Long Covid - mechanisms, risk factors and management

The 'Treatment and Management of Long Covid" section of this clinical review, I think, is the most interesting part. For me it highlights how wooly the NICE guidelines in the management of Long Covid are and therefore why we are getting such substandard care. Saying Rest and Pacing several times over a 30 minute zoom call just doesn't cut it I'm afraid when we have chest pain, palpitations and dizziness on standing, breathlessness climbing the stairs and such severe brain fog that our livelihoods are threatened......

However the section on current trials is encouraging and I have left links to the trials in the text for you.

Like me you have probably already started using some of these potential therapies through your own research, and/ or desperation. I am currently using:

Flushing Niacin, Melatonin, Probiotics, Antihistamines, Hyperbaric oxygen, Vitamin C - but not high dose intravenous, breathing exercises and swimming.

I am privileged as I currently afford these therapies however to some they will be unaffordable especially if they are not, as yet, recommended by NICE guidelines. We will have to wait and see.

Treatment and management of Long Covid

WHO and the Long Covid Forum Group agree that research priorities for Long Covid include improving clinical characterization and the research and development of therapeutics.

Clinical characterization of patients with Long Covid is essential to provide appropriate treatment options. Gaining an understanding of why certain disease phenotypes arise in different individuals is an important piece of the puzzle. A review, which included perspectives from patients with Long Covid, suggested that the condition may actually be four different syndromes. Recognizing which patients belong to which subgroup of long covid, and understanding the pathophysiology, will be important in deciding the treatment they receive


Guidelines Various guidelines focus on treating and managing Long Covid, or have included recommendations for Long Covid in their guidelines for treating covid-19. Guidelines recommend how to identify, refer, and treat patients with Long Covid. The holistic assessment, investigation, and management approaches suggested by NICE are outlined in Figure 3.

Figure 3 Overview of the NICE rapid guideline: managing the long term effects of covid-19

In January 2021, WHO updated its covid-19 guidance to include a new chapter focused on caring for patients post-covid-19. These guidelines go into little detail about Long Covid, however. Similarly, the NIH has released treatment guidelines for covid-19, but little guidance on managing Long Covid.

The CDC is expected to release guidance on long covid management soon. The European Society of Cardiology has also released guidelines on the diagnosis and management of cardiovascular disease during the pandemic. The guidelines for treating and managing Long Covid will undoubtedly evolve as new evidence comes to light; however, other general guidelines, such as Evidence Based Medicine’s guidance on post-infectious syndromes may be useful for treating Long Covid.

Pulmonary symptoms Pulmonary symptoms are common during Long Covid.

NICE recommends that breathlessness may be investigated using an exercise tolerance test suited to the person’s ability, for example the one minute sit-to-stand test, and treatment and management should be multidisciplinary, with advice and education given on managing breathlessness.

Furthermore, the guidelines recommend offering patients with continuing respiratory symptoms a chest radiograph by 12 weeks after infection. Blood oxygen levels can be monitored using a pulse oximeter. Recommendations from the Mayo Clinic suggest that shortness of breath can be self-managed by limiting factors that exacerbate dyspnea, including stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising, however, chronic shortness of breath may require further intervention. Recognized non-pharmacological strategies for managing dyspnea include breathing exercises, pulmonary rehabilitation, and maintaining optimal body positioning for postural relief.

Meanwhile, a systematic review has found that oral opioids can be used to treat dyspnea, therefore this class of drugs may prove useful for treating the condition in people with Long Covid. Patients with pulmonary fibrosis resulting from covid-19 should be managed in accordance with NICE guidelines on idiopathic pulmonary fibrosis, while antifibrotic therapies may be advantageous. Exacerbations of bronchiectasis should be treated with antimicrobial prescribing, while non-antimicrobial therapies, including airway clearance, may be considered. Modified rehabilitation practices, including stretching, body rotations, acupressure, and massage have shown beneficial long term effects on respiratory symptoms in mild covid-19 patients in a small trial.

Cardiovascular symptoms

The NICE guidelines on Long Covid state that exercise tolerance tests may be undertaken to measure heart function, while lying and standing blood pressure and heart rate recordings should be performed if postural orthostatic tachycardia syndrome (POTS) is suspected. Urgent referral should occur for people that have symptoms of a life threating complication, such as cardiac chest pain.

