Until the results of the longest and largest long COVID-19 study to date will brake ground with discoveries on treatment, let’s take a look at its prevention and current treatment options.
We should try to address first the risk factors that increase the chance of acquiring this syndrome. According to this study from JAMA these are the most important risk factors:
* Biological sex: women below age 50 (8.5%)are almost 2 times more likely to develop symptoms of fatigue, shortness of breath, brain fog, muscle aches, anxiety, or depression after a COVID-19 infection vs men. In women there is a probable overlap with more commonly present autoimmune conditions like ME/CFS (myalgic encephalomyelitis, or chronic fatigue syndrome). The persistence of the COVID-19 infection may affect hormonal (estradiol) production and amplify symptoms of perimenopause and menopause like menstrual irregularities. Identifying women with exacerbated hormonal changes becomes a priority at the long COVID clinics. A trial with hormonal replacement treatment helps alleviate respective symptoms.
* Age: adults ages 35–49 are the age group most likely to ever have (8.9%) or currently have (4.7%) Long COVID.
* Pre-existing co-morbidities. UK meta-analyses suggest that pre-existing poor mental health was associated with a 50% increase in the likelihood of reporting Long COVID and asthma with 32% increase. A prospective cohort study of COVID-19 mentions that individuals reporting having asthma, chronic constipation, G-I reflux, rheumatoid arthritis, seasonal allergies, or depression/anxiety were at significantly increased risk for the later development of PASC. When adding severity of acute SARS-CoV-2 infection and depression/anxiety to the model, only the presence of an autoimmune condition and seasonal allergies remained statistically significantly associated with long COVID. A JAMA study analyses also other comorbidities – chronic kidney disease, COPD, Diabetes, ischemic heart disease, obesity.
* Multiple symptoms early in the course of the acute infection predict a chance of 3.5 times higher for later development of a protracted course of COVID. Hospitalization and ICU admission during the acute phase of COVID-19 increases risk of developing PCC according to same JAMA study.
* High viral load is more likely to predict persistence of symptoms according to a review in Cell.
* Previous Epstein-Barr infection reactivates early on after SARS-CoV-2 infection, which is associated with the development of persistent symptoms according to the same review as above.
* Autoantibodies – two thirds of patients who developed Long Covid had autoantibodies and and as their levels increased, protective SARS CoV-2 antibodies decreased. In separate research the levels of the 1st antibodies to appear (that is IgM) may predict predict who had a moderate, high or very high risk of developing ongoing COVID-19 symptoms.
* Gut microbiome – a study published in Gut suggests that alterations in the variety and volume of the resident intestinal bacteria during the acute COVID-19 infection increases the risk of experiencing COVID-19 symptoms beyond 6 months.
* Vaccination status – A Lancet study suggests that those vaccinated reduce the risk of long CIOVID by half. Data published by the UK’s Office for National Statistics support the protective effect of vaccination, but not fully preventing long COVID.
* Genetics – a study published in July 2023 identifies the first genome-wide significant association for Long COVID at the FOXP4 locus. This locus has been previously associated with COVID-19 severity, lung function, and cancers, suggesting a broader role for lung function in the pathophysiology of Long COVID. The risk of the key FOXP4 locus variant was, in aggregate, 1.6-fold for its association with Long COVID but it varies widely by different ancestries and ethnicities.
In children long COVID is incredibly rare according to JAMA Pediatrics citing other studies.
Preventative measures to avoid developing PCC should stratify the above risk factors and address at the primary care and specialist levels the symptoms persisting beyond the acute phase of the COVID infection.
CDC suggests using a COVID-19 plan to prevent infection and re-infection and an Appointment Checklist for Post-COVID Conditions to track long COVID symptoms.
US Department of Health lists several actions to protect ourselves and others by following recommendations to prevent illness from COVID-19.
You can find here a long COVID clinic by state in the US. NIH RECOVER sites has a map of specialized clinics here and a map of long CIOVID prevalence by state. Usually, such large sites address both medical and mental health problems.
Therapeutic trials for long COVID-19 have been presented in studies of different sizes. The interventions taskforce of the RECOVER initiative mentions that there’s no standard of care for long COVID and no agreed upon treatment. Therefore, current management of long COVID is focused exclusively on symptomatic treatment.
However, there is promising early data on pharmaceutical interventions – some of which are currently listed in ClinicalTrials.gov*.
The following agents address different organs/ systems affected by long COVID-19. An emphasis is placed on those improving mental health and particularly cognitive impairment.
* Several antiviral medications are supposed to clear the virus and reduce the inflammation.
* Respiratory Agents like Montelukast help improve mild-moderate respiratory symptoms in patients with long-COVID-19.
* Cardiac Agents may improve cardiac function – like Metoprolol (a beta-blocker) which can lower also “stage fright” or performance anxiety.
* Metformin (antidiabetic medication) as Long and Short-term Consumption as a Potential Therapy to Prevent Complications of COVID-19 in a study. A 10 months study was following-up patients treated with Metformin, Ivermectin, and Fluvoxamine for the development of Long Covid with the conclusion that the Metformin group was more likely to decrease in the incidence of Long Covid.
* Atorvastatin (cholesterol lowering drug) undergoes a clinical trial to determine whether it can improve neurocognitive function in adults with long COVID neurological symptoms.
* Cannabinoid containing formulations may act as anti-inflammatory and can help ameliorate the neurological symptoms of long COVID. A study was using broad spectrum cannabidiol (CBD) formulation for treating fatigue, breathlessness, pain, sleep disturbances and dysautonomia in people with a diagnosis of Long COVID.
