For a year now, I’ve been trying to keep up with articles about long COVID, and I’m sure many of you have been doing the same. We’re coming up with the same problem: Although there are many articles on the condition, too few of them offer positive solutions.   

Unfortunately, this is confirmed by a new survey of drug treatments for long COVID conducted by a team from Singapore. The study, published in the Journal of Medical Virology, gives an overview of trials through the end of July 2022 and states, “Although the 6 published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability.”  

I shall try to end on a more positive note. 

Randomized control trials and the basic rules for how treatment trials for long COVID should be done 

The basic rules for testing medical treatments have been developed over the last 70 years, and the best model that has emerged is the randomized controlled trial (RCT).   

When COVID-19 came on the scene as a massive threat to human health in March 2000, large simple RCTs were set up in the United Kingdom to test various hospital treatments. This program, called RECOVERY, showed that big RCTs could produce clear and actionable results within just 3 months with the right amount of organization and willpower.   

Here are some basic rules for producing good evidence about drug treatments:  

• Have a clear definition of the condition you’re treating.  
• Identify a drug that seems to be safe and may work (this often involves animal tests and what are called phase 1 and 2 studies).  
• Recruit enough people to ensure that your results apply to most.  
• Use the best existing treatment as the standard, but give half of the participants the new treatment instead of or in addition to this.
• Make sure those giving, receiving, and assessing the treatment don’t know who is in which group (this is called blinding).  
• Choose a set of outcome measures according to what matters most to people living with the condition.   
• Choose a period that reflects the reality of the condition. When this is over, stop the trial and “unblind” the results.  
• Report the results honestly and without bias, using standard statistical methods.  

So why is there so little trial evidence for drug treatment after long COVID has been known for 2 and a half years? 

The takeaway from completed trials for Long Covid as of July 2022 

When the Singapore team looked at the long COVID drug trials that had been fully reported through July, they found none that met the quality standards I’ve just listed. Normally, if a condition affects millions of people, pharmaceutical companies and academic centers fall over themselves and compete to fill the market with treatments.   

The research landscape is typically like a rich forest of activity, densest in the United States, followed by the United Kingdom and Europe. But with long COVID, all the study investigators could find were a few stunted research shrubs in Tunisia, India, Italy, and Saudi Arabia. They started with 230 trials in their initial search but only six published ones met their criteria for inclusion.   

Looking at the six trials, they found that only one from Tunisia used a recognized definition of long COVID. The study, published in Frontiers in Cardiovascular Medicine, claimed a positive effect of sulodexide on symptoms of chest pain and palpitations. Sulodexide is a mixture of heparins (which reduce clotting) and an additive intended to help these be absorbed when given orally.   

The other trials all involved relatively small numbers, lacked proper blinding, and gave either negative results or results of doubtful significance.   

What’s in the long COVID treatment pipeline? 

The Singapore investigators went on to track existing trials of long COVID drug treatments that either still need to be published or are incomplete. This work is even more challenging than looking at the published trial literature, and we should be very grateful to them, even if the results are probably incomplete.   

By looking at many trial registries, they discovered 474 different trials, which they whittled down to 54 by applying broad quality criteria. I can’t mention all of them here, but you can check them out by clicking the link to the review mentioned in the introduction of this article.   

Cardiopulmonary symptoms and anticoagulation 

I’ve mentioned sulodexide as a possible treatment for chest pain and palpitations. It’s undergoing a longer trial at the same center in Tunisia, but unfortunately, this doesn’t compare it with other anticoagulants (blood thinners), including injected heparin, which seems like a missed opportunity.   

Other centers are conducting separate trials using standard anticoagulants. The largest of these is HEAL-COVID, which combines apixaban and atorvastatin in people with long COVID who have been discharged from the hospital (rather than a community-acquired long COVID group).  

Many people with long COVID have palpitations, a symptom that has most healthcare providers reaching for beta-blockers. However, most of these people also experience faintness on getting up or standing for a few minutes, and beta-blockers worsen this.  

Beta-blockers (like metoprolol) are nevertheless undergoing trials, as is a possible alternative called ivabradine.   

Lung symptoms 

Some people who develop long COVID following a mild acute infection experience breathlessness, as do many more who had a severe initial infection. In the latter group, computerized tomography (CT) scanning often reveals lung damage in the form of fibrosis (damaged or scarred tissue).   

Here as in most long COVID research, I think it’s important to distinguish between the two groups. People hospitalized for COVID are far more likely to have structural damage due to their severe illness. Treatments to alleviate this may not work for community patients with similar symptoms but no apparent lung damage.   

Corticosteroids, anti-inflammatory drugs, often relieve respiratory symptoms and make people feel better. They’re easy to start and harder to stop. Their benefits are immediate (as in the phrase “he must be on steroids”) but their harm soon accumulates. A few ongoing trials are trying to determine the use of corticosteroids in treating long COVID.   

A less problematic agent is montelukast, which blocks the action of the inflammatory agent called leukotriene. It's generally safe and free of common side effects. However, it can cause insomnia and agitation in a few people.   

For people with established lung fibrosis due to a severe initial infection, pirfenidone is a drug that may help to slow down worsening or, better still, promote healing. Trials of this drug for this demographic are ongoing but unlikely to show results for a long period.   

Long COVID, food-related supplements, and the gut 

The general population widely takes fish oil supplements, and they’re also undergoing trials in people with long COVID.   

More specifically, a range of products called probiotics has been suggested to combat the abnormal balance of gut microorganisms often seen in long COVID. Some trials of these are underway.   