The European Society of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular disease during the covid-19 pandemic. The range of cardiovascular conditions that can manifest in Long Covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and observation of cardiac biomarkers is important. NICE guidelines recommend β blockers for several cardiac complaints, including angina, cardiac arrhythmias, and acute coronary syndromes, therefore, β blockers may be useful in the treatment of cardiovascular manifestations of Long Covid.

Myocarditis may resolve naturally over time; however, supportive and/or immunomodulating therapy may improve recovery. A review has also suggested that anticoagulants may be used to reduce the risks associated with hypercoagulability. Meanwhile, advice and education, agents to maintain vascular tone, and agents to manage palpitations have been shown by a randomized controlled trial and discussed in a review to be advantageous in the treatment of POTS.

Treating fatigue, cognitive, and neuropsychiatric symptoms

Chronic fatigue is a common manifestation of Long Covid. NICE recommends that self-management and support are important in managing fatigue, owing to the poor availability of covid-19 specific treatment. A condition that may overlap with Long Covid fatigue is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), therefore, the treatment algorithm designed for treating ME/CFS may prove useful in treating post-covid-19 fatigue. NICE has specific guidelines that outline how to refer and treat ME/CFS patients; these include cognitive behavioral therapy (CBT) and graded exercise therapy (GET). Following backlash over these guidelines from the ME Association, however, NICE aims to publish revised guidelines in August 2021. Randomized controlled trials have shown that CBT is beneficial in the treatment of chronic fatigue, however, this is conflicted by findings from a re-analysis of a Cochrane review which question its effectiveness and show a high incidence of adverse events. This re-analysis study states that if a trial of a drug or surgical procedure demonstrated similarly high rates of adverse effects, then it would not be accepted as a safe treatment option, therefore CBT should have to adhere to the same level of scrutiny. Another management strategy for fatigue is pacing, whereby patients manage tasks and activities to avoid over-exertion and exacerbating fatigue. NICE guidelines for ME/CFS describe pacing as a self-management strategy, however guidance and education from healthcare professionals may be useful for patients. Evidence from randomized controlled trials for the use of pacing in Long Covid is yet to be seen. The implementation of group therapy via videoconferencing in people with early psychosis during the covid-19 pandemic shows promising results, with a pilot study showing improvements in psychotic symptoms and self-esteem, however, a review article provides information to suggest that CBT is ineffective in reducing Long Covid symptoms, including fatigue, with only 10% of participants achieving clinically meaningful improvements. GET is a structured intervention plan consisting of physical activities with a therapeutic goal. A systematic review of exercise therapy for CFS concluded that patients with ME/CFS generally feel less fatigued and have improved sleep and physical function following completion of exercise therapy, to a greater degree than following a program of either adaptive pacing or supportive listening. The NICE guidelines on ME/CFS recommend GET; however, in July 2020 NICE released a statement urging caution when implementing GET for people recovering from covid-19, stating that with guidelines currently being updated, these recommendations may change. This statement accompanies concerns over the potential negative effects of GET, including post-exertional malaise. Evidence specific to covid-19 is lacking, therefore cognitive impairment should be managed with support, including setting tailored, achievable goals and implementing validated screening tools. Managing cognitive impairment will require a holistic approach, however, patients should be advised that most people gradually recover from cognitive impairment following severe illness.

The holistic approach to treatment should extend to the services offered, with professionals including occupational and speech and language therapists addressing cognitive changes. Cognitive impairment in Long Covid, sometimes called “brain fog,” has been compared to “chemobrain.” The Mayo clinic recommendations suggest strategies to manage chemobrain including repeating exercises, tracking what influences deficits, and using stress relief and coping strategies. Furthermore, medications including methylphenidate, donepezil, modafinil, and memantine may be considered. These strategies may prove useful for Long Covid. Specific to Long Covid, luteolin, a natural flavonoid, may alleviate cognitive impairment by inhibiting mast cell and microglia activation, but clinical trials are required. Sleep disturbances may be managed by following relevant guidelines on insomnia, and a range of treatment strategies can be considered. Patients with mental health problems alongside or as a result of Long Covid can be managed following the relevant guidelines: depression, anxiety, PTSD, obsessive-compulsive disorder, and other mental health problems. Care home residents, including those with dementia, who acquire Long Covid have additional needs. Discussing mental health problems with patients requires compassion and understanding.

