While awaiting the results of key clinical trials, long COVID patients are working to change traditional clinical trial methods. A patient named Lisa McCorkell founded a patient-led non-profit organization aimed at providing advice and direction for long COVID research.

Lisa McCorkell contracted COVID-19 in March 2020 and initially experienced only mild symptoms. Although doctors instructed her to self-isolate and told her she would recover in a few weeks, her road to recovery turned out to be far more difficult than expected. As a graduate student of public policy at the University of California, Berkeley, McCorkell found herself caught in a range of weak and hard-to-explain symptoms. Severe fatigue, dizziness, and shortness of breath made it difficult for her, an avid runner, to even carry out normal activities.

She couldn't understand what was happening to her body, and her doctors seemed powerless over these long-term symptoms. In the early stages of the COVID-19 pandemic, due to the scarcity of high-quality testing resources, many doctors even began to question whether McCorkell's symptoms were related to COVID-19. This greatly undermined her trust in the medical system, as McCorkell herself said, "Not a single clinic could take my condition seriously."

Later on, McCorkell found many others with similar bizarre symptoms and struggles, and joined their support groups. Their symptoms eventually were all classified as so-called long COVID. Based on this, she established an organization called "Patient-Led Research Collaborative" (PLRC), which is a non-profit organization dedicated to participating in designing, guiding, and even funding foundational and clinical research of chronic diseases such as long COVID.

In 2021, a survey initiated by the organization revealed more than 200 different symptoms suffered by long COVID patients, playing a crucial role in bringing long COVID into the spotlight. Dr. Lucinda Bateman of Salt Lake City, an expert in the treatment of long COVID and related diseases, mentioned that "these studies have drawn wider attention and have led the public to begin to realize the existence of this disease."

Over the past few years, such patient-led research has had a huge impact on shaping long COVID scientific research projects and has driven preliminary clinical trials of certain treatment methods. Many patient groups call for the importance of these studies and insist that their results are more practical than those produced by multiple projects funded by the National Institutes of Health (NIH) to understand long COVID.

Patients suffering from the sequelae of COVID-19 for a long time, and their support groups, have questioned the effectiveness of the RECOVER program, believing that this research program has not fully considered their specific needs. Because long COVID involves a variety of complex symptoms, making it a huge challenge for patients to participate in related clinical trials. However, many patients and supporters expressed that, faced with the torment of symptoms, they have no choice but to actively seek solutions.

According to Margaret O'Hara, she is currently on sick leave due to a prolonged illness. As an employee of a hospital in the UK's National Health Service (NHS), she assists with arranging for patients to participate in long COVID research. She articulated the necessity of taking part in such research: "You can only go ahead and do it, because if you don't, you'll be the one in trouble. Yet, at the same time, you have to deal with all the troubles that come from being ill."

The symptom survey for long COVID, as the first large-scale study of this condition, has provided valuable data and analysis for understanding a wide range of symptoms. The survey covered about 3,800 patients from 56 countries, many of whom were members of global long COVID support groups, including the Body Politic online community. Researchers identified a multitude of symptoms across at least 10 different organ systems in patients when analyzing the related data.

The study results show that the most common symptoms include: extreme fatigue, discomfort after exertion, and cognitive dysfunction referred to as "brain fog." About 86% of participants reported that exertion would cause a relapse of their symptoms; approximately 87% stated that fatigue was their main symptom; and 88% exhibited brain fog, with no significant difference in cognitive issues among patients of different ages. This research is widely recognized for its in-depth analysis, having been cited over 1,000 times and mentioned in about 60 policy documents, becoming a key literature in the field of long COVID research.

McCorkell commented on the impact of this paper, saying: "This survey demonstrates that patients can also lead and participate in high-quality scientific research, which is crucial to our comprehensive understanding of the disease." It is worth mentioning that most of the leaders of this study were uncompensated volunteers, the majority of whom were people with disabilities, and the research did not receive any financial support.

McCorkell pointed out, in contrast, that many long COVID research projects have focused only on a small subset of symptoms. He believes this approach might miss the importance of understanding the disease as a whole: "It is necessary to face the complexity within the disease." Research scientist Beth Pollack from MIT, who focuses on chronic illnesses related to infections such as long COVID, agrees that diseases with multiple symptoms and insufficiently deep research need to start by listening to patients' experiences and recognizing the nuances of their conditions.

