A cross-sectional, observational study to characterise Long-COVID in an urban sample of South African adults
Background
“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. A Delphi-informed initial 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.
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.
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.
Long-COVID reported symptoms are extraordinarily broad. Over 50 symptoms were reported in a recent review, with over 80% of COVID-19 survivors having at least one symptom after infection. The diagnosis is one of exclusion, and symptoms may fluctuate although tend to resolve with time. It is unclear whether disability and organ damage may be permanent in some patients. No specific treatment exists, and interventions are typically symptom-directed. SARS-CoV-2 vaccination appears to benefit many symptomatic survivors. At the time of writing, no African data characterising the clinical features of Long-COVID have been published.
Rationale
Characterizing Long-COVID and related disability in local populations is an important first step to understanding the burden of morbidity and potential requirements of the health system in addressing symptoms and disability.
Almost all studies on Long-COVID have been undertaken in higher income countries, and largely in hospitalised patients, with almost no data emerging yet from Africa. This study aims to characterise Long-COVID in South African patients by leveraging an existing patient base (including asymptomatic outpatients, symptomatic outpatients, and hospitalised patients with severe COVID-19) and local research expertise.
The study is anticipated to add significantly to understanding Long-COVID, and to contribute African data to current efforts to develop syndrome diagnostic criteria (including the WHO case definition) and an understanding of the therapeutic needs of symptomatic survivors, thus informing South African health care.
Design
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 three large, well- described clinical cohorts of African patients surviving SARS-CoV-2 prior to vaccination:
- Cohort 1: unvaccinated, asymptomatic outpatients found to be PCR/antigen/antibody-positive during routine screening for SARS-CoV-2 infection
- Cohort 2: unvaccinated, symptomatic outpatients who were confirmed to have COVID-19 through a positive PCR/antigen test
- Cohort 3: unvaccinated, inpatients surviving hospitalisation for severe COVID-19 disease and who were PCR/antigen-positive. These cohorts will be compared to a control group:
- Cohort 4: participants vaccinated in clinical trials in 2020, and hence protected from severe disease (and presumably 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 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. HIV testing will be performed for participants consenting to this optional assessment.
After the baseline visit, participants who are suitable for one, or more, sub-study will be identified. A randomly selected sub-group for each of the following sub-studies and additional investigations will be drawn from eligible participants within each cohort:
- Respiratory evaluation: high-resolution CT scan, lung function studies including spirometry and diffusion capacity (DLCO)
- Cardiac evaluation: speckle tracking echocardiogram, high sensitivity cardiac troponin (hs-cTn), prohormone brain natriuretic peptide (pro-BNP)
- Sleep evaluation: actigraphy and polysomnography
- Pain evaluation: quantitative sensory testing (QST) and conditioned pain modulation (CMT) assessments
- Glucose metabolism evaluation: oral glucose tolerance test (OGTT) including assessment of glucose, insulin, and c-peptide to estimate insulin sensitivity and beta- cell function.
Abnormalities detected in the assessments (including undiagnosed mental health issues) will be managed by on-study medical personnel with referral as appropriate.
Population
Adults of at least 18 years of age with previous confirmed SARS-CoV-2 infection (symptomatic or asymptomatic) or who were enrolled into a non-placebo arm of a COVID- 19 vaccine study during 2020, will be invited to participate.
The following eligibility criteria will be used to select study participants for the main study (baseline visit only):
- Inclusion criteria (baseline visit/main study):
- 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] 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, received a COVID-19 vaccine in a non-placebo arm of a COVID-19 vaccine study during 2020 [Cohort 4 only]. - Access to a reliable telephone or other device permitting information transfer.
- Receipt of a COVID-19 vaccine prior to initial infection with SARS-CoV-2 (symptomatic or asymptomatic) [Cohorts 1, 2 and 3].
- Symptomatic SARS-CoV-2 infection at any stage prior to the baseline visit [Cohort 1 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.
Exclusion criteria (baseline visit/main study):
Additional eligibility criteria will be used to identify study participants who are eligible for random selection for any of the sub-studies:
- Inclusion criteria (sub-studies):
- Enrolled into main study and completed baseline visit.
- Able and willing to provide written or electronic informed consent for the
relevant sub-study.
- Exclusion criteria (sub-studies):
- Pregnant women [Respiratory sub-study only].
