Treatment algorithm

Your Organizational Guidance

ebpracticenet urges you to prioritize the following organizational guidance:

Opvolging en revalidatie van patiënten met aanhoudende klachten na COVID-19 in de eerste lijnPublished by: KU Leuven | Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2023Suivi et revalidation des patients présentant des symptômes persistants après la COVID-19 en première lignePublished by: KU Leuven | Groupe de Travail Développement de recommmandations de première ligneLast published: 2023

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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all patients

1st line – individualized therapy

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all patients
1st line – 

individualized therapy

Use a holistic, person-centered approach. It is important to form a comprehensive and goal-oriented treatment program for the patient with long COVID through shared decision making and a therapeutic partnership.[1][4] Recognize that the symptoms of long COVID can have a major impact on the patient’s day-to-day life, ability to function, and sense of wellbeing. Ask the patient which symptoms are most troubling and use this to direct the management, if needed. Keep in mind that the patient may have comorbidities that need to be managed. If considering pharmacotherapy, base the decision to use drugs and the choice of specific drug on the nature and severity of the patient’s ongoing symptoms along with pertinent comorbidities. Have a detailed discussion of potential risks and benefits before starting any drug.

There are no evidence-based treatments targeting the underlying pathophysiology of, and no effective universal treatments for, long COVID. Treatments are targeted at symptom palliation and improvement in quality of life. Such treatments have little evidence from well-designed randomized controlled trials for treatment of long COVID in particular, and are often based on expert guidance and management of similar conditions (e.g., myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]). It is important to treat coexisting symptoms when present, as symptoms are often connected (e.g., pain and fatigue or insomnia and cognitive impairments). The presentation of long COVID is heterogeneous. Covered in this section are the most common symptoms, but these are not the only symptoms of long COVID or the only treatable symptoms.

Many patients with long COVID can be managed effectively in primary care.[78] Referral to a specialist may be required for ongoing management, particularly if there is concern for underlying organ-specific dysfunction (see specific symptoms listed below). Referral to a specialized or multidisciplinary long COVID specific clinic is recommended for those with severe or treatment refractory long COVID, where such services are available.[1][4]

Appropriately manage or refer the patient to the relevant acute service if they have signs or symptoms of a life‑threatening complication, including:

  • New hypoxemia or oxygen desaturation at rest or on exercise[1]

  • Signs of severe lung disease[1]

  • Cardiac chest pain[1]

  • Syncope on exertion[78]

  • Focal neurologic signs, new-onset confusion, new severe or “thunderclap” headache, or any other symptoms suggestive of a stroke[78]

  • In children, pediatric inflammatory multisystem syndrome – temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1]

Urgently refer for psychiatric assessment any patients with severe psychiatric symptoms or who appear to be at risk of self‑harm or suicide.[1]

Plus – education and lifestyle modifications

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all patients
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with fatigue
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education and lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Treat comorbid conditions that can contribute to fatigue, for example pain, insomnia/sleep disturbance, and mood issues.[82] Evaluate patients for polypharmacy, which may be contributing to fatigue.[39]

Educate patients with fatigue on energy conservation strategies such as the "four Ps" framework (pacing, prioritizing, positioning, and planning) to avoid relapsing symptoms and to allow individuals to better manage their day-to-day lives.[3][36][78][82][110] Specifically, pacing refers to the concept of avoiding a "pushing and crashing" cycle. Some potential ways to pace include limiting activity (shorter or less strenuous bouts of activity) and including rest breaks. Patients should be educated not to exert to the point where they develop significant post-exertional malaise.[82]

Advise the patient to monitor for any triggers that cause worsening of symptoms.[4]

Consider referral to a rehabilitation specialist, such as a physical therapist.[3][82][88] If the patient is able to manage their day-to-day life without significant relapsing of symptoms but with continued fatigue, they should undergo a cautious return-to-activity program. This should be tailored to the patient and guided by their individual symptoms.[82] Patients should only advance activity if they have been able to tolerate their current level of activity without progression of symptoms or significant post-exertional malaise.[82] Of note, this is not a graded exercise program. Consider whether the patient has any exertional desaturation and cardiac impairment before embarking on any physical training programs.[3]

Encourage good nutrition and hydration.[82]

A specific plan for returning to work may be required.[82]

There is limited evidence to suggest the use of specific drugs in the treatment of fatigue related to long COVID, for example, low-dose naltrexone, neurostimulants (e.g., methylphenidate), modafinil/armodafinil, and amantadine.[82][111] However, there are no data from clinical trials examining these drugs specifically in populations with long COVID.[82] One small double-blind randomized controlled study demonstrated the efficacy of methylphenidate for fatigue and concentration in some individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).[112] The potential benefits of these treatments need to be weighed against risks of adverse effects. In general, consider drugs only once comorbid conditions have been addressed and if conservative measures have not adequately managed fatigue.

For more on how fatigue and activity intolerance is managed in ME/CFS, see Myalgic encephalomyelitis (chronic fatigue syndrome).

