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

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews

- Reports having begun recovery from an acute SARS/CoV2 infection in the past 5 years

- Provides documentation of a positive COVID-19 PCR, NAA, or other EUA Approved test to confirm active COVID infection. A positive home Antigen test is acceptable when documentation of a photograph of the test with a phone-based date and time stamp is provided. A positive anti-Spike antibody test is also accepted in unvaccinated individuals and in participants who had antibody testing prior to vaccination. A positive anti-nucleocapsid antibody test is acceptable in vaccinated individuals. OR Post-COVID-19 Neurological Sequelae (n=250)

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews

- Reports having developed neurological symptoms as a consequence of an acute SARS/CoV2 infection

- 5. Provides documentation of a positive COVID-19 PCR, NAA, or other EUA Approved test to confirm active COVID infection. A positive home Antigen test is acceptable when documentation of a photograph of the test with a phone-based date and time stamp is provided. A positive anti-Spike antibody test is also accepted in unvaccinated individuals and in participants who had antibody testing prior to vaccination. A positive anti-nucleocapsid antibody test is acceptable in vaccinated individuals. OR Test-Negative COVID-19 with Persistent Symptoms (n=50)

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews

- Reports having developed persistent symptoms as a consequence of an acute SARS/CoV2 infection

- Provides documentation of a clinical diagnosis of an acute SARS/CoV2 infection from a medical practitioner OR meets the Clinical Criteria of the 2020 CDC Interim Case Definition for Probable SARS/CoV2 infection.

- Has either negative or absent COVID-19 PCR testing for the documented SARS/CoV2 infection.

- Provides documentation of a negative COVID-19 antibody test prior to vaccination. OR COVID-19 vaccine related medical conditions (n=50)

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews

- Reports having developed persistent symptoms as a consequence of a COVID 19 vaccination

- Provides documentation of COVID-19 vaccination

- Provides documentation of a COVID-19 vaccine related medical condition from a medical practitioner OR Participants enrolled in protocol 20CC0113: Cardiopulmonary Inflammation and Multi- System Imaging During the Clinical Course of COVID-19 Infection in Asymptomatic and Symptomatic Persons (N=150)

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews Co-enrollment in 20CC0113 OR Participants enrolled in protocol 000102-CC: COVID-19, Chronic Adaptation, and Response to Exercise (COVID-CARE) (N=90)

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews

- Co-enrollment in 000102-CC OR Participants with a history of multiple SARS-CoV-2 infections (N=100)

- Participants 18 and older

- Ability to provide informed consent

- Stated willingness to complete telephone interviews

- Reports having more than one SARS-CoV-2 infection

- Provides documentation of at least one positive COVID-19 PCR, NAA, or other EUA Approved test to confirm active COVID infection. A positive home Antigen test is acceptable when documentation of a photograph of the test with a phone-based date and time stamp is provided. A positive anti-Spike antibody test is also accepted in unvaccinated individuals and in participants who had antibody testing prior to vaccination. A positive anti-nucleocapsid antibody test is acceptable in vaccinated individuals. The elements of the 2020 CDC Interim Case Definition for Probable COVID-19 used for this protocol will be the Clinical Criteria: Clinical Criteria: At least two of the following symptoms: fever (measured or subjective), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s) OR At least one of the following symptoms: cough, shortness of breath, or difficulty breathing OR Severe respiratory illness with at least one of the following:

- Clinical or radiographic evidence of pneumonia, OR

- Acute respiratory distress syndrome (ARDS). AND No alternative more likely diagnosis. For Phase B Evaluation: 240 persons who are recovering or have recovered from COVID-19 within the last five years will participate. The goal will be to identify 80 unexplained PASC participants and 80 post-COVID fully recovered healthy volunteers to enroll into Phase C. Time since infection (i.e. within first six months, six months to one year, one year to two years, and two years to five years) will also be considered, with a goal of recruiting at least 20 PASC participant and 20 post-COVID fully recovered participants within each of these four time frames. Inclusion Criteria for all Phase B participants:

- Adult participants aged 18-60 years at the time of enrollment.

- Self-reported completion of at least the 7th grade of school.

- Fluency in English.

- Willing and able to complete all study procedures

- Participant has a primary care provider at the time of enrollment.

- Able to provide informed consent

- Participants must be at least six weeks out since the onset of COVID-19 symptom with no fever for at least one week.

- Participants must be within five years since starting to recover from acute COVID-19 symptoms. The date of the start of recovery can be determined by:

- Does not have an active SARS-CoV-2 infection. The protocol will conform with NIH CC standards for documenting a participant does not have active SARS-CoV-2 infection. This may include screening interviews and/or testing. Inclusion Criteria for Mild to Moderate Illness COVID-19 with severe PASC symptoms:

- Licensed Independent Practitioner documentation of a stable state of general wellhealth and physical function prior to contracting SARS-CoV-2. This may include medical records, correspondence letters, or information gathered from telephone calls with study personnel.

