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12th October 2021
The presence of continued symptoms after resolution of an acute infection with COVID-19 has become recognised and termed “Long-COVID“. For example, in one study, symptoms including fatigue or muscle weakness and sleep difficulties were the most common symptoms 6 months after the initial infection. Moreover, one small study with 83 patients, found that even after 12 months, radiological lung changes persisted in a quarter of patients. However, to date, there are no specific tools for an assessment of the ongoing symptom burden of COVID-19 although some evidence suggests that the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) may be of value. The CAT has been shown to provide some insight into the severity of symptom burden for patients following a hospitalisation for COVID-19 and might be of use in the assessment of ongoing symptoms following COVID-19.
In an attempt to determine the outcomes and symptom burden of patients with Long-COVID, a team from the Department of Respiratory Medicine, Daping Hospital, Chongqing, China, invited all adult patients with COVID-19 discharged from two hospitals in Wuhan, between February and April 2020, to participate in the follow-up study. Enrolled participants were interviewed by telephone and asked a series of questions on persistent symptoms as well as the CAT questionnaire, for which a score of 10 or more indicates a medium disease impact. Clinical and demographic data on each of the patients was obtained from electronic hospital records.
A total of 2,433 patients with a median age of 60 years (49.5% male), of whom, 27.9% had severe COVID-19 infection, were included in the analysis. At the one-year follow-up, 1338 (55%) of patients were completely symptom-free, with the remaining 45%, reporting at least one symptom. In addition, a patients hospitalised with more severe disease were more likely to report persistent symptoms (odds ratio, OR = 1.31, 95% CI 1.04 – 1.65, p = 0.02). The most common one-year follow-up symptoms were fatigue (27.7%), sweating (16.9%) and chest tightness (13%). The presence of fatigue was also more likely in those with a higher initial disease severity (OR = 1.36, 95% CI 1.10 – 1.68).
Among the 2,433 participants, the median CAT score was 2 although 6.6% had a CAT score greater than 10. As with persistent symptoms, more patients with severe infection had a CAT score > 10 (11.6% vs 4.7%, p < 0.01, severe vs non-severe infection). Furthermore, higher disease severity and co-existing cerebrovascular disease, were independent predictors of a CAT score > 10 (OR = 1.95, 95% CI 1.07 – 3.54, p = 0.03).
The authors concluded that their findings provided valuable information about the long-term health outcomes of COVID-19 survivors and risk factors for sustained symptoms and poor respiratory health status.
Zhang X et al. Symptoms and Health Outcomes Among Survivors of COVID-19 Infection 1 Year After Discharge From Hospitals in Wuhan, China. JAMA Netw Open 2021.
23rd August 2021
Symptoms including fatigue, dyspnoea have been identified in those with long COVID though the underlying pathophysiological mechanisms responsible for the symptoms of long COVID are yet to be determined. One clinical feature in patients after their acute COVID-19 infection, is the presence of an elevated D-dimer level in just over a quarter (25.3%) of hospitalised patients some 4 months later though this was also observed in non-hospitalised COVID-19 patients. Several autopsy studies of patients who died of COVID-19 have revealed the presence severe endothelial damage and widespread vascular thrombosis, raising the possibility that this higher incidence of thromboembolic events might be due to a COVID-19-induced coagulopathy. In fact, autopsies have revealed how thrombosis is a prominent feature in multiple organs, despite full anticoagulation. Furthermore, a systemic analysis of 41 autopsies demonstrated the presence of endothelial dysfunction as evidenced by expression of markers of endothelial damage and concluded that COVID-19 infection largely occurs in the lungs. Further support for the notion that endothelial dysfunction is an important contributor to COVID-19 comes from a single centre study that observed elevation of markers associated with such dysfunction e.g., von Willebrand Factor (VWF) antigen, were significantly higher among intensive care patients.
These autopsy findings led a team from the Irish Centre Vascular Biology, Royal College of Surgeons, Dublin, Ireland, to speculate that the presence of persistent endothelial cell activation may be a contributing factor or even underlying cause for long COVID. The team enrolled patients from a post-COVID-19 review clinic at a single hospital, a minimum of 6 weeks after symptom resolution in both hospitalised and non-hospitalised patients. Plasma samples were analysed for several markers of endothelial dysfunction including VWF antigen, VWF propeptide, Factor VII activity and soluble thrombomodulin.