Plus – self-management and cognitive exercises

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all patients
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with cognitive impairment
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self-management and cognitive exercises

Treatment recommended for ALL patients in selected patient group

Evaluate the patient for comorbid medical issues that may be contributing to cognitive impairment (for example, pain, insomnia, or mood disorders). Consider whether the patient is taking any drugs that may affect cognition.[88]

Self-management strategies and cognitive exercises may lead to improvement.[3]

Refer patients with persistent cognitive symptoms to a specialist with expertise in cognitive remediation, including restorative and compensatory therapy. The patient may benefit from seeing a speech-language pathologist, occupational therapist, or neuropsychologist.[92]

Consider neurostimulants (such as methylphenidate, amantadine, or modafinil) only in specific patients whose symptoms have not improved with conservative management. Generally, use of neurostimulants for cognitive impairment is discouraged because of the possible adverse effects; ideally, these agents should only be used when cognitive impairment has been confirmed by a specialist.[113]

If you suspect any severe neurologic complications, such as stroke or seizures, refer the patient to a neurologist.[6] Also consider referral to a neurologist if the signs or symptoms persist (or worsen) after 12-24 weeks, or if they affect the patient's daily function and quality of life, despite attempted treatment and rehabilitation.[88]

Plus – treatment of underlying cause

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all patients
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with dizziness
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treatment of underlying cause

Treatment recommended for ALL patients in selected patient group

Address the specific type and etiology of dizziness. Treat any underlying autonomic issues (see "with autonomic dysfunction" patient group). Advise on falls prevention, if needed. Consider vestibular or autonomic physical rehabilitation.

Plus – lifestyle modifications and/or pharmacotherapy

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all patients
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with autonomic dysfunction
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lifestyle modifications and/or pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Initial treatment of autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS) and symptomatic tachycardia, includes lifestyle modifications such as use of compression garments, increased hydration (>3 L per day), and increased salt intake (up to 10 g per day).[87] However, use caution when recommending an increased salt intake in patients with heart failure, altered renal function, or elevated blood pressure.[87][88] See Postural orthostatic tachycardia syndrome.

If symptoms persist after these conservative measures, consider pharmacotherapy. Base the decision to use drugs and the choice of specific drug on the nature and severity of the patient’s ongoing symptoms along with pertinent comorbidities. Have a detailed discussion of potential risks and benefits before starting any drug. First-line options include low-dose beta-blockers, fludrocortisone, and midodrine. A number of second-line drugs are available but these should only be considered by a specialist.[39][87]

Consider an individualized autonomic rehabilitation program. This may require starting in a supine or sitting position to avoid exacerbating autonomic symptoms and should not exacerbate fatigue or post-exertional malaise. Education on physical counterpressure maneuvers may also be beneficial.[87]

Advise the patients to avoid alcohol consumption and strenuous activity in hot weather.[88]

Plus – treatment of underlying cause and pharmacotherapy

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all patients
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with sleep impairment
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treatment of underlying cause and pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Treat any comorbid conditions that may be causing impaired sleep (see Restless legs syndrome, Obstructive sleep apnea in adults, Gastoesophageal reflux disease, and Generalized anxiety disorder).

Explain to the patient the importance of sleep hygiene.

If sleep hygiene is ineffective, initially consider treatment with cognitive behavioral therapy for insomnia, where available; follow with pharmacotherapy, if required.

Pharmacotherapy options for insomnia include melatonin, trazodone, doxepin, and non-benzodiazepine drugs. The specific choice of drug is determined by patient factors, the nature of insomnia, and comorbid symptoms such as pain or mental health symptoms.[94]

See Insomnia.

Plus – lifestyle modifications and analgesia

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all patients
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with headache
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lifestyle modifications and analgesia

Treatment recommended for ALL patients in selected patient group

There is no unique treatment for long COVID related headaches. Instead, determine if the headache is primary or secondary.[94]

If primary, treat based on the headache type. For most headache types, recommend simple analgesia with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen initially (while advising on the potential for medication overuse headaches), and consider if any prescription drugs are required.[88] Consider lifestyle modifications that the patient can make, for example with sleep, nutrition, and exercise.[88][94] Refer to a neurologist if there is no initial improvement or if any concerning features are found on exam.[88] See Tension headache, Migraine headache in adults, Migraine headache in children.

Headache and migraine can accompany autonomic dysfunction (see "with autonomic dysfunction" patient group).[87]

Primary options

acetaminophen: 325-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

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ibuprofen: 200-400 mg orally every 4-6 hours when required, maximum 2400 mg/day

Plus – breathing exercises, oxygen, and/or pulmonary rehabilitation

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all patients
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with dyspnea
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breathing exercises, oxygen, and/or pulmonary rehabilitation

Treatment recommended for ALL patients in selected patient group

Initial treatment of dyspnea is targeted at treating any underlying etiology.

