A case definition for long COVID has yet to be adopted but is referred to by the WHO as “usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis”; the CDC considers persistent symptoms, or the onset of long-term symptoms, =4 weeks after acute COVID-19 infection.
Many studies and systematic reviews refer to COVID-related symptoms that persist or emerge beyond 4 weeks of infection as consisting of two subsequent phases: 1) 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.
Post Acute Sequalae of COVID (PASC) is often referred to in studies and systematic reviews and is commonly understood as “the presence of at least 1 abnormality diagnosed by (1) laboratory investigation, (2) radiologic pathology, or (3) clinical signs and symptoms that were present at least 1 month after COVID-19 diagnosis or after discharge from the hospital”. It can be further classified as short-term PASC as 1 month; intermediate-term, 2 to 5 months; and long-term, as 6 or more months after COVID-19 diagnosis or hospital discharge.
In previous reviews, we have referred to “long COVID” synonymously to the above terms (ie. OSC, PCS, PASC) but for clarity, will move toward using these specific terms as they appear in the literature as well as simply using the time frames reported in each study/review. For example, where needed, we have replaced “long COVID” with the more concise “PASC” or “symptoms beyond 4 weeks of infection”.
Recommendations set out in our 2021 report can be relied upon with an important update to follow-up times (previously 2-3 months). Now, a 4-week follow-up is recommended for diagnosing and managing any PASC, especially for patients who suffered severe acute COVID-19 manifestation, where severe typically refers to those requiring medical attention, such as hospitalization for respiratory difficulty, to manage symptoms during the acute phase. In addition, these follow-ups should include mental health assessments in addition to any relevant clinical testing in response to each patient’s specific symptoms.
The clinical care burden of ongoing COVID-19 symptoms (OCS) is significant in the 3 months after infection and can place great demands on primary care services. Both OSC and PCS have consistently been shown to affect a large portion of the population with complex and persistent challenges that will also place strain on healthcare systems. This involves:
o Complications pertaining to multiple care specialties, with 20-75% of individuals reporting at least 1 persistent symptom 12 or more weeks following COVID-19 diagnosis.
o Neuropsychiatric manifestations (or “NeuroCOVID”) such as smell/taste disorder, memory complaints, anxiety, depression, post traumatic stress disorder (PTSD), concentration difficulties, and sleep disturbances are reported in 20-50% of individuals beyond 4 weeks from infection.
Functional disabilities and incapacity to return to work has been reported in 5% to 90% of individuals, where some are unable to reach their pre-COVID employment level at 12 weeks or longer post-infection; this has the potential to impact all sectors, including various levels of healthcare.
A significant number of individuals suffer from severe clinical conditions, such as acute cardiac, lung, and kidney injury.
A key focus will be to support individuals and populations who experience other persistent yet less severe conditions and symptoms such as fatigue, dyspnea, and mental health challenges including depression, anxiety, and sleep disorders.
July 12, 2021
Long COVID-19 is likely to increase demands across the health system, including emergency departments, hospital admissions, primary care visits, specialist appointments, and home care and rehabilitation services.
The clinical care burden of long COVID-19 is the greatest in the first 3 months after infection (revised from ‘testing’ in the previous report) 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 after the infection) on specialist care due to respiratory, circulatory, endocrine, metabolic, psychiatric and unspecified conditions.
Groot, G; Reeder, B; Hammond, B; Badea, A; Howell-Spooner, B; Ellsworth, C. What are long COVID's demands on the healthcare system, and its severity of the illness? 2022 Jun 20, Document no.: EPM210602v002 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2022. 23 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 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.
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.
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).
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.
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).
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.
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)
Williams-Roberts, H; Groot, G; Dalidowicz, M; Young, C; Mueller, M. What are the risk factors for severity and death associated with COVID-19? 2020 May 17; Document no.: EPM050901 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 14 p. (CEST rapid review report)
Vanstone, J; Reeder, B; Duncan, V. What is the relationship between antibody development and viral shedding and infectiousness? 2020 May 19; Document no.: LAB041601v2 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 5 p. (CEST rapid review report)
COVID-19 is primarily transmitted by symptomatic patientsand presymptomatic individuals.·Moderate grade evidence estimates that approximately 20% of COVID-19 transmission may bedue to that from presymptomatic individuals.However, estimates range from 6.4% -47%.·Asymptomatic individuals and environmental contaminationappear to contributelessto disease transmission,with estimated proportionsof 6% and 10%, respectivelyfrom modelling studies
Wang, H; Reeder, B; Howell-Spooner, B; What proportion of disease transmission is due to asymptomatic, pre-symptomatic and symptomatic cases? 2020 May 8; Document no.: LAB040701v2 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 12 p. (CEST rapid review report)
Vanstone, J; Reeder, B; Duncan, V. At what time in the disease timeline of COVID-19 do antibodies develop? 2020 Apr 15; Document no.: LAB041402 RR. In: COVID-19 Rapid Evidence Reviews [Internet]. SK: SK COVID Evidence Support Team, c2020. 4 p. (CEST rapid review report)
Low grade evidence shows IgG and IgM antibody response correlates with neutralizingantibody titerand viral clearance, which is suggestive of protective humoral immunity inCOVID-19 patients with mild to moderate symptoms.
There is no available evidence with which to estimate the durability of this protective response. However, if the immune response to SARS-CoV-2 resembles that toward SARS-CoV, this protective humoral immunity may persist for several years.
Higher IgG antibody titersand a robustresponse were noted in severe to criticallyill patients and were associated with lower viral clearance and a worse clinical prognosis.
Low grade evidence suggests that convalescent plasma treatment may improve the clinical status of critically ill COVID-19 patients(one case series with only five patients enrolled).