I burst into tears during a RECOVER-Treating Long COVID virtual working group meeting and quickly turned off my camera when a parent, with the best of intentions, suggested scheduling the low-dose naltrexone study during summer break so it would not interfere with schoolwork. I sat there listening to my daughter moaning in pain from the simple act of shifting in bed; schoolwork had vanished from her world three years earlier.
After that meeting, I wrote a long email to the program director requesting to be excused from this working group. I explained that I could not maintain my emotional well-being when everything revolved around mild to moderate cases, and that I needed to preserve the limited energy I have for caring for my daughter. It was an impulsive and highly emotional decision, but it is difficult to expect otherwise from a mother who has lived in a form of hell for three years.
The RECOVER-TLC program was launched by the National Institutes of Health (NIH) to identify and test treatments for Long COVID, promising to represent every level of illness. This was the third group I had been invited to serve with under RECOVER-TLC because I’m both a neurologist and the mother of a very severe Long COVID teen. Yet the conversation had never evolved to include people with very severe Long COVID who cannot leave their beds.
I and other advocates have encouraged RECOVER-TLC to include these patients since the program launched. At the 2024 workshop, I gave a brief speech sharing our family’s experience. I explained how difficult it has been, even as two physician parents, to navigate our child’s severe illness in a system with almost no clinical knowledge about very severe Long COVID.
After that, RECOVER-TLC leadership invited people with lived experience into its working groups, reflecting an effort to include patient perspectives. But most of these representatives are individuals with mild or moderate illness, as those who are most severely affected are often unable to advocate for themselves under current meeting and participation requirements that require real-time participation, spoken communication, or sustained cognitive engagement.
Several participants at the second RECOVER-TLC workshop, held on September 9–10, 2025, raised concerns that many trials currently in progress, particularly those requiring extensive in-person visits, exclude people with severe Long COVID. Advocates urged the program to develop decentralized, home-based options and warned against “mildwashing,” or the tendency to focus primarily on less severe cases.
RECOVER-TLC needs to address this gap directly by creating study designs that allow home- and bedbound people to participate. These people represent the most clinically urgent population, yet they remain absent from the evidence base that guides care. Their exclusion is not a procedural oversight but a scientific failure, and correcting it is essential for any program committed to understanding the full spectrum of the disease.
Their exclusion is not a procedural oversight but a scientific failure, and correcting it is essential for any program committed to understanding the full spectrum of the disease.
Sevda Sarikaya
For example, severe people may not react to medications in the same way as those with milder symptoms. Our daughter experienced life-threatening reactions during several emergency room visits to medications as common as Reglan and Benadryl. Through my social media account, which I created only to connect with Long COVID patients globally, I learned that our experience is not unique. Others have reported the same dangerous medication reactions, and we do not know how many more remain unheard because they were not as fortunate as we were.
As the most severe Long COVID cases are excluded from research, we are unable to understand or predict why these reactions disproportionately affect them. These incidents are preventable. Even a few basic clinical studies in emergency settings could save lives. Such work could be as simple as retrospectively reviewing charts of people with Long COVID who presented to the ER for any reason and documenting their reactions to standard medications. It requires no logistics, no home visits, and no complex infrastructure.
Some research groups have already begun to include people with the disease who are unable to leave their homes, demonstrating that scientific quality and accessibility can coexist. Yale, in particular, has been a pioneer. The PAX-LC trial, a fully decentralized antiviral study, allowed participants to complete the entire protocol remotely. Yale’s LISTEN study also created a platform for decentralized participation across Long COVID, post-vaccine syndrome, and related conditions, and recently published findings from its fully remote cohort.
Similarly, Scripps Research launched the fully remote Long COVID Treatment Trial-Tirzepatide, in which medications, wearables, and smart scales are mailed directly to participants’ homes so the entire study can be completed without clinic visits. The study of 1,000 participants closed its eligibility screening within 41 days, showing the demand for at-home trials.
