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

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

"Long-COVID'' (also known as post-COVID-19 syndrome, post-acute sequelae of COVID-19, or chronic COVID syndrome, used here as 'Long-COVID' for brevity), is a complex array of postconvalescence symptoms following SARS-CoV-2 infection. The syndrome, common in COVID-19 survivors, can affect every organ system through as-yet uncharacterised but presumed immunological mechanisms. Prevalence depends on the definition used and time-period of follow-up, as well as the population being studied. The syndrome has been associated with significant and persistent disability in some survivors but has been hampered, until recently, by lack of a clinical definition, diagnostic criteria, and objective measures of disease or disability [1]. A Delphi-informed initial World Health Organisation (WHO) clinical definition was released in early October 2021 but has attracted much criticism from both clinicians and survivors for a host of reasons, ranging from a lack of precision to a lack of inclusion [2].

Further complicating the syndrome is the context in which the SARS-CoV-2 epidemic occurred, which was associated with severe lockdowns in many countries (including South Africa) with social isolation, widespread fear and disinformation, widespread economic hardship, and loss of family and acquaintances, all of which contribute to symptoms (psychiatric and sleep disturbances, pain, and other syndromes) reported to be associated with Long-COVID. Finally, many Long-COVID symptoms overlap with those seen in patients hospitalised for any severe illness, especially those admitted to intensive care and ventilated. However, the proliferation of literature reporting associations of Long-COVID symptoms with more severe COVID-19 disease, and objective immunological, radiological, and organ-specific dysfunction in those reporting symptoms, suggests that the entity is real. The pathogenesis of Long-COVID is poorly understood, but this association with more severe disease - where immune dysregulation plays a major role in those with hospitalization, respiratory failure, and death - suggests an immune-mediated inflammatory dysfunction that may impact all organs [3-14].

The sheer rapidity of four major infection waves in South Africa, the initial focus on containing the hospital burden of those with severe illness, and subsequent emphasis on the roll-out of a mass vaccination program, has left little space for studying SARS-COV-2 sequalae in survivors. This group, loosely and inaccurately termed "recovered'' in South African reporting, were largely unvaccinated or partly vaccinated at the time of infection, leaving them at risk of developing Long-COVID.

Study Overview

• Status: Active, not recruiting
• Conditions: Long COVID

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Bukani X Dyariwe; Phone Number: 011 084 4961; Email: bdyariwe@ezintsha.org
• Study Contact Backup: Name: Nompumelelo Nzuza; Phone Number: 011 084 4949; Email: nnzuza@ezinths.org

Study Locations

• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Sunnyside Office Park
    • Johannesburg, Gauteng, South Africa, 2198
      • Charlotte Maxeke Johannesburg Academic Hospital (CMJAH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

Adults at least 18 years of age with previous confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) will be invited to participate. Approximately 400 participants will be enrolled.

Description

Inclusion Criteria:

1. Able and willing to provide written or electronic informed consent for the baseline visit prior to any study-specific assessment or procedure.
2. Age at least 18 years at the time of signing the informed consent form.
3. 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].
4. Willing to consent to verification of vaccination status on the national Electronic Vaccination Data System (EVDS).
5. Access to a reliable telephone or other device permitting information transfer.

Exclusion Criteria:

1. Symptomatic SARS-CoV-2 infection at any stage prior to the baseline visit [Cohort 1 only].
2. 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].
3. COVID-19 within three months of the baseline visit.
4. 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.
5. 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.
6. 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.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To characterise Long-COVID in four cohorts of patients	Incidence, severity, and duration of Long-COVID symptoms.	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory markers	High sensitivity C-reactive protein (hs-CRP)	6 Months
Inflammatory markers	Interleukin-1	6 Months
Inflammatory markers	Interleukin-6 (IL-6)	6 Months
Inflammatory markers	Interleukin-8 (IL-8)	6 Months
Inflammatory markers	Tumour necrosis factor alpha	6 Months
Inflammatory markers	Tumour necrosis factor alpha receptor-1 (TNFR1)	6 Months
Inflammatory markers	Monocyte chemoattractant protein-1 (MCP-1)	6 Months
Psychological profiles	Headache Impact Test-6	6 Months
Psychological profiles	Patient Health Questionnaire-9	6 Months
Psychological profiles	Generalised Anxiety Disorder 7	6 Months
Psychological profiles	PTSD Checklist for DSM-5 - Civilian Version	6 Months
Psychological profiles	Mood Disorder Questionnaire; a short screening tool evaluating the symptoms of bipolar disorder	6 Months
Psychological profiles	Montreal Cognitive Assessment	6 Months
Psychological profiles	Daily Fatigue Impact Scale; a survey tool that assesses physical, cognitive, and psychosocial dimensions of fatigue in everyday life	6 Months
Psychosocial exposures	COVID-19 related stress questionnaire	6 months
Psychosocial exposures	Multidimensional Scale of Perceived Social Support; a brief research tool designed to measure perceptions of support from 3 sources - family, friends, and a significant other; the scale is comprised of a total of 12 items, with 4 items for each subscale	6 months
Psychosocial exposures	Perceived Stress Scale	6 months
Psychosocial exposures	Adverse Childhood Experiences tool	6 months
Work performance in employed participants	Normal activities and work productivity questionnaire; daily diaries	6 months
Sleep quality and disorders	Pittsburgh Sleep Quality Index	6 months
Sleep quality and disorders	Epworth Sleepiness Scale	6 months
Sleep quality and disorders	Berlin Questionnaire for risk of sleep apnoea	6 months
Sleep quality and disorders	International Restless Legs Syndrome Severity Scale	6 months
Sleep quality and disorders	Sleep quality and mood visual analogue scale	6 months
Pain experience	Brief Pain Inventory	6 months
Cardiorespiratory function	Modified Medical Research Council Dyspnoea Scale	6 months
Cardiorespiratory function	Six-minute walk test (distance)	6 months
Cardiorespiratory function	ECG parameters and morphology	6 months
Standard laboratory parameters	Full blood count	6 months
Standard laboratory parameters	Serum chemistry	6 months
Standard laboratory parameters	Liver function tests	6 months
Standard laboratory parameters	Glucose, HbA1C	6 months
Renal function	Creatinine clearance	6 months
Renal function	Cystatin-C	6 months
Renal function	Urine dipstick parameters	6 months
Renal function	Urine albumin-to-creatinine ratio	6 months
Host genetic factors that may be associated with Long-COVID	Genotyping results	6 months
Host genetic factors that may be associated with Long-COVID	DNA sequencing results	6 months

Collaborators and Investigators

• Sponsor: University of Witwatersrand, South Africa
• Investigators: Principal Investigator: Francois WD Venter, MBBCh, Ezintsha, a division of Wits Health Consortium; Study Director: Simiso M Sokhela, MBBCh, Ezintsha, a division of Wits Health Consortium; Study Chair: Nonkululeko Mashabane, BPharm, Ezintsha, a division of Wits Health Consortium

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): June 25, 2024

Study Registration Dates

• First Submitted: July 4, 2022
• First Submitted That Met QC Criteria: July 4, 2022
• First Posted (Actual): July 6, 2022

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Chronic Disease; Post-Infectious Disorders; COVID-19; Post-Acute COVID-19 Syndrome
• Other Study ID Numbers: EZ-FV-028

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data that will be shared is all of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: Immediately following publication
• IPD Sharing Access Criteria: Anyone who wishes to access the data
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No