- A self-reported illness narrative of the development of persistent PASC symptoms after recovering from a SARS-CoV-2 infection. These include symptoms such as fatigue, cognitive difficulties, orthostatic intolerance, unrefreshing sleep, neuropathic pain, mood change, and post-exertional malaise.

- Laboratory documentation of a positive COVID-19 PCR, NAA, or other EUA Approved test to confirm active COVID infection at the time of the SARS-CoV-2 infection. Participants with positive home tests during Phase A will be required to have a positive anti-SARS nucleocapsid antibody test.

- Meets WHO Clinical Progression Scale of 2 - 6:

- Functional Criteria: Substantial symptom severity as determined using SF-36v2: score of <=70 physical function subscale, or <=50 on role physical subscale, or <=75 on social function subscale. Inclusion Criteria for Mild or Moderate Illness COVID-19 without PASC symptoms:

- Licensed Independent Practitioner documentation of a stable state of general well health and physical function prior to contracting SARS-CoV-2. This may include medical records, correspondence letters, or information gathered from telephone calls with study personnel.

- A self-reported illness narrative of recovery to prior health after a SARS/CoV2 infection.

- Laboratory documentation of a positive COVID-19 PCR, NAA, or other EUA Approved test to confirm active COVID infection at the time of the SARS-CoV-2 infection. Participants with positive home tests during Phase A will be required to have a positive nucleocapsid antibody test

- Meets WHO Clinical Progression Scale of 2 - 6:

- Licensed Independent Practitioner documentation of a stable state of general well health and physical function prior to contracting SARS-CoV-2. This may include medical records, correspondence letters, or information gathered from telephone calls with study personnel.

- Either a self-reported illness narrative of near recovery to prior health or a narrative of the development of persistent PASC symptoms after recovering from a SARS-CoV-2 infection. These include symptoms such as fatigue, cognitive difficulties, orthostatic intolerance, unrefreshing sleep, neuropathic pain, mood change, and post-exertional malaise.

- Laboratory documentation of a positive COVID-19 PCR, NAA, or other EUA Approved test to confirm active COVID infection at the time of the SARS-CoV-2 infection. Participants with positive home tests during Phase A will be required to have a positive Anti-SARS nucleocapsid antibody test.

- Meets WHO Clinical Progression Scale of 2 - 6:

- Functional Criteria: Mild to moderate symptom severity as determined using SF-36v2: score of between 71 and 84 on the physical function subscale, or between 51 and 84 on role physical subscale, or between 76 and 84 on social function subscale. For Phase C Deep Phenotyping: Inclusion Criteria for Mild to Moderate Illness COVID-19 with PASC symptoms (unexplained PASC):

- Met inclusion and exclusion criteria for Mild to Moderate Illness COVID-19 with severe post-acute COVID-19 symptoms after completing Phase B.

- No alternative explanation for PASC symptoms identified by adjudication committee during Phase B.

- Fluency in English Inclusion Criteria for Mild or Moderate Illness COVID-19 without PASC symptoms:

- Met inclusion and exclusion criteria for Mild to Moderate Illness COVID-19 without post-acute COVID-19 symptoms after completing Phase B.

- Fluency in English

- Not willing to provide personal identifying information to investigative team

- Cognitive impairment that is severe enough to limit consent capacity Exclusion criteria for Phase B Evaluation: Information collected from Phase A interviews, review of medical records, and discussions with consented Phase A participants will be used to determine if a participant will be excluded from participation.

- Current or past psychotic disorder including depression with psychosis, bipolar disorder with psychotic symptoms and schizophrenia

- Major depression disorder, generalized anxiety disorder, post-traumatic stress disorder, panic disorder, or obsessive-compulsive disorder unless managed for more than six months with a stable treatment regimen

- Current or past substance use disorder within last five years. Marijuana use within the past five years will not be an exclusion.

- History of head injury leading to moderate or severe traumatic brain injury. Persons having a history of mild TBI (mTBI) will not be excluded.

- Women who are pregnant, breastfeeding, or are within one-year post-partum.

- Current or previous malignancy. A history of malignancy that has fully resolved with surgical resection only (e.g. no chemotherapy, radiation therapy, or immunotherapy) will be allowed.

- Current systemic immunologic disorders (e.g. Type 1 diabetes, rheumatoid arthritis). Local immunological disorder (e.g. atopic dermatitis, stable autoimmune thyroid disease) and allergic disorders will be allowed.

- Current or previous long-term immune suppressive therapy. Recent or current steroid use for the treatment of COVID-19, PASC, recent allergic reactions, and topical steroid use is allowed.

- Any premorbid medical condition that would potentially cause fatigue and exercise intolerance that would exclude from participation in Phase C. This includes many chronic medical diseases, such as congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, severe arthritis, uncontrolled asthma, renal failure, fibromyalgia, and ME/CFS.

- Active participation in a clinical protocol (e.g. anti-inflammatory drug intervention study) which includes an intervention that may affect the results of the current s...