Research Summary-What are the current treatments being trialled for Long COVID? 

February 21, 2022


February 2022 

Audio commentary from Katrina Pears of the MEA

It is currently predicted that 10% of people who are infected with covid fail to fully recover, and develop what is being called Long Covid. Currently the diagnosis is made 3 months or more after the infection where symptoms are still being experienced as well as impaired functionality. 

There are a number of studies showing the striking resemblance between Long Covid and ME/CFS (such as: Bornstein et al., 2021; van Campen et al., 2021; González-Hermosillo et al., 2021; Jason et al., 2021; Paul et al., 2021; Sukocheva et al., 2021; Twomey et al., 2021; Mirfazeli et al., 2022).  

Differences do exist between the two conditions, such as symptoms more common with Long Covid are: shortness of breath and/ or cough, loss or change of taste and smell etc. The ME Association takes the view that Long Covid and ME/CFS are both examples of a serious and debilitating condition that can follow any type of viral infection. 

This research summary reviews what we currently know about the treatments which are being investigated for Long Covid. We have contacted each of the researchers, but to date we have no current updates available. 

Apheresis 

Lead researcher: Dr Beate Jaeger 
Study location: Mülheim, Germany

Apheresis is probably the most well-known treatment that is being researched following articles in The Guardian and the BBC news. Following these two news articles, the MEA has previously reported this treatment option as well in October 2021. 

Apheresis is based on the fact that Covid can cause blood clots (micro-clots) and damage to the lining of small blood vessels and this may also be a causative factor in Long Covid. Furthermore, the blood clots can block microcapillaries which inhibits oxygen exchange leading to the range of symptoms experienced in Long Covid (Pretoruis et al., 2021a). 

To date there has been reported success in Germany with the use of H.E.L.P (heparin-induced, extracorporeal, lipoprotein/fibrinogen, precipitation) apheresis. The apheresis technique essentially involves a dialysis style treatment where microclots and inflammatory molecules can be filtered out ofthe blood. 

The H.E.L.P apheresis treatment has been around for almost 40 years and is commonly used on patients with refractory hypercholesterolemia (otherwise known as high blood cholesterol), coronary artery disease. The lead researcher, Dr Beate Jaeger has a website information page but it doesn’t give away much more information. Results from Apheresis treatment needs to be verified, but it is reported that this technique has helped over 100 patients so far. 

In a similar way to the reported success with the Apheresis treatment in removing microclots, studies have shown that treatments such as antiplatelet and anticoagulation (Pretoruis et al., 2021b) could beneficial. The preprint paper by Pretoruis et al., 2021b reports patients main symptoms of fatigue to resolve as well as a decrease in microclots. However, this study throws caution as antiplatelet and anticoagulation should only be taken under strict and qualified medical guidance, due to dangers of bleeding. 

There have previously been studies on the use of immunoadsorption which is a selective Apheresis method for ME/CFS patients. These studies have reduced the neurotransmitter receptor antibodies in the blood resulting in improvements in symptoms (Scheibenbogen et al., 2018; Tölle et al., 2020; Bornstein et al., 2021). However, all of these studies are small, at most using 10 ME/CFS patients, therefore, evidence is lacking for the effectiveness of Apheresis as a treatment. 

AXA1125  

Lead researcher: Dr Betty Raman  
Study location: Oxford Centre for Clinical Magnetic Resonance Research, based at the John Radcliffe Hospital 

We reported this new development in Long Covid treatment back in November 2021, where the AXA1125 drug is being trialled with 40 long Covid patients. This drug targets muscle weakness and fatigue, by targeting mitochondrial dysfunction. The trial consists of patients either receiving 67.8g of the drug or a placebo for 28 days

It is currently thought that the Covid-19 virus “attacks” the mitochondria in cells leaving them damaged. Covid-19 patients have also been found to have lactic acid building up in their muscles, pointing to further evidence of mitochondrial dysfunction. It is thought that mitochondrial dysfunction is contributing to the fatigue experienced. It is hoped that AXA1125 can help to normalise the mitochondria’s function. 

