What are the common manifestations of post‑acute sequelae of SARS‑CoV‑2 infection and how should they be evaluated and managed?

Long COVID Symptoms: Clinical Manifestations, Evaluation, and Management

Definition and Timeline

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), encompasses symptoms persisting 4 or more weeks after initial infection, though the most clinically relevant definition considers symptoms lasting beyond 12 weeks that cannot be explained by alternative diagnoses. 1

• The CDC defines PASC as symptoms present ≥4 weeks post-infection 1
• The WHO and UK NICE guidelines use a more conservative threshold of symptoms persisting ≥12 weeks (3 months) that last at least 2 months 1
• Critically, patients can develop PASC even if they were asymptomatic during acute infection 1

Common Clinical Manifestations

Most Frequent Symptoms

Fatigue and breathlessness are the two most common symptoms, but over 200 different manifestations have been documented. 1, 2

Primary symptoms include: 1, 3, 4

• Fatigue (most common)
• Dyspnea and exercise intolerance
• Cognitive impairment/"brain fog" (affects 16% at 2 months, increasing to 26% at 12 months) 5
• Post-exertional malaise
• Sleep disturbances/insomnia (affects 22-44% of patients) 6
• Chest pain and palpitations
• Tachycardia (particularly postural orthostatic tachycardia syndrome/POTS) 1

Secondary manifestations include: 1, 3

• Musculoskeletal pain/spasms
• Headache
• Altered smell/taste perception
• Memory impairment and attention deficits
• Depression and anxiety
• Cough
• Hair loss (more common at 1 year than 2 months post-infection) 7

Cardiovascular Manifestations

The American College of Cardiology differentiates between PASC-CVD (identifiable cardiovascular disease) and PASC-CVS (cardiovascular symptoms without objective findings on standard testing). 1

PASC-CVD includes: 1

• Myocarditis and other myocardial involvement
• Pericarditis
• New or worsening myocardial ischemia
• Nonischemic cardiomyopathy
• Pulmonary thromboembolic disease
• Arrhythmias (atrial fibrillation, ventricular arrhythmias)
• Pulmonary hypertension and right ventricular failure

PASC-CVS presents with: 1

• Exercise intolerance with tachycardia
• Chest pain without ischemia
• Dyspnea without structural abnormalities
• POTS (heart rate increase >30 bpm upon standing, often >120 bpm) 1

Neurological Manifestations

Neurovascular disorders and cognitive dysfunction represent significant long-term sequelae. 1, 8

• Ischemic stroke, hemorrhagic stroke, cerebral venous thrombosis 1
• Myalgic encephalomyelitis/chronic fatigue syndrome 1
• Cognitive impairment persisting ≥2 years 5, 6
• Sensorimotor symptoms 6

Risk Factors for Developing Long COVID

Key predictors include: 3

• Female sex
• Older age
• Cigarette smoking
• Pre-existing medical conditions
• Lack of COVID-19 vaccination
• Infection with pre-Omicron variants
• Greater number of acute phase symptoms
• Higher viral load
• Severe/critical acute COVID-19 illness
• Invasive mechanical ventilation

However, young, previously healthy individuals with mild COVID-19 are also at substantial risk. 1, 4

Clinical Evaluation Approach

Initial Assessment

Conduct an initial consultation (video, phone, or in-person based on shared decision-making) for any patient with symptoms persisting ≥4 weeks after acute COVID-19. 1

Essential history elements: 1

• Severity of acute COVID-19 (hospitalization, ICU admission, mechanical ventilation)
• Timeline of symptom onset and evolution
• Impact on work, education, mobility, independence, and activities of daily living
• Presence of fever, lightheadedness, chest pain, dyspnea, GI symptoms (may suggest hyperinflammatory state like MIS-A) 1
• Screen for post-intensive care syndrome in critically ill survivors 1

Physical examination priorities: 1

• Vital signs including orthostatic measurements (supine and standing heart rate/blood pressure after 5-10 minutes)
• Cardiovascular examination
• Pulmonary examination
• Neurological assessment including cognitive screening

Diagnostic Testing Strategy

For patients with cardiovascular symptoms (chest pain, dyspnea, palpitations, exercise intolerance): 1

Initial testing:

