Long COVID and post-acute sequelae — NIH Funding Overview

Why this matters now

PASC affects millions of Americans and remains poorly understood mechanistically. Continuing congressional appropriations to RECOVER and adjacent programs at NHLBI, NINDS, NIAID, and NIMH make long COVID one of the few research areas with stable, predictable federal investment through the late 2020s.

How NIH funds this area

Most long COVID awards are U01, U19, U54 cooperative agreements tied to RECOVER, with R01 and R21 grants supporting mechanistic substudies. The data below covers all NIH ICs mentioning long COVID or PASC in award text.

Yearly NIH Awards for Long COVID and post-acute sequelae

Counts and total funding per fiscal year from NIH RePORTER. Recent fiscal years may understate final totals because of reporting lag.

Open the full interactive trends view for Long COVID and post-acute sequelae →

Top NIH Institutes (last 90 days)

Which NIH institutes funded the most Long COVID projects in the most recent 90-day window.

Common Activity Codes (last 90 days)

Which grant mechanisms (R01, R21, U01, P30, etc.) appeared most often for Long COVID in the recent period.

Most Active Institutions (last 90 days)

Universities and research organizations with the most Long COVID awards in the most recent 90-day window.

1. OHIO STATE UNIVERSITY — 2 awards
2. UNIVERSITY OF TEXAS HLTH SCIENCE CENTER — 1 awards
3. VANDERBILT UNIVERSITY MEDICAL CENTER — 1 awards
4. JOHNS HOPKINS UNIVERSITY — 1 awards
5. MONELL CHEMICAL SENSES CENTER — 1 awards
6. UNIVERSITY OF ALABAMA AT BIRMINGHAM — 1 awards
7. EMORY UNIVERSITY — 1 awards
8. SCRIPPS RESEARCH INSTITUTE, THE — 1 awards

Recently Awarded Long COVID and post-acute sequelae Grants

Twelve most recent awards mentioning Long COVID, drawn from NIH RePORTER. Click through to Find PIs for the full investigator search.

• 2026 Sleep Regulation and Function Gordon Research Conference and Gordon Research Seminar

  1R13NS149701-01
  YING-HUI FU · GORDON RESEARCH CONFERENCES, RI · $20,000 · awarded Apr 24, 2026 · R13

  SUMMARY: The 2026 Gordon Research Conference (GRC) on Sleep Regulation and Function, themed “Sleep for the Whole Organism,” will mark the seventh installment of this highly successful series. Over the course of the last decade, sleep research has experienced remarkable growth across a variety of disciplines, spanning molecular biology, systems neuroscience, and mental health. Advances in state-of-the-art technologies have enabled significant progress in our understanding of the neurocircuitry underlying non-REM and REM sleep, wakefulness, the roles of neurotransmitters and neuromodulators, genetic contributions to sleep regulation, and the impact of sleep loss on transcriptional and translational dynamics. The 2026 GRC will build on this strong foundation while expanding into new frontiers. The program will explore sleep as a whole-organism behavior, integrating both brain and body perspectives. In addition to core sessions on sleep regulatory mechanisms and emerging findings from non- mammalian species, the conference will highlight recent findings on sleep’s roles in cognition, consciousness, interoception, and waste clearance from the brain. A session will examine the interplay between sleep and post- infectious disease states, reflecting growing interest in how immune challenges—including long-term consequences of viral infections—impact sleep regulation and homeostasis. The program will further emphasize bidirectional brain-body communication, with discussions on the bi-directional interaction between sleep and peripheral physiology, metabolic state, and systemic signals. Finally, the growing interface between artificial intelligence/machine learning (AI/ML) and sleep science will be showcased, illustrating how advanced computational tools are transforming data analysis, predictive modeling, and mechanistic discovery in the field. This GRC will comprise 50 invited speakers and discussion leaders, poster sessions, in the main meeting. It will be preceded by the GRS, which will provide opportunities specifically for graduate students and post-docs. The GRC and GRS will bring together scientists of all career stages in an interactive and safe environment.