AXA1125 is an oral drug and was developed to help treat liver disease (NASH- nonalcholic steatohepatitis) by the biotechnology company Axcella. It consists of six amino acids and an amino acid derivative that works via multiple biological pathways. The amino acids can promote glucose uptake, increase insulin sensitivity, and decrease lipotoxicity. This drug has already been shown to have a number of potential uses, such as: increasing fatty acid oxidation, ATP production, ketogenesis and mitochondrial bioenergetics. You can read more about the properties of AXA1125 here

There isn’t currently any new data available from this trial on the current effectiveness and no published results to date. Results are expected in mid-2022. The trial will primarily assess the outcomes by variations in phosphocreatine (PCr)which serves as a rapidly mobilizable high energy reserve. Secondary outcomes measured by the trial will look at: lactate levels, fatigue scores, a walk test for six minutes, and safety and tolerability. 

This trial offers hope for ME/CFS suffers as mitochondrial dysfunction is commonly reported in research studies (for example; see references to studies on mitochondrial dysfunction in our Index of Published Research, p60). Therefore, if AXA1125 drug can target cell energy production, it could help make way for treatments for ME/CFS suffers. 

Dr Shepherd has been in contact with Dr Raman, who is well aware of the overlaps between Long Covid and ME/CFS, about the possibility of including a cohort of people with ME/CFS in this clinical trial. 

Probiotics 

Lead researcher: Professor Robert Thomas 
Study location: Cambridge University Hospitals (CUH) NHS Foundation Trust, Bedfordshire Hospitals NHS Foundation Trust, the University of Bedfordshire 

Another UK based study is aiming at tackling another commonly reported problem in Long-Covid- dysbiosis – reduction in microbial density and an unbalancing of the ratio of friendly to unfriendly bacteria. This unbalance causes a range of gastrointestinal (GI) symptoms, like nausea, indigestion and diarrhoea. Studies so far have shown that GI symptoms can persist over 5 months after a Covid infection (Noviello et al. 2022). 

Specific blends of probiotics have been trialled in a year-long investigation, in the UK Phyto-V study. The study tested the use of two capsules per day (one containing phytochemical rich foods and the other probiotic) for 30 days on 126 people who had had an acute Covid infection and lasting symptoms over 100 days later. 

The probiotic tested consists of five different gut friendly bacteria belonging to the lactobacillus family with chicory-rich inulin. Inulin is an important part of the blend as it is a prebiotic which helps feed the lactobacillus in the capsule and other friendly bacteria in the gut. The probiotic used in this study was of the brand “yourgutplus”. 

Furthermore, studies have already shown that taking probiotics frequently reduce the risk of catching Covid (Baud et al., 2020). This trial on probiotics shows that probiotics can lead to improvements in fatigue, gut, health, cough and general well-being, with gut symptoms improving in 82%

The preliminary results from this study have been published in a peer-reviewed journal (Thomas et al., 2021). Probiotics are thought to help in a number of ways, for example: they encourage gut colonisation of anti-inflammatory strains of bacteria, encourage the breakdown of poorly digestible carbohydrates, provide sources of energy for the gut and break down polyphenols which lower systemic inflammation. 

The next stages of this study will look at whether phytochemical rich whole food supplements will further enhance the benefits seen. The research group also hopes to evaluate whether “yourgutplus” could also enhance antibody presence and levels post Covid vaccination. 

Another research group based in Italy has also shown promising results from the use of probiotics, with probiotic use reducing fatigue especially during hospitalisation (Santinelli et al. 2022). Other published research studies have reviewed the current evidence for the use of probiotics in five other research studies finding a role for probiotics in viral infections and reducing the severity of Covid (Kurian et al., 2021). 

Gastrointestinal symptoms are also very common in ME/CFS and studies have frequently looked at the role of gut microbiota in ME/CFS. Studies commonly report, for example: altered microbiomes, reduced microbial dysbiosis (decreased microbial diversity), greater gut heterogeneity of microbes and increased gut permeability (such as: Varsei et al., 2021; Xiong et al., 2021). However, the role of the gut in disease remains unclear and it is not known whether the change in microbiome causes ME/CFS or are these changes caused by patients being ill; many people with ME/CFS change their diet, for example as a result of increasing food intolerances or the change in ability to cook decreases food diversity. 