Treating other organ impairments

Current evidence for the recovery of renal function following covid-19 is lacking. Considering that early and close follow-ups with nephrologists have previously been beneficial, post-covid-19 patients with renal dysfunction may benefit from early and ongoing monitoring. Covid-19 can disrupt and alter the microbiome of the gut, which may allow for opportunistic infections. Covid-19 associated destructive thyroiditis can result in incident hyperthyroidism, which can be treated with corticosteroids Overall, close follow-up of patients with long covid and adequate investigative procedures should be kept up to accurately diagnose and treat specific symptoms.

Repurposing drugs for Long Covid

Antihistamines have been implicated as a possible treatment for covid-19, with a study that employed cellular experiments suggesting that histamine-1 antagonists may be able to reduce the covid-19 infection rate by inhibiting SARS-CoV-2 from entering ACE2 expressing cells. Systematic reviews and molecular studies have suggested that histamine-1 and histamine-2 antagonists are viable candidates for further clinical trials in covid-19. It remains to be seen whether antihistamines have potential for treating Long Covid. Antidepressants have been proposed to reduce the effects of long covid. Antidepressant use has been associated with reduced risk of intubation or death in covid-19, while a meta-analysis of antidepressant drug treatment for major depressive disorder has shown that use of antidepressants, including serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, results in a reduction in peripheral inflammatory markers.

Emerging treatments

Clinical trials exploring the efficacy of hyperbaric oxygen (NCT04842448), montelukast (NCT04695704), and deupirfenidone (NCT04652518) to treat respiratory conditions in Long Covid are ongoing. A trial of breathing exercises and singing is also under way to assess their utility in improving breathing abnormalities in patients with Long Covid (NCT04810065). A trial to assess the effectiveness of an 8 week exercise program in patients with Long Covid and fatigue is ongoing (NCT04841759). Vitamin C supplementation may prove useful in treating fatigue in patients with Long Covid, with a systematic review concluding that high dose intravenous vitamin C could be a beneficial treatment option. Two trials examining the effects of nicotinamide riboside, a dietary supplement, are ongoing (NCT04809974, NCT04604704) with the expectation that the molecule reduces cognitive symptoms and fatigue by modulating the pro-inflammatory response. A clinical trial is currently ongoing assessing the effectiveness of a probiotic supplement to normalize the composition of the gut microbiome and reduce inflammation in Long Covid (NCT04813718). The understanding of long term sequalae of covid-19 infection in the gastrointestinal tract will evolve, with studies currently ongoing (NCT04691895), which will subsequently affect treatment. Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-19. Leronlimab is a monoclonal antibody that blocks the function of CCL-5. It has been shown to be effective and safe in HIV and reduces plasma interleukin-6 levels in covid-19. Clinical trials are ongoing to evaluate the efficacy of leronlimab post-covid-19 (NCT04343651, NCT04347239, NCT04678830). Another antibody treatment, tocilizumab, blocks interleukin-6 receptors and has shown efficacy in a small trial of patients with covid-19 patients. Trials to explore the effects of tocilizumab are ongoing (NCT04330638). The anti-oxidative and anti-inflammatory function of melatonin may also be useful in treating long covid. Lastly, adjuvant treatments, such as adaptogens, are being explored for their effectiveness in treating Long Covid (NCT04795557).


With many people having been infected and continuing to be infected with covid-19, the long term implications are of increasing concern. Here, we have reviewed the studies that have explored the persisting symptoms of Long Covid, and have addressed the possible risk factors associated with developing Long Covid and the treatment options that may be useful in alleviating its symptoms. Currently, Long Covid remains enigmatic and, with the question of the impact that new variants of covid-19 will have on the incidence and severity of Long Covid still looming large, it is important that research continues to explore post-covid-19 syndrome.

Greater understanding of the pathogenesis, risk factors, symptoms, and methods of treating Long Covid is required to reduce the strain and demand on people with the condition and the healthcare systems that will endeavor to support them.


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