Statement of Work.pdf

Statement of Work

TITLE:

Prospective long-term follow-up of COVID-19 infection with neurological manifestations

SECTION 1 BACKGROUND

Throughout the COVID pandemic, it has become increasingly apparent that there are many extra-respiratory manifestations of SARS-CoV-2 infection. Among the important manifestations have been neurologic complications, including stroke, seizures, encephalopathy, and others. Although many people fully recover from SARS-CoV-2 infection, there are some whose symptoms persist or recur after the acute infectious period. Patients with long lasting symptoms of COVID often report a combination of multiorgan symptoms such as shortness of breath, fatigue, post-exertional malaise, muscle pain, low grade fevers, palpitations, and difficulties with sleep and concentration.

From a neurological standpoint, one of the most frequent complaints from patients with post-acute sequalae of COVID-19 has been coined “brain fog”, a condition characterized by cognitive impairments such as confusion, difficulty thinking, and overall mental sluggishness.

The COVID-19 pandemic has disproportionately impacted minorities and uncovered longstanding healthcare disparities. As of October 2023 in New York City, approximately 188,000 individuals from Northern Manhattan communities (Washington Heights, Inwood and Harlem) have been infected with COVID-19, approximately 60% of whom identified as Hispanic/Latinx. The cumulative hospitalization rate of the Hispanic/Latinx population in Manhattan is currently 2,350 per 100,000 people. Understanding factors associated with neurocognitive impairment in patients recovering from COVID-19 in the predominantly Hispanic/Latinx communities is essential to identifying public health strategies to effectively care for these vulnerable populations overtime.

To date, neurologic manifestations following SARS-CoV-2 infection, including cognition, psychological disturbances, headaches, fatigue, and malaise that may impact daily living activities, have been minimally studied longitudinally in multi-ethnic and multilingual populations. There have been very few projects looking at cohorts of persons with long-term neurologic complications of COVID, but fewer with prospective design and control subjects.

Our study of COVID-19 and its effects on the nervous system started during the initial surge of SARS-CoV-2. Patients admitted with COVID-19 to Columbia University Irving Medical Center

New York Presbyterian Hospital (CUIMC/NYP) in New York City between March 1, 2020, and August 31, 2020 were included in our initial study. Inclusion criteria was a definitive SARS-CoV- 2 infection diagnosed by reverse transcriptase polymerase chain reaction (rtPCR) of a nasal swab specimen within 6 weeks prior to their acute COVID-19 hospitalization. Patients from all neurology services were reviewed as well as every 10th patient from the hospital-wide COVID-

Cares database, which documented every COVID-19 patient seen at CUIMC. A matched case-control retrospective study of this cohort was conducted reviewing clinical data and potential risk factors of patients diagnosed with neurological syndromes during their COVID-19 hospitalization.

A similar cohort retrospective analysis was performed of patients admitted to CUMC for COVID- 19 between December 1, 2021 and February 28, 2022. This timeframe corresponding with the first Omicron (B.1.1.529) variant wave in New York City was used to identify positive cases in lieu of verification by genetic sequencing. The findings of these two studies have been published in Neurology Clinical Practice in August 2022 and Annals of Clinical and Translational Neurology in June 2023, respectively.

A subset of these patients were enrolled in the second phase of investigation of the neurologic and neurocognitive outcomes of SARS-CoV-2 infection in a prospective longitudinal study. Between June 30, 2022, and January 3, 2023, 155 subjects with neurologic sequelae secondary to SARS- CoV-2 infection from the retrospective matched case-control study and an internal CUMC-based comparison group that did not have neurologic manifestations were enrolled. Their primary baseline visit, which took place approximately two years after their index COVID-19 hospitalization, included a detailed clinical intake, neurologic exam, and a comprehensive battery of neurocognitive assessments and psychosocial surveys. The neurocognitive assessments together measured global cognition and subdomains of memory, executive function, processing speed, and verbal fluency. The surveys explored subjective assessments of financial security, social support, stress, security, neurocognitive function, psychological disturbances, and general wellbeing. The data analysis of this first prospective arm is currently in progress.

Age and gender matched participants of the Washington Heights, Inwood Columbia Aging Project (WHICAP)/(WHICAP Offspring) a community-based longitudinal study of aging and dementia identifying biological and sociocultural mechanisms of disparities in cognitive function will be selected as part of an internal comparison group. Plasma and serum samples were also collected at this time point for exploratory untargeted metabolomics and cytokine profiling. These components are in development.

A secondary remote follow-up visit comprising of a neurocognitive assessment and two surveys was recently completed. This will be followed by a third remote follow-up visit that includes three more surveys. The fourth study visit will include an MRI Brain scan to assess neuroradiologic features and additional blood sample collection for further biomarker profiling including transcriptomics. The subset of participants will have a brain MRI acquisition on a Siemens 3 Tesla scanner in a single 1.25 hour session that has been generally tolerated well. Primary neuroimaging outcome variables will include regional volumetry and cortical thickness; regional white matter hyperintensity volume; presence, number, and region of cerebral microbleeds; and number and distribution of infarcts. We will also derive regional diffusion metrics, metabolite concentrations, regional blood flow, resting state connectivity, hippocampal subfield anatomy, perivascular spaces, and large vessel morphology.

