Data from Israel of adults 60 years and older who received a 4th dose of mRNA vaccine found that the rate of confirmed infection decreased ~2 fold following the 4th dose, and the rate of severe illness decreased by ~4-fold in those who received a 4th dose versus those with 3 doses, both results were found to be statistically significant
NACI recommends a 4th dose at least 6 months following a 3rd dose for severely immunocompromised individuals who are not only at higher risk of severe outcomes, but also at higher risk of decreased protection over time following vaccination – this recommendation has been echoed by Public Health Ontario, the Northwest Territories Health and Social Services
The FDA has also authorized the use of the Pfizer mRNA vaccine as a 4th dose for adults over 50 years and those over 12 years with compromised immune systems
A small study of Israeli healthcare workers compared the incidence of COVID-19 in those who had received a 4th dose of vaccine to those who had received only three doses. It found that protection from Omicron infection was only slightly higher in the four-dose vaccine group compared to the three-dose control group (31% for Pfizer as a 4th dose, 11% for Moderna as a 4th dose), and that neither result was statistically significant. Breakthrough infections were mild, yet with high viral loads
Small-scale studies of solid-organ transplant and hemodialysis patients found that while a 4th dose increased antibody titers in most participants, those with severe immune deficiencies such as those taking anti-rejection medication were still unable to mount an immune response to vaccination – in addition, these studies have not assessed the presence or strength of functional immunity in these populations
Badea, A; Groot, G; Reeder, B; Miller, L; Howell-Spooner, B. What is the efficacy of a 4th booster dose for COVID-19? 2022 Mar 31, Document no.: EOC220304 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2022. 10 p. (CEST rapid review report).
Since the previous rapid review, a large amount of new research and reviews are available to draw upon. Many studies have addressed aspects previously identified as limitations such as the use of validated questionnaires, documenting pre-COVID health status, and control cohorts. Many studies now include only participants with RT-PCR verified infections and also focus on a range of disease severities from severe (hospitalized) to mild (managed in the community); PCR-validated infections ensure a higher quality of comparison between test-positive and control groups. Studies involving control groups contributed illuminating findings about prevalence and incidence of long COVID, which is lower than previous thought when compared to control groups. Comorbidities/factors that potentially indicate increased risk of developing long COVID-19 have been identified and widely agreed-upon, such as diabetes, cardiovascular diseases, obesity, and gender (female).
A case definition for long COVID has yet to be adopted but is commonly defined as COVID-related symptoms that persist or emerge beyond 4 weeks of infection with two subsequent phases: “ongoing symptomatic COVID-19 (OSC; signs and symptoms from 4 to 12 weeks from initial infection) and 2) post-COVID-19 syndrome (PCS; signs and symptoms beyond 12 weeks) with respect to symptomatology, abnormal functioning, psychological burden, and quality of life”. Long COVID includes both OSC and PCS.
It is estimated that 32% of non-hospitalized and 51% of hospitalized people experience Long COVID symptoms within 12 weeks of infection; however, higher estimates up to 92% have been reported in studies with a greater proportion in persons who were previously hospitalized. More than 200 symptoms affecting 10 organ systems have been identified in various reports or systematic reviews. Many patients (49%), experience at least one COVID-related symptom 12 months after infection (compared to 68% at 6 months).
For many persons, symptoms improve over time while others experience persistent and/or new symptoms. At 3 months post-infection the most frequently reported symptoms are fatigue (up to 98%), dyspnoea (up to 88%), headache (up to 91%) and taste/smell disorders (up to 58%).
Mechanism(s) leading to long COVID remain unclear, but these comorbidities/factors have been found to indicate potentially increased risk of developing long COVID:
o Age (60+)
o Greater number of symptoms during the acute phase of illness (typically 5+)
o Manifestation of specific symptoms
o Diabetes
o Cardiovascular disease
o Obesity or high BMI
o Gender (female)
There is limited evidence to support the contention that vaccination lowers incidence of long COVID.
Key Findings
July 9, 2021
The frequency of Long COVID symptoms varies widely across studies based on populations studied, duration of follow up and methods of assessment of symptoms.
It is estimated that 1 in 50 persons experience Long COVID symptoms after 12 weeks; however, higher estimates up to 80% have been reported in studies with a greater proportion of persons who were previously hospitalized. A recent study of a mixed cohort of 96 persons found that only 22.9% had no symptoms at 12 months post diagnosis.