- Self-reported diabetic or on treatment for diabetes mellitus (Type 1 or 2)
[Glucose metabolism sub-study only].
- Serum glucose and/or glycosylated haemoglobin (HbA1C) assessment at baseline consistent with a diagnosis of diabetes mellitus [Glucose metabolism sub-study only].
Participants may be enrolled into more than one sub-study.
Treatment
No treatment will be administered during this observational study.
Objectives and Endpoints
Primary Objective
To characterise Long-COVID in three cohorts of patients (asymptomatic, symptomatic, and severely symptomatic requiring hospitalisation) who were unvaccinated prior to documented PCR/antigen-positive SARS-CoV-2 infection, compared to early vaccinated individuals.
Primary Endpoint
Incidence, severity, and duration of Long- COVID symptoms.
Secondary Objectives
To describe the following characteristics in three cohorts of patients (asymptomatic, symptomatic, and severely symptomatic requiring hospitalisation) who were unvaccinated prior to documented PCR/antigen-positive SARS-CoV-2 infection, compared to early vaccinated individuals
- Inflammatory markers
- Psychological profiles
- Psychosocial exposures
- Work performance in employed participants
- Sleep quality and disorders
- Pain experience
- Cardiorespiratory function
- Standard laboratory parameters
- Renal function
- Host genetic factors that may be associated with Long-COVID
Secondary Endpoints
- High sensitivity C-reactive protein (hs- CRP)
- Interleukin-6 (IL-6)
- Interleukin-8 (IL-8)
- Tumour necrosis factor alpha receptor- 1 (TNFR1)
- Monocyte chemoattractant protein-1 (MCP-1)
- Patient Health Questionnaire-9
- Generalised Anxiety Disorder 7
- PTSD Checklist for DSM-5 – Civilian Version
- Mood Disorder Questionnaire • Oxford Cognitive Screen
- Daily Fatigue Impact Scale
- COVID-19 related stress questionnaire
- Multidimensional Scale of Perceived Social Support
- Perceived Stress Scale
- Adverse Childhood Experiences tool
- Normal activities and work productivity questionnaire
- Pittsburgh Sleep Quality Index
- Epworth Sleepiness Scale
- Berlin Questionnaire for risk of sleep apnoea
- International Restless Legs Syndrome Severity Scale
- Brief Pain Inventory
- Six-minute walk test distance
- ECG parameters and morphology
- Full blood count
- Serum chemistry
- Liver function tests
- Glucose, HbA1C
- Creatinine clearance
- Cystatin-C
- Urine dipstick parameters
- Urine albumin-to-creatinine ratio
- Genotyping results
- DNA sequencing results
Exploratory Objectives
- The association between various specialised respiratory, cardiac, sleep, pain, and glucose metabolism parameters and Long-COVID symptomatology will be explored in three cohorts of participants previously infected with SARS-CoV-2 compared to early vaccinated individuals (controls).
Sample Size
One hundred (100) participants will be enrolled into each cohort (400 participants overall).
Enrolled participants will be assessed for their suitability for various sub-studies. From the eligible participants, up to 30 from each cohort will be randomly selected to participate in each sub-study. The same participant may participate in more than one sub-study.
No formal sample size calculation was performed for this observational study.
Duration
The duration of participation for each participant will either be a single visit (of approximately 5 hours), or two or more visits depending on whether they are enrolled into any sub-studies.
Participants selected for the sleep study will have an overnight admission at the Wits Faculty of Health Sciences sleep laboratory.
Enrolment to the study is expected to complete within one year.
Statistical Analysis
Participants enrolled in the main, and various sub-studies, will be summarised. Demographic data and other baseline characteristics will be summarised overall and per cohort.
All primary and secondary endpoints will be summarised descriptively overall, per cohort and for various risk factors as deemed appropriate in this exploratory study. Associations between outcomes, COVID-19 history, COVID-19 risk factors for severe disease, and vaccination status since infection may be explored. Co-factors such as time since initial SARS-CoV-2 infection, and possible confounders such as vaccination, exposure to potential disease-modifying repurposed drugs, and undisclosed vaccination or prior infections, will be accounted for.
Raw genetic genotyping results will be quality controlled by experienced SBIMB bio- informaticists. Association and fine-mapping will be used to investigate links between host genetics and Long-COVID variables generated by the broader study.
