There are lots of studies, and here are a few I’m following! Hyperbaric Oxygen Therapy in Long Covid (HOT – LoCo) Where is it? Karolinska Institutet, Sweden What are they doing? An ongoing randomised, placebo-controlled, double blind, clinical trial, previously healthy subjects with post Covid Condition are assigned to receive hyperbaric oxygen therapy sessions or placebo sessions. (when patients go into the chamber, they won’t know if they are really getting HOT or not). What are they hoping to measure? They will assess physical tests and patient symptoms after 13 weeks. They want to know if patients who receive HOT do better. What else are they measuring? Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). There is an independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Status: Study is ongoing. They published an interim (which means they aren’t finished) safety report January 2023. There have been an unexpectedly high number of adverse events (31 in total) so far, mostly new cough, chest pain, and shortness of breath. It isn’t certain yet if they are related to the HOT, but safety monitoring is continuing. My verdict so far: The safety data so far would suggest that we would need more information: we need to know that patients would be more likely to benefit than to be harmed before recommending it. Also, there is no proposed mechanism as to how the HOT would treat long Covid.   Low Dose Naltrexone Current ongoing studies: A Double Blind Randomized Trial of Low-dose Naltrexone for Post-COVID Fatigue Syndrome Where is it? University of British Columbia, Canada What has been done so far? 2 very small studies were published where long covid patients were given LDN; Some of those patients did seem to have some improvement but the studies could not make the connection that the LDN was the reason they felt better. Why weren’t those studies good? These studies had very few patients, and all the patients had been told they were receiving a treatment. In one of the studies, they went back and looked at some data later. In none of the studies were patient randomised or blinded to the treatment. The authors of both studies actually wrote in their publications that they recommended that better studies should be done as a next step for patients. What does the new study aim to show? This study aims to determine if low-dose naltrexone (LDN) reduces fatigue, improves related symptoms, and reduces inflammatory markers in peripheral blood in cases with Post-COVID-19 Fatigue Syndrome (PCFS) from COVID-19 (i.e. confirmed SARS-CoV-2 case). LDN refers to naltrexone given in doses of 1-4.5 mg. It may help to reduce pain and inflammation and improve well-being and immune function (but still not sure exactly how.) Status: Recruitment was due to start December 2023. No published updates yet. Projected study completion June 2024. My verdict: This is a much needed study. LDN has been used off-license in several conditions over past decade (including fibromyalgia, MS) but the evidence for its use is severely lacking (no study so far actually proves that it works or shows how the drug should work). Researchers still aren’t exactly how does the drug is supposed to do what they think it can do (also called the mechanism of action.) In studies, the side effects of LDN are commonly described as mild but do include headache, fatigue, sleep problems, change in appetite, dizziness – many of the same symptoms long covid patients are already suffering.   RECOVER – VITAL Where is it? Duke University, USA What is it doing? RECOVER-VITAL (viral persistence and reactivation, and immune dysregulation) is focused on viral persistence, which is when the virus that causes COVID-19 stays in the body and causes damage to organs or the immune system (the body’s system that fights off illnesses) to not function properly. Researchers think that viral persistence may lead to Long COVID symptoms. RECOVER-VITAL is studying whether PAXLOVID (a combination of nirmatrelvir and ritonavir), an antiviral drug used to treat mild-to-moderate COVID infections, can be used to treat Long COVID. PAXLOVID works to stop the virus that causes COVID-19 from multiplying. Status: First patient enrolled July 2023. Study is projected to be complete April 2024. My Verdict: Interesting study to watch. But this one is complicated: “Viral persistence” (that the Covid virus stays in the body and causes long covid symptoms) is a theory, but has not been proven. Researchers don’t know yet if that is actually happening, or if it is, does that cause long covid symptoms. It’s a big step to say that even if it does happen, and does cause symptoms that this type of treatment would work. You can learn more about RECOVER: Researching COVID to Enhance Recovery projects in USA at https://recovercovid.org/  RECOVER – NEURO Where? Duke University, USA What is this study doing? RECOVER-NEURO is studying possible treatments to improve memory, attention, and brain processing speed for people who have Long COVID. All enrolled participants will do BrainHQ, an interactive online brain training program. Participants will complete BrainHQ activities that are designed to improve memory, attention, and brain processing speed — the time it takes to understand and respond to information. The activities adapt to each participant and will get a little easier or harder depending on the participant’s progress. Some patients will be randomised to also receive SC-CoRE (PASC Cognitive Recovery) is an online goal management training program for people with PASC (post-acute sequelae of SARS-CoV-2 infection), including Long COVID. In virtual meetings, trained study staff will help participants Plan and manage goals, learn mindfulness-based ways to work through distractions, learn skills to focus attention on goal-oriented tasks, and develop strategies to manage mental tiredness. Some patients will be randomised to also receive transcranial direct current stimulation (tDCS) is a safe, noninvasive form of brain stimulation. Participants will wear a headset that delivers a mild electrical current to specific parts of the brain to increase activity. Status: Enrollment started September 2023. Study completion projected to be December 2024. My verdict: This study is among the most promising with potential for real impact for patients. Using evidence-based techniques that have already been used in patients with brain injury, this study could guide occupational therapists, in particular, to structure effective rehabilitation strategies for long covid patient. The fact that this study is designed using online and virtual interventions also means that this has potential to be used in resource-limited settings.  

Here are just some of the problems challenging researchers around the world: There are differences in how we’re defining long COVID – there still isn’t international diagnostic criteria. This is important because there is a theoretical possibility that there isn’t “one kind of long covid”. It might actually be more than one condition, and this may be one reason the symptoms are so different among patients and some research doesn’t make sense with other research. o We don’t understand the risk factors: We know that being unvaccinated or having certain metabolic risk factors – low HDL, insulin resistance, and Type 2 diabetes – increases risk but patients without those risk factors also get long covid. o Some research includes only patients who definitely had a positive Covid test; others are less strict. o When are we sampling patients for research?  How long after the infection? How long after they have had symptoms? After re-infection? o Does which variant(s) the patient have matter? o Did the patients have in-person medical consultation to look for post-viral complications or other health problems? In some studies, patients just identified as long covid and/or reported their symptoms on an app (so can’t be sure that there isn’t something else going on with their health)? o Huge differences among populations being studied: age, sex, gender, ethnicity, occupation – these things can all really impact health outcomes.

There have been many hypotheses – which just means ideas – about what causes long covid, including dysautonomia (affecting part of the nervous system), “viral reservoir” (meaning that there is virus staying in places in the body), and microclots (meaning that really, really, really small blood clots cause long covid).  There are also ideas around serotonin and insulin resistance. There is an important difference between having an idea that could make sense based on what we know so far — and proving that the idea is correct. It is important to follow the scientific method: have an idea, create a way to test it, look at the evidence/proof, and form a conclusion. When we look for evidence in medicine, we often look at “Randomised Controlled Trials”. There are many, many rules for doctors and researchers conducting studies to make sure that we are doing this ethically to protect patients from harm and exploitation. If you are interested in a study that isn’t offered through your hospital or specialist care team, ask: 1) are you being asked to pay anything? You should never pay for experimental treatments that are done as part of a study 2) especially if the treatment is abroad, ask your own doctor or make an appointment with a consultant or professor in Ireland to discuss the trial before you go. They can help guide you and advise if the study is approved and safe.