"Long-COVID'' (also known as post-COVID-19 syndrome, post-acute sequelae of COVID-19, orchronic COVID syndrome, used here as 'Long-COVID' for brevity), is a complex array ofpostconvalescence symptoms following SARS-CoV-2 infection. The syndrome, common inCOVID-19 survivors, can affect every organ system through as-yet uncharacterised butpresumed immunological mechanisms. Prevalence depends on the definition used andtime-period of follow-up, as well as the population being studied. The syndrome has beenassociated with significant and persistent disability in some survivors but has beenhampered, until recently, by lack of a clinical definition, diagnostic criteria, andobjective measures of disease or disability [1]. A Delphi-informed initial World HealthOrganisation (WHO) clinical definition was released in early October 2021 but hasattracted 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 epidemicoccurred, which was associated with severe lockdowns in many countries (including SouthAfrica) with social isolation, widespread fear and disinformation, widespread economichardship, and loss of family and acquaintances, all of which contribute to symptoms(psychiatric and sleep disturbances, pain, and other syndromes) reported to be associatedwith Long-COVID. Finally, many Long-COVID symptoms overlap with those seen in patientshospitalised for any severe illness, especially those admitted to intensive care andventilated. However, the proliferation of literature reporting associations of Long-COVIDsymptoms with more severe COVID-19 disease, and objective immunological, radiological,and organ-specific dysfunction in those reporting symptoms, suggests that the entity isreal. The pathogenesis of Long-COVID is poorly understood, but this association with moresevere disease - where immune dysregulation plays a major role in those withhospitalization, respiratory failure, and death - suggests an immune-mediatedinflammatory dysfunction that may impact all organs [3-14].The sheer rapidity of four major infection waves in South Africa, the initial focus oncontaining the hospital burden of those with severe illness, and subsequent emphasis onthe roll-out of a mass vaccination program, has left little space for studying SARS-COV-2sequalae in survivors. This group, loosely and inaccurately termed "recovered'' in SouthAfrican reporting, were largely unvaccinated or partly vaccinated at the time ofinfection, leaving them at risk of developing Long-COVID.
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:
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.
Sunnyside Office Park
Johannesburg, Gauteng, South Africa
Charlotte Maxeke Johannesburg Academic Hospital (CMJAH)
Johannesburg, Gauteng, South Africa