In patients with mild symptoms and not requiring supplemental oxygen, recommend breathing exercises and self-management strategies via self-directed educational resources, in-person rehabilitation, or online programs.[3][78][83]

For more severe pulmonary symptoms, resting or exertional hypoxia, or unexplained abnormal lung function test or imaging results, refer the patient to a respiratory specialist. Also consider pulmonary rehabilitation for these patients.[36][78][83] If the patient has concurrent post-exertional malaise or fatigue, the most physically limiting symptom should dictate the pace of activity.

Provide supplemental oxygen, if required, on the basis that oxygen therapy improves survival in patients with lung disease that results in chronic hypoxemia.[83][88] If patients require home oxygen, provide education on its optimal use and aim to provide a portable oxygen device to maximize mobility, so that the patient can participate in rehabilitation exercises.[83]

Do not routinely use pharmacotherapy (e.g., oral corticosteroids, inhaled bronchodilators, inhaled corticosteroids) in the absence of underlying lung dysfunction.[83][88]

Plus – treatment of underlying cause and/or pharmacotherapy

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all patients
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with cough
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treatment of underlying cause and/or pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Address any underlying primary lung disease, such as pulmonary fibrosis or asthma, or non-pulmonary underlying disorders such as acid reflux or postnasal drip. Educate patients with persistent copious secretions on airway clearance techniques.[83] Manage allergic or non-allergic rhinitis, if present; for detailed management approaches, see Allergic rhinitis and Non-allergic rhinitis.

For ongoing cough that is not improving or is worsening, consider treatment with albuterol as needed, inhaled corticosteroids, and inhaled corticosteroids/long-acting beta agonists.[88]

Refer to a specialist if the patient has a continued cough that lasts for >12 weeks despite initial treatment.[88]

Plus – olfactory training and/or pharmacotherapy

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all patients
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with anosmia/dysgeusia
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olfactory training and/or pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Evaluate for any change to appetite, which could lead to decreased intake or nutritional deficiencies and weight loss.[94]

Recommend online olfactory training/smell therapy (regular exposure to strong aromas with the aim of regaining a sense of smell).[3][39][80][88]

For persistent symptoms or for individuals with upper airway symptoms, consider consultation with an otolaryngologist or a specialized smell and taste center if available.

Oral or intranasal corticosteroids, theophylline, alpha-lipoic acid, vitamin A drops, and sodium citrate have been shown to cause an improvement in olfactory function.[114] However, the risks versus benefits of using corticosteroids should be considered. The conclusion of an expert panel was that they were less likely to recommend using theophylline, alpha-lipoic acid, vitamin A drops, or sodium citrate compared with olfactory training or corticosteroids.[114]

Plus – treatment of underlying cause

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all patients
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with chest pain
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treatment of underlying cause

Treatment recommended for ALL patients in selected patient group

Initial treatment should target any underlying pulmonary or cardiac disorders. These individuals may need referral to a cardiologist or pulmonologist. Also evaluate for, and manage, in conjunction with a cardiologist, any new or worsening symptoms, such as myocarditis/pericarditis, arrhythmias, structural heart disease, or coronary heart disease.[81]

For pleuritic pain or pain caused by costochondritis, consider stretching and breathing exercises and a short course of a nonsteroidal anti-inflammatory drug.[88]

Suspect cardiac impairment in a patient with rapid breathing or difficulty breathing, high resting or exertional heart rate, chest pain, or palpitations.[3]

Educate the patient on how to modify risk factors for cardiovascular disease.[81]

See Overview of acute coronary syndrome.

Plus – psychotherapy and/or pharmacotherapy

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all patients
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with psychological symptoms
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psychotherapy and/or pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Individuals with long COVID are at risk of persistent psychological disorders, including depression, anxiety, and post-traumatic stress disorder.[115] These are often secondary to physical and cognitive symptoms and are generally not the cause of the persistent physical symptoms. Despite this, given the interplay between psychological and physical symptoms, manage any psychological issues that are identified on screening in the same way as primary mental health disorders, including with psychotherapy and pharmacotherapy.[113] See Generalized anxiety disorder, Depression in adults, Depression in children, and Post-traumatic stress disorder.

Urgently refer for psychiatric assessment any patients with severe psychiatric symptoms or who appear to be at risk of self‑harm or suicide.[1]

Plus – analgesia

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all patients
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with musculoskeletal symptoms
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analgesia

Treatment recommended for ALL patients in selected patient group

Initially, provide analgesia with acetaminophen or a nonsteroidal anti-inflammatory drug.

The patient may have symptoms consistent with fibromyalgia, a common comorbid disorder in those with long COVID, and should be treated accordingly with aerobic exercise as tolerated, serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentinoids.[116][117][118]

See Fibromyalgia.

Refer patients with evidence of active synovitis or systemic rheumatologic conditions to a rheumatologist for further directed treatments.

Primary options

acetaminophen: 325-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

OR

ibuprofen: 200-400 mg orally every 4-6 hours when required, maximum 2400 mg/day

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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