A total of 50 patients with a mean age of 50 years, the majority of whom (74%) had been hospitalised because of their infection, were assessed a median of 68 days after acute COVID-19 symptom resolution. Thrombin lag times (which is a measure of clotting time) were significantly shorter in symptomatic patients compared with healthy, non-hospitalised controls (6.2 minutes vs 8.2 minutes, p < 0.0001). There were also significantly higher endogenous thrombin potential and peak thrombin levels in hospitalised patients. However, these pro-thrombotic changes were found to be independent of acute infection phase markers such as C-reactive protein, which had normalised. In addition, endothelial dysfunction biomarkers such as VWF antigen were also elevated in hospitalised patients compared with controls.
In discussing their findings, the authors speculated that this sustained endothelial cell activation, as evidenced by elevated markers of endothelial dysfunction up to 10 weeks after resolution of the acute COVID-19 symptoms, could help explain the symptoms of long COVID. They concluded that further work is required to determine if this sustained endothelial cell activation has a role in the pathogenesis of long COVID.
Fogarty H et al. Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome. J Thromb Haemost 2021
3rd August 2021
While early in the COVID-19 pandemic, there was considerable focus on mortality, an emerging theme has been the presence of prolonged symptoms, even among those with mild disease and which has been termed long COVID. However, a precise definition of long COVID has remained elusive and a wide range of symptoms have been ascribed to the condition. In the US, the Centers for Disease Control and Prevention have preferred the term “post-COVID conditions”, as an umbrella term for the wide range of health consequences that are present four of more weeks after infection with the virus. In trying to more clearly define the patient experience and recovery process, a team from Sainsbury Wellcome Centre, University College London, UK, conducted an online survey among those who have suffered with long COVID symptoms. The aim was to better understand the lived experience with an emphasis on symptom trajectory and severity over time and the return to baseline. The research team worked closely with a patients who had themselves suffered with COVID-19 and who helped to create the survey. In addition, the researchers worked with a number of other patients to compile the list of symptoms and questions related to how long COVID symptoms impacted on daily life. The final survey included 257 questions that required over an hour to complete although respondents were permitted up to 30 days to complete it. Though created in English, the questionnaire was translated into several other languages including Spanish, French, Portuguese, Italian, Dutch and Russian. It was distributed via support groups e.g., Body Politic, Long COVID Support Group and social media, e.g., Twitter, Facebook and data collected between September 2020 and November 2020. The team quantified disease duration, severity and symptom prevalence and respondents were asked to indicate the number of days that each of a listed number of symptoms persisted.
There were 3,762 usable responses received from predominately women (78.9%), of white ethnicity (85.3%) with the highest proportion (31%) aged between 40 and 49 years. Overall, 91.9% of respondents answered the questions in English. For the complete cohort, 2454 individuals (65%) experienced symptoms which lasted for at least six months and the authors calculated the probability of symptoms lasting beyond 35 weeks as 91.8%. Symptoms affected 10 different organ systems and the most frequent still present after 6 months were fatigue (>95%), post-exertional malaise (approx. 90%) and cognitive dysfunction (88%). Moreover, 85.9% of respondents experienced a relapse of long COVID symptoms often triggered by exercise (70.7%), mental activities (46.2%) and stress (58.9%) and 45.2% had to reduce their work schedule because of symptoms.
Commenting on these findings, the authors reported on how long COVID symptoms appeared to be a heterogenous mix affecting many different organ systems. The authors also felt that the morbidity of COVID-19 has often been greatly overlooked and created a hugely negative impact upon sufferers’ quality of life, highlighting the need for multidisciplinary research to develop effective treatments.
Davis HE et al. Characterising long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine 2021.