A wide range of symptoms affecting multiple organ systems has been reported. For many persons symptoms improve over time while others experience persistent and/or new symptoms. Among studies with the longest duration of follow up, the most frequently reported symptoms included fatigue (up to 65%), dyspnea (up to 50%), headache (up to 45%), anosmia/ageusia (up to 25%), cognitive memory/concentration (up to 39.6%) and sleep disorders (up to 26%).
Few studies estimated the duration of symptoms with estimates ranging from 2.2% for 6 months and 27% for 7-9 months.
The mechanism(s) leading to Long COVID remain unclear but those experiencing post acute sequelae tend to be older, have a greater number of symptoms during the acute phase of illness or manifest specific symptoms and live with multiple comorbid conditions such as obesity.
The lack of consensus on a definition of Long COVID contributes to marked variations in robust prevalence estimates.
Notes
A significant amount of evidence was produced since the previous review. This updated review was rewritten with extensive changes which have not been identified in red.
Hammond, B; Badea, A; Groot, G; Reeder, B; Howell-Spooner, B; Mueller, M. What is the incidence and duration of long COVID cases? 2022 Mar 31, Document no.: EPM210601v2 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2022. 18 p. (CEST rapid review report).
6-month to 1 year survival rates of critical COVID-19 patients are similar to those of non-COVID-19 patients admitted to ICU
COVID-19 patients who have survived intensive care (ICU) admission are at risk of developing both post intensive care syndrome (PICS) and Long COVID. PICS includes impairments in physical, cognitive and psychological dimensions
Long-term survival follow up of COVID patients indicates that they experience similar levels of impairments in physical, cognitive and psychological dimensions as historical non-COVID reference populations.
The most common long-term impairments reported by COVID patients are persistent dyspnea/breathlessness, general weakness/fatigue and ongoing psychological symptoms such as anxiety, depression and PTSD
Badea, A; Reeder, B; Groot, G; Miller, L; Mueller, M. What are the one year outcomes for ICU COVID patients? 2022 Feb 18, Document no.: EOC220201 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2022. 11 p. (CEST rapid review report).
The diagnostic accuracy of Rapid Antigen Tests (RAT) has been widely studied in various applications and in diverse populations.
Sensitivity, in the order of 75% in pooled estimates, is significantly influenced by the presence or absence of symptoms, viral load, and the timing of sampling relative to the onset of symptoms.
Specificity, in the order of 99% in pooled estimates, is consistently high across tests, populations, and sampling methods.
Post-test probability of being an infectious case following a positive test is highest in individuals with a high pre-test probability (population prevalence > 5%), such as those with COVID-19 symptoms, and those in settings with a high level of community transmission. Here, the positive predictive value is in the order of 95%. However, when used in settings with a lower pre-test probability (population prevalence < 0.5%), as in screening asymptomatic individuals, the positive predictive value is considerably reduced, as low as 25%.
Post-test probability of being an infectious case following a negative test is less than 1% (negative predictive value > 99%) in all settings except those with the highest levels of community transmission.
Badea, A; Reeder, B; Groot, G; Muhajarine, N; Minion, J; Miller, L; Howell-Spooner, B. In real world settings, what is the validity of Rapid Antigen Tests (RATs) in identifying SARS-CoV-2 and how well do they predict disease? 2022 Jan 12, Document no.: EOC211201 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2022. 15 p. (CEST rapid review report).
Ontario Immunization Advisory Committee recommended that if an 11 and 12-year-old child is inadvertently given a second dose of the Pfizer-BioNTech vaccine that is not authorized for their age, the dose should be considered valid and the series complete.
National Advisory Committee on Immunization (NACI) recommends that a booster dose of an authorized mRNA COVID-19 vaccine should be offered to vulnerable population and > 50 years old, =6 months after completion of a primary COVID-19 vaccine series.
Australian Technical Advisory Group on Immunization (ATAGI) recommends COVID-19 booster vaccination with either Pfizer (Comirnaty) or Moderna (Spikevax), which are considered equally acceptable, for anyone aged 18 and older who completed their primary course of COVID-19 vaccination 5 or more months ago.
On December 8th, 2021 in a press release by Pfizer-BioNTech said that preliminary laboratory studies demonstrate that three doses of the Pfizer-BioNTech COVID-19 vaccine neutralize the Omicron variant while two doses show significantly reduced neutralization titers. Data indicate that a third dose of BNT162b2 increases the neutralizing antibody titers by 25-fold compared to two doses.
