Progress on the pathway to long COVID treatments

Meeting report https://doi.org/10.1038/s41590-025-02336-y Progress on the pathway to long COVID treatments Check for updates The US National Institute of Allergy and Infectious Diseases and Foundation for the National Institutes of Health convened a 2-day workshop announcing four agents to enter RECOVER–Treating Long COVID clinical trials and obtained input on future directions. I n 2025, long COVID continues to represent a serious public health concern and challenge affecting millions of people in the USA and worldwide — further underscoring the critical need for safe and effective treatment interventions to help those adults, adolescents and children affected by one or more of the 200 symptoms associated with this health condition1,2. Recent estimates indicate a pooled global prevalence of ever having long COVID at 36% among individuals with a confirmed COVID-19 diagnosis, with substantial geographic variation ranging from 29% in the USA to 51% in South America1. Although progress is being made in studying the immunological and pathophysiological mechanisms associated with long COVID and some clinical trials are underway, many crucial questions remain and the urgency to identify efficacious therapies is increasing daily. In 2024, the US National Institute of Allergy and Infectious Diseases (NIAID) launched a new clinical trials initiative to test novel and innovative approaches to bring safe and effective therapeutics rapidly to patients with long COVID. On 9–10 September 2025, NIAID and the Foundation for the National Institutes of Health (FNIH) co-hosted the second annual RECOVER-TLC (Researching COVID to Enhance Recovery–Treating Long COVID) workshop in Bethesda, Maryland. The workshop, entitled ‘Pathways to treatments’, marked one year since the launch of the NIAID clinical trials initiative and represented a unique opportunity to highlight and share the significant steps forward that the TLC initiative has made, as well as to obtain crucial input from the long COVID communities and stakeholders. The workshop was co-chaired by Upinder Singh nature immunology Host genetic factors Immune system inflammation/ dysregulation Persistent antigen and/or infection Illness experience Microbiological factors Neural network alterations Fig. 1 | Pathogenesis of long COVID. The pathogenesis of long COVID involves the interactions of host genetic factors, microbiological factors and illness experience, resulting in persistent antigen and/or infection, neural network alterations and immune system inflammation and dysregulation. Findings from long COVID research will help inform better treatments for other infection-associated chronic conditions. (University of Iowa, Carver School of Medicine) and Joseph Breen (NIAID). Over 1,100 registrants attended virtually or in-person during the 1.5-day workshop, including persons living with long COVID, health care and family care providers, US and international researchers, biopharmaceutical scientists, US federal and state government representatives, congressional staff and members of the press. Opening remarks by Jayanta Bhattacharya, NIH director, noted his commitment and prioritization of long COVID research and RECOVER-TLC. Welcoming comments by Julie Gerberding (FNIH) and Jeffery Taubenberger (NIAID) underscored the crucial need for persons with long COVID to be intricately involved in the identification of potential treatments and NIAID TLC’s rapid response to this public health concern, respectively. In the opening session, Elizabeth Geerling (FNIH) highlighted that since the RECOVER-TLC intervention information submission portal was activated on 30 September 2024, over 570 submissions of potential therapeutics and biologics have been submitted for consideration for testing in TLC clinical studies, with the majority coming from persons with long COVID and categorized as antiviral and immunomodulatory agents, followed by neurological and metabolic agents. Geerling described the agent prioritization process, including review of any pre-clinical and/or clinical data for each agent by members of the newly established prioritization working groups, consisting of subject matter experts, clinicians, persons with lived experience and scientists. John Beigel (NIAID) described the principles for agent selection and process used by the scientific oversight committee (SOC) in analyzing the six highly ranked agents identified by the prioritization Volume 26 | December 2025 | 2126–2129 | 2126 Meeting report working groups. The SOC provided final recommendations to an executive committee, including NIH and FNIH leadership. Beigel reported the executive committee’s final decision to proceed with four agents in the first round of TLC clinical trials, including low-dose naltrexone (LDN), an opioid receptor antagonist and immunomodulatory agent; the Janus kinase–signal transducer and activator of transcription ( JAK–STAT) inhibitor baricitinib, an immunomodulatory agent to reduce production and signaling of cytokines; glucagon-like peptide-1 (GLP-1) receptor agonists, which are anti-inflammatory, anti-thrombotic and anti-obesogenic agents; and stellate ganglion block, a procedure to inhibit the stellate ganglion to cause a blockade of autonomic (sympathetic) nerve fibers and reduce neuropathic pain from the head, neck and upper extremities. The overall scientific and clinical rationale for testing each of these four agents and the targeted study population were discussed in separate workshop sessions. Trial of LDN in children with long COVID The urgent need for safe and effective treatments for children with long COVID was underscored in a presentation by Rachel Gross (New York University), which mentioned that 2–70% of children infected with SARS-CoV-2 have persistent symptoms and that 2–10% are likely to have long COVID3–5. With 65 million antibody-positive children in the USA, it is estimated that between 1.3 million and 6.5 million children have long COVID. Gross noted that each case has significant impact on families’ health, educational, social and economic costs. Additionally, new cases of long COVID among children are still occurring, with symptom patterns similar yet distinguishable across different age groups6. Stephani Stancil (Children’s Mercy Hospital) described the safety and tolerability of LDN in three randomized clinical studies of 8–21-year olds using doses of 3–250mg, with no differences in serious adverse events between the agent and placebo. Stancil noted that LDN functioned as an immunomodulatory agent and was used to treat post-exertional malaise, persistent fatigue and difficulty concentrating in pediatric patients. Kay Tomashek (NIAID) outlined the establishment of the LDN protocol working group, which is currently planning a randomized, double-blind, placebo-controlled TLC clinical trial in children, adolescents and young adults aged 6–25 years old. A protocol synopsis that outlines an approximately 100-sit (...truncated)