• Role of the Non-canonical Inflammasome in SARS-CoV-2-mediated Pathology and Coagulopathy

  5P01AI175399-03
  Amal Amer · OHIO STATE UNIVERSITY, OH · $2,974,582 · awarded Apr 21, 2026 · P01

  OVERALL - ABSTRACT COVID-19 is a world-wide health problem caused by SARS-CoV-2 viral infection in the lung with long-term symptoms in at least one third of patients. Many COVID-19 patients suffer from silent or identified thrombi in major organs such as the lung and the brain and have increased occurrence of cardiac events. They also experience high levels of inflammatory cytokines collectively called cytokine storm. Combined, these reactions lead to organ damage and long- term sequelae of infection commonly termed Long-COVID. Our Program team will join forces to determine the host cell mechanisms underlying tissue damage in the lung and how SARS-CoV- 2 alters immune responses (Project 1), as well as in the brain and blood circulation (Project 2). Identification and targeting of host mechanisms that control the multi-organ inflammatory pathologies of COVID-19 will synergize with the targeting of cellular enzymes that control SARS- CoV-2 replication (Project 3). Together, our team will reveal and test novel therapeutic targets to collectively tame inflammation, neuroinflammation and thrombosis and to restrict viral replication. To achieve such a comprehensive overall goal, the three Projects by four Cores that will offer administration, biostatistical and bioinformatic support, animal models and purified viral strains, and relevant primary cell types with genetic manipulations to perform the planned experiments. Our Program will spearhead efforts to better understand the mechanisms of COVID-19 pathology in different organs and to identify novel drug targets to limit the severity of COVID-19 and the development of Long-COVID.

• Blood-Brain Barrier Integrity and Immune Dynamics in Neuropsychiatric Sequelae of Post-SARS-CoV-2 onset ME/CFS versus Pre-Pandemic ME/CFS Patients

  1R01NS147100-01
  Alba Azola · JOHNS HOPKINS UNIVERSITY, MD · $633,378 · awarded Apr 17, 2026 · R01

  PROJECT SUMMARY/ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a long-term disabling condition with a wide range of symptoms, often triggered by acute infection. The CDC estimates that in 2022, over 3.5 million Americans are living with ME/CFS, and this number continues to increase as many Long COVID patients develop ME/CFS. Profound neurocognitive sequelae are highly prevalent in ME/CFS. The underlying pathophysiologic mechanism that drives neurocognitive impairments in post-infectious chronic conditions remains poorly understood, hindering the development of therapeutic interventions. Studies in chronic viral infections recognize that the trafficking of proinflammatory monocytes in the brain drives disruption of the blood-brain barrier and promotes a neuroinflammatory state. We hypothesize that post-SARS-CoV-2 onset ME/CFS patients and pre- pandemic ME/CFS patients have similar blood-brain barrier (BBB) disruption that is mechanistically linked to circulating proinflammatory analytes (cytokines and chemokines), altered BBB endothelial integrity, and a subtype of proinflammatory peripheral blood mononuclear cells (PBMCs) known as intermediate monocytes. Thus, disruption in BBB integrity promotes persistent neuroinflammation and altered neuronal activity, contributing to neuropsychiatric sequelae in both pre- and post-pandemic ME/CFS patients.Additionally, there is evidence supporting glymphatic system dysfunction in ME/CFS, which further contributes to the perpetuation of the neuroinflammatory state. We propose cross-sectional imaging to assess BBB integrity, with neuropsychiatric assessments and immunophenotyping in 100 post-SARS-CoV-2 onset ME/CFS patients and 100 who have pre- pandemic ME/CFS patients. In addition, we will incorporate 100 participants as a control group of SARS-CoV-2 infected individuals who fully recovered without lingering symptoms from our team NIH-funded similar study in a Long COVID cohort. First, we aim to assess BBB integrity in post-pandemic ME/CFS (vs. pre-pandemic ME/CFS) and its contribution to neuropsychiatric conditions. BBB integrity will be evaluated with a non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment and are currently using this technique in other neuro-infectious diseases. Second, we aim to assess cross-sectional links between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules in post SARS CoV-2 onset ME/CFS patients and pre pandemic ME/CFS. We hypothesize that both groups will exhibit similar levels of soluble markers promoting PBMC trafficking to brain and promoting monocyte activation, disruption of soluble markers that promote endothelial integrity & higher levels of cell-surface proteins that promote PBMC diapedesis into brain will be associated with higher PS values and greater alterations in the cognitive and psychiatric domains. Findings will inform next steps in the development of therapeutic approaches to minimize neuroinflammation in Long COVID.