Probiotics have been studied for treating gastrointestinal and irritable bowel symptoms in ME/CFS patients, with many patients reporting improvements in gut related symptoms. However, the current evidence relating to probiotic interventions  treating other ME/CFS symptoms remains poor and limited (such as: Corbitt et al., 2018; Roman et al., 2018). I’m in two minds about the use of probiotics in ME/CFS, as if probiotics are the answer to resolving all ME/CFS symptoms then there would be more studies showing positive results. However, the gut is a hugely important part of the immune system, therefore, it is likely the role of the gut has not been fully resolved yet. 

Other trials and case reports for Long Covid treatment: 

There are a range of other small-scale studies and case reports we have come across in writing this article. Below is a summary of other potential treatments: 

  • BC-007: a German drug trail has been reported to successfully fully cure one Long Covid patient with two on the road to recovery. The published case report can be found here. A report has also been published on whether this drug will work for ME/CFS, which can be found here
  • Pulsed electromagnetic field: pulsed electromagnetic field therapy has been used to penetrate body tissues allowing improvements in physical symptoms. The published case report can be found here
  • Trigger point injections and dry needling: this technique which is similar to acupuncture has been shown to help manage myalgia symptoms (pain and muscle ache) due to Long Covid. The published case report can be found here
  • Repurposed drug trial– This is another UK trial and is awaiting approval. It is led by Prof Amitava Banerjee at University College London. This trial will look into drugs such as antihistamines and aspirin. Furthermore, it has been shown that some Long Covid suffers have developed Mast Cell Activation Syndrome, where the body releases too much histamine, therefore antihistamines would be appropriate. More details can be found here
  • Antihistamines– antihistamines are a highly accessible therapy available for use, this easy to understand news article explains why they might be potentially helpful. There have also been two published research papers on this topic. One is a case report showing that two patients have reported rapid symptom resolution with use. The other study reporting antihistamine use in 49 Long Covid patients can be found here.  

HEAL-COVID 

A national clinical trial has been set up to compare different treatments to determine whether they can improve the longer-term outcomes for patients who have been hospitalised due to COVID-19, called HEAL-COVID. The trial involves a number of collaborators, including the University of Cambridge and the University of Liverpool. Although it is important to note that this only focuses on hospitalised patients, while a vast majority who have persistent symptoms have not been hospitalised. 

Patients are being recruited for the trial shortly before they are discharged, and will randomly receive: 

  • Apixaban, an anti-coagulant or “blood thinner”, twice a day for 2 weeks or 
  • Atorvastatin, a statin with anti-inflammatory properties, once a day for 12 months or 
  • The usual standard care offered by their hospital, as appropriate to their symptoms and conditions. 

References to published peer-viewed studies 

Baud D et al. (2020) Using Probiotics to Flatten the Curve of Coronavirus Disease COVID-2019 Pandemic. Front Public Health 8: 186. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227397/ 

Bornstein SR et al. (2021) Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?. Molecular Psychiatry. Link: https://www.nature.com/articles/s41380-021-01148-4 

van Campen C et al. (2021) Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Medicina58: 28. Link: https://www.mdpi.com/1648-9144/58/1/28 

Corbitt M et al. (2018) A Systematic Review of Probiotic Interventions for Gastrointestinal Symptoms and Irritable Bowel Syndrome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Probiotics and Antimicrobial Proteins. Link: https://pubmed.ncbi.nlm.nih.gov/29464501/ 

González-Hermosillo JA et al. (2021) Post-Acute COVID-19 Symptoms, a Potential Link with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A 6-Month Survey in a Mexican Cohort. Brain Science 11: 760. Link: https://pubmed.ncbi.nlm.nih.gov/34201087/ 

