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About this publication
Most people will experience COVID-19 as a mild and transient disease, although some may experience a prolonged period with symptoms before recovery. Long-term and nonspecific symptoms have previously been reported following other viral infections, and it is thus not surprising that some patients experience long-term symptoms after COVID-19. It is also known that people who are admitted to the intensive care unit due to severe lung failure caused by other diseases than COVID-19, can report long-term functional impairments such as impaired cognitive function and reduced lung function after discharge.
In this rapid review, we summarise research on the proportion of patients who get long-term symptoms, which long-term symptoms occur after COVID-19, how long the symptoms persist and which patient groups that have the greatest risk of experiencing long-term symptoms.
This rapid review “COVID-19: Post COVID-19 condition” is the 2nd update in the series “COVID-19: Long-Term Effects of COVID-19” replacing our previous report published on August 10th, 2021. In this review, we included controlled studies with more than 100 laboratory test positive COVID-19 cases, as well as uncontrolled studies with more than 500 laboratory test positive COVID-19 cases and a follow-up time of six months or longer. We excluded studies mainly reporting on laboratory or radiological findings and uncontrolled studies that had not been peer-reviewed.
The findings are based on systematic searches in MEDLINE and WHO Global research on coronavirus disease (COVID-19) database on October 29th, 2021. One researcher screened the search results. Two researchers selected studies for inclusion and summarised study findings. Experts in the field assisted with study inclusion and provided input during the review process.
We assessed included studies in terms of quality and risk of bias using the NIH Quality Assessment Tool for Case-Control Studies and Observational Cohort and Cross-Sectional Studies. Meta-analysis was not feasible; therefore, we present the results of this rapid review narratively, supplemented by tables and graphics.
Characteristics of included studies
Nine controlled studies met the inclusion criteria, two of which were not peer-reviewed and only published as preprints. Four studies compared SARS-CoV-2-positive versus -negative subjects from the general population, and two studies included a group of influenza patients as controls. Most studies reported outcomes available from registries and medical records, such as hospital stay and health care use. Two studies collected self-reports of sequelae symptoms, and two studies used standardised questionnaires to assess specific symptoms or conditions. The size of the included COVID-19 populations ranged from 291 to 273 618 participants. In addition to the nine controlled studies, we identified eleven eligible uncontrolled studies providing additional information about typical symptoms and symptom burden. The uncontrolled studies mostly included patients hospitalised with non-critical COVID-19, but all studies also included some patients from ICU wards (up to 29% in one study). Three studies included a mixed population of hospitalised and non-hospitalised patients. Study population size ranged from 518 – 8679 participants. One study included only children, the others mainly middle-aged adults. Our quality assessment indicated that all included studies were of good to fair quality. All studies used laboratory testing to diagnose COVID-19, mainly PCR.
Symptoms around six to 12 months follow-up
Patients admitted to the hospital with COVID-19 seem to be at higher risk of subsequent hospital admissions, new diagnoses, and self-reported symptoms at follow-up than those not hospitalised or SARS-CoV-2-negative controls. Health-related quality of life (HRQoL) seemed to be lower in previously hospitalised COVID-19 patients than in the general population, although only compared in one controlled study. As compared with a cohort of hospitalised influenza patients, patient with severe COVID-19 requiring hospitalisation had a higher number of symptoms and longer durations of symptoms. The difference in symptom burden between non-hospitalised influenza patients and patients with mild COVID-19 (non-hospitalised) was less pronounced, as seen in other studies not finding differences in new hospital admissions between patients with mild/moderate COVID-19 disease and general population controls. Some uncontrolled studies showed good improvement of symptoms over time, a trend not clear in all studies at an average of eight months follow-up. Only Children remain little studied but appear much less commonly affected by long-term symptoms.
Overview of grouped signs and symptoms around six to 12 months follow-up
Visualisation of granular data on reported symptoms by ICD symptoms groups of twelve studies with mainly hospitalised patients revealed the broadest range of prevalence of symptoms among General symptoms. Symptoms under the General, Neurological and Pulmonary ICD symptom blocks were most prevalent (see Appendix 2 for list of symptom groups and symptoms). Uncontrolled studies and studies with fewer participants appeared to report more extreme values. The Neurological symptom block stands out with the largest variety of symptoms, and most frequently reported symptoms.
Predicting factors for long-term symptoms
Across four uncontrolled and one controlled study analysing predicting factors for length of symptoms, female sex was the most consistent variable associated with duration of symptoms, independent of hospitalisation status. In addition, severity of COVID-19, multiple symptoms at diagnosis, and prior comorbidities were also correlated with length of symptoms.
Most studies assessing self-reported symptoms included initially hospitalised COVID-19 patients. The studies with mixed populations were mostly based on registry data lacking information on less severe symptoms that do not require medical attention. It is therefore uncertain how long less severe symptoms persist in people with mild to moderate COVID-19. Few studies reported on health-related quality of life. Although COVID-19 patients seemed to score lower on these outcomes than the general population, the effect of COVID-19 on health-related quality of life remains uncertain due to limited evidence.
Our findings continue to reflect studies conducted early in the pandemic, and we assume that therapeutic advancements, and vaccination may impact outcomes in the future and lead to milder disease and potentially a lower prevalence of long-term symptoms. The heterogeneity across studies impairs direct comparison of risk estimates, and hence meta-analysis was not feasible. It should be noted that causal relationships cannot be confirmed or refuted based on the included study designs. Large, controlled studies including SARS-CoV-2 test negative and positive participants (vaccinated and unvaccinated) from the general population, questionnaires, clinical measurements, and health-related quality of life are needed to assess the proportion affected by long-term symptoms, as well as type, duration, clustering, and severity of symptoms among people with initial mild to moderate COVID-19.
Severe COVID-19, requiring hospitalisation or intensive care treatment, correlates with more symptoms after six to 12 months. The range of long-term symptoms for hospitalised patients is widest, with General, Neurological and Pulmonary symptoms the most common. Women stand out with a higher risk for developing long-term symptoms. Many patients who have had moderate COVID-19 (non-hospitalised) report prevailing symptoms six to 12 months after infection, but controlled studies now show that many of these symptoms are also reported by uninfected controls. For patients who have had mild covid-19, there may appear to be an increase in some self-reported symptoms, but the symptoms are less pronounced than for patients who have been moderately or severely ill. The extent of long-term impact of mild or moderate COVID-19 on the quality of life in the general population remains unclear, as most studies included patients with severe COVID-19.