In early 2020, Martha Eckey, a pharmacist in Minneapolis, contracted an illness similar to COVID-19. She experienced a condition of overwhelming fatigue no matter how much she slept, sometimes needing several consecutive days of rest to recover. When she sought help from doctors but could not find the cause, she was plunged into despair. In this helplessness, she sought assistance from online communities of long COVID patients and found that many had already tried various methods, including prescription medications and over-the-counter supplements, but most to limited effect.

In her effort to gain a deeper understanding of long COVID and the effectiveness of treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Martha Eckey launched a research project called TREAT ME. The project aims to collect real treatment experiences from patients with long COVID and ME/CFS, particularly regarding the use of a range of over 150 different drugs and supplements. The survey questionnaires attracted positive responses from more than 4,000 patients.

After an in-depth analysis, Eckey found that there is an overlap in the use of certain medications between long-COVID patients and patients with other chronic diseases. The results indicate that the most effective treatment methods for the long-COVID syndrome include β-blockers and Corlanor (ivabradine), which is used for treating heart failure. These medications are also commonly used to treat Postural Orthostatic Tachycardia Syndrome (POTS), a neurological condition that may be triggered by COVID-19.

In addition, the survey results point out that some patients find relief in symptoms after using naltrexone, which as a non-opioid medication for treating substance abuse disorder, exhibits anti-inflammatory and analgesic effects when taken in low doses.

Regarding the original purpose of the TREAT ME survey, David Putrino, a physical therapist specializing in rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai in New York City, stated: "The core issue we care about is, which treatments are actually effective for patients?" The results of this survey are providing clear direction for his research on long-COVID.

The TREAT ME project, which is receiving a great deal of attention from the scientific community and research foundations alike, is considered to potentially guide future research directions—such as the work of the non-profit California organization Open Medicine Foundation, which focuses on exploring infection-related chronic diseases like long-COVID and ME/CFS. Linda Tannenbaum, founder of the organization and a clinical laboratory scientist, confirmed the symptoms to be evaluated in a forthcoming clinical trial of low-dose naltrexone (LDN) and pyridostigmine through the TREAT ME project. Ms. Tannenbaum remarked, "It was because of the strong demand from patients that we chose LDN for our first trial."

Meanwhile, the TREAT ME study also revealed that many long-COVID patients experienced a reduction in brain fog symptoms after using LDN, prompting the Open Medicine Foundation to decide to include cognitive function testing in its trial.

For both LDN and pyridostigmine, although they are used for treating long-COVID, many patients report that doctors are often reluctant to prescribe these medications due to the lack of definitive clinical trial evidence. As stated by Bateman, doctors typically prefer to choose medications that have been approved or at least have undergone medical review. Similarly, insurance companies are often unwilling to cover the costs of these drugs for ME/CFS and long-COVID patients in the absence of sufficient evidence.

Many patients and medical experts have expressed concerns about the inadequacies in the current pharmacotherapy field, pointing out that widely used drugs on the market lack necessary clinical research validation. Against this backdrop, the RECOVER Initiative received $515 million in funding support in February, slated to test more treatments over the next four years and to delve deeply into the long-term effects of COVID-19. However, of the clinical trials initiated under this program so far, only the antiviral drug Paxlovid (nirmatrelvir tablets/ritonavir tablets) plans to start patient recruitment from July 2023, along with an experiment involving ivabradine and intravenous immunoglobulin, the latter having begun recruiting its first participants only a few months ago.

Lauren Nichols, one of the leading members of the Body Politic support group and a representative of long COVID patients, has been actively engaged in advocacy. The RECOVER Initiative's attempt to test a computer game for treating brain fog has met with criticism, with many deeming the approach ineffective at providing substantial symptom relief. Similarly, the program's experiments on physical exercise have drawn dissatisfaction, as many long-term sufferers have experienced "post-exertional malaise." "Most of the current clinical trials focus on behavioral and non-pharmacological treatments, which are far from meeting the urgent needs of patients," said McCorkell, "Many studies fail to grasp the severity of this disease and its profound impact on patients' lives."

