Post-Viral Syndromes

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Objective: The primary objective is to explore the clinical and biological phenotypes of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) and post-acute sequelae of COVID-19 (PASC). The secondary objectives are to explore the pathophysiology of fatigue and post-exertional malaise (PEM) and to test immunotherapy for post-viral syndromes. Study population: Up to 1890 persons will be enrolled as part of the protocols. For ME/CFS, up to 150 persons aged 18-60 will be part of 3 study groups: 50 ME/CFS patients whose fatigue began after an infection, 50 non-fatigued participants with a documented history of Lyme disease exposure and treatment, and 50 healthy volunteers. The study has a target of completing all study procedures on 20 enrolled participants in each group. Up to an additional 176 persons reporting a community diagnosis of ME/CFS will be enrolled into focus groups to discuss the experience of post-exertional malaise. Up to an additional 10 healthy volunteers and 10 ME/CFS patients may be enrolled to refine the protocols' electrophysiological and neuroimaging techniques. For PASC, up to 1540 persons 18 years of age or older will participate in a Survey study, in which telephone interviews and internet-based questionnaires will be collected for both descriptive research and participant screening purposes. From this group, up to 240 PASC patients and SARS-CoV-2 recovered volunteers will be enrolled in an inpatient evaluation visit. From this group, up to 110 PASC patients and SARS-CoV-2 recovered volunteers will be enrolled in an inpatient exercise stress visit. Design: This is a single-center, exploratory, cross-sectional study of PI-ME/CFS and PASC. Participants will have an initial visit, which will encompass 5 day long inpatient admission at the NIH Clinical Center. Case status for ME/CFS and PASC participants will be determined after the visit by a case adjudication process utilizing an expert physician committee and published guidelines. Adjudicated participants meeting inclusion criteria may be invited back to participate in an exercise stress visit, which will encompass a 5 day long inpatient admission. Detailed subjective and objective measurements and biological specimens will be serially collected before and up to 96 hours after a peak exercise test capable of inducing post-exertional malaise during this visit. All procedures will be completed on all three study groups to allow for optimal inter-group comparisons. Outcome Measures: The primary purpose of this protocol is to perform exploratory analysis of collected samples for the generation of new hypotheses regarding ME/CFS and PASC. The types of analyses to be performed will be wide ranging. Planned areas of focus include: 1. Characterization of the immune system and inflammatory signaling in collected samples at baseline and following maximal exercise exertion. 2. Characterization of the pattern of microbiome in collected samples at baseline and following maximal exercise exertion. 3. Characterization of bioenergetics, autonomic, and metabolic function in collected samples at baseline and following maximal exercise exertion. 4. Characterization of physical and cognitive fatigue using functional magnetic resonance imaging and transcranial magnetic stimulation at baseline and following maximal exercise exertion. 5. Characterization of neurocognition at baseline and following maximal exercise exertion. 6. Characterization of brain function and connectivity at baseline and following maximal exercise exertion. 7. Characterization of autonomic function at baseline and following maximal exercise exertion. 8. Characterization of gene expression profiles in collected samples at baseline and following maximal exercise exertion. Additionally, there is a protocol that is evaluating the clinical and laboratory effects of intravenous immunoglobulin therapy (0.4g/kg/day for 5 days) compared to placebo (equivalent volume of Normal Saline for 5 days) using a cross-over trial design. Male and female participants ages 18 and older with persistent neurologic symptoms after mild-moderate COVID-19 infection. Up to 45 persons will be recruited to achieve completion of 34 participants. The primary outcome is the proportion of participants with a clinically meaningful change in Health Utilities Index Mark 3 (HUI3) 2 weeks after intravenous immunoglobulin therapy compared with 2 weeks after placebo. Additionally, with evidence that viral remnants of SARS-CoV-2 can persist after resolution of the acute infection, we have initiated a protocol to better understand how to recover and characterize SARS-CoV-2 viral remnants from humans. Here we are recruiting 6 persons with PASC and 6 persons who have fully recovered from a SARS-CoV-2 infection and performing biopsies of a wide array of tissues to characterize the biochemical nature of SARS-CoV-2 recovered viral remnants, determine if there are quantifiable differences in remnants between PASC and recovered participants. Samples being collected include blood, urine, endobronchial tissue, upper and lower gastrointestinal tract tissue, cerebrospinal fluid, skin, muscle, salivary gland, tongue, sinonasal, and lymph node tissue. Results Summary (To Date): PI-ME/CFS: Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. (Walitt, Nature Communications, 2024) PASC: In our first publication of the cohort (Huff, Front. Neurol 2025), participants with PASC were mostly female (71.8%), with a mean age of 44 years. The median time of evaluation was 8 months after COVID-19, and most (84%) had a history of only a mild infection. The most frequent neurologic symptoms post COVID-19 were fatigue, concentration/memory difficulties, unrefreshed sleep, and dysarthria/word finding difficulties. Long-COVID has a high burden of long lasting and severe neurological sequelae. These sequelae are independent of pre-existing self-reported neurologic and psychiatric conditions, as well as previous hospitalization. Data from this cohort also observed that self-report of PEM is common in Long COVID. However, observable PEM following an exercise stressor was not frequent in a small cohort of PASC participants. When present, PEM descriptions during QI were less severe in Long COVID than in ME/CFS. Positive responses after an exercise stressor were common in Long COVID (Stussman, Front Neurol.2025). Our in-person studies revealed alterations in immune function and neurocirculation in Cerebral Spinal Fluid (CSF). CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials. (Mina, Neurol Neuroimmunol Neuroinflamm. 2023). These findings were shown to persist one year later (Goldstein, Neurology 2024). The Immunotherapy in neuro-PASC and Tissue Procurement in neuro-PASC protocols do not yet have findings to report.