|
Post by Admin on Apr 24, 2022 22:18:05 GMT
A new UK study of more than 2,000 patients after hospitalization with COVID-19 presented at this year's European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2022, Lisbon 23-26), and published in The Lancet Respiratory Medicine shows that, one year after having COVID-19, only around one in four patients feel fully well again. The study is led by Professor Christopher Brightling, Dr Rachael Evans, and Professor Louise Wain, National Institute for Health Research Leicester Biomedical Research Centre, University of Leicester, UK and colleagues.
The authors found that being female versus being male (32% less likely), having obesity (half as likely) and having had mechanical ventilation in hospital (58% less likely) were all associated with a lower probability of feeling fully recovered at one year. The most common ongoing long-COVID symptoms were fatigue, muscle pain, physically slowing down, poor sleep, and breathlessness.
This research used data from the post-hospitalization COVID-19 (PHOSP-COVID) study which assessed adults (aged 18 years and over) who had been hospitalized with COVID-19 across the UK and subsequently discharged. Patients from 39 UK National Health Service (NHS) hospitals were included, who agreed to five-month and 1-year follow-up assessments in addition to their clinical care. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge. The researchers also took samples of participants' blood at the five month visit to analyze it for the presence of various inflammatory proteins.
A total of 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (33%) participants completed both the 5-month and 1-year visits at the time of analysis (and the study is ongoing). These 807 patients had a mean age of 59 years, 279 (36%) were women and 28% received invasive mechanical ventilation. The proportion of patients reporting full recovery was similar between 5 months (501 [26%] of 1965) and 1 year (232 [29%] of 804).
In an earlier publication from this study the authors had identified four groups or 'clusters' of symptom severity at five months, which were confirmed by this new study at one year. Of the 2320 participants, 1636 had sufficient data to allocate them to a cluster: 319 (20%) had very severe physical and mental health impairment, 493 (30%) had severe physical and mental health impairment, 179 (11%) moderate physical health impairment with cognitive impairment, and 645 (39%) mild mental and physical health impairment. Having obesity, reduced exercise capacity, a greater number of symptoms, and increased levels of the inflammatory biomarker C-reactive protein were associated with the more severe clusters. In both the very severe and the moderate with cognitive impairment clusters, levels of the inflammatory biomarker interleukin-6 (IL-6) were higher when compared with the mild cluster.
Dr Evans says: "The limited recovery from 5 months to 1 year after hospitalization in our study across symptoms, mental health, exercise capacity, organ impairment, and quality-of-life is striking."
She adds: "We found female sex and obesity were major risk factors for not recovering at 1 year… In our clusters, female sex and obesity were also associated with more severe ongoing health impairments including reduced exercise performance and health-related quality of life at 1 year, potentially highlighting a group that might need higher intensity interventions such as supervised rehabilitation."
|
|
|
Post by Admin on Apr 25, 2022 18:32:10 GMT
Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study The PHOSP-COVID Collaborative Group
Introduction As of April, 2022, more than 500 million cases of SARS-CoV-2 infection have been reported worldwide,1 with 21·7 million cases in the UK2 and over 820 000 patients in the UK admitted to hospital for COVID-19. This population is at high risk of persisting health impairments 6 months after discharge associated with reduced physical function and health-related quality of life.3, 4 It is essential to understand both the longer-term trajectory of recovery to identify ongoing health-care needs and the required response by health-care systems and policy makers for this already large and ever-increasing population. Much remains unknown about the longer-term sequelae of COVID-19. In the largest cohort study to date from Wuhan, China, nearly half of patients had persistent symptoms 12 months after discharge from hospital for COVID-19.5 6–12 months after discharge, patients had no change in 6-min walk distance, but had some improvement in the results of pulmonary imaging.5 The mechanisms underlying long-term persistence of symptoms are unknown. A potential hypothesis is that the hyperinflammation associated with acute COVID-19 leads to a persistent inflammatory state following COVID-19, associated with dysregulated immunity and multiorgan dysfunction. Although multiple studies have highlighted increased inflammatory markers, including interleukin-6 (IL-6), associated with severity of acute illness,6, 7 no large studies have investigated the association between systemic inflammation and ongoing health impairments after COVID-19.