A spokesperson for RECOVER disclosed to the media that clinical trials examining the effects of the computer game on brain fog have started recruiting participants, while the experiments on physical exercise are still in the planning stages. According to the spokesperson, these intervention methods are easy to access and might provide some patients with relief, given the wide range of COVID-19 symptoms. The organizers claim that conducting these trials is beneficial for testing more treatments in the future and has established a framework for this purpose.

Just a few weeks after the initial infection of COVID-19, Hannah Davis suffered from severe brain fog, to the extent that she could not even string two sentences together. At that time, Davis, a data analyst and artist focused on bias issues in machine learning technology, was eager to regain her cognitive functions as soon as possible. However, her cognitive state failed to improve. "I've experienced terribly frightening cognitive impairments that just haven't gotten better," shared Davis, co-founder of the PLRC.

Brain fog has had a significant impact on patients' lives, observed Wes Ely, an ICU physician and scientist at Vanderbilt University Medical Center, who noticed cognitive impairments in long COVID patients similar to "mild to moderate dementia." Dr. Ely, a scientist who has long researched Alzheimer's disease and related dementia treatments, decided to study cognitive dysfunctions associated with long-term COVID-19 in 2020, and quickly recognized the complex nature of the condition, which involves symptoms beyond cognitive impairment. To more comprehensively understand the phenomenon, he reached out to the affected patient community, and eventually collaborated with Davis and ME Action's Director of Scientific and Medical Outreach, Jaime Seltzer, to design a clinical trial for the drug baricitinib – an immunomodulatory medication that treats rheumatoid arthritis, alopecia areata, and the acute infection of COVID-19.

Ely expressed his desire to understand the perspectives of people with this disease. Hence, he and other American researchers designed a clinical trial encompassing 550 participants. This study aims to explore the potential efficacy of baricitinib in treating long COVID. Funded by the NIH, this trial plans to begin recruiting participants in the second half of this year.

Seltzer believes that close collaboration between patients and researchers can achieve a win-win situation, enhancing both the efficiency and relevance of research. She said: "Our resources can help you achieve more with less." She further explained that patients' personal experiences focus the research in multiple critical aspects, including the efficient allocation of limited research funds based on the burden of symptoms, providing information related to the frequency and severity of symptoms, and discovering the most effective trial designs to determine symptom relief. Seltzer argued that all of this could help find treatment breakthroughs more quickly, benefiting both patients and researchers.

At the end of fall 2022, McCorkell traveled to New York City to participate in a clinical trial initiated by Putrino's team. The trial aimed to investigate the presence of microclots (tiny blood clots) in long COVID patients. The researchers believe that these microclots may disrupt the blood flow to the brain and other parts of the body, causing symptoms like fatigue and brain fog. Current information about microclots is incomplete, including how many long COVID patients have them, how they form, and whether there is a causal relationship with symptoms. After analysis with fluorescence microscopy techniques, McCorkell confirmed the presence of microclots in her blood sample. She described this as a "wake-up call," realizing her body might be experiencing some ongoing damage, prompting her to start taking supplements reported to be effective by some interviewees.

Although Eckey's research results have not been published in peer-reviewed journals, data indicates that among 668 long COVID patients surveyed, 40%-70% experienced symptom relief after using supplements such as nattokinase, serrapeptase, and lumbrokinase alone or in combination. Upon seeing these results, Putrino decided to conduct a clinical trial on these supplements. He plans to commence a lumbrokinase study of 120 participants in the coming months and has already invited patients at various stages to participate in the trial's design.

Putrino said: "Every clinical trial we conduct will plan for patient participation." This includes deciding which trials have priority, assessing which symptoms, and determining the questions to ask them, such as how many hospital visits are needed, and setting up the testing environment, all aimed at minimizing the risk of worsening their symptoms.

McCorkell stated that the supplements she has been taking have improved her overall health by about 20%. Although the improvement may seem modest, she feels it is a substantive progress. Despite the numerous difficulties encountered in long COVID research, she firmly believes that besides continuing to participate in studies, there is no other way.

While confronting the challenges of long-term COVID-19 sequelae, patients are actively participating in research, hoping to find potential solutions. Although no definitive cure for this condition has been discovered yet, the persistence of the patients and their pursuit to improve their quality of life remain their greatest motivation.