Patient-led groups have directed further remote research. The Patient-Led Research Collaborative conducted one of the first large international online surveys of Long COVID and now maintains a remote registry in which participants can complete follow-up surveys about their symptoms every three months. Meanwhile, Renegade Research supports at-home, protocol-based projects such as the Remission Biome initiative, in which people with myalgic encephalomyelitis (ME) and Long COVID follow a structured regimen and track their symptoms from home, generating decentralized data outside traditional research settings.
These studies remind us that inclusion is not a logistical burden but a measure of a study’s integrity and vision. Making research accessible to the most severely affected is not about lowering standards; it is about meeting the true standard of science itself, understanding every part of the spectrum we aim to heal.
This principle is not new to medicine. In genetics and complex disease research, scientists often apply what is known as the extreme phenotype strategy: they focus on the most severe, resistant, or atypical cases to uncover mechanisms that may be hidden in milder forms. Studying those at the farthest ends of the spectrum amplifies biological signals and accelerates the discovery of causal pathways and potential drug targets.
For instance, in the 1970s, a child named David Vetter who had severe combined immunodeficiency (SCID) helped researchers provide direct insight into the indispensable role of the immune system in controlling infection. Study of his case contributed to the identification of the gene responsible for X-linked SCID and advanced understanding of how viruses can cause cancer.
This approach has also been used in hypertension research: scientists focused on individuals at the extremes of blood pressure to clarify biological pathways involved in disease severity. And extreme phenotype strategies are not limited to disease severity. In HIV research, scientists have compared people at opposite extremes of HIV exposure — those who remain uninfected despite repeated, high-risk exposure and those who become infected after lower exposure — using this contrast to uncover host immune mechanisms that protect against infection.
By applying this approach to Long COVID, researchers can advance our understanding of its underlying pathophysiology. The most severely affected people may reveal what drives the disease at its core, mechanisms that remain invisible in milder cases. Once these mechanisms are better understood, it will lay the groundwork for defining subtypes, which is already an urgent task in current studies.
The most severely affected people may reveal what drives the disease at its core, mechanisms that remain invisible in milder cases.
Sevda Sarikaya
Several groups have identified possible patterns using large electronic health record datasets. But many of these studies, including RECOVER study groups, are organized around symptoms or symptom clusters. Symptom-based trials are important and can offer meaningful relief by targeting specific manifestations of illness. However, lasting progress is more likely to come from studies built around clearly defined biological or syndromic subtypes of Long COVID.
Achieving this will require validated biomarkers. A small but growing number of Long COVID trials are now beginning to move beyond symptom-based enrollment toward more clearly defined subtypes. These include studies grounded in viral persistence hypotheses, trials targeting autoantibody-positive patients, and investigations focused on ME-like presentations characterized by post-exertional malaise. As studies increasingly center biomarkers and phenotypes, it becomes even more important to include very severe patients, who already represent the extreme end of the disease spectrum.
Ignoring the most severe cases of Long COVID not only hinders our understanding of the disease’s underlying biology but also distorts public perception of its seriousness. It risks diminishing the urgency of funding future Long COVID research, even though the condition already constitutes a major public health crisis.
Several research groups have already shown that severe patients can be included. With proper organization, modest logistical support, and home-based blood collection or bedside testing, participation can be made accessible to those too ill to travel. As RECOVER-TLC moves into its next phase of trials, it must ensure that patients with the most severe disease are included, and other studies should follow that lead.
If we truly want to understand this disease, it is these patients, the ones most severely affected, whom we cannot afford to leave behind. They are not beyond the reach of science; they are where real progress begins.
This inclusion must become the standard, built into how studies are designed, reviewed, and funded. The most severely affected are not on the margins of Long COVID; they represent its truest and most revealing form. The future of Long COVID research will be measured not by how many trials are launched, but by how many lives they truly represent.
The most severely affected are not on the margins of Long COVID; they represent its truest and most revealing form. The future of Long COVID research will be measured not by how many trials are launched, but by how many lives they truly represent.
Sevda Sarikaya
Sevda Sarikaya, M.D., is a neurologist and dementia specialist with 25 years of clinical experience and an advocate and caregiver to her daughter with post-COVID complications. She lives in Seattle, Washington, and shares much of her advocacy work on X at @NeurologistMom.
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