• Neuromodulation for Rehabilitation of Post-Stroke Fatigue: An rTMS Pilot Study

  5IK2RX003790-05
  John Kindred · VETERANS HEALTH ADMINISTRATION, GA · $0 · awarded Apr 17, 2026 · IK2

  The long-term goal of this proposed career development award (CDA-2) is to accelerate my training and development so that I can establish an independent line of research unraveling the causes and consequences of fatigue and to develop effective evidence-based therapies for fatigue in Veterans with neurological conditions. Before my collegiate studies, I served nine years on active duty in the United States Marine Corps and received an Honorable Discharge upon the expiration of my service contract. I completed my Ph.D. in Human Bioenergetics at Colorado State University in 2017. Upon graduation, I began a post-doctoral position at the Medical University of South Carolina working with Dr. Mark G. Bowden, PT, Ph.D. Shortly after starting my post- doc position, I acquired a WOC appointment at the Ralph H. Johnson VA Medical Center and was awarded a VA Rehabilitation Research and Development Career Development Award – 1 that began in Oct 2019. Since the beginning of my research journey, I have published 22 peer-reviewed manuscripts, 12 as the first author. My most recent publications have centered on measuring the neurophysiological state of the nervous system and relating that state to post-stroke disability. These most recent manuscripts are based on data collected at the laboratories at Ralph H. Johnson before my arrival and the co-authors include several of the members of this proposal’s mentorship team. Upon completing my CDA-1 (end date Sep 30, 2021), I have focused my attention on the neurophysiological biomarkers of post-stroke fatigue. This CDA-2 proposal will provide me with the opportunity to learn new neurophysiological assessment methods and advance my knowledge and ability to apply neuromodulatory treatments. These skills will provide me the foundation to build an independent VA- backed research program focusing on reducing the impact of fatigue in Veterans with an array of neurological conditions. The assembled mentorship team is composed of experts in post-stroke rehabilitation, neuromodulation, neuroimaging, and clinical assessment. Up to 92% of people post-stroke experience fatigue. Fatigue negatively affects physical and mental performance leading to a lower quality of life. Fatigue is also present in many other neurological populations within the Veteran community, such as traumatic brain injury, multiple sclerosis, and the newly coined phenomenon of Long-COVID. Advances in the knowledge and understanding of post-stroke fatigue are likely to lead to advances in other clinical populations within the Veteran community. The first aim is to test the effects of a well-established neuromodulatory therapy, repetitive transcranial magnetic stimulation (rTMS), on reducing the severity of post-stroke fatigue. This aim is predicated on theoretical principles obtained from the study of other neuro-psychiatric/-cognitive disorders and therapeutic attempts to reduce fatigue in other neurological illnesses. Participating Veterans will receive high-frequency rTMS to the frontal lobe, either the left prefrontal dorsolateral cortex or bilaterally to the motor cortices. These locations have been implicated in fatigue in other neurological conditions. I expect to show rTMS can be used to reduce post-stroke fatigue severity. However, the effectiveness and location of treatment may partially be dependent on individual characteristics. The second aim of the study is based on the skills and knowledge developed in the CDA-1, I plan on identifying additional neurophysiological biomarkers of fatigue. In this project, I will assess glutamatergic activity/signaling of the upper and lower extremity sensorimotor network of Veterans with and without post-stroke fatigue. I expect to show that the fatigued group will show glutamatergic dysfunction, measured by greater asymmetries in intracortical facilitation and the facilitatory response to paired associative stimulation, compared to the non-fatigued group. Identification of glutamate and related metabolites as a pathophysiological contributor to post-stroke fatigue may help in the development of new therapeutic approaches for post-stroke fatigue and fatigue in other neurological conditions.