What’s missing? 

Reading this article had me rubbing my eyes a bit. Surely this can’t be everything? But I’ve read it more than once, and this really does sum up most of what the Singapore group was able to discover, despite a lot of hard work going through the trial registers. The following are some of the more obvious gaps: 

Drugs that target persisting SARS-CoV-2 virus 

There’s now plenty of evidence that a persisting response drives long COVID to the SARS-CoV-2 virus. There may be reservoirs of the virus which persist in the body, especially in the gut.   

People with long COVID have long been asking why there are so few trials of antiviral agents. They’re not mentioned in the article I’m discussing here, but antiviral trials exist and can be expected to increase over the coming year.   

However, existing off-the-shelf antivirals may prove ineffective against the hidden reservoirs of SARS-CoV-2, and completely new antivirals may take years to develop and go through the necessary processes of testing.    

Drugs that target reactivated Epstein-Barr virus 

In contrast with SARS-CoV-2, there are plenty of available drugs for treating Epstein-Barr virus (EBV).  

There’s also very compelling evidence that EBV is reactivated in people with long COVID. Seeing if any of these treatments help in long COVID seems an obvious way forward. 

Treatments to change the gut microflora 

The mixture of bacteria, viruses, and fungi in the bowel is staggering and complex and certainly has a bearing on many human diseases. By contrast, our methods of approaching treatment are crude and simple.  

I mentioned probiotics briefly, but I don’t hold out much hope of eliminating long COVID from the large bowel by taking live cultures of lactobacilli and similar microorganisms by mouth.  

Unpleasant though it may sound, there’s a much better chance of using safe preparations of human waste (feces) in quantity. This can be done by mouth in the form of pellets with a slow-dissolving covering, but it’s much more likely to be effective using actual human waste introduced via the rectum. This could be done with or without adding locally acting antiviral drugs.  

Neuroprotective treatments 

Most people with long COVID experience overwhelming fatigue after physical exercise and the same applies after mental exercise too. This is brain fatigue. There’s also the pervasive problem of brain fog, which is slightly different, as it may come on without reason or be present most of the time.   

It may be that we’ll have to wait for a cure for long COVID in the whole body before we can expect an improvement in the brain symptoms. But in the meantime, it might be worth carrying out trials of a small range of psychoactive drugs known to be safe.  

Few trials address the neural component of postural orthostatic tachycardia syndrome (POTS) or alleviate the other autonomic and peripheral sensory elements of long COVID.   

Looking for a better landscape 

The Singapore paper is a valiant attempt to cover the field, but its authors admit that it’s not as comprehensive as it might have been. Since it appeared, several studies have thrown important new light on important mechanisms involved in long COVID. The gaps in the survey and the fact that we are now 4 months on leave room for hope.   

New initiatives and trials are being funded all the time, especially in the United States under the RECOVER partnership of leading research centers. Although most of the drug trials will take a while to produce results, I’m hopeful that the next year will see some genuine advances in treatment.   

The gist  

Long COVID can be seen as a showcase of all that’s wrong with the existing medical research model, especially its slow response and lack of coordination. Some excuses can be offered, but we must find ways to do things better and faster.  

Fortunately, there are signs of improvement, especially in the United States. You may feel a bit weary of watching this space but keep looking.   

Article resources: 

• Chee YJ, Fan BE, Young BE, Dalan R, Lye DC. Clinical trials on the pharmacological treatment of long COVID: a systematic review. Journal of Medical Virology. Published online November 8, 2022:jmv.28289. DOI: 10.1002/jmv.28289 
• Hariton E, Locascio JJ. Randomised controlled trials—the gold standard for effectiveness research. BJOG. 2018;125(13):1716. DOI: 10.1111/1471-0528.15199 
• Charfeddine S, Ibnhadjamor H, Jdidi J, et al. Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-covid-19: insights from tun-endcov study. Front Cardiovasc Med. 2022;0. DOI: 10.3389/fcvm.2022.866113 
• Hoppensteadt DA, Fareed J. Pharmacological profile of sulodexide. Int Angiol. 2014;33(3):229-235.  
• Vazquez J, LaFee S. (2021). Existing heart failure drug may treat potential covid-19 long-hauler symptom. UC San Diego Health.  
• Goel N, Goyal N, Nagaraja R, Kumar R. Systemic corticosteroids for management of “long-COVID”: an evaluation after 3 months of treatment. Monaldi Arch Chest Dis. 2021;92(2). DOI: 10.4081/monaldi.2021.1981 
• Zhou X, Yang D, Kong X, et al. Case report: pirfenidone in the treatment of post-covid-19 pulmonary fibrosis. Front Med (Lausanne). 2022;9:925703. DOI: 10.3389/fmed.2022.925703 
• Yang CP, Chang CM, Yang CC, Pariante CM, Su KP. Long COVID and long chain fatty acids (Lcfas): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19. Brain Behav Immun. 2022;103:19-27. DOI: 10.1016/j.bbi.2022.04.001 
• Make-up of gut microbiome may be linked to long COVID risk. (2021). British Medical Journal.  
• Leigh S. (2022). COVID drug may also erase symptoms of long COVID. University of California San Fransico.  
• Pagano JS, Whitehurst CB, Andrei G. Antiviral drugs for ebv. Cancers (Basel). 2018;10(6):197. DOI: 10.3390/cancers10060197 
• Chen M. (2022). Yale researchers discover potential long COVID causes and treatments. Yale Daily News.