Kurian SJ et al. (2021) Probiotics in Prevention and Treatment of COVID-19: Current Perspective and Future Prospects. Archives of Medicial Research 52 (6): 582-594. Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972717/ 

Jason LA et al. (2021). COVID-19 symptoms over time: comparing long-haulers to ME/CFS. Biomedicine, Health & Behavior. Link: https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1922140 

Mirfazeli FS et al. (2022) Chronic fatigue syndrome and cognitive deficit are associated with acute-phase neuropsychiatric manifestations of COVID-19: A 9-month follow-up study. Neurology Sciences. Link: https://link.springer.com/article/10.1007/s10072-021-05786-y 

Noviello D et al. (2022) Functional gastrointestinal and somatoform symptoms five months after SARS-CoV-2 infection: A controlled cohort study. Neurogastroenterology and Motility 34 (2): e14187. Link: https://pubmed.ncbi.nlm.nih.gov/34060710/ 

Paul BD et al. (2021) Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the Unites States of America 118 (34): e2024358118. Link: https://pubmed.ncbi.nlm.nih.gov/34400495/ 

Pinto MD et al. (2022) Antihistamines for Postacute Sequelae of SARS-CoV-2 Infection. The Journal for Nurse Practitioners. [Epub ahead of print]. Link: https://www.sciencedirect.com/science/article/pii/S155541552100547X 

Pretorius E et al. (2021a) Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovascular Diabetology 20: 172. Link: https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7 

Pretoruis E et al. (2021b) Combined triple treatment of brin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms. Nature Portfolio. Research Square [Preprint] [Epub ahead of print]. Link: https://www.researchsquare.com/article/rs-1205453/v1 

Roman P et al. (2018) Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review. Beneficial Microbes 9 (4): 603-611. Link: https://www.ncbi.nlm.nih.gov/pubmed/29695180  

Santinelli L et al. (2022) Oral Bacteriotherapy Reduces the Occurrence of Chronic Fatigue in COVID-19 Patients. Frontiers in Nutrition 8: 756177. Link: https://pubmed.ncbi.nlm.nih.gov/35096923/ 

Scheibenbogen C et al. (2018) Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One 13 (3): e0193672. Link: https://pubmed.ncbi.nlm.nih.gov/29543914/ 

Sukocheva OL et al. (2021) Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Advance Research. [Epub ahead of print.] Link: https://www.sciencedirect.com/science/article/pii/S2090123221002320 

Thomas R et al. (2021) The Influence of a blend of Probiotic Lactobacillus and Prebiotic Inulin on the Duration and Severity of Symptoms among Individuals with Covid-19. Infectious Disease Diagnosis & Treatment 5: 182. Link: https://www.gavinpublishers.com/article/view/the-influence-of-a-blend-of-probiotic-lactobacillus-and-prebiotic-inulin-on-the-duration-and-severity-of-symptoms-among-individuals-with-covid-19 

Tölle M et al. (2020) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Efficacy of Repeat Immunoadsorption. Journal of Clinical Medicine 9 (8): 2443. Link: https://pubmed.ncbi.nlm.nih.gov/32751659/ 

Twomey R et al. (2021) Chronic fatigue and post-exertional malaise in people living with long COVID. medRxiv 2021.06.11.21258564. [Pre-print] Link: https://www.medrxiv.org/content/10.1101/2021.06.11.21258564v2.full 

Varesi A et al. (2021) The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications. Journal of Clinical Medicine 10 (21): 5077. Link: https://pubmed.ncbi.nlm.nih.gov/34768601/ 

Wagner B et al. (2022) Successful application of pulsed electromagnetic fields in a patient with post-COVID-19 fatigue: a case report. Wiener Medizinische Wochenschrift:1–6. [Epub ahead of Print]. Link: https://pubmed.ncbi.nlm.nih.gov/35006516/ 

Xiong R et al. (2021) Multi-‘omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). bioRxiv. [Epub ahead of print.] Link: https://www.biorxiv.org/content/10.1101/2021.10.27.466150v1 

Dr Katrina Pears
MEA Research Correspondent

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