* Fluvoxamine (an SSRI) may improve olfactory deficiency following Covid-19- associated parosmia (disturbed sense of smell). Other agents to treat postinfectious hyposmia have been studied previously for non-COVID-19 patients including pentoxifylline, caffeine, theophylline, statins, minocycline, zinc, intranasal vitamin A, omega-3, and melatonin. Different combinations of the above agents may be of use in long COVID.
* Vortioxetine, a serotonergic antidepressant with established pro-cognitive properties, has been documented to improve anticipatory and consummatory measures of reward function/anhedonia, improve general functioning, and measures of motivation and energy without emotional blunting and it improves sleep behavior and circadian rhythms. It is hypothesized to be more effective than placebo in the treatment of cognitive impairment in persons with post-COVID-19 condition. Other antidepressants (e.g., SSRIs) can reduce respiratory complications secondary to COVID-19.
* Vitamin D has been known to counteract several respiratory virus infections as well as beneficial functions in multiple organs. It is recommended to supplement it when deficit is recognized (commonly due to less sunlight exposure during the cold season).
* Commensal microbiota in lung and intestinal tracts exert protective functions against virus infections and, through its metabolite and axis links, has anti-inflammatory actions and homeostasis in multiple organs. Regulating gut microbiota with supplemental probiotics may have a role in faster recovery from long Covid.
* Low Dose Naltrexone (opiate antagonist) may also act as anti-inflammatory. A current study aims to improve persistent fatigue and quality of life in post-COVID-19 syndrome by using it together with NAD+.
* Lithium, an anti-manic agent, has been investigated for improving fatigue and brain fog. Its efficacy and benefit–risk profile in patients with long COVID have not been proven.
* Stimulants of the amphetamine class have investigated to address brain fog and fatigue, which are the most prevalent neuropsychiatric symptoms of long COVID. Given their use in attention-deficit/hyperactivity disorder, these agents may be suitable for use in long COVID patients to improve brain fog. Long-term methylphenidate (Ritalin) intake has been used in chronic fatigue syndrome with positive impact on fatigue, concentration, and daily life activities.
* Amantadine and Memantine are suggested to ameliorate consequences of a COVID 19 infection in another study. Amantadine (an antiviral) moderately ameliorates motor symptoms in Parkinson’s disease. Memantine improves memory function in patients with advanced Alzheimer’s disease. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with the above-mentioned diseases.
* Pimozide (dopamine receptor antagonist used to control motor or verbal tics) has been investigated in COVID-19 induced tinnitus.
* Abilify (another Dopamine modulating drug used as mood stabilizer and antidepressant) in low dose shows promise as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) related “brain fog” in a retrospective study.
* Cyclobenzaprine (muscle relaxant) is currently studied in the management of multi-site pain associated with Long COVID.
* Guanfacine (α2A-adrenoceptor agonist) combined with the antioxidant N-acetylcysteine (NAC) reduced the cognitive deficits (“brain fog”) associated with long-COVID19 in eight out of twelve patients in small study.
* C1 Esterase Inhibitor Ruconest has been evaluated in a study to help patients that have developed “Post-Viral Fatigue Syndrome” which can include symptoms such as: extreme fatigue, loss of taste, brain fog, and/or seizures.
* Modafinil (dopamine reuptake inhibitors) can help regulate the sleep-wake cycle and alleviate more severe cases of fatigue.
* Portable Oxygen Concentrator (POC) was used in a study on brain hypoxia, peripheral oxygen saturation and cognitive function in adults with long term-COVID.
* Allogeneic marrow stromal cells (MSCs) infusion was recently hypothesized to attenuate post-covid inflammation and reduce the resulting neuropsychiatric symptoms.
* A Homeopathic treatment was used in a study to improve fatigue and quality of life for patients suffering from the symptoms of Post-acute COVID-19 Syndrome.
* Another study was evaluating the efficacy of adaptogens (herbs, roots and other plant substances that help our bodies manage stress) in patients with Long COVID-19. The substances aim at decreasing the duration of the convalescence, alleviation of fatigue, headache, attention deficit, difficult and rapid respiration, depression, anxiety and other symptoms of Long COVID-19.
* Cognitive and neurorehabilitation interventions using cognitive training or brain stimulation have been utilized in different studies.
* A few studies utilized physiotherapy and physical rehabilitation-based interventions with varied outcomes including depression, anxiety, cognition, quality of life, and a range of physiological and functional outcomes.
* A recent study was investigating the use of l-Arginine Plus Vitamin C Supplementation in Long COVID-19.
* Ginseng Radix et Rhizoma has a long history in traditional Chinese medicine and has shown clinical anti-fatigue effects. It has been suggested as a promising treatment for the fatigue associated with long-COVID-19.
* Nano-Antioxidants and Nanomedicine have a potential for recovery from neurological and psychiatric disorders linked to Long COVID Syndrome. The article cites several neuroprotective agents (curcumin, quercetin, vitamins C, E and D, melatonin, rosmarinic acid, N-acetylcysteine, and Ginkgo Biloba derivatives) in therapeutic strategies for neuroregeneration.
* Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs have shown effects in treating mood and neurocognitive disorders, reduce chronic inflammation and counteract the negative effects of long COVID on the brain, behavior, and immunity.
Other studies are investigating roles of substances such as steroids, growth hormone, immunomodulatory agents, Ketamine, Immunoglobulins.
As more such research studies will be published in the near future, we will learn about other interventions to address long COVID-19.