematology) when diagnosis remains elusive after initial workup or when specific organ system pathology is identified 1, 6

Follow-Up Strategy

• Schedule follow-up within 2-4 weeks to review test results before making major treatment decisions 6
• Use regular scheduled visits rather than sporadic urgent appointments for effective long-term management 5
• Reassess systematically rather than repeating normal laboratory studies without clinical indication (repeat testing affects management in only 5% of patients) 5