Natural History of Post-Coronavirus Disease 19 Convalescence at the National Institutes of Health

  • End date
    Dec 31, 2027
  • participants needed
  • sponsor
    National Institute of Neurological Disorders and Stroke (NINDS)
Updated on 13 October 2022



People who get COVID-19 have a wide range of symptoms. They also recover from COVID-19 in different ways. In this study, researchers will use survey data to describe the different ways people experience and recover from COVID-19. They will also use the data to help create future studies to understand why some people do not fully recover.


To learn more about the range and timing of symptoms that people have before, during, and after COVID-19 infection.


People ages 18 and older who can give documentation of a positive COVID-19 or antibody test.


Participants will be screened with a telephone interview. It will take 15 minutes. They will provide their COVID-19 test results and medical records.

Participants will complete a second telephone interview. It will take 30 60 minutes. They will also take online surveys every 3 months for 3 years.

The interview and surveys will ask participants about their health before they got COVID-19, what happened while they had COVID-19, and what their recovery has been like.

Participants will get log-in data to take the online surveys. Completing all of the surveys the first time may take up to 3 hours. Follow-up surveys will take up to 30 minutes. Participants do not have to complete the surveys in one sitting. They will be able to save their progress and finish the surveys later.

Participants may be contacted to take part in other research studies.


Study Description

In late 2019, the novel coronavirus SARS/CoV2 appeared in Wuhan, China. The various ways that humans will recover from COVID-19 is just starting to be observed and it is clear there will be a wide range of convalescent experiences. A year into the pandemic, the post-acute sequelae of SARS/CoV2 infection (PASC) is known to be common and includes a broad range of symptoms and potential pathologies. This phased protocol is designed to observe and study the convalescence and recoveries from acute SARS/CoV2 infections.

Phase A Phase A Surveying (Phase A) will enable people in the community that are convalescing from COVID-19 to be studied using telephone interviews and internet-based questionnaires. The objective of Phase A Surveying is to observe and describe the range of medical syndromes that occur in the wake of an acute SARS/CoV2 infection.

Participants are required to be within the first year of their recovery and have documentation of a positive laboratory test for COVID-19. Additional cohorts of persons with neurological sequelae, persons with a clinical diagnosis of COVID-19 with negative testing, persons with adverse complications after COVID 19 vaccination and participants co-enrolled in other research studies within the Division of Intramural Research will also be studied. The data collected during Phase A will describe the range of symptoms and patterns of symptom clustering of PASC. This data will also characterize the patient populations which have been or will be evaluated at the NIH Clinical Center in more detail.

Phase B Evaluation (Phase B) will allow surveyed participants of research interest from Phase A to be invited to the NIH Clinical Center for a medical evaluation and to undergo a panel of standard research measurements. Each participant will be medically and psychologically characterized to best understand if their complaints can be attributed to known disorders. The observations made during Phase B will provide insights into the range, character, and subtypes of PASC. Individuals found to have disorders being studied within the Division of Intramural Research at NIH will be appropriately referred.

Evaluated individuals with persistent symptoms in the absence of demonstrable medical disease and individuals who fully recovered from a confirmed SARS/CoV2 infection will be invited back to the NIH Clinical Center for broad and deep research measurements.

Phase C Deep Phenotyping (Phase C)employed will be synchronized with other NIH-approved deep phenotyping protocols to foster crossphenotype comparison research with other medical syndromes, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI). Deep phenotyping characterizations would be used to generate scientific hypotheses for testing in future studies and for cross-comparisons with other fatiguing disorders.

Evaluated individuals with PASC may be invited to participate in Phase D Longitudinal Evaluation phase (Phase D). This would enable the observation of the natural history of PASC and allow for exploration of the biological mechanisms underlying successful

recovery and how recovery can go awry.

Previous epidemics have created unique medical syndromes in the past. Data from this protocol may be used to characterize PASC and any Post-COVID 19 Syndrome subtypes that may be discovered. If warranted, a Criteria Development phase will develop data-driven research consensus criteria for defining PASC and any Post-COVID 19 Syndromes.

The results of this protocol will provide novel insights into COVID- 19 convalescence and its potential outcomes.

This current version of the protocol provides the details for Phase A, Phase B, and Phase C. Additional phases will be detailed in planned protocol amendments.


Primary Objective:

Phase A: To observe and describe the range of medical syndromes that occur in the wake of acute SARS/CoV2 infection.

Phase B: To describe and medically characterize patients with PASC and those who fully recovered from SARS/CoV2 infection.

Phase C: To compare the clinical and biological phenotypes between persons with unexplained PASC and those who fully recovered from SARS/CoV2 infection.

Secondary Objectives:

Phase A:

  • To observe and describe recovery trajectories following an acute SARS/CoV2 infection.
  • To observe and describe the range of medical syndromes and recovery trajectories of participants who report adverse effects after COVID-19 vaccination
  • To compare the range of medical syndromes and recovery trajectories of participants with a confirmed SARS/CoV2 infection to other cohorts, such as participants who have a medically confirmed diagnosis of COVID-19 without laboratory confirmation and participants who report adverse complications after COVID-19 vaccination.

Phase B:

  • To determine the relations between acute SARS/CoV2 severity, subjective functional impairment, and objective functional performance.
  • To explore the pathophysiology of PASC and its cardiopulmonary, neurologic, and unexplained subtypes.

Phase C:

  • To compare the clinical and biological phenotypes between persons with unexplained PASC to historic data and samples collected on persons with post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and veterans with Gulf War Illness.
  • To explore the pathophysiology of fatigue and postexertional malaise in unexplained PASC. Fatigue will be explored using tasks designed to create muscular and cognitive fatigue. Post-exertional malaise will be explored using an exercise stress test and measuring the symptomatic

and biological changes.


Outcome measures

Phase A: The number and severity of persistent symptoms associated with COVID-19 convalescence. Collected data will be used to characterize different narratives of COVID-19


Phase B: Collected data and samples for use to perform exploratory analyses for the generation of new hypotheses regarding PASC.

Phase C: Identification of hypothetical mechanisms of PASC using collected data and samples. The types of analyses to be performed will be wide ranging. Planned areas of focus may

  1. Characterization of the immune system and inflammatory signaling in collected samples at baseline and following maximal exercise exertion.

-Flow cytometry of blood and cerebrospinal fluid, RNA sequencing of PBMC subtypes, multiplex immunochemical analysis, NK cell functional analysis.

2. Characterization of the pattern of microbiome in collected samples at baseline and following maximal exercise exertion.

-Shotgun metagenomics of bacterial genetic material.

3. Characterization of bioenergetics, autonomic, and metabolic function in collected samples at baseline and following maximal exercise exertion.

-Mitochondrial plasmid genotyping, pulmonary spirometry, gas exchange measurements during exercise, metabolic chamber measurements of total body energy use, metabolomic analysis of stool, mitochondrion proteomics and metabolomics from muscle, and functional respiration of PBMCs using extracellular flux mitochondrial stress assay.

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.

Condition Post-Coronavirus Disease 19
Clinical Study IdentifierNCT04573062
SponsorNational Institute of Neurological Disorders and Stroke (NINDS)
Last Modified on13 October 2022


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