Key Findings
December 3, 2021
The Therapeutic Goods Administration (TGA) has granted provisional approval to Moderna for the use of its vaccine in children (two 10µg doses) and as booster shot for adults (one 30µg dose) in preparation for the recent emergence of the Omicron variant. This is in addition to Pfizer, which was also recently approved.
The National Advisory Committee on Immunization (NACI) recommends that a complete series with the Pfizer-BioNTech COVID-19 vaccine (10 mcg) may be offered to children 5-11 years of age who do not have contraindications to the vaccine, with a dosing interval of at least 8 weeks between the first and second dose.
NNACI also recommends that children aged 5-11 years with a history of previous SARS-CoV-2 infection should be considered no longer infectious and symptoms of an acute illness should be completely resolved prior to vaccination.
Health Canada has authorized Moderna's COVID-19 vaccine (also known as Spikevax) to be used as a booster shot, using a half-dose of the vaccine.
In October, WHO released a consensus definition of post COVID-19 condition that includes 12 domains. This development should lead to better standardization of reporting and contribute to more precise prevalence estimates and better understanding of associated risk factors.
The effects of Variants of Concern (VoC) and COVID vaccination on progression of Long COVID symptoms remains unclear.
Risk factors for developing Long COVID symptoms were similar but limited evidence suggests that pre-pandemic psychological distress and poor general health were associated with developing persistent symptoms. Evidence is too limited to determine whether vaccination reduces the risk of developing Long COVID among persons with breakthrough infections.
Given the protean manifestations of Long COVID symptoms, the underlying causes are likely multifactorial; however, strong evidence to substantiate the theories of causation remains limited.
Research related to longer-term consequences of SARS CoV-2 infections in pediatric populations is growing but remains limited.
Key Findings
March 15, 2021
There is a lack of consensus around the clinical definition of Long COVID which in turn causes challenges with understanding the incidence and prevalence as well as the potential impact for the health care system
Information about the natural history of Long COVID is incomplete but limited evidence suggests that the immune response trajectories differ for those with few or no symptoms compared to those with severe disease. Individuals with severe disease are more likely to exhibit immunological marker abnormalities but anyone can experience functional limitations.
The mechanisms underlying the development of persistent symptoms in Long COVID remain an enigma. Despite multiple theories, there is little empirical evidence for specific immunological and or biochemical abnormalities in samples of individuals with symptoms consistent with Long COVID.
Risk factors for Long COVID include female gender, older age, higher body mass index, pre-existing asthma and the number of symptoms.
Few studies explored the short-term impact of Long COVID on health care utilization patterns and found a higher impact for those with severe disease compared with mild disease.
Williams-Roberts, H; Groot, G; Mueller, M; Dalidowicz, M. Long COVID: What does it mean for the healthcare system and programs? 2021 Oct 29. Document no.: EOC021901v2 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2021. 14 p. (CEST rapid review report).
Long COVID-19 is likely to increase healthcare demands across the health system, including emergency departments, hospital admissions, primary care visits, specialists appointments, and home care and rehabilitation services.
The clinical care burden of long COVID-19 is the greatest in the first 3 months after testing and is likely to place the greatest demand on primary care services.
Patients with severe COVID-19 illness are more likely to place longer-term demands (4-6 months) on specialist care due to respiratory, circulatory, endocrine, metabolic, psychiatric and unspecified conditions.
McLean, M; Williams-Roberts, H; Reeder, B; Howell-Spooner, B; Ellsworth, C. What are long COVID's demands on the healthcare system, and its severity of the illness? 2021 Jul 12, Document no.: EPM210602 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2021. 23 p. (CEST rapid review report).
Although rapid antigen point-of-care tests (POCT) to detect SARS-CoV-2 (COVID-19) infection have the advantage of rapid result turn-around time compared to laboratory-based reverse-transcriptase polymerase chain reaction (RT-PCR) test, their sensitivity to correctly detect positive cases is lower (Larremore et al., 2020).
Increased frequency of testing compensates for lower test sensitivity of POCTs (See et al., 2021; Larremore et al., 2020). The majority of policy guidelines and public health directives recommend basing frequency of POCT on rates of community transmission or outbreak status of the setting (Public Health Canada, 2021; Ontario Ministry of Long-term Care [LTC], 2021; CDC, 2021; Arizona Department of Health Services, 2020).
Recommended POCT frequency for screening asymptomatic individuals is 3 times per week of staff, including designated support persons, and residents if the home is in an outbreak situation and once per week of staff and designated support persons in a non-outbreak situation (Ontario Ministry of LTC, 2021; CDC, 2021; Larremore et al., 2020).