• Modulation of food preference through the integration of gustatory and olfactory circuits

  1F31DC022476-01A1
  Angel Okoro · BROWN UNIVERSITY, RI · $50,114 · awarded Apr 1, 2026 · F31

  Neural circuits allow animals to gather various types of sensory information from the complex environment and integrate this information to produce the appropriate behavioral responses. To decide whether to ingest potential food substances, animals must discriminate between nutrients and toxins. To this end, they integrate sensory information, such as taste, smell, texture, temperature, and visual cues, with internal states, such as hunger and satiety. It is well established that the integration of taste and smell, perceived as flavor in humans, is especially important for food discrimination. However, the precise points of integration between the taste and smell circuits remain unknown in humans due to the complexity of the nervous system. Studies monitoring feeding behavior upon smell stimulation in the fruit fly, Drosophila melanogaster, suggest that the taste and smell circuits also integrate in the fly. Since the neural circuits in fruit flies are simpler than those in humans, flies are an ideal organism for evaluating the anatomical and functional connections between taste and smell. Our laboratory has developed trans-Tango, a method for neural circuit mapping and manipulation in fruit flies. Using trans-Tango, we mapped the first and second-order neurons in the taste and smell circuits, showing that gustatory receptor neurons, which detect tastants, and olfactory receptor neurons, which detect odors, relay information to gustatory and olfactory projection neurons, respectively. Some of these projection neurons target the same higher-order brain areas, suggesting the possibility that shared neurons exist that integrate sensory inputs from both systems to influence feeding behavior. This proposal takes a two-pronged approach to investigate the integration of the gustatory and olfactory circuits. First, I will test how olfactory inputs affect feeding by activating, or silencing, olfactory projection neurons tuned to food-derived odors. In these studies, I will use the OptoPAD paradigm to measure feeding. I hypothesize that activating neurons tuned to attractive odors would enhance feeding, while activating those tuned to aversive odors would suppress it. Second, I will identify neurons in the lateral horn that receive inputs from both gustatory and olfactory projection neurons and integrate these inputs to produce the appropriate feeding responses. To this end, I have been developing trans-Tango(hub), a tool for identifying circuit nodes of integration. My experiments will determine whether these nodes maintain the valence of the stimuli. Further, since the gustatory and olfactory systems in insects and mammals are functionally homologous, identifying the mechanisms of this multisensory integration in fruit flies will provide insight into how the perception of flavor is formed in humans. This is crucial for understanding the pathologies associated with olfactory deficiencies, such as anosmia and hyposmia, and gustatory deficiencies, such as ageusia. Finally, this research program is at the core of a training plan that includes activities to develop professional skills for preparing Angel Okoro for a career in academic research.

• Investigating Relationships of the Upper Airway Microbiota with SARS-CoV-2 Susceptibility and Coronavirus Disease 2019 Disease Presentation

  1F31AI191421-01A1
  Allison Chan · VANDERBILT UNIVERSITY, TN · $34,934 · awarded Apr 1, 2026 · F31

  PROJECT SUMMARY/ABSTRACT Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a worldwide impact with an estimation of over 775 million cases and seven million deaths. In 2020 and 2021, the United States saw a decline in life expectancy due to excess deaths due to COVID-19. Fortunately, the current era with effective vaccinations and therapeutic treatments has seen a reduction in overall disease severity and number of deaths due to COVID- 19. Despite these achievements, COVID-19 remains clinically unique with differential disease presentations. Some remain asymptomatic, others develop symptoms, require intubation, and some result in death in the most severe scenarios. However, due to changing variants, SARS-CoV-2 is likely to remain in circulation for the foreseeable future. Thus, the concern for adverse outcomes will continue to remain a public health threat. Although we already know factors that increase the risk for disease severity (i.e., age, underlying comorbidities, smoking), we must continue to improve our understanding of underlying factors that increase risk for susceptibility and symptoms. The microbiota has been linked to susceptibility and symptom manifestation for respiratory viruses such as influenza and respiratory syncytial virus. Therefore, since SARS-CoV-2 emerged, the microbiota has been a candidate predictor in the same sense for COVID-19. Despite numerous studies assessing COVID-19 and the upper respiratory microbiota, results have remained inconsistent. These studies are challenging due to confounding, which can bias results. We recognize many lifestyle factors influence the microbiota and, in most studies, these data are not collected to account for these biases. Additionally, most studies have been cross-sectional, which restricts their ability to understand temporality between the exposure and outcome (microbiota vs disease susceptibility and clinical presentation). The objective of this proposed work is to leverage data from a nationwide prospectively collected household transmission study to evaluate the relationship of the upper respiratory microbiota and SARS-CoV-2 susceptibility and COVID-19 disease presentation. Given SARS-CoV-2 exposed household members were tested daily and reported symptoms, I will use this unique data to evaluate whether characteristics of the upper airway microbiota prior to infection are associated with virus susceptibility and/or disease presentation (Aim I). I also will evaluate whether susceptibility of SARS-CoV-2 is associated with reductions in microbiota diversity and/or changes in bacterial abundance (Aim II). Lastly, I will investigate the generalizability of Aims I and II by using a second dataset that includes weekly testing and a longer follow-up period (Aim III). These aims intertwine to investigate this unclear relationship and will be the first in the field to include microbiota specimens prior to infection. Given the longitudinal nature of these data, I can address the temporality challenges encountered by previous studies (microbiota before infection). These results can indicate whether the upper respiratory microbiota should be considered a target for reducing SARS-CoV-2 risk and disease severity. 1

