What are the differential diagnoses and initial evaluation for an adult patient presenting with fatigue and shortness of breath?

Differential Diagnosis and Initial Evaluation for Fatigue and Shortness of Breath

Begin with chest X-ray, complete blood count, electrocardiogram, and basic metabolic panel as your initial diagnostic battery, while simultaneously obtaining a focused history targeting symptom quality, triggers, and associated findings to systematically narrow the differential diagnosis. 1

Key Differential Diagnoses to Consider

Cardiac Causes

• Heart failure with preserved ejection fraction (HFpEF) - particularly common in women, who present with more dyspnea and worse health status than men 2
• Heart failure with reduced ejection fraction - may present with fatigue, dyspnea, and evidence of volume overload 2
• Arrhythmias - including complete heart block, atrial fibrillation, or exercise-induced arrhythmias, especially in younger patients 2, 1
• Valvular heart disease - assess for murmurs on cardiac examination 1

Pulmonary Causes

• Chronic obstructive pulmonary disease (COPD) - a leading cause of chronic dyspnea 3
• Interstitial lung disease - suggested by fine bibasilar crackles ("Velcro rales") on examination 1
• Asthma/exercise-induced bronchoconstriction - particularly if patient describes "chest tightness" 1
• Pulmonary hypertension - may require echocardiography to detect elevated right ventricular systolic pressure 2, 4

Hematologic Causes

• Anemia - a frequently overlooked but treatable cause, particularly iron deficiency anemia in young adults 1
• Anemia from chronic kidney disease - contributes through multiple mechanisms 5

Renal Causes

• Chronic kidney disease/renal failure - causes dyspnea through metabolic acidosis (stimulating respiratory drive), fluid overload, and anemia 1, 5
• Nephrotic syndrome - can mimic heart failure with edema 2

Metabolic/Endocrine Causes

• Hyperthyroidism - can cause dyspnea through cardiovascular effects and respiratory muscle weakness 4
• Metabolic acidosis - from renal tubular acidosis or other causes, directly stimulates respiratory drive 1

Other Systemic Causes

• Severe obesity - may cause peripheral edema and respiratory limitation 2
• Liver failure/cirrhosis - can present with edema mimicking heart failure 2
• Cardiac amyloidosis - consider in patients with increased left ventricular wall thickness, carpal tunnel syndrome, and lumbar spinal stenosis 2
• Deconditioning - but only after excluding cardiopulmonary disease 1

Critical History Elements

Symptom Characterization

• Quality of dyspnea - "chest tightness" suggests bronchoconstriction/asthma; orthopnea suggests heart failure 1
• Triggers - exertion level, time of day patterns, environmental exposures, positional changes 1
• Onset, pattern, duration - acute versus chronic, progressive versus stable 2
• Associated symptoms - orthopnea, paroxysmal nocturnal dyspnea, edema, chest pain, palpitations 2

Disease Status Assessment

• Current disease status - evaluate for cancer recurrence or progression if applicable 2
• Treatment history - type and duration of treatments that may induce fatigue 2
• Comorbidities - hypertension, diabetes, obesity, atrial fibrillation, chronic kidney disease 2

Review of Systems

• Cardiac - palpitations, chest pain, edema 2
• Pulmonary - cough, wheezing, sputum production 1
• Constitutional - weight changes, fever, night sweats 2
• Other - pain, emotional distress, sleep disturbance, medication side effects 2

Physical Examination Priorities

Cardiovascular Examination

• Volume status - jugular venous distension, peripheral edema, pulmonary rales 1, 4
• Cardiac auscultation - murmurs, gallops (S3/S4), irregular rhythm 1
• Vital signs - heart rate, blood pressure, presence of cannon waves suggesting AV dissociation 2

Pulmonary Examination

• Auscultation - fine bibasilar crackles suggest interstitial lung disease; wheezing suggests bronchoconstriction 1
• Respiratory pattern - tachypnea, use of accessory muscles 1

Other Key Findings

• Digital clubbing - suggests chronic lung disease 1
• Pallor - suggests anemia 1
• Body habitus - severe obesity may contribute 2

Initial Diagnostic Testing

First-Line Tests (Obtain in All Patients)

• Chest X-ray - evaluate for pulmonary edema, infiltrates, masses, pleural effusions 1
• Complete blood count - assess for anemia 1
• Electrocardiogram - identify arrhythmias, conduction abnormalities, ischemia 1, 4
• Basic metabolic panel - creatinine elevation identifies kidney disease; low bicarbonate suggests metabolic acidosis 1

Second-Line Tests (If Initial Testing Nondiagnostic)

• BNP or NT-proBNP - helpful when cardiac etiology suspected, but interpret cautiously in renal dysfunction 1, 4
• Transthoracic echocardiography - evaluate ventricular function, valvular disease, pulmonary pressures 2, 1, 4
• Pulmonary function tests with DLCO - assess for obstructive or restrictive lung disease 1, 4
• High-resolution CT chest - if interstitial lung disease suspected 1
• Thyroid function tests - if hyperthyroidism suspected 4

Additional Testing Based on Clinical Context

• Urinalysis - assess for proteinuria if nephrotic syndrome suspected 2
• Abdominal ultrasound - if cirrhosis suspected 2
• Six-minute walk test - objectively assess exercise capacity and oxygen saturation 2, 4
• Diastolic stress echocardiography - if diastolic dysfunction suspected with normal resting echo 6

Age-Specific Considerations

Young Adults

• Prioritize - asthma, iron deficiency anemia, exercise-induced arrhythmias, early interstitial lung disease, diastolic heart failure 1
• Avoid - extensive cardiac workup without abnormal cardiac findings on examination or ECG, particularly if anemia is present 1

Older Adults

• Consider - heart failure (both HFpEF and HFrEF), COPD, cardiac amyloidosis, multifactorial causes 2
• Approach - multidisciplinary evaluation may be necessary 6

Critical Pitfalls to Avoid

• Do not attribute dyspnea to deconditioning without first excluding cardiopulmonary disease 1
• Do not pursue extensive cardiac evaluation before addressing obvious anemia (e.g., from menorrhagia) 1
• Do not overlook environmental/occupational exposures that may cause hypersensitivity pneumonitis 1
• Do not dismiss "chest tightness" as anxiety without considering asthma 1
• Do not forget cardiac mimics - recognize that cardiac amyloidosis can present with HFpEF features plus specific clues (carpal tunnel syndrome, lumbar spinal stenosis) 2
• Interpret BNP/NT-proBNP cautiously in renal dysfunction - levels are elevated independent of heart failure when creatinine ≥2 mg/dL 1

When to Consider Specialty Referral

• Diagnosis remains elusive after completing initial workup 1
• Suspected pulmonary hypertension - consider right heart catheterization after non-invasive workup 4
• Complex cardiac disease - cardiology consultation for advanced heart failure, arrhythmias, or valvular disease 4
• Advanced lung disease - pulmonology consultation for interstitial lung disease or severe COPD 4
• Significant symptom burden - palliative care consultation for advanced disease with refractory symptoms 6