SECTION 2 PURPOSE

This prospective cohort study enrolls and follows COVID-19 hospitalized patients with neurological signs/symptoms and/or conditions and comparison groups. The aim is to prospectively follow these patients for long-term outcomes related to neurological signs/symptoms and/or conditions. The study enrolls patients who belong to critical populations, specifically minorities and those with low socioeconomic status.

Objectives:

1. To determine potential clinical, psychosocial, and socioeconomic risk factors that may contribute to the development of adverse neuropsychological effects of neurological COVID-19 in predominantly Hispanic/Latinx community dwelling COVID-19 survivors.

2. To analyze the development of neurocognitive effects post SARS-CoV-2 infection within the domains of memory, visuospatial ability, psychomotor speed, attention, executive functioning, language, and functional ability.

3. To determine abnormalities in neuroinflammatory or neurodegenerative biomarkers (i.e., cytokines/chemokines) in blood samples of patients.

4. To determine how COVID-19 affects the transcriptome of PBMCs using single cell RNA sequencing.

5. To identify neuroradiological features by MRI Brain in COVID-19 patients with neurologic sequelae and neurocognitive impairment.

6. Define the effect of neurologic diagnoses during acute hospitalization on longitudinal COVID-19-related outcomes including neurocognitive impairment.

SECTION 3 SCOPE OF WORK

Independently, and not as an agent of the United States Government, the contractor shall develop, obtain human subjects approval for, and implement a study of hospitalized patients with neurological signs/symptoms and/or conditions. Specifically, persons admitted with neurologic illness, or developing neurologic illness within 6 weeks of hospitalization, and fulfilling clinical and laboratory criteria for acute SARS-CoV-2 infection will be eligible for enrollment in the study.

With the retrospective analyses of risk factors of neurological manifestation in acute COVID-19 infection completed, we aim to characterize neurologic sequelae and neurocognitive with greater granularity and accuracy in a prospective longitudinal study design. This study will follow participants for at least 24 months, with follow up visits at 6, 12, 18, and 24 months.

SECTION 4 TASKS TO BE PERFORMED

Task 1: Development

a. The contractor will design the study and write a protocol, including data collection tools, for submission to (i.e., Institutional Review Board). The contractor will draft a study protocol in accordance with national regulations and ethical standards. CDC Subject Matter Experts (SMEs) will review the study protocol and provide feedback to the contractor on the design the of the study, including data collection tools and human subject’s considerations. The contractor shall make revisions and submit a final copy of the study protocol to CDC within 7 days.

b. The contractor will develop the required databases to collect and store data from the study. CDC SMEs will review the proposed design and management of the database.

Task 2: Training Workshops and Approvals

a. The contractor will submit and obtain human subjects approval from their Institutional Review Board, and in coordination with CDC, CDC’s Institutional Review Board (or a reliance on another appropriate4 human subject’s determination made by agency representatives).

b. The contractor will provide training to local staff for study implementation. This training will include background information, protocol content following ethical guidelines, collection and storage of specimens, and collection of data from medical charts and patient interviews.

Task 3: Data and specimen collection

a. The contractor will recruit and enroll (with informed consent) approximately 150 human subjects research participants to participate in the study. The contractor shall provide a draft screening tool for potential study participants to CDC SMEs for review and approval.

b. The contractor will collect data from the research participants.

i. The contractor will collect medical and patient provided data at specified time points for each study participant.

ii. Biological specimen will be prospectively collected. The collected blood specimens will be used for future analysis of biological markers of neuronal and axonal injury. To maintain subject confidentiality, all biospecimen will be identified by a coded number which will be considered an indirect identifier; specimens will be linked to patient demographic and clinical information. Specimens will be stored in freezers in a secured room at the research facility; biological specimens will not be sent to the CDC. Written, informed consent will be obtained from all subjects prior to collection of blood specimens.

c. The contractor will enter collected data into the database, validate, clean data entered and provide a copy of the database to CDC for review and validation. (Note: CDC shall validate and clean all data entered).

d. The contractor will amend collection tools, as needed, for improved data collection over the course of the study.

Task 4: Delivery of data and summary reports

a. The contractor will routinely (as needed, on a monthly basis at a minimum) submit data to CDC for technical review and assistance as defined in the previous tasks.

i. The contractor will participate in (at a minimum) biweekly conference calls with CDC SMEs to review participant screen, data collection, data validation, and data analysis activities. Conference calls may be substituted by email exchanges, as agreed upon by CDC technical experts, if needed at certain timepoints.

b. The contractor will conduct interim summaries of the tasks at defined periods during the period of performance.

Task 5: Publications and Travel

a. The Contractor will work with CDC staff to publish any findings from this project. Any publications developed will adhere to CDC authorship/publications guidelines. The contractor will be responsible for all publication fees.

b. The Contractor will have opportunities to present project findings at relevant meetings and workshops. All conference meetings and/or presentations will be discussed with CDC staff prior to registration and acceptance.