• Long-Term Impact of the COVID-19 Pandemic on Self-Management of Chronic Conditions: The C3 Study

  5R01AG075043-05
  MICHAEL WOLF · NORTHWESTERN UNIVERSITY AT CHICAGO, IL · $606,057 · awarded Apr 1, 2026 · R01

  ABSTRACT We will extend an active NIA cohort study of diverse, middle age and older adults with ≥1 chronic conditions to assess COVID-19’s long-term and disparate impact on health and healthcare experiences. COVID-19 has become an unprecedented public health threat in modern times, especially for older adults with a chronic illness. As of January 2021, 94% of COVID deaths have been among adults over 55; 92% of those who have died had ≥1 underlying health conditions. Beyond consequences to personal health associated with acquiring COVID-19, the impact of the pandemic may likely extend to non-COVID-19 outcomes as a patient’s ability to self-manage chronic conditions during and after a pandemic may be compromised for several reasons. In March 2020, our team rapidly launched the COVID-19 & Chronic Conditions (C3) study as cases of COVID-19 emerged in the U.S. to assess how adults with ≥1 chronic conditions were responding to the pandemic. Five active studies with uniform data collection on a range of patient-reported outcomes prior to COVID-19 and with electronic health records access were leveraged to establish the C3 cohort; 673 adults in Chicago were interviewed during the 1st week of the outbreak. The cohort was immediately expanded using two of the ‘parent studies’ that also had sites in New York City (n=200; N=873). C3 participants are diverse by socioeconomic status, race, ethnicity, gender, health literacy, and comorbidity. An NIA COVID-19 supplement was awarded in August 2020 to expand the cohort via the parent studies (N=1200) and continue data collection up to 2022; 5 of 7 planned survey waves have been completed (83-94% retention). C3 findings reveal many adults exhibit sustained, high stress due to COVID-19 that impacts lifestyle, treatment adherence, and healthcare use. Disparities by sex, race, ethnicity, and SES also are present. Health professionals and researchers are now voicing concern for possible long-term consequences of COVID-19 on personal health & healthcare. In response, we propose to continue to follow the C3 cohort to capture data 5 years post onset of the U.S. outbreak. All participants will have a ‘Pre-COVID’ baseline and 7+ follow-up assessments to assess trajectories in health care use, patient-reported & chronic disease outcomes. Our primary aims are to: 1) evaluate changes in lifestyle, health behaviors, healthcare use, health status, and chronic disease outcomes from a pre-pandemic baseline through 5 years after onset of COVID-19; 2) determine the extent to which stress, anxiety, and depression contribute to poor health status and chronic disease outcomes through 5 years after the pandemic’s onset. Our secondary aim is to: 3) identify factors that mediate or moderate associations between stress, anxiety, and depression during/after the pandemic with health status and chronic disease outcomes, while our exploratory aim is to: 4) explore whether health disparities by age, sex, race, ethnicity, or socioeconomic status emerge or worsen during/after the pandemic and the contributing role of stress, anxiety, and depression.