25th June 2021
The presence of continued symptoms after an acute infection with COVID-19 or long COVID has become increasingly recognised and accepted. Typically, reported long covid symptoms have been varied and included fatigue, brain fog, sleep difficulties, myalgia and headaches. But could these symptoms be due to something else and not simply a systemic reaction to infection with the virus? This was the question posed by a team from the World Health Organization in a retrospective study of patients who presented with long covid. The team proposed that reactivation of the Epstein-Barr virus (EBV) might be a potential cause of long COVID symptoms.
The EBV is a ubiquitous virus, infecting approximately 90% of the worldwide population and 95% of healthy adults. Moreover, symptoms of EBV are known to include fatigue, brain fog, myalgia and headaches. Using online adverts, the team sought to recruit patients aged 21 years and over, who had recovered from COVID-19. In an effort to minimise bias, potential subjects were informed that the purpose of the study was to collect data related to their experience of having COVID-19 and nothing else. The researchers then divided subjects into two groups of long-term and short-term sufferers. In each of the two cohorts, one arm included symptomatic individuals, i.e., those reporting one or more recognised long COVID symptoms and the second arm served as a non-symptomatic control group. Both long-term group arms included those who had tested positive for COVID-19 at least 90 days prior to enrolment, whereas in the short-term group, participants had tested positive for the virus 21 – 90 days prior to enrolment. All subjects provided blood samples for analysis that were tested for markers of EBV infection which provided evidence of viral reactivation.
A total of 185 participants provided evidence of confirmed COVID-19 infection, of whom nearly a third (30.3%) reported continued covid symptoms at least 30 days after their positive test. There were 50 participants in the long-term COVID group (30 symptomatic) with an overall mean age of 43.8 years (76.7% female). There were 18 subjects (9 per group) in the short-term covid group with a similar age (70% female).
Among the symptomatic long-term group, 66.7% had evidence of EBV reactivation based on antibody titre levels compared to 10% in the control group and this difference was significant (p < 0.001). Similarly, among the short-term, symptomatic covid group, roughly two-thirds (66.7%) showed evidence of EBV reactivation with only one case in the short-term control group, which was also significant (p = 0.05).
Commenting on their findings, the authors suggested that while it was not possible to determine when EBV reactivation occurred, the presence of measurable antibody titre levels of the virus in those who were symptomatic with long covid, tentatively suggested that the infection with COVID-19 could reactivate EBV and this should be considered as a cause in a proportion of those with long COVID.
Gold JE et al. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens 2021
9th April 2021
The continuation of symptoms after infection with COVID-19 (colloquially termed ‘long COVID’) has been seen in many patients. Rather than a single entity, long COVID includes a number of symptoms including fatigue, headache and upper respiratory complaints such as shortness of breath and sore throat and in the UK, NICE has already issued guidance on the management of the long-term effects of infection. As a part of the ongoing COVID-19 infection, survey, the Office for National Statistics (ONS) has, since February 2021, asked respondents if they would “describe yourself as having ‘long COVID”, that is, you are still experiencing symptoms more than 4 weeks after you first had COVID-19, that are not explained by something else?”. In cases where someone answers yes, they are then asked “Does this reduce your ability to carry-out day-to-day activities compared with the time before you had COVID-19?”. Possible answers include “yes, a lot”, “yes, a little” and “not at all”. A limitation of this method of data collection however, is that the responses are self-reported rather than being clinically diagnosed as symptomatic post-COVID syndrome.
According to the ONS data, over the 4-week period ending on 6 March 2021, an estimated 1.1 million people in private households in the UK were experiencing long COVID. Interestingly, among those with long COVID, 697,000 were infected at least 12 weeks earlier, 473,000 6 months earlier and 70,000 more than a year ago. Among those with self-reported long COVID, the majority (91.2%) reported experiencing at least one symptom at the time of their infection with the most commonly reported symptoms lasting for at least 12 weeks being fatigue (8.3%), headache (7.2%) and cough (7%). In addition, approximately half (50.6%) of those with long COVID had more mild and were not hospitalised.
In terms of the impact, 61.6% of those with long COVID reported that it causes some limitation in day-to-day activities and 17.9% stated that their day-to-day activities had been limited a lot. The highest prevalence of long COVID after 12 weeks was among those aged 25 to 34 (18.2%) and lowest in the 2 to 11 years age band (7.4%).
Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 1 April 2021