A Cross-sectional, Observational Study to Characterise Long COVID-19 in an Urban Sample of South African Adults

This is a single-centre, follow-up, observational, cross-sectional study of four distinct, longitudinal cohorts. Extensive clinical history will be obtained from each participant, and symptom questionnaire characterisation of Long-COVID (with a strong focus on organ-specific dysfunction, psychiatric, sleep, and pain parameters - all of which appear to be major features of Long-COVID), as well as laboratory and genetic characterisation will be performed. A subset of each cohort will be randomly selected for more specific syndrome characterisation related to sleep and pain, respiratory, cardiology, renal and glucose metabolism.

The consequences of Long-COVID will be described and compared in four large, well-described clinical cohorts of African patients surviving SARS-CoV-2:

• Cohort 1: asymptomatic subjects found to be PCR/antigen/antibody-positive during routine screening for SARS-CoV-2 infection
• Cohort 2: symptomatic outpatients who were confirmed to have COVID-19 through a positive PCR/antigen test
• Cohort 3: inpatients surviving hospitalisation for severe COVID-19 and who were PCR/antigen-positive
• Cohort 4: participants vaccinated in clinical trials in 2020 prior to widespread community exposure, and hence protected from severe COVID-19 (and possibly Long-COVID) if subsequently infected.

After obtaining informed consent from potential participants, a single cross-sectional, baseline visit will be conducted for each participant. Demographic data, clinical history (including COVID-19 history, targeted symptoms, and risk factors), COVID-19 vaccination dates (if administered), and details of previous and concomitant medications will be collected. Multiple questionnaires related to psychiatric screening, psychosocial factors, work function assessment, sleep quality, and pain assessment will be administered. Respiratory and cardiac function will be evaluated through a dyspnoea scale, walking test and an ECG. Laboratory evaluations will include a full blood count, serum chemistry, liver function tests, renal function assessment, inflammatory markers, and DNA extraction for genotyping. Blood and urine samples will be stored locally for possible future analysis. Human immunodeficiency virus (HIV) testing will be performed for participants consenting to this optional assessment.

After the baseline visit, participants with Long-COVID will be identified using the WHO clinical definition and general health assessments [2]. Randomly selected sub-groups of participants with, and without, Long-COVID will be selected from each of the four cohorts for additional investigations through participation in the following sub-studies:

• Respiratory evaluation: dyspnoea assessment, high-resolution computed tomography (CT) scan, lung function studies including spirometry and diffusion capacity (DLCO) [Section 7.2.2.1]
• Cardiac evaluation: clinical history and examination, serial blood pressure, six minute walk test (distance), ECG, echocardiogram including speckle tracking, cardiac magnetic resonance imaging (MRI), creatine kinase MB fraction (CK-MB), cardiac troponin T (cTnT), prohormone brain natriuretic peptide (pro-BNP), and possible coronary angiography in patients with acute coronary syndromes and unstable angina [Section 7.2.2.2]
• Psychiatric and neuroendocrine evaluation: questionnaires/surveys, semi-structured interview, home visit, saliva cortisol analysis, collection of diary data, actigraphy, adrenocorticotropic hormone (ACTH) challenge (cosyntropin sensitivity test [CST]), cellular immunity assessment [Section 7.2.2.3]
• Sleep evaluation: questionnaires, actigraphy with sleep diaries, polysomnography (PSN) [Section 7.2.2.4]
• Pain evaluation: quantitative sensory testing (QST) and conditioned pain modulation (CPM) assessments [Section 7.2.2.5]
• Glucose metabolism evaluation: oral glucose tolerance test (OGTT) including assessment of glucose, insulin, and c-peptide to estimate insulin sensitivity and beta-cell function [16]. [Section 7.2.2.6] Abnormalities detected in the assessments (including undiagnosed mental health issues) will be managed by on-study medical personnel with referral as appropriate.

Inclusion criteria

• Able and willing to provide written or electronic informed consent for the baseline visit prior to any study-specific assessment or procedure.
• Age at least 18 years at the time of signing the informed consent form.
• Previous asymptomatic SARS-CoV-2 infection, confirmed through a documented positive PCR, antigen, or antibody test, at least six months prior to the baseline visit [Cohort 1 only] or, previous symptomatic SARS-CoV-2 infection for which hospitalisation was not required, confirmed through a documented positive PCR or antigen test at the time, at least six months prior to the baseline visit [Cohort 2 only] or, previous hospitalisation for management and treatment of COVID-19 confirmed through a documented positive PCR or antigen test at the time, at least six months prior to the baseline visit [Cohort 3 only] or, previous asymptomatic or symptomatic SARS-CoV-2 infection, confirmed through a documented positive PCR, antigen, or antibody test, at least six months prior to the baseline visit and received a COVID-19 vaccine in a non-placebo arm of a COVID-19 vaccine study during 2020 [Cohort 4 only].
• Willing to consent to verification of vaccination status on the national Electronic Vaccination Data System (EVDS).
• Access to a reliable telephone or other device permitting information transfer.

Exclusion criteria

• Symptomatic SARS-CoV-2 infection at any stage prior to the baseline visit [Cohort 1 only].
• SARS-CoV-2 infection, confirmed through a documented positive PCR, antigen, or antibody test, prior to vaccination in a non-placebo arm of a COVID-19 vaccine study during 2020 [Cohort 4 only].
• COVID-19 within three months of the baseline visit.
• Personnel (e.g., investigator, sub-investigator, research assistant, pharmacist, study coordinator or anyone mentioned in the delegation log) directly involved in the conduct of the study.
• Any physical, mental, or social condition, that, in the Investigator's judgment, might interfere with the completion of the baseline assessments and evaluations. The Investigator should make this determination in consideration of the volunteer's medical history.
• Participant is judged by the Investigator to be at significant risk of failing to comply with the provisions of the protocol as to cause harm to self or seriously interfere with the validity of the study results.