• Understanding Co-morbidities: COVID-19 in individuals living with HIV/AIDS

  5R01AI170197-05
  Dhiraj Singh · TEXAS BIOMEDICAL RESEARCH INSTITUTE, TX · $983,567 · awarded Mar 27, 2026 · R01

  Summary While COVID-19 continues to be a health challenge, very little is known about how COVID-19 affects people living with HIV (PLHIV). Based on the most recent reports originating from CDC and WHO, however, it appears that people with HIV may have a 30% greater likelihood of developing severe COVID-19 disease when infected with SARS-CoV-2. We will leverage the established rhesus macaque models of SARS-CoV-2 infection resulting in COVID-19 and SIV infection to characterize the effects of underlying SIV infection on the manifestation of both acute and post-acute COVID-19 sequelae. Our group was amongst few that established the rhesus macaque models of COVID-19 infection early on during the pandemic. Our model has been utilized to both study the immunological mechanisms of protection from SARS-CoV-2 infection, as well as for accelerated development of vaccine and therapeutics against COVID-19. Here we propose to couple this model with the long-standing, highly validated, pathogenic AIDS NHP model in SIV infected rhesus macaques to study a central hypothesis that underlying SIV infection and the resulting immunodeficiency/immune activation promotes the progression of a more severe COVID-19 presentation due to SARS-CoV-2 infection. As corollary, we hypothesize that ART does not completely suppress the ill effects of chronic immune activation due to SIV, it will not completely prevent the progression of severe COVID-19 due to SARS-CoV-2 infection in the macaque model. We have the experience in infecting rhesus macaques with SIV and treating these animals with ART to suppress viral replication and study immune mechanisms. By profiling the differences in dynamics of viral titers, induced tissue pathology, and underlying immunological perturbations, we will provide definitive knowledge in whether SIV infected rhesus macaques exhibit higher susceptibility to severe COVID-19. Furthermore, our studies will also be able to hint at the specific mechanisms which result in this susceptibility. Delineating these comorbid immunological factors driving susceptibility will enable better clinical monitoring and informed decisions for patient care. Mechanistic insights developed by this study is also imperative for the development of host-directed immunotherapeutic interventions for combating COVID-19 in PLHIV.

• Statistical Methods in COVID-19/PASC Clinical Research

  5R01HL162373-04
  Andrea Foulkes · MASSACHUSETTS GENERAL HOSPITAL, MA · $419,114 · awarded Mar 25, 2026 · R01

  Project Summary This proposal aims to develop, evaluate and disseminate novel statistical tools for rigorous investigation of the clinical spectrum, biological underpinnings and social determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, COronoVIrus Disease (COVID-19), and Post-Acute Sequelae of SARS- CoV-2 infection (PASC). Given the enormous scale of the COVID-19 pandemic, the potential severity of PASC, the complexity of available and anticipated data streams, and the paucity of biological and clinical knowledge, there is an urgent need for novel and robust statistical methods to address the most pressing PASC related research questions. Advanced statistical methods for observational data can be leveraged to address many of these questions; however, the identification, rigorous application and advancement of apropos methods requires sophisticated understanding of both the clinical context and the nuanced capabilities of available methods. To this end, we propose statistical innovations and novel translation of existing methods to significantly advance PASC clinical research, bringing together a team of physician-scientists and biostatisticians who are deeply embedded in COVID-19 clinical research to achieve the following specific aims: Aim 1: Develop and evaluate a causal mediation analysis framework for investigating the mechanistic pathways from SARS-CoV-2 infection to PASC and PASC recovery, including methods to accommodate time-varying and unevenly spaced mediators and time-to-event outcomes; Aim 2: Apply, evaluate, and extend marginal structural models as a framework to assess the impact of interventions on likelihood of PASC associated severe outcomes, in the context of time- varying confounding, competing and semi-competing risks, interval censoring and unobserved disease subtypes; Aim 3: Develop and apply methods for positive unlabeled data, using an expectation-maximization approach that leverages measured covariates and information on patient-level outcomes. The proposed methods will be applied using local and national emerging observational and EHR data resource. These statistical innovations will transform our understanding of the clinical course of PASC as we lead rigorous application to several leading-edge data resources.