Designated support persons (i.e. family caregivers) should be tested at the same frequency as LTC staff (Ontario Ministry of LTC, 2021; Micocci et al., 2020; Vilches et al., 2020; Tennessee Department of Health, 2020).
Recommendations are consistent regarding test interpretation and follow-up actions, with the majority of policies and directives recommending a high degree of caution and follow-up RT-PCR testing after a negative POCT if there is a high pre-test probability for COVID-19 infection (i.e. symptomatic, known contact exposure)(Public Health Canada, 2021; CDC, 2021). All reviewed guidelines recommend confirmatory RT-PCR test following a positive POCT if the individual is asymptomatic in order to avoid unnecessary isolation of residents and work restrictions of staff. Contrary to other guidelines, the Oregon Health Authority (2020) considers all positive antigen tests in a symptomatic individual as a positive test regardless of follow up testing.
Modelling studies consistently show that regular POCT screening of asymptomatic staff and residents in LTC during both outbreak and non-outbreak situations results in significant decreases in projected cases when combined with a multipronged approach to prevent transmission (Larremore et al., 2021; Holmdahl et al., 2020; See et al., 2021; Vilches et al., 2020).
Barriers to frequency of testing are availability of test kits, training of testers, human resources for testing, and a reporting strategy (Micocci et al., 2020).
Prioritization of testing should be given to symptomatic healthcare providers and residents first, then screening for residents and staff during outbreaks (See et al., 2020).
The Saskatchewan Health Authority (SHA) Point of Care COVID Testing: Long Term Care Algorithm contains most of the elements present in other algorithms. Additional information should be added on actions taken for presumptive positive or negative tests in different scenarios. Additional information should be provided on frequency of testing and the context for “high-risk contact”.
Ward, H; Tupper, S; Dalidowicz, M; Mueller, M. What are the efficacies and outcomes of Point-of-Care/Antigen testing in Long Term care? 2021 Feb 26; Document no.: LTC020201 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 37 p. (CEST rapid review report)
· Studies suggest that antigen-based rapid diagnostic tests (Ag-RDTs) can be used in a population level with high prevalence of COVID-19 disease where health systems are overwhelmed or where nucleic acid amplification tests (NAATs) such as real time reverse transcription polymerase chain reaction (rRT-PCR) are not available.
· The Canadian COVID-19 Testing and Screening Expert Advisory Panel recommends the use of frequent screening with rapid diagnostic tests in selected groups to limit outbreaks.
· WHO and European Center for Disease Prevention and Control recommend using Ag-RDTs with high sensitivity and specificity when NAATs are not available or turnaround time negatively affects NAATs’ clinical utility. For example, COVID-19 Ag-RDTs can be used to surveil health care workers or residents of congregate dwellings during outbreaks or when community transmission rates are high, to screen at-risk individuals to support outbreak investigations, or to screen suspected COVID-19 outbreaks in early stages in settings where NAATs are not available.
· WHO does not recommend Ag-RDTs usage when expected prevalence is low (e.g., screening at points of entry) unless an Ag-RDT’s specificity is high (>99%).
· Studies have shown that Panbio™ COVID-19 Ag Test (Abbott) can have overall sensitivity of 72.6% to 95.2% and specificity of 98.0% to 100% and suggest that this test is appropriate for contagious case identification and asymptomatic case screening, especially in high prevalence (>5%) settings.
· WHO recommends that iterative Ag-RDT testing or confirmatory rRT-PCR testing be done in symptomatic patients or asymptomatic contacts of COVID-19 cases since a negative Ag-RDT result cannot completely exclude an active COVID-19 infection.
· Challenges of population level testing (whether they succeed or fail) such as required logistics and resources (e.g., immunizers, access to Ag-RDTs and equipment), performance accuracy of Ag-RDTs (e.g., false positive or negative rates in real world settings), and public trust and engagement in testing and future measures (e.g., vaccine uptake) are yet to be considered.
Generally speaking, data indicate that adult cancer patients and those who have recently received or are receiving anti-cancer therapy are at a higher risk of severe outcomes and death resulting from COVID-19 compared to those without cancer. However, more data are beginning to elucidate the nuances of these risks depending on patient specific factors.
Limited data indicate that pediatric cancer patients are not at a high level of risk of severe outcomes from COVID-19.
Limited evidence indicates some differences in the course and severity of SARS-CoV-2 infection depending on the type of immunosuppressive therapy a patient receives.
