What is the diagnostic approach and management for patients with suspected Long Covid (Post-Acute Covid-19 Syndrome)?

Long COVID Diagnosis

Long COVID is a diagnosis of exclusion requiring symptoms persisting beyond 12 weeks after acute COVID-19 infection, with mandatory referral to medical care for systematic evaluation after ruling out life-threatening complications and alternative diagnoses. 1

Diagnostic Criteria and Timeline

Refer all patients with symptoms lasting >12 weeks after acute COVID-19 to medical care for formal assessment. 1, 2

For symptoms at 4-12 weeks, assess case-by-case based on:

• Severity of symptoms 1
• Trajectory (worsening vs. stable vs. improving) 1
• Impact on functional capacity and quality of life 2

Classification Framework

The diagnostic classification depends on both timing and confirmation of acute infection 1:

At 4-12 weeks:

• Confirmed post-acute COVID: Typical symptoms + positive laboratory results during acute phase 1
• Probable post-acute COVID: Typical symptoms + negative lab results but suggestive epidemiology 1
• Possible post-acute COVID: Typical symptoms + negative lab results and negative epidemiology 1

At >12 weeks (Long COVID):

• Confirmed persistent Long COVID: Typical symptoms + positive laboratory results during acute phase 1
• Probable persistent Long COVID: Typical symptoms + negative lab results but suggestive epidemiology 1
• Possible persistent Long COVID: Typical symptoms + negative lab results and negative epidemiology 1

A prior positive COVID-19 test is NOT required to diagnose Long COVID. 3, 4

Mandatory Exclusions Before Diagnosing Long COVID

First, rule out life-threatening conditions and complications of acute COVID-19 before considering Long COVID: 1, 2

Critical Exclusions:

• Thromboembolic events (pulmonary embolism, deep vein thrombosis) 1, 2
• Myocarditis 1, 2
• Encephalitis 1
• Previously overlooked malignancy 1
• Secondary bacterial pneumonia or superinfection 5

Additional Considerations:

• Previous underlying conditions that may explain current symptoms 1, 2
• Iatrogenic causes from acute COVID-19 treatment 1, 2
• Post-intensive care syndrome in critically ill patients (difficult to distinguish from Long COVID) 2

Clinical History Requirements

Collect detailed history focusing on: 1, 2

• Symptom trajectory since initial infection (continuous, relapsing-remitting, or progressive) 3
• Previous underlying conditions that could explain symptoms 1
• Complications during acute COVID-19 and treatment received 1, 2
• Severity of acute COVID-19 (outpatient, hospitalized non-ICU, ICU admission) - strongest risk factor for Long COVID 1
• Sex - women have 2-fold increased risk (OR 1.3-5) 1, 2
• Impact on quality of life - 57% report decreased quality of life beyond 12 weeks 2

Most Common Symptoms to Assess

The most prevalent Long COVID symptoms at 3-6 months are: 2

• Fatigue: 31-58% prevalence 1, 2
• Dyspnea: 25-37% prevalence 1, 2
• Anosmia: 15-22% prevalence 1, 2
• Dysgeusia: 13.5-23% prevalence 1, 2
• Cognitive impairment (brain fog) 3, 6, 4
• Postexertional malaise (PEM)/postexertional symptom exacerbation (PESE) 3, 4
• Dysautonomia 3
• Myalgia/joint pain: 9-11% prevalence 1, 2
• Cough: 8-29% prevalence 1, 2
• Depression: 8% prevalence 1, 2
• Sleep disorders 1
• Headache 1, 4

Over 200 symptoms have been reported in total. 3, 6

Required Laboratory and Diagnostic Testing

Basic Laboratory Panel (All Patients):

Order the following for all patients with suspected Long COVID to rule out alternative diagnoses: 1, 2

• C-reactive protein 1, 2
• Complete blood count 1, 2
• Kidney function tests (creatinine, BUN) 1, 2
• Liver function tests 1, 2

Interpret with caution: Blood tests may show persistent abnormalities after acute infection that do not necessarily indicate ongoing pathology. 1

Symptom-Specific Testing:

For cardiac symptoms (chest pain, palpitations): 1, 2

• Troponin 1, 2
• CPK-MB 1, 2
• B-type natriuretic peptide (BNP) 1, 2

For suspected thyroiditis: 1, 2

• Complete thyroid function tests (TSH, free T4, free T3) 1, 2

For diabetes risk or metabolic concerns: 1, 2

• Fasting glucose 1, 2
• Glycated hemoglobin (HbA1c) 1, 2

For persistent dyspnea: 2

• Consider pulmonary function testing with diffusion capacity (DLCO) at 3 months for all patients with severe/critical acute COVID-19, regardless of current symptoms 2
• Consider pulmonary function testing for any patient with persistent dyspnea at 4-12 weeks 2

Tests to AVOID:

Do NOT order D-dimer in patients without respiratory symptoms - it lacks utility in this context. 1, 2

Blood gases have limited benefit even with decreased oxygen saturation. 1, 2

Chest Imaging Indications

Use chest imaging when: 2

• Clinical suspicion of complications (pneumonia, pulmonary embolism, pulmonary fibrosis) 2
• Deciding on hospital admission versus home discharge for symptomatic patients with high-risk comorbidities (diabetes, hypertension, heart disease, obesity, age >60) 2

Quality of Life Assessment

Conduct structured interview to assess: 2

• Symptom severity 2
• Impact on activities of daily living 2
• Work capacity 2
• Overall quality of life using validated scales (e.g., modified Medical Research Council dyspnea scale for respiratory symptoms) 2

Common Diagnostic Pitfalls

Avoid these errors: 2, 5

• Do not assume positive antigen tests at 3 weeks represent reinfection - persistent antigen shedding from original infection is far more likely 5
• Do not delay antibiotics if bacterial superinfection is possible - bacterial coinfection occurs in ~40% of viral respiratory infections requiring hospitalization 5
• Do not dismiss patient symptoms - validation is essential as many patients have had symptoms dismissed by clinicians and loved ones 3
• Do not recommend standard exercise programs - overly intense activity can trigger PEM/PESE and worsen muscle damage; physical activity must be carefully tailored to current tolerance 3, 4

Key Diagnostic Principles

Long COVID remains a diagnosis of exclusion - there is no single laboratory finding that definitively confirms or rules out the diagnosis. 1, 2, 3, 6

Current global prevalence is estimated at 6-10% of all COVID-19 cases, though some estimates range up to 30%. 3, 6, 4

Higher prevalence occurs in: 3

• Female gender 1, 2, 3
• Certain racial and ethnic groups 3
• Individuals living in non-urban areas 3
• Those with severe acute COVID-19 1, 2

Anyone can develop Long COVID after SARS-CoV-2 infection, regardless of age or severity of initial symptoms. 3, 6