What are the treatment options for long COVID (post‑acute sequelae of SARS‑CoV‑2 infection)?

Treatment Options for Long COVID

While there is no single broadly effective cure for long COVID, a symptom-targeted treatment approach using specific pharmacological and non-pharmacological interventions has shown benefit for subsets of patients, with energy management through pacing as the foundational first-line strategy. 1

Critical First Step: Energy Management and Pacing

• Pacing is the essential foundation for all patients with long COVID, particularly those experiencing postexertional malaise (PEM). 1
• Exercise is contraindicated and harmful in patients with PEM—physical activity worsened symptoms in 75% of patients with less than 1% showing improvement. 1
• Graded exercise therapy and cognitive behavioral therapy focused on increasing activity are explicitly contraindicated. 1
• Energy conservation strategies must be implemented before any other interventions to prevent symptom exacerbation. 2

Symptom-Specific Pharmacological Treatments

For Dysautonomia/POTS (Postural Orthostatic Tachycardia Syndrome)

Pharmacological options:

• β-blockers (first-line for tachycardia) 1
• Pyridostigmine 1
• Fludrocortisone 1
• Midodrine 1

Non-pharmacological interventions:

• Increase salt and fluid intake 1
• Intravenous salt administration 1
• Compression stockings 1

For Neuroinflammation, Pain, and Fatigue

• Low-dose naltrexone shows promise for pain, fatigue, and neurological symptoms, with substantial anecdotal success in the patient community. 1
• Low-dose aripiprazole for fatigue, unrefreshing sleep, and brain fog. 1

For Mast Cell Activation Symptoms

• H1 and H2 antihistamines, particularly famotidine, are used to alleviate a wide range of symptoms (though not curative). 1

For Immune Dysfunction

• Intravenous immunoglobulin (IVIG) for documented immune dysfunction—consider consulting an immunologist for implementation. 1

Emerging Treatments with Preliminary Evidence

Anticoagulation Therapy

• Triple anticoagulant therapy showed complete symptom resolution in all 24 patients in one study addressing abnormal clotting. 1
• This approach targets microclot formation, a proposed mechanism in long COVID pathophysiology. 1

Antiviral Treatment

• Paxlovid (nirmatrelvir/ritonavir) demonstrated a 25% reduction in long COVID incidence when used for acute COVID-19, with case reports showing resolution of established long COVID symptoms. 1
• Further investigation is warranted for both prevention and treatment. 1

Other Experimental Options

• BC007 for autoimmunity (neutralizes G protein-coupled receptor autoantibodies). 1
• Apheresis has shown promise but is expensive with uncertain benefits. 1
• Sulodexide for endothelial dysfunction showed reduced symptom severity in small trials. 1

Non-Pharmacological Interventions

Cognitive Dysfunction

• Cognitive pacing (implement alongside physical pacing). 1
• Postconcussion syndrome protocols. 1

Gastrointestinal Symptoms

• Elimination diets. 1
• Probiotics showed potential for both GI and non-GI symptoms in pilot studies. 1

Supplements

• Coenzyme Q10 and D-ribose for fatigue (evidence from ME/CFS literature). 1
• Pycnogenol showed statistically significant improvement in oxidative stress and quality of life scores. 1

Pulmonary-Specific Management

For Organizing Pneumonia/Interstitial Lung Disease

• Corticosteroids (maximum 0.5 mg/kg prednisolone) for patients with persistent symptoms, functional abnormalities, and parenchymal CT abnormalities at 6 weeks post-discharge showed significant improvement. 1
• However, spontaneous recovery also occurs, making the benefit uncertain. 1
• Evidence is insufficient to provide a strong recommendation for or against this intervention. 1

For Olfactory Dysfunction

• Olfactory training is the only intervention with consistent benefit across 11 studies (though not COVID-specific). 1
• Topical or systemic steroids, theophylline, and sodium citrate may be considered but lack strong evidence. 1

Rehabilitation Approach

• Multidisciplinary rehabilitation services should be initiated early, ideally within the first 30 days post-acute phase. 1
• Rehabilitation must be carefully titrated to avoid triggering PEM. 3, 2
• Physical, cognitive, and emotional domains should all be addressed. 3

Critical Pitfalls to Avoid

• Never prescribe standard exercise programs—this can cause severe deterioration in patients with PEM. 1
• Avoid overmedication with unproven supplements that may interact with other medications. 4
• Do not dismiss patient symptoms—validation is essential as many patients have had their experiences invalidated. 2
• Physical activity recommendations must be tailored to current tolerance, not pushed to "normal" levels. 2

Assessment Requirements Before Treatment

• Rule out alternative diagnoses including thromboembolic events, thyroiditis, and cardiac complications. 1, 4
• Basic laboratory assessment: C-reactive protein, complete blood count, kidney and liver function. 1
• For cardiac symptoms: troponin, CPK-MB, B-type natriuretic peptide. 1
• D-dimer should not be routinely used in patients without respiratory symptoms. 1

Current Evidence Limitations

• No standardized definition of long COVID exists across studies. 1, 5
• Most evidence comes from ME/CFS literature rather than long COVID-specific trials. 1
• Evidence is insufficient to provide strong recommendations for neurological, cognitive, or psychiatric interventions. 1
• Current therapy options are rated as poor by practicing physicians. 6