What are the common manifestations of post‑acute sequelae of SARS‑CoV‑2 infection (long COVID) and the recommended supportive management strategies?

Long COVID Symptoms and Management

Definition and Timeline

Long COVID is defined as one or more symptoms persisting or relapsing for more than 12 weeks after acute COVID-19 diagnosis, without an alternative explanation. 1 The CDC uses a more liberal 4-week threshold, but the WHO and European guidelines require symptoms lasting at least 12 weeks (3 months) and persisting for at least 2 months. 1, 2 This condition can affect anyone who had COVID-19, regardless of whether the acute infection was severe or even symptomatic. 1, 2

Most Common Clinical Manifestations

Primary Symptoms (Highest Prevalence)

• Fatigue is the most common symptom, affecting 31-58% of patients with long COVID and representing one of the two most frequent manifestations alongside breathlessness. 1, 2

• Dyspnea (shortness of breath) occurs in 24-40% of patients and is the second most common complaint. 1, 2

• Cognitive impairment ("brain fog") affects 12-35% of patients initially, but increases over time—approximately 16% at 2 months rising to 26% at 12 months after infection. 1, 2

• Sleep disturbances and insomnia are reported in 11-44% of individuals, representing a significant neurological manifestation that often co-exists with fatigue and cognitive symptoms. 1, 3

• Musculoskeletal pain (including myalgia, joint pain, and muscle spasms) affects 9-19% of patients. 1, 2

Secondary Symptoms

• Anosmia/dysgeusia (loss of smell/taste) persists in 10-22% of patients beyond the acute phase. 1

• Cough continues in 7-29% of recovering patients. 1, 2

• Chest pain is reported by 6-17% of individuals and may occur with or without identifiable cardiac pathology. 1, 2

• Palpitations and postural tachycardia (POTS) are characterized by heart rate increases >30 bpm (often >120 bpm) upon standing. 2

• Hair loss tends to appear later in the disease course, being more common at approximately 1 year than at 2 months post-infection. 2

Cardiovascular Manifestations

The American College of Cardiology distinguishes between PASC-CVD (identifiable cardiovascular disease with objective findings) and PASC-CVS (cardiovascular symptoms without objective abnormalities). 2

PASC-CVD (Identifiable Disease)

• Myocarditis and myocardial involvement with inflammation visible on cardiac MRI and elevated troponin levels. 2

• Pericarditis presenting with pericardial effusion or positional chest pain. 2

• New or worsening myocardial ischemia with evidence of coronary artery disease. 2

• Non-ischemic cardiomyopathy with reduced ejection fraction without obstructive coronary disease. 2

• Pulmonary thromboembolic disease confirmed on CT pulmonary angiography. 2

• Arrhythmias including atrial fibrillation and ventricular arrhythmias documented on ECG or Holter monitoring. 2

• Pulmonary hypertension and right ventricular failure with elevated pulmonary pressures. 2

PASC-CVS (Symptoms Without Objective Disease)

• Exercise intolerance with tachycardia often meeting POTS diagnostic criteria. 2

• Chest pain without evidence of ischemia on standard cardiac testing. 2

• Dyspnea despite normal structural cardiac and pulmonary studies—a critical caveat is that normal testing does not exclude PASC. 2

Neurological Manifestations

• Neurovascular events including ischemic stroke, hemorrhagic stroke, and cerebral venous thrombosis are recognized complications. 2

• Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may develop after COVID-19, with similar pathophysiologic mechanisms. 2, 4

• Cognitive impairment can persist for at least 2 years in a subset of patients. 2, 3

• Neuroinflammation and immune dysregulation affecting brain regions involved in sleep regulation contribute to both cognitive and sleep symptoms. 3

Risk Factors for Developing Long COVID

• Female sex confers an estimated two-fold increased risk (OR: 1.3-5) compared to males. 1

• Severe acute COVID-19 (requiring hospitalization or ICU care) is the strongest predictor, particularly for fatigue. 1

• Older age increases the likelihood of persistent symptoms. 1, 2

• Pre-existing medical conditions (cardiovascular disease, diabetes, obesity) are associated with higher risk, though results are mixed. 1, 2

• Greater number of acute-phase symptoms predicts subsequent long COVID development. 2

• Lack of COVID-19 vaccination prior to infection is a modifiable risk factor. 2

• Infection with pre-Omicron variants carries higher risk than later variants. 2

• Important caveat: Young, previously healthy individuals with mild acute illness can also develop debilitating long COVID, so initial disease severity is not the sole determinant. 2

Clinical Evaluation Approach

Initial Assessment

Any patient with symptoms persisting ≥4 weeks after acute COVID-19 should receive an initial consultation (in-person, video, or telephone). 2 However, long COVID is a diagnosis of exclusion—other serious conditions must be ruled out first, including previously overlooked malignancies or acute COVID-19 complications such as thromboembolic events, myocarditis, or encephalitis. 1

Key history elements to obtain:

• Severity of acute infection (hospitalization, ICU admission, oxygen requirement). 2
• Timeline of symptom onset (persistent vs. new symptoms after initial recovery). 2
• Impact on work, education, and activities of daily living. 2
• Presence of fever, chest pain, dyspnea, or gastrointestinal symptoms suggesting hyperinflammatory state. 2

Physical examination priorities:

• Orthostatic vital signs: measure supine and standing heart rate/blood pressure after 5-10 minutes to evaluate for POTS. 2
• Cardiovascular examination for murmurs, gallops, or signs of heart failure. 2
• Pulmonary examination for crackles, wheezing, or decreased breath sounds. 2
• Brief neurological and cognitive screening. 2

Diagnostic Testing Strategy

For Cardiovascular Symptoms

Initial tests (perform in all patients with cardiac complaints):

• 12-lead ECG to identify arrhythmias or ischemic changes. 2
• Transthoracic echocardiography—shows diastolic dysfunction in approximately 55-60% of recovering patients; left ventricular systolic dysfunction is rare. 2
• Basic laboratory tests: troponin, BNP, inflammatory markers (CRP, ESR). 2
• Orthostatic vital signs for POTS evaluation. 2

Advanced imaging (when initial work-up is unrevealing but symptoms persist):

• Cardiac MRI with late gadolinium enhancement identifies myocardial inflammation in approximately 17% of symptomatic patients. 2
• FDG-PET correlates with cardiac MRI abnormalities and inflammatory markers. 2

Functional testing:

• Pulmonary function tests to assess restrictive or obstructive patterns. 2
• Cardiopulmonary exercise testing to characterize exercise intolerance objectively. 2

Critical caveat: Standard cardiac testing may be completely normal despite debilitating symptoms; normal results do not exclude PASC. 2

For Respiratory Symptoms

At 3 months, consider routine chest imaging and pulmonary function tests for patients with persistent respiratory symptoms. 1 Other tests should be performed mainly to exclude alternative conditions according to specific symptoms. 1

For Neurological Symptoms

• Administer cognitive screening tools for all patients reporting brain fog or memory problems. 2
• Reserve neuroimaging (CT or MRI) for focal neurological deficits or acute changes. 2
• Evaluate for thromboembolic complications if acute neurological symptoms develop. 2

Management Strategies

Framework for Treatment Decisions

Management is individualized based on whether identifiable cardiovascular disease (PASC-CVD) is present or symptoms are unexplained (PASC-CVS). 2 There are no evidence-based interventions for long COVID—all recommendations are conditional guidance based on limited data. 1

PASC-CVD (Identifiable Disease)

• Myocarditis: Treat with guideline-directed heart failure therapy; strictly avoid exercise during active inflammation. 2

• Ischemic heart disease: Antiplatelet agents, statins, and revascularization as indicated by standard cardiology guidelines. 2

• Arrhythmias: Rate or rhythm control per standard ACC protocols. 2

• Thromboembolic disease: Anticoagulation according to established ACC recommendations. 2

PASC-CVS and General Symptom Management

Exercise and Activity

Exercise is contraindicated in patients with brain fog or post-exertional malaise—approximately 75% experience worsening with activity, and less than 1% improve. 2 This is a critical pitfall to avoid, as traditional cardiac rehabilitation approaches can be harmful in this population.

Cognitive Impairment and Fatigue

• Pacing strategies adapted from ME/CFS management: break activities into smaller segments with rest periods. 2

• Low-dose aripiprazole for fatigue and brain fog (emerging evidence from case reports). 2

• Low-dose naltrexone for pain and fatigue symptoms. 2

POTS and Autonomic Dysfunction

• Pharmacologic options: β-blockers, pyridostigmine, fludrocortisone, or midodrine. 2

• Non-pharmacologic measures: Increase dietary salt and fluid intake; consider IV saline for severe cases; compression stockings. 2

Sleep Disturbances

• Implement sleep hygiene measures as first-line approach. 2, 3

• Consider pharmacologic therapy if non-pharmacologic measures fail. 2

• Address co-existing cognitive impairment and fatigue, as these often occur together. 3

Emerging Therapies

• Early Paxlovid (nirmatrelvir-ritonavir) during acute infection reduces long COVID incidence by approximately 25%. 2

• Intravenous immunoglobulin (IVIG) shows benefit in case reports for immune dysregulation. 2

• Triple anticoagulant regimens for suspected microclotting (investigational). 2

• BC007 peptide for auto-antibody neutralization (investigational). 2

Physical and Respiratory Rehabilitation

Physical and respiratory rehabilitation should be considered, but only after ruling out post-exertional malaise. 1 Traditional rehabilitation protocols must be modified for patients who worsen with exertion.

Multidisciplinary Care Coordination

A patient-centered, multidisciplinary team is recommended, with the primary care clinician serving as the care coordination hub. 2 Team members should include:

• Pulmonologists for persistent respiratory symptoms. 2
• Cardiologists for cardiovascular manifestations. 2
• Neurologists for cognitive and neurological symptoms. 2
• Rheumatologists for autoimmune considerations. 2
• Psychiatrists for mental health support. 2
• Infectious disease specialists for complex cases. 2
• Social workers and psychologists for psychosocial support. 2
• Physical therapists for modified rehabilitation. 2

Prognosis and Long-Term Outlook

• Long COVID affects approximately 10-20% of all infected individuals, with prevalence ranging from 9% to 63% depending on case definition and population studied. 2, 5

• Symptoms may persist for months to years—cognitive impairment and sleep disturbances have been documented at least 2 years after infection. 2, 3

• Quality of life is significantly impacted: 57% of patients with symptoms persisting beyond 12 weeks report decreased quality of life. 1

• Persistence of symptoms: Follow-up studies document long COVID symptoms lasting up to 12 months or longer after acute disease. 1