No effective treatments exist for long COVID or post-COVID-19 condition. Long COVID is defined by the National Institute for Health and Care Excellence (NICE) as ongoing symptoms beyond 4–12 weeks after COVID-19 and post-COVID-19 condition by WHO as occurring “in individuals with a history of probable or confirmed SARS CoV-2 infection, 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”.8, 9 Improved characterisation of this population with an emphasis on elucidating underlying mechanisms is needed to identify potential therapeutic targets. We previously described four clusters of patients according to clinical recovery (very severe, severe, moderate with cognitive impairment, and mild) defined by severity of ongoing physical health, mental health, and cognitive impairment 5 months after a hospital admission with COVID-19.3 We sought to answer the following questions using the ongoing post-hospitalisation COVID-19 study (PHOSP-COVID) longitudinal study cohort: first, what proportion of patients discharged from hospital with COVID-19 felt fully recovered 1 year later and what are the characteristics associated with non-recovery? Second, are there inflammatory mediators associated with severity of ongoing health impairments and therefore potential therapeutic targets? Third, are there differences in the trajectory of recovery at 1 year after discharge across different health domains and between our previously described clusters?
Methods Study design and participants Recruitment in the PHOSP-COVID multicentre, prospective cohort study has been described previously.3 In brief, we recruited patients aged 18 years and older who were discharged from 83 National Health Service (NHS) hospitals across the four UK nations following admission to a medical assessment unit or ward for confirmed or clinician-diagnosed COVID-19 before March 31, 2021. The current analysis involves participants who consented to attend two additional in-person research visits (tier 2, 39 sites; appendix p 16) within 1 year after discharge alongside routine clinical care. Written informed consent was obtained from all study participants. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107). Procedures Participants were invited to attend research visits at 2–7 months after discharge (5-month visit) and at 10–14 months (1-year visit). Participants were also able to attend a 1-year visit only if they were outside the time period for a 5-month visit at the time of consent and were discharged before Nov 30, 2020. The core set of data variables collected at each visit and included in this study are listed in the appendix (pp 17–18). These variables included baseline demographics, information about disease severity and treatment during their hospital admission, as well as symptoms using a bespoke study-specific questionnaire and other patient-reported outcome measures for anxiety (Generalised Anxiety Disorder 7-item scale [GAD-7]), depression (Patient Health Questionnaire-9 [PHQ-9]), post-traumatic stress disorder (Post-Traumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders [PCL-5]), fatigue (Functional Assessment of Chronic Illness Therapy—Fatigue [FACIT-Fatigue]), breathlessness (Dyspnoea-12), and health-related quality of life (EQ-5D-5L), physical performance measures including the short physical performance battery (SPPB) and the incremental shuttle walk test (ISWT), cognitive impairment using the Montreal Cognitive Assessment (MoCA), and pulmonary function tests and blood test results reflecting multiorgan function and systemic inflammation obtained at clinical and research visits (appendix p 17). Patients were also asked to complete the EQ-5D-5L, Washington Group Short Set Functioning (WG-SS) scale, and visual analogue scale for breathlessness and fatigue retrospectively to assess their perceived pre-COVID-19 health (appendix pp 17–18). Plasma samples obtained at the 5-month visit were analysed using the Olink Explore 384 Inflammation panel (Uppsala, Sweden). Sample processing and assay details are provided in the appendix (p 13).
The primary outcome for this analysis was patient-perceived recovery, assessed using a study-specific questionnaire and the question “Do you feel fully recovered?”; participants could answer “yes”, “no”, or “not sure”. Other secondary outcomes included symptoms since COVID-19 hospital admission that were collected on the bespoke study-specific questionnaire, validated patient-reported outcome questionnaires, and physiological measures (including physical performance and spirometry; appendix p 17). Statistical analysis Continuous variables were presented as median (IQR) or mean (SD). Binary and categorical variables were presented as n (%; by row or by column as indicated in table legends). Participants were stratified by patient-perceived recovery: yes (recovered), not sure, or no (not recovered).
