What is the recommended approach to diagnose Long COVID in a patient with a history of COVID-19 infection and persistent symptoms?

Diagnosing Long COVID: A Structured Approach

Long COVID is fundamentally a diagnosis of exclusion that requires symptoms persisting beyond 12 weeks after acute COVID-19 infection, with the critical first step being to rule out life-threatening complications and alternative diagnoses before attributing symptoms to post-acute sequelae. 1

Temporal Framework for Diagnosis

The diagnostic approach depends on timing from acute infection 1:

• 4-12 weeks post-infection: Classified as "post-acute COVID" - assess on a case-by-case basis according to symptom severity and trajectory 1
• ≥12 weeks post-infection: Threshold for formal Long COVID diagnosis when persistent symptoms warrant comprehensive investigation 1, 2

Diagnostic Certainty Classification

Long COVID diagnosis is stratified by the strength of evidence for prior SARS-CoV-2 infection 1:

• Confirmed: Typical symptoms with positive laboratory results (PCR or antigen test)
• Probable: Typical symptoms with negative laboratory results but suggestive epidemiology
• Possible: Typical symptoms with negative laboratory results and negative epidemiology

A prior positive COVID-19 test is NOT required to diagnose Long COVID - clinical diagnosis based on typical symptoms and epidemiological context is sufficient. 3, 4

Step 1: Exclude Life-Threatening Conditions First

Before considering Long COVID, immediately rule out serious complications that require urgent intervention 1, 5, 6:

• Thromboembolic events (pulmonary embolism, deep vein thrombosis)
• Myocarditis or other cardiac complications
• Encephalitis or severe neurological manifestations
• Previously overlooked malignancy
• Severe hypoxemia (oxygen saturation ≤93% at rest) 5
• Respiratory distress (respiratory rate >30 breaths/minute) 5

Step 2: Obtain Targeted Clinical History

Document specific elements to differentiate Long COVID from other conditions 1, 5:

• Pre-existing conditions that may explain current symptoms
• Iatrogenic causes from treatments during acute infection
• Complications directly related to the acute COVID-19 episode
• Symptom timeline: onset, duration, pattern (persistent vs. relapsing-remitting)
• Functional impact: effect on daily activities, work capacity, quality of life 5, 3

Key Symptom Clusters to Document

The most common Long COVID symptoms with their prevalence ranges 1:

• Fatigue: 31-58% of patients
• Dyspnea: 24-40%
• Cognitive impairment ("brain fog"): 12-35%
• Sleep disturbances: 11-44%
• Musculoskeletal pain: 9-19%
• Anosmia/dysgeusia: 10-22%
• Cough: 7-29%
• Chest pain: 6-17%

Step 3: Basic Laboratory Assessment

All patients with suspected Long COVID should receive a basic laboratory panel 1, 6:

• Complete blood count
• C-reactive protein
• Kidney function tests (creatinine, BUN)
• Liver function tests (ALT, AST, bilirubin)

Symptom-Specific Additional Testing

Order these tests only when clinically indicated by specific symptoms 1, 5:

For cardiac symptoms (chest pain, palpitations):

• Troponin
• CPK-MB
• B-type natriuretic peptide (BNP)

For suspected thyroiditis:

• Complete thyroid function tests (TSH, free T4, free T3)

For patients at diabetes risk:

• Fasting glucose
• Glycated hemoglobin (HbA1c)

Tests to AVOID

Do NOT routinely order 1:

• D-dimer in patients without respiratory symptoms (limited utility and high false-positive rate)
• Blood gases even with decreased oxygen saturation (limited benefit according to guidelines)
• Extensive autoimmune panels without specific clinical indication

Important caveat: Laboratory abnormalities are uncommon in Long COVID - normal labs do not exclude the diagnosis. 1

Step 4: Assess for Risk Factors

Document established risk factors that increase likelihood of Long COVID 1, 6:

Consistent risk factors with strong evidence:

• Female sex: approximately 2-fold increased risk (OR 1.3-5) 1, 6
• Severe acute COVID-19: strongest association with persistent fatigue 1

Inconsistent risk factors (mixed evidence):

• Age
• Obesity
• Presence of comorbidities 1, 6

Step 5: System-Specific Evaluation

After basic assessment, consider targeted evaluation based on predominant symptom patterns 1:

• Respiratory symptoms: Pulmonary function testing, chest imaging at 12-week mark 5
• Cardiac symptoms: ECG, echocardiography if indicated
• Neurological symptoms: Cognitive assessment, neuropsychological testing if severe
• Autonomic symptoms: Orthostatic vital signs, tilt table testing for suspected POTS

Common Diagnostic Pitfalls to Avoid

1. Premature diagnosis: Avoid labeling symptoms as Long COVID before 12 weeks unless severe and progressive 1, 2

2. Over-investigation at early timepoints: Fatigue and dyspnea at 1.5-4 weeks are expected acute illness symptoms and do not warrant extensive workup unless red flags present 2

3. Dismissing symptoms: Many patients have had symptoms dismissed by clinicians - validation of their experience is essential even when diagnosis is uncertain 5, 3

4. Missing alternative diagnoses: Always maintain clinical vigilance for other conditions that may mimic Long COVID, particularly in patients with atypical presentations 1

5. Requiring positive COVID test: Do not exclude Long COVID diagnosis solely based on lack of prior positive test, especially in patients infected early in pandemic when testing was limited 3, 4

Documentation for Diagnosis

Formal Long COVID diagnosis requires 1:

• Symptoms persisting ≥12 weeks from acute infection
• No alternative explanation after appropriate investigation
• Documentation of functional impairment
• Classification of diagnostic certainty (confirmed/probable/possible)

The diagnosis should be revisited if symptoms evolve or new concerning features develop, as this may indicate complications requiring different management. 1, 5