Key Findings
Generally speaking, data indicate that adult cancer patients and those who have recently received or are receiving anti-cancer therapy are at a higher risk of severe outcomes and death resulting from COVID-19 compared to those without cancer.
Pediatric cancer populations may not be at the same level of risk as adult populations.
There is not enough evidence at this time to determine if there are differences in the course of SARS-CoV-2 infection in patients receiving chemotherapy vs. those who are not aside from outcomes and severity.
Vanstone, J; Groot, G; Miller, L; Mueller, M. What are the differences in the clinical course of COVID-19 between patients undergoing chemotherapy and otherwise healthy individuals? 2021 Jan 22; Document no.: EOC062201v2 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 5 p. (CEST rapid review report)
· Diagnostic accuracy of tests for SARS CoV-2 varies based on the type of test, target antigen, type of sample and time of testing.
· There is heterogeneity in clinical performance of rapid antigen tests; however, clinical sensitivity is lower than amplification-based assays.
· Information is limited about test strategies that combine multiple approaches (e.g. molecular and serological methods) but may add value by increasing sensitivity and specificity.
Williams-Roberts, H; Waldner, C; Dalidowicz, M; Howell-Spooner, B. What is the accuracy of diagnostic tests for the detection of SARS-CoV-2? 2020 Jul 23; Document no.: EPM072101 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 13 p. (CEST rapid review report)
The majority of studies show elderly persons (>65 years) have significantly longer COVID-19 incubation periods compared to younger adults with a mean difference of +3.9 days (Lieu J et al. 2020; Kong TK et al. 2020; Jiang et al. 2020; Guo et al. 2020). One study showed no difference between those >60 years and younger patients (Lian et al. 2020).
Median incubation period across all studies (all ages) was 5 days (5.4 days mean). Jiang et al. (2020) report a mean incubation period of 7 days for younger adults and 10.9 days for those over age 65.
Upper limit of incubation period is 12-14 days with one study reporting 27 days (Nanda et al. 2020).
Median duration from symptom onset to death is 11.5 days in persons >70 years vs. 14 days in younger adults (Geriatric Emergency department collaborative March 2020).
Older age and more severe infections are associated with higher viral loads; however, viral shedding is not associated with infectivity. (European Centre for Disease Prevention and Control, 2020).
Doubling time of COVID-19 among residents from a single long-term care home was estimated to be 3.4 days compared to 5.5 days in the general population in the surrounding county (Arons et al. 2020).
Infected patients over the age of 65 years remain contagious for a significantly longer period (22 days vs. 19 days, p=0.015; Ziao et al. 2020).
Viral shedding may be longer for immune compromised patients (BC CDC 2020).
Symptom duration varies by nature of the symptom with a median time from diagnosis to discharge from hospital ranging from 13 days (range = 7-17; Ki et al. 2020) to 18.5 days (range = 11-27; Kim et al. 2020).
There is limited information on basic reproduction number in older adult populations. These values vary by region and over time. R0 values for whole populations (all ages) have been reported as low as 0.48 (Ki et al. 2020) to 2.5 (Lewnard et al. 2020)
Please see related reports by the Laboratory Working Group available in the SHA COVID-19 repository (not specific to elderly).
o LAB041601 RR Antibody development, viral shedding and infectiousness.
o LAB040701-01 RR Proportion of disease transmission due to asymptomatic, pre-symptomatic and symptomatic cases.
Tupper, S; Ward, H; Dalidowicz, M; Ellsworth, C. What is the incubation period, rate of spread, and duration of infectivity of COVID-19 in older adults? 2020 Jun 19; Document no.: LTC060202 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 28 p. (CEST rapid review report)
· A wide range of tests are available for detection of viral RNA as well as serological and immunoassays for antibodies developed due to exposure to SARS CoV-2 in infected persons. Despite the emerging research, information about clinical validity of tests is limited.
· Multiple factors affect test performance including the nature of the specific test, type of specimen and its quality, severity and duration of illness at the time of testing. These individual variations hamper assessment of diagnostic accuracy and suggest that a combination of tests on multiple types of specimens at serial time points might be needed to confirm a COVID 19 diagnosis.
· Point of care tests are desirable and needed to scale up testing in low resource settings; however, tests are of variable quality and more research is needed before they can be relied on for clinical decision making.
Notes
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Williams-Roberts, H; Waldener, C. What is the accuracy of diagnostic tests for COVID-19 detection? 2020 May 12; Document no.: EPM051201 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. (CEST rapid review report)