Missing data were reported within each variable and per category. Within visit, a χ2 test was used to identify differences in proportions across multiple categories. To test differences across categories, ANOVA was used for normally distributed continuous data and Kruskal Wallis test for non-normally distributed continuous data. For paired data between the 5-month and 1-year visit, a McNemar's χ2 test with continuity correction was used for binary variables and a McNemar's χ2 test was used for variables with more than two levels. We used a paired t test for normally distributed continuous data and a Wilcoxon signed-rank test for non-normally distributed continuous data. As previously described,3 univariable and hierarchical multivariable logistic regression models (admission hospital included as random effect) were used to explore risk factors associated with patient-perceived recovery. Missing data were addressed using multiple imputation (ten datasets, ten iterations, and final models combined using Rubin's Rules), with the outcome used in imputation models, but not itself imputed.
To assess any potential bias as a result of patients not yet attending their 1-year visit at the time of analysis (Oct 6, 2021), we compared characteristics and patient-perceived recovery between those who attended a 1-year visit with those who had not yet attended but were discharged from hospital during the same range of dates. Multiple imputation was used to complete missing outcomes for participants who had not yet attended their 1-year follow-up. The imputation model used age, sex, ethnicity, index of multiple deprivation, and WHO clinical progression scale and all comorbidity variables. Ten datasets with ten iterations were created and combined using Rubin's rules.
In this cohort, we repeated our previous unsupervised cluster analysis3 of patient recovery, which was measured using symptom questionnaires (patient-reported outcome measures) and physical performance and cognitive assessment data (Dyspnoea-12, FACIT-Fatigue, GAD-7, PHQ-9, PCL-5, SPPB, and MoCA as continuous variables) from the 5-month visit (discharge dates March 7, 2020, to April 18, 2021) using the clustering large applications k-medoids approach.10 Scores were centred, normalised, and transformed so that higher burden of disease represented higher values. A Euclidean distance metric was used and the optimal number of clusters chosen using a silhouette plot. Cluster membership was determined for each individual using 5-month visit data. Characteristics at 1 year and change in characteristics between 5 months and 12 months are presented as cluster-stratified tables. All tests were two-tailed and p values of less than 0·05 were considered statistically significant. We did not adjust for multiple testing. Plasma protein concentrations were compared between clusters using the mildest recovery cluster as baseline and using multinomial regression with age, body-mass index (BMI), and number of comorbidities as covariates (appendix p 14). Significance was defined as a p value of less than 0·1 after false discovery rate adjustment for multiple testing. We used R (version 3.6.3) with the finalfit, tidyverse, mice, cluster, ggplot2, ggalluvial, radiant, dabestr, and recipes packages for all statistical analyses.
Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
|
|
|
Post by Admin on Apr 25, 2022 20:50:07 GMT
Results At the time of analysis (Oct 6, 2021), 2468 participants (discharged from hospital between March 7, 2020, and April 18, 2021) had attended a 5-month visit (median 5 months [IQR 4-6] after discharge, 148 [6·0%] of whom were excluded; figure 1). 