Five years since the start of the COVID-19 pandemic, long COVID remains a concern. More than 400 million people are currently affected, with many seeking treatment for symptoms such as post-exertional malaise, brain fog and paroxysmal orthostatic tachycardia. However, despite ongoing research efforts, there is still no specific treatment.
In Mexico, few of us researchers are discussing the impact of long COVID, and we are fighting for visibility of the illness, following the international fervor of groups like those of Etheresia Pretorius, PhD, and Michael Peluso, MD, MHS. We are working on the creation of the first clinical practice guideline with Mexico’s National Center for Technological Excellence in Health, while also consulting with patients with acute and persistent COVID, providing support in diagnosis and treatment. We also participate in the Spanish Long COVID Research Network, or REiCOP, and in an international expert consensus group seeking answers about this condition.
As a researcher who has studied the main theories behind long COVID, including working to establish a diagnostic pattern and develop a diagnosis and treatment proposal, it’s an opportune moment to reflect on the current therapeutic landscape. (1, 2, 3)
Failed clinical trials
Clinical trials have been attempted with promising medications. However, many have not met their primary therapeutic objectives and have been discontinued. This is the case with the drug temelimab, a disease-modifying drug for multiple sclerosis, tested in 203 patients with neuropsychiatric symptoms of long COVID. However, researchers did not observe a clinically significant improvement compared to placebo in the primary endpoint, which assessed fatigue, or in most secondary endpoints.
Another drug, BC007, designed to neutralize functional autoantibodies seen in patients with long COVID, did not demonstrate superiority over placebo in its Phase II trial, so the trial was suspended.
Promising clinical trials
AER002, a long-acting human immunoglobulin, is currently being tested in patients with long COVID with the goal of neutralizing the virus’s spike protein, whose persistence causes various alterations in patients with this chronic condition.
Baricitinib, an immunomodulatory drug commonly used to treat rheumatoid arthritis, alopecia and COVID-19, is being tested in patients with long COVID who present with immune dysregulation and chronic inflammation.
Polymerized type I collagen, a drug with immunomodulatory properties, binds to LAIR1, and this binding downregulates STAT1 phosphorylation. In hyperinflammatory syndromes such as COVID-19, its administration decreases the M1 subset, chemokines and growth factors associated with STAT-1, improving the acute phase of infection and potentially preventing long COVID.
Nirmatrelvir/ritonavir is a peptidomimetic inhibitor of the main protease of SARS-CoV-2, and is used to treat COVID-19. However, extended treatment with this drug has reduced symptoms of long COVID in some patients. Other clinical trials with mixed results have not found evidence to support its use. However, additional studies are still underway.
Ensitrelvir, a 3CL protease inhibitor, did not demonstrate a statistically significant reduction in the proportion of participants with long COVID at three months. However, a higher percentage of participants who received the treatment reported having returned to their pre-COVID-19 health status and no longer experienced fatigue compared to the placebo group. Further clinical trials are needed to demonstrate further evidence.
Nonpharmacological interventions
Numerous researchers have studied the relief of neuropsychiatric symptoms associated with long COVID using nonpharmacological interventions such as transcranial direct current stimulation (NCT05780450, NCT05092516), acupuncture (NCT06633666, NCT06476496, NCT05890508, NCT05212688), vagus nerve stimulation (NCT05918965) and stellate ganglion block (NCT06055270). Additionally, numerous studies focus on rehabilitation exercises (NCT06492577, NCT06404047, NCT05855356) and psychological support (NCT06045338) to address the wide spectrum of symptoms associated with long COVID. (4)
Conclusion
Although a specific and successful treatment for long COVID is still uncertain, research is ongoing in the hope of finding an answer for the many people affected by the condition, which is behaving like a chronic degenerative disease and will surely require a treatment that combines pharmacological and nonpharmacological interventions as well as specific rehabilitation therapies.
Global efforts such as the RECOVER-TLC initiative, endorsed by the National Institutes of Health and the Foundation for the National Institutes of Health, have been created to seek answers to the problems that long COVID encompasses.
However, funding for this initiative and for other COVID-19-related research in the U.S. has recently been cut, jeopardizing future progress, a concerning development that U.S. lawmakers should urgently address. (5)
Image: Logo of the study group for the diagnosis and treatment of COVID-19 in Veracruz, Mexico, led by Luis Del Carpio-Orantes, MD.
References
- Al-Aly Z, Davis H, McCorkell L, et al. Long COVID science, research and policy. Nat Med. 2024;30:2148–2164.
- Del Carpio-Orantes L. Etiopathogenic theories about long COVID. World J Virol. 2023;12(3):204-208.
- Ewing A, Joffe D, Blitshteyn S, et al. Long COVID Clinical Evaluation, Research and Impact on Society: A Global Expert Consensus. Available at SSRN: https://ssrn.com/abstract=4931063 or http://dx.doi.org/10.2139/ssrn.4931063
- Zhang R, Gu X, Zhang H, et al. Long COVID: Current research and future directions. Infect Dis Immun. Published online: March 4, 2025.
- Cohen, J. Saying ‘pandemic is over,’ NIH starts cutting COVID-19 research. Science. Published online: March 25, 2025.