• Low-dose naltrexone (LDN) for the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

  1UG3NS141843-01A1
  Jarred Younger · UNIVERSITY OF ALABAMA AT BIRMINGHAM, AL · $556,686 · awarded Mar 6, 2026 · UG3

  In this UG3/UH3 Exploratory Clinical Trial, we will test low-dose naltrexone (LDN) as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). ME/CFS affects approximately 1 million people in the United States, with incidence rates increasing with the SARS-CoV-2 pandemic. ME/CFS is characterized by profound fatigue, cognitive issues, pain sensitivity, and post-exertional malaise (PEM). Several studies support the hypothesis that ME/CFS involves chronic inflammatory activity in the central nervous system (CNS) that is driven by hyperactive microglia. More than 35 years since recognizing ME/CFS as a distinct medical condition, there is still no FDA-approved medications and no consensus on optimal treatment of the disorder. There is an urgent need to identify treatments that are safe and effective in reducing the severity of ME/CFS. Low dose naltrexone (LDN) involves daily doses of naltrexone in the 0.5mg to 6.0mg range. LDN crosses the blood-brain barrier, pushes microglia from an inflammatory to a resting state, and reduces the production of pro-inflammatory chemicals in the brain. LDN reduces fatigue severity in conditions such as ME/CFS, fibromyalgia, and Long-COVID. LDN is an ideal first treatment for ME/CFS because it is generically available, inexpensive, safe, and well-tolerated. LDN also has no abuse potential. In this Phase II trial, several questions will be answered to optimize a future Phase III efficacy trial of LDN for ME/CFS. This trial uses a remote design where individuals can enroll from anywhere in the United States and can complete all study tasks from their home. This approach allows individuals who are homebound or bedbound to participate in the clinical trial. Study 1 is a dose-finding study where 75 ME/CFS participants will receive LDN at 1.5mg/day, 3.0mg/day, 4.5mg/day, and 6.0mg/day for 2 months each, in blinded order. This study will be used to determine the best dose of LDN to be used in future trials. Study 2 is a randomized controlled trial (RCT) in 150 individuals with ME/CFS. Participants will be randomized to receive LDN or placebo. This study will be used to test safety and tolerability, determine the likely side-effects, determine the best measure to use as a primary outcome, identify predictors of a positive LDN response, and preliminarily measure the strength of the LDN effect. A subgroup of participants (25 LDN and 25 placebo) will be recruited close to the University of Alabama at Birmingham (UAB) to complete advanced neuroimaging and blood tests of neuroinflammation, neurodegeneration, and oxidate stress. These tests may yield biomarkers of LDN response for predicting who is a good LDN candidate, or for tracking improvement with the treatment. Neuroimaging will focus on brain lactate and temperature, two measures of brain inflammation. Study 3 is an extended-duration study where participants may be switched between placebo and LDN, in order to collect additional safety, tolerability, efficacy, and durability information. Ultimately, we hope this study will lead to the first widely accepted pharmaceutical treatment for ME/CFS.

• Molecular pathogenesis of COVID-19-associated coagulopathy and new therapeutic approaches

  5R01HL172048-03
  Roberto Aiolfi · SCRIPPS RESEARCH INSTITUTE, THE, CA · $695,610 · awarded Mar 6, 2026 · R01

  Project Summary Many studies have highlighted a large incidence of hemostatic derangements in the form of hypercoagulable and hypofibrinolytic states following SARS-CoV-2 infection. These hemostatic disturbances are fueled by and a consequence of the concomitant activation of the endothelium following a severe inflammatory response, with likely contribution from many other pathways and components, such as the complement pathway and neutrophil activation. In COVID-19 patients, the resulting hyperinflammation, vascular dysfunction, and systemic hypercoagulability, collectively referred to as COVID-19-associated coagulopathy (CAC), manifests as the increased tendency of micro-thrombosis of different organs leading to organ dysfunction, venous thromboembolism, pulmonary embolism, and deep vein thrombosis. Reducing the deleterious impact of CAC during severe SARS-CoV-2 infections continues to represent a major therapeutic challenge. Despite the enormous effort exerted during the pandemic to understand the pathological mechanisms responsible for the severity of SARS-CoV-2 infections, a major knowledge gap about the drivers and mechanisms underlying CAC still exists. Furthermore, as the link between CAC and long COVID becomes more apparent, understanding CAC is more urgent than ever. Proposed studies are designed to gain knowledge on the drivers and mechanisms underlying CAC and will test the feasibility of several potential pharmacological approaches to blunt it. Levering our novel and carefully optimized mouse model of COVID-19 and CAC, relying on a human pathological SARS- CoV-2 strain and recapitulating major pathological alterations and development of CAC observed in human patients presents a unique opportunity for hypotheses-driven research in a controlled and systematic manner to gain important new insights on CAC. Mimicking worldwide observations that males are more susceptible to severe disease after SARS-CoV-2 infection compared to females, a sex-dependent bias in disease severity was also observed in our model that was accompanied by striking temporal, quantitative, and qualitative differences in the development of CAC. Aim 1 will characterize the major molecular determinants of the sex-biased disease severity and development of CAC in our mouse model of COVID-19 and CAC. Key questions that will be addressed are the extent to which the sex bias originates from hormonal differences, whether estrogens are protective and/or androgens are deleterious, and whether hormonal supplementation therapy can alter the development of CAC. These studies will help identify novel pathways and targets for CAC. Aim 2 will expand on our preliminary data to characterize von Willebrand Factor (VWF)’s function(s) and protein/protein interaction(s) that are responsible for modulating survival during SARS-CoV-2 infection and development of CAC. The results of these studies will increase our knowledge of the mechanisms involved in regulating the finely tuned interaction between the immune, endothelial, and coagulation systems upon SARS-CoV-2 infection, possibly leading to the identification of new therapeutical targets for the treatment of CAC.