924 (37·4%) participants (discharged Feb 28, 2020, to Nov 28, 2020) returned for a 1-year visit (13 months [12–13] after discharge) and 807 (32·7%) participants attended both visits (figure 1). The individual and hospital admission characteristics including severity of acute illness were similar between those who attended the 5 five-month visit, 1-year visit, and both visits, except for the proportion of patients who received acute treatment with corticosteroids (table 1). At 5 months, 1965 (84·7%) of 2320 patients, and at 1 year 804 (34·7%) patients, had both attended a research visit and answered whether or not they felt fully recovered (figure 1). At 5 months, 501 (25·5%) of 1965 patients felt fully recovered, with 385 (19·6%) feeling not sure and 1079 (54·9%) not recovered (figure 2A; appendix p 19). At 1 year, 232 (28·9%) of 804 patients felt fully recovered, 180 (22·4%) were not sure, and 392 (48·8%) were not recovered (figure 2A; appendix p 19). Similar proportions were observed in those with paired data (appendix p 22). The individual responses were also similar between 5 months and 1 year (appendix p 39). In multivariable analysis, female sex (odds ratio [OR] 0·68 [95% CI 0·46–0·99]), BMI 30 kg/m2 or greater (0·50 [0·34–0·74]), and receiving invasive mechanical ventilation (WHO category 7–9; 0·42 [0·23–0·76]) were all independent factors associated with being less likely to recover at 1 year (figure 2B; appendix p 25). We found no effect of receiving systemic corticosteroids (1·05 [0·66–1·65]) during the acute admission on patient-perceived recovery at 1 year for the whole cohort (figure 2B; appendix p 26). We also found no effect of time from discharge to the research visit (1·00 [1·00–1·01]). 751 participants discharged between Feb 28, 2020, and Nov 28, 2020, did not return for a 1-year visit but had similar characteristics and 5-month recovery status to the 924 participants who had attended (appendix p 27). The proportion of recovered patients was similar after imputation for outcome (499 [29·8%] of 1675). For the 5-month dataset, the previously identified four clusters3 were confirmed using participants with complete data for the cluster analysis (n=1636; figure 1). The distribution of the four clusters was very severe physical and mental health impairment (n=319 [19·5%]), severe physical and mental health impairment (n=493 [30·1%]), moderate physical health impairment with cognitive impairment (n=179 [10·9%]), and mild mental and physical health impairment (n=645 [39·4%]; appendix p 29). 664 (86·7%) of 766 individuals included in the previous study3 were reassigned to the same recovery cluster as before; the cluster of moderate with cognitive impairment had the most assignment alterations (60 [47·2%] of 127). Characteristics of individuals in each recovery cluster are shown in the appendix (p 30). Compared with the mild cluster, the very severe cluster had a higher proportion of women (165 [53·9%] of 306 vs 177 [28·4%] of 624) and obesity (BMI ≥30 kg/m2; 204 [70·8%] of 288 vs 288 [50·2%] of 568). After quality control, plasma proteome data for 296 protein features and complete clinical data for cluster assignment were available at 5 months for 626 participants: 111 (17·7%) in the very severe cluster, 173 (27·6%) in the severe cluster, 73 (11·7%) in the cluster moderate with cognitive impairment, and 269 (43·0%) in the mild cluster. Age, BMI, and two or more comorbidities were associated with cluster membership, whereas receiving invasive mechanical ventilation during the acute illness was not (analysis done in participants with plasma proteome data and a cluster assignment; appendix p 32). After adjustment for age, BMI, and comorbidity count, 13 proteins were significantly increased in participants in the very severe recovery cluster compared with those in the mild cluster (appendix p 33; figure 3). These proteins were trefoil factor 2 (TFF2), transforming growth factor α (TGFA), lysosomal associated membrane protein 3 (LAMP3), CD83 molecule (CD83), galectin-9 (LGALS9), urokinase plasminogen activator surface receptor (PLAUR), interleukin-6 (IL-6), erythropoietin (EPO), FMS-related receptor tyrosine kinase 3 ligand (FLT3LG), agrin (AGRN), secretoglobin family 3A member 2 (SCGB3A2), follistatin (FST), and C-type lectin domain family 4 member D (CLEC4D; appendix p 33). Additionally, IL-6 and CD70 molecule were significantly increased in the moderate with cognitive impairment cluster compared with the mild cluster (appendix p 34).
