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

- INCLUSION CRITERIA:

For Phase A Surveying:

1590 persons who are recovering or have recovered from an acute SARS/CoV2 infection will
participate.

Inclusion criteria for Phase A:

Post-COVID-19 Convalescence (n=1190)

1. Participants 18 and older

2. Ability to provide informed consent

3. Stated willingness to complete telephone interviews

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

a.For participants who don t have a known recovery date, a date of 6 weeks from infection
will be imposed

5 Provides documentation of a positive COVID-19 Test. Approved test can include the
following:

1. PCR, NAA, or other EUA Approved test to confirm active COVID infection.

2. 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.

3. A positive anti-Spike antibody test is accepted in unvaccinated individuals or those
who had antibody testing prior to vaccination.

4. A positive anti-nucleocapsid antibody test

OR

Test-Negative COVID-19 with Persistent Symptoms (n=50)

1. Participants 18 and older

2. Ability to provide informed consent

3. Stated willingness to complete telephone interviews

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

5. 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.

6. Has either negative or absent COVID-19 PCR, NAA, or other EUA Approved testing
for the documented SARS/COV2 infection.

7. Provides documentation of a negative COVID-19 antibody test prior to vaccination.

OR

COVID-19 vaccine related medical conditions (n=50)

1. Participants 18 and older

2. Ability to provide informed consent

3. Stated willingness to complete telephone interviews

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

5. Provides documentation of COVID-19 vaccination

6. Provides documentation of a COVID-19 vaccine related medical condition from a
medical practitioner

OR

Participants with a history of multiple SARS-CoV-2 infections (N=100)

1. Participants 18 and older

2. Ability to provide informed consent

3. Stated willingness to complete telephone interviews

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

5. Provides documentation of at least one positive COVID-19 Test. Approved test can
include the following:

5. PCR, NAA, or other EUA Approved test to confirm active COVID infection.

6. 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.

7. A positive anti-Spike antibody test is accepted in unvaccinated individuals or those
who had antibody testing prior to vaccination.

8. A positive anti-nucleocapsid antibody test

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 accrual ceiling is 120 PASC and 120 healthy volunteers,
with a goal to identify 80 PASC participants and 80 post-COVID fully recovered healthy
volunteers who may be eligible for 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
participants and 20 post- COVID fully recovered participants within each of these four
time frames.

Inclusion Criteria for all Phase B participants:

1. Adult participants aged 18 years and older

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

3. Fluency in English.

4. Willing and able to complete all study procedures

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

6. Able to provide informed consent

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

8. 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:

- The date that fever broke for the first time

- The date the participant recalls starting to improve

- If a participant is unable to report a reliable date, a date of six weeks
from the onset of COVID-19 symptoms may be imputed.

9. 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.

Additional Inclusion Criteria for Mild to Moderate Illness COVID-19 with severe PASC
symptoms:

1. 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.

2. 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.

3. 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.

4. Meets WHO Clinical Progression Scale of 2 - 6:

- 2: Ambulatory; symptomatic, independent

- 3: Ambulatory; symptomatic, assistance needed

- 4: Hospitalized; no oxygen therapy

- 5: Hospitalized; oxygen by mask or nasal prongs

- 6: Hospitalized; oxygen by non-invasive ventilation or high flow oxygen

5. 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.

OR

Additional Inclusion Criteria for Mild or Moderate Illness COVID-19 without PASC
symptoms:

1. 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.

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

3. 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.

4. Meets WHO Clinical Progression Scale of 2 - 6:

- 2: Ambulatory; symptomatic, independent

- 3: Ambulatory; symptomatic, assistance needed

- 4: Hospitalized; no oxygen therapy

- 5: Hospitalized; oxygen by mask or nasal prongs

- 6: Hospitalized; oxygen by non-invasive ventilation or high flow oxygen

Functional Criteria: No substantial symptom severity as determined using SF-36v2:
score of >=85 physical function subscale, and >= 85 on role physical subscale, and >=
85 on social function subscale.

OR

Additional Inclusion Criteria for Mild or Moderate Illness COVID-19 with mild to
moderate PASC symptoms:

1. 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.

2. 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.

3. 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.

4. Meets WHO Clinical Progression Scale[61] of 2 - 6:

- 2: Ambulatory; symptomatic, independent

- 3: Ambulatory; symptomatic, assistance needed

- 4: Hospitalized; no oxygen therapy

- 5: Hospitalized; oxygen by mask or nasal prongs

- 6: Hospitalized; oxygen by non-invasive ventilation or high flow oxygen

5. 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:

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

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

3. Fluency in English

OR

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

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

2. Fluency in English

EXCLUSION CRITERIA:

Exclusion criteria for Phase A:

1. Not willing to provide personal identifying information to investigative team

2. 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.

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

2. 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

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

4. Positive urine toxicology screening for anything other than marijuana

5. Current suicidal ideation

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

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

8. 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.

9. 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.

10. 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.

11. 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.

12. 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 study.

13. Not willing to allow for research data and samples to be shared broadly with
other researchers.

14. Employees at NIH that are under the direct supervision of the study investigators
(family members of NIH employees are permitted to participate).

15. Symptom severity that makes it impossible for the volunteer to travel to NIH.

Exclusion criteria for Phase C Deep Phenotyping:

Exclusion criteria for all Phase C participants:

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

2. Current DSM-5-defined 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

3. Current or past substance use disorder within last five years as diagnosed on the
Structured Clinical Interview for DSM-5 (SCID-5). Mar...