• ECG
• Echocardiography (note: diastolic dysfunction found in 55-60% of recovering patients, but LV systolic dysfunction rare) 1
• Basic laboratory work (troponin, BNP, inflammatory markers)
• Consider orthostatic vital signs testing for POTS evaluation 1

Advanced testing when initial workup is unrevealing but symptoms persist:

• Cardiac MRI with late gadolinium enhancement (may identify myocardial inflammation in ~17% of symptomatic patients) 1
• FDG-PET (correlates with CMR abnormalities and inflammatory markers) 1
• Pulmonary function testing
• Cardiopulmonary exercise testing (assess for exercise intolerance patterns)

Critical caveat: Standard cardiac testing may be normal despite debilitating symptoms, which is a source of frustration but does not invalidate the patient's experience. 1

For neurological symptoms:

• Cognitive screening tools
• Consider neuroimaging if focal deficits present
• Evaluate for thromboembolic complications if acute neurological changes 1

Management Strategies

Framework for Treatment

Management must be individualized based on whether identifiable cardiovascular disease is present (PASC-CVD) versus unexplained symptoms (PASC-CVS), requiring different therapeutic approaches. 1

For PASC-CVD (Identifiable Disease)

Follow existing guideline-directed medical therapy for the specific condition identified: 1

• Myocarditis: standard heart failure management, avoid exercise during active inflammation
• Ischemic heart disease: antiplatelet therapy, statins, revascularization as indicated
• Arrhythmias: rate/rhythm control per standard protocols
• Thromboembolic disease: anticoagulation per established protocols 1

For PASC-CVS and General Symptom Management

Critical principle: Exercise is contraindicated in patients with brain fog and post-exertional malaise, as 75% worsen with physical activity and <1% improve. 5

Cognitive and fatigue management: 5

• Implement cognitive pacing protocols adapted from ME/CFS management to maintain energy envelope
• Low-dose aripiprazole for fatigue, unrefreshing sleep, and brain fog
• Low-dose naltrexone for pain, fatigue, and neurological symptoms

POTS and autonomic dysfunction: 5

• β-blockers, pyridostigmine, fludrocortisone, or midodrine
• Increase salt and fluid intake
• Consider IV saline or compression stockings

Sleep disturbances: 6

• Address insomnia as it co-exists with cognitive impairment and fatigue
• Standard sleep hygiene measures
• Consider pharmacotherapy for persistent insomnia

Emerging therapies with evidence: 5

• Paxlovid: 25% reduction in long COVID incidence when used for acute COVID-19; case reports document symptom resolution with treatment of established long COVID
• Intravenous immunoglobulin for immune dysfunction
• Triple anticoagulant therapy for patients with abnormal clotting
• BC007 to neutralize G protein-coupled receptor autoantibodies

Multidisciplinary Care Coordination

Establish patient-centered care models with coordination by multidisciplinary teams including: 1

• Primary care clinicians (care coordination hub)
• Pulmonologists
• Cardiologists
• Neurologists
• Rheumatologists
• Psychiatrists
• Infectious disease specialists
• Social workers
• Psychologists
• Physical therapists

Common Pitfalls and Caveats

Avoid premature reassurance: Symptoms can persist for ≥2 years and may fluctuate unpredictably. 5, 6 Normal initial testing does not exclude PASC. 1

Do not recommend graded exercise therapy: This worsens outcomes in the majority of patients with post-exertional malaise. 5

Recognize delayed-onset symptoms: Patients asymptomatic during acute infection can still develop PASC, and some symptoms (like hair loss) emerge later in the disease course. 1, 7

Address comorbid symptoms comprehensively: Brain fog commonly co-exists with insomnia, GI symptoms, and mood disturbances—all require simultaneous management. 5, 6

Provide empathetic validation: Listen with empathy and acknowledge the impact on daily life, work, and wellbeing, as this condition causes tremendous frustration when testing is unrevealing. 1

Prognosis and Follow-up

Long COVID affects 10-20% of infected individuals, with cumulative prevalence ranging 9-63% depending on definition used. 3, 2 Symptoms can persist for months to years, with cognitive and sleep symptoms documented at 2 years post-infection. 5, 6 The condition represents an unprecedented health and economic burden requiring ongoing research into diagnostic biomarkers, risk factors, and targeted treatments. 2