|
|
|
Post by Admin on Apr 25, 2022 21:32:30 GMT
The ten most common persistent symptoms at 1 year after discharge were fatigue (463 [60·1%] of 770 patients), aching muscles (442 [54·6%] of 809), physically slowing down (429 [52·9%] of 811), poor sleep (402 [52·3%] of 769), breathlessness (395 [51·4%] of 769), joint pain or swelling (382 [47·6%] of 803), slowing down in thinking (377 [46·7%] of 808), pain (359 [46·6%] of 770), short-term memory loss (360 [44·6%] of 808), and limb weakness (341 [41·9%] of 813; appendix p 35). Overall, symptoms were unchanged in prevalence from 5 months to 1 year, with small reductions in rates of limb weakness (47·6% at 5 months vs 41·7% at 1 year; p=0·010), paraesthesia (40·6% vs 35·2%; p=0·014), and balance problems (34·9% vs 30·0; p=0·0076). We found either no or minimal improvement in patient-reported outcome measures, physical function, cognitive impairment, or organ function at 1 year compared with 5 months after discharge (paired data in table 2 and presented stratified by patient-perceived recovery in appendix p 19). At 1 year, 147 [21·5%] of 684 patients had clinically relevant symptoms of anxiety, 169 (24·9%) of 680 participants had clinically relevant symptoms of depression, 68 (10·0%) of 680 had post-traumatic stress disorder, and 55 (8·8%) of 623 had significant cognitive impairment (table 2). Measures of symptoms and physical function were significantly different across participants who reported being fully recovered, not sure, or not fully recovered at 5 months and 1 year, but cognitive impairment and measures of organ function were not (except for forced vital capacity; table 2). Health-related quality of life was significantly different across participants who reported being fully recovered, not sure, or not recovered at both 5 months and 1 year (figure 2D; appendix p 19). In addition to higher proportions of women and obesity (appendix p 30), at 1 year the very severe cluster was associated with a lower proportion of patients who reported feeling fully recovered (4 [4·7%] of 86 vs 107 [49·1%] of 218; figure 2C; reduced exercise capacity [ISWT 44·4% predicted vs 72·4% predicted]; greater number of symptoms [20 vs 4]; and greater proportion of patients with increased C-reactive protein concentration >5 mg/L [38·4% vs 14·5%]) compared with the mild cluster (table 3; figure 4A). A comparison of health outcomes across the four clusters between the 5-month and 1 year timepoints (n=602) showed minimal change across the two timepoints for the four clusters (table 3). In the very severe cluster, symptoms of anxiety, depression, breathlessness, and fatigue significantly improved between 5 months and 1 year, but with minimal change in physical performance and no overall change in systemic inflammation measured by C-reactive protein concentration (table 3). Cognitive impairment significantly improved at 1 year in the moderate with cognitive impairment cluster and was unchanged in the other clusters (table 3). Compared with patient-perceived health before COVID-19, decrements were seen at 5 months and sustained at 1 year across health-related quality of life (EQ-5D-5L; figure 4B), disability (WG-SS), and severity of breathlessness and fatigue experienced in the past 24 h (appendix p 43). Discussion In adults admitted to hospital with COVID-19 in the UK, we found that a minority of participants felt fully recovered 1 year after hospital discharge, with minimal improvement after a 5-month assessment. The most common ongoing symptoms were fatigue, muscle pain, physically slowing down, poor sleep, and breathlessness. The major risk factors for not feeling fully recovered at 1 year were female sex, obesity, and receiving invasive mechanical ventilation during the acute illness. We found substantial impairments in health-related quality of life at 5 months and 1 year compared with retrospective self-reported scores before COVID-19. Cluster analysis using the 5-month assessments corroborated four different clusters: very severe, severe, moderate with cognitive impairment, and mild, which were based on the severity of physical, mental, and cognitive impairments with similar characteristics to those previously reported.3 We showed that obesity, reduced exercise capacity, a greater number of symptoms, and increased serum C-reactive protein concentration were associated with the more severe clusters.3 In the largest post-hospital cohort with systemic inflammatory profiling to date, inflammatory mediators consistent with persistent lung and systemic inflammation were increased in the very severe, moderate with cognitive impairment, and mild clusters. We therefore highlight traits to identify individuals at high risk of non-recovery and potential targetable pathways for interventions. Comparing the systemic inflammatory profiling at 5 months after discharge between the very severe and mild cluster, the most increased protein concentration, TFF2, is a protein released with mucin from mucosal epithelium including lung and gastric mucosa. TFF2 has postulated roles in repair of damaged epithelium11 and, in combination with interferon-κ, reduced duration of infection in a small open-label randomised controlled trial of patients with acute COVID-19.11 In a study6 of patients during acute illness with COVID-19 using Olink Proteomics, IL-6 was the most upregulated protein at day 7 among patients who developed acute respiratory distress syndrome (ARDS) and subsequently