• Psychological symptoms in healthcare workers following the COVID-19 pandemic and relationship to long-term cardiovascular risk

  5R01HL157341-05
  Bernard Chang · COLUMBIA UNIVERSITY HEALTH SCIENCES, NY · $716,507 · awarded Mar 6, 2026 · R01

  Over the past year, the entire world has been upended by the COVID-19 pandemic. As of February 2021, there have been over 112 million confirmed cases and over 2.5 million deaths globally. In New York City, the initial US epicenter of the pandemic, there have been >700,000 cases, >89,000 hospitalizations, and >29,000 deaths. Healthcare workers (HCWs) have experienced alarming rates of anxiety, stress, and insomnia due to COVID-19, which are likely to persist beyond the pandemic. In the proposed work, we will examine the presence and predictors of long-term psychological symptoms and the consequences for cardiovascular health among emergency department (ED) HCWs following the COVID-19 pandemic. This work is necessary to understand the scope of the problem and to inform efforts to protect the health of these frontline HCWs who have risked their lives to ensure our safety. Pre-COVID, ED HCWs were already known to be at greater psychological risk than nearly every other subgroup of clinicians. Psycho-physiologic stress factors have been dramatically magnified during the COVID period, in what has been referred to as a “parallel pandemic” of surging mental and physical harm faced by HCWs. It is critical to understand the presence of sustained psychological symptoms seen in HCWs who treated COVID patients, as well as downstream impacts on cardiovascular health. Our preliminary work showed that HCWs experienced significant acute psychological distress during the initial COVID peak in New York City. In a survey of hospital HCWs conducted in April 2020, we found high rates of acute stress disorder (65%), anxiety (36%), and insomnia (70%). Early evidence points to persistence of psychological symptoms. In these participants, 25% experienced post-traumatic stress disorder (PTSD) and 39% experienced insomnia at a 10 week follow-up. In the proposed study, we will (1) examine the prevalence and predictors of sustained psychological symptoms in ED HCWs who provided care during the COVID pandemic; (2) characterize the relationship of psychological symptoms to 3-year progression of atherosclerotic cardiovascular disease (ASCVD) risk; and (3) examine a potential protective factor (i.e., resilient coping) in the development of COVID-related psychological symptoms. To achieve these aims, we will conduct a prospective 3-year study of psychological and cardiovascular health in ED HCWs exposed to some of the highest COVID case rates in the world. At study baseline (Year 0) and at each annual follow-up (Years 1-3), we will conduct a thorough psychological test battery that includes measures of COVID-related PTSD, COVID- related fear, insomnia, and resilient coping. Each participant’s ASCVD risk score will be computed annually. Our primary exposure and predictor of psychological symptoms will be the computed “Covid burden,” quantified as the number of shifts worked between March 1, 2020 (date of our hospital’s index case) and study enrollment, in which COVID admissions exceeded 15% of total ED patients. Findings will inform interventions to protect mental and physical wellbeing in HCWs as we navigate this and future public health crises.

Related topics

• Microbiome research
• Mental health and psychiatric research