Procedures/Methods

DESIGN

Statement of purpose: This toolkit is designed to provide state and local health departments with the tools needed to investigate suspected cases of SARS-CoV-2 reinfection.

How investigational design meets objectives: This toolkit can be used in conjunction with surveillance (passive or active) for suspected cases of SARS-CoV-2 reinfection. Once the study population is identified, chart abstraction and reviews of existing surveillance reporting will be used to characterize suspected cases. Additionally, paired specimens might undergo confirmatory RT-PCR, viral culture, sgmRNA, and genomic sequencing to provide evidence of reinfection.

Description of risks: This research involves little to no risk to participants. Adherence to the HIPAA Privacy Rule and deidentification of collected data will ensure participant anonymity. If additional nasal wash specimens are collected, adverse effects are expected to be mild but could include nosebleeds and nasal irritation. If additional serum is collected, adverse effects are expected to be mild but could include hematoma or bruising. There is also minimal risk to the medical professionals. For sub-studies pursuing additional specimen collection we recommend following universal precautions and COVID-19 guidance on specimen collection and transport (Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19).

Description of anticipated benefits to the research participant: We anticipate that research participants will benefit from the improved COVID-19 prevention guidelines that will result from this research.

Description of the potential risks to anticipated benefit ratio: The potential risks posed by specimen collection are outweighed by the societal and individual benefit of enhanced surveillance and improved prevention guidelines that could reduce transmission of SARS-CoV-2 within communities.

STUDY POPULATION

Description and source of study population: The study population can include all individuals with a suspected or confirmed case of COVID-19 within the surveillance catchment area or the health department’s jurisdiction.

Investigative criteria:

Prioritize persons with detected SARS-CoV-2 RNA ≥90 days since first SARS-CoV-2 infection:

Persons with detected SARS-CoV-2 RNA* ≥90 days after the first detection of SARS-CoV-2 RNA, whether or not symptoms were present

AND

Paired respiratory specimens (one from each infection episode) are available

*If detected by RT-PCR, only include if Ct value <33 or if Ct value unavailable

 

Consider persons with COVID-19–like symptoms and detection of SARS-CoV-2 RNA 45–89 days since first SARS-CoV-2 infection:

Persons with detection of SARS-CoV-2 RNA* ≥45 days after the first detection of SARS-CoV-2 RNA

AND

With a symptomatic second episode and no obvious alternate etiology for COVID-19–like symptoms OR close contact with a person known to have laboratory-confirmed COVID-19

AND

Paired respiratory specimens (one from each infection episode) are available

*If detected by RT-PCR, only include if Ct value <33 or if Ct value unavailable

 

Adaptation considerations:

  • If resources are limited, further prioritize the sampling of persons in high-risk groups (e.g. healthcare workers).
  • If investigating suspected reinfection cases among severely immunocompromised persons, consider a prospective study dedicated to this population, as results will not be generalizable to the general population.

Participant exclusion criteria:

  • Laboratory specimen from either first or second illness episode is unavailable.

Estimated number of participants: The estimated monthly enrollment is expected to vary by jurisdiction, duration of local outbreak intensity, and referral testing operational factors. Consider taking these factors, as well as prior number of suspected SARS-CoV-2 cases reported, into account during local protocol adaptation.

Sampling: No a priori sampling will be undertaken; instead all suspected cases reported will be investigated per protocol. When necessary, eligibility criteria may be narrowed per adaptation considerations provided in this common investigation protocol.

Recruitment and Enrollment: Options for enrollment are as follow:

  1. Passive surveillance: Cases reported to the health department that meet eligibility criteria
  2. Active surveillance: Routinely analyze RT-PCR data with individual unique IDs over time to identify those with recurrent positive tests beyond the given time intervals
  3. Once cases are identified, optionally enroll case-patients in a sub-study to characterize the clinical course of reinfection events.
  4. If interested in investigating duration of viral shedding, presence of replication-competent virus, and serologic response to suspected reinfection, optionally enroll case-patients in a sub-study to collect serial respiratory and serum specimens.

Description and justification of reimbursements or incentives that will be used: Any reimbursements or incentives provided to participants are at the discretion of the institution using this protocol.

Statement of extra costs to participants due to involvement in the study: Participants may incur extra costs in the form of travel expenses and time lost to interviews. These costs will only be incurred if participants consent to the collection of additional nasal specimens and follow up interviews.

Procedures for implementing and documenting informed consent: Whenever appropriate, obtain informed consent from participants that require interviews for data collection, complete 14-day symptom logs, or enroll them in a sub-study for subsequent respiratory and serum specimen collection.

 

VARIABLES/INTERVENTIONS

Variables:

Demographics: Age (years), sex, race, ethnicity, occupation, and residence

Medical history: Immunomodulating agents and conditions, comorbidities, medications received for first episode and subsequent episode

Clinical course: Date of initial illness onset, date of initial clinical resolution, date of symptom onset or positive test for suspected reinfection, level of care received, duration of isolation, and complications

Diagnostic test results: Dates, type of testing, platform or laboratory assay used, site of specimen collection, and results (including Ct value) for all SARS-CoV-2 diagnostic tests

Epidemiologic data: Exposure history and residing in or visiting congregate settings

Extract these data from medical records, public health surveillance records, or interviews, and use descriptive epidemiology to characterize the suspected cases of reinfection

Specimen Collection:

Consider serial collection of respiratory specimens and sera for suspected cases of reinfection, detailed below.

Serial respiratory specimen collection: If participant is enrolled in a sub-study to investigate viral shedding and transmissibility, collect respiratory specimens daily for 7 days and then every other day for 7 additional days following the date of symptom recurrence or RT-PCR positive diagnosis of suspected reinfection (if asymptomatic).

Serial serum collection: Collect stored sera from first episode, any sera available between first and second episode, and sera available at the time of suspected reinfection. Collect sera at 3 days, 7 days, 14 days, 21 days and 6 weeks following suspected reinfection.

Study instruments:  

Case report form (CRF) and data dictionary: Provided to facilitate systematic data collection [Appendix 1].

Training for all study personnel:

Prior to using the CRF, review the corresponding data dictionary to ensure that all data are collected properly.



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