died. Similarly, other proteins that we identified such as LAMP3, Gal-9, and CD83 are involved in T-cell macrophage and dendritic cell activation and were associated with increased morbidity and mortality during acute COVID-19 infection.12, 13, 14 These changes suggest persistent mucosal epithelial abnormalities and inflammatory cell activation. Increased serum concentrations of the C-terminal fragment of agrin have been reported in older adults (aged age 65–87 years) with sarcopenia, possibly related to breakdown of the neuromuscular junction.15 The increased agrin concentrations seen here might therefore have contributed to the high prevalence of physical impairment. Interestingly, in the moderate with cognitive impairment cluster versus the mild cluster, IL-6 and CD70 concentrations were increased, suggesting possible neuroinflammation contributing to the cognitive impairment because CD70 has been implicated in inflammation in the CNS16 via a role in differentiation of proinflammatory pathogenic lymphocytes. We found small improvements at 1 year in cognition in the moderate with cognitive impairment cluster, indicating that some of this deficit was not pre-existing and is potentially modifiable; however, considerable deficit persisted at 1 year. The associations with the inflammatory mediators remained after adjusting for age, BMI, and number of comorbidities, and the proportion having received invasive mechanical ventilation was similar across the clusters—all factors known to be associated with systemic inflammation.17 Taken together, the increased mediators provide biological plausibility for the persistent severe impairments seen in physical health, mental health, and cognitive impairment after COVID-19. The limited recovery from 5 months to 1 year after hospitalisation in our study across symptoms, mental health, exercise capacity, organ impairment, and quality-of-life is striking. There are few similar detailed, prospective, longitudinal studies for patients hospitalised with COVID-19, but in this larger cohort we support those findings of minimal recovery.18, 19, 20 Although the large-scale study from Wuhan, China, suggests a greater magnitude of recovery compared with our findings, new-onset symptoms persisted in half of the patients (620 of 1272).5 Notably, the Wuhan cohort included a smaller proportion of patients with severe acute illness than ours did, with only 1% requiring invasive mechanical ventilation and 7% requiring high flow nasal oxygen or continuous positive airway pressure. The Wuhan cohort also had fewer pre-existing comorbidities and a higher proportion of never-smokers compared with patients in our study. In patients with non-COVID-19-related ARDS, little recovery in health-related quality of life is observed beyond 6 months after hospital discharge, but larger improvements in walking distance have been found21, 22 than we report following COVID-19 in our cohort, over 70% of whom did not receive invasive mechanical ventilation. In non-hospitalised patients after COVID-19, the proportion that develop long COVID appears to be lower than in those admitted to hospital with COVID-19.23, 24 The responses for patient-perceived recovery were discriminatory across all the patient-reported outcome measures and exercise measures, providing additional validity for this outcome measure. We found female sex and obesity were major risk factors for not recovering at 1 year, supporting results from smaller cohorts25 and non-hospitalised cohorts.26, 27, 28 Female sex was similarly associated with worse recovery for fatigue, mental health, and lung function at 12 months in the Wuhan cohort.5 In our clusters, female sex and obesity were also associated with more severe ongoing health impairments, including reduced exercise performance and health-related quality of life at 1 year, potentially highlighting a group that might need higher-intensity interventions such as supervised rehabilitation. Health-related quality of life before COVID-19 was substantially greater than at 5 months after discharge across all four clusters, indicating that the persistent burden of impaired physical and mental health is not simply explained by pre-existing morbidity. The total number and range of ongoing symptoms at 1 year was striking, positively associated with the severity of long COVID, and emphasises the multisystem nature of long COVID. Other studies have shown that the number of symptoms during the acute illness was associated with the likelihood of developing long COVID.29 Whether the number of ongoing symptoms—a simple, widely available measure—could underpin a future risk score deserves further attention. Taken together, we suggest that our data will help to inform decisions about patient stratification for follow-up after hospital discharge. We advocate a proactive approach because of the high proportion of patients who do not recover, highlighting the usefulness of a screening questionnaire to assess whether patients feel fully recovered; the total number of symptoms might be a guide to the intensity or complexity of care required. Similar to our 5-month data3, we highlight the need for a holistic assessment including mental health, physical function, and cognitive impairment. Any assessment of ongoing organ impairment will need to be further individualised. No specific therapeutics exist for long COVID and our data highlight that effective interventions are urgently required. Our findings of persistent systemic inflammation, particularly in those in the very severe and moderate with cognitive impairment clusters, suggest that these groups might respond to anti-inflammatory strategies. The upregulation of IL-6 suggests that anti-IL-6 biologics that were successful for patients admitted to hospital with COVID-1930 might also have a place in the treatment of long COVID. Similarly, activation of the urokinase-type plasminogen activator receptor pathway suggests that IL-1 activation might play a role, with soluble uPAR a biomarker in acute COVID-19 associated with good response to the recombinant IL-1 receptor antagonist anakinra.31 Impaired exercise capacity was also associated with the more severe clusters and showed minimal improvement at 1 year (below the minimum clinically important difference for other long-term conditions).32, 33, 34 Available therapies for some adults with long COVID include rehabilitation,35 but the optimal exercise prescription is contentious because of concerns of post-exertional symptom exacerbation. Our data suggest a high prevalence of musculoskeletal symptoms including muscle ache, fatigue, breathlessness, physically slowing down, and limb weakness.5, 16 This finding supports the need to investigate rehabilitation in combination with other therapies to improve skeletal muscle function, such as mitochondrial energetics, mitophagy enhancers, and drugs to combat cell senescence (associated with ageing). The concordance of the severity of physical and mental health impairment in long COVID highlights the need not only for close integration between physical and mental health care for patients with long COVID, including assessment and interventions, but also for knowledge transfer between health-care professionals to improve patient care. The finding also suggests the need for complex interventions that target both physical and mental health impairments to ameliorate symptoms. However, specific therapeutic approaches to manage post-traumatic stress disorder might be needed.36 With obesity being associated with both non-recovery and severity of long COVID, whether weight reduction using combined pharmacological and non-pharmacological approaches can ameliorate long COVID warrants further investigation. Beyond diet and lifestyle interventions, GLP-1 analogues have been reported to achieve clinically important weight reduction in adults.37 Our cohort study is ongoing, and we report these 1-year findings to help direct clinical care and further investigation. However, there are limitations. There will be selection bias for participants returning for a 1-year visit, although we have not found overt differences between the demographics or 5-month recovery status between attendees and non-attendees of the 1-year visit. Our cohort has a higher proportion of patients with COVID-19 requiring invasive mechanical ventilation than is typically seen in UK hospitals,38 and therefore our results might not be directly generalisable to the wider population. We also had a lower-than-expected proportion of women, which might mean that the wider population have worse outcomes than we report because women appear to have worse recovery. To reduce uncertainty of the effect of pre-existing illness, we asked participants whether they felt fully recovered (ie, back to their normal selves). We also asked participants retrospectively to estimate their pre-COVID-19 health status, including the most prevalent symptoms, disability, and health-related quality of life; we recognise that there might be recall bias. Data linkage to electronic patient records is in process but not currently available; therefore, in the current report, pre-existing comorbidities were self-reported and data regarding hospital admissions and mortality in the first year are unavailable. Our study suggests that persistent inflammation might underlie ongoing impairment in some participants; the specific mechanisms underlying this signal require further investigation and replication. We described several associations with more severe health impairments at 1 year. Our findings cannot confirm causality but suggest that these associations should be further investigated as part of mechanistic studies and clinical trials. Our results require interpretation in the context of the COVID-19 pandemic. Our 1-year findings included patients discharged from hospital in 2020 and therefore would not include those infected with newer SARS-CoV-2 variants such as B.1.1.529 (omicron) and included patients who would not have been vaccinated before contracting COVID-19. Although our data are relevant to patients discharged under similar conditions, further research is needed to understand the effect of current acute care, newer SARS-CoV-2 variants, and vaccination status before and after contracting COVID-19. In summary, our study highlights an urgent need for health-care services to support this large and rapidly increasing patient population in whom a substantial burden of symptoms exists, including reduced exercise capacity and large decrements in health-related quality of life 1 year after hospital discharge. Without effective treatments, long COVID could become a highly prevalent new long-term condition. Our study also provides a rationale for investigating treatment strategies for long COVID with a precision-medicine approach to target treatments to the relevant phenotype to restore health-related quality of life.
|
|