Long COVID: Only 1 Out Of 4 Hospitalized COVID-19 Patients Feeling Fully Recovered After One Year

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A new study by researchers from the  PHOSP-COVID Collaborative Group which is a consortium of over 168 researchers focused on Long COVID research and which is led by the National Institute for Health Research Leicester Biomedical Research Centre, University of Leicester-UK has found that Long COVID is more predominant than though with only 1 out of 4 hospitalized COVID-19 patients feeling fully recovered after one year.

The study findings were published in the peer reviewed journal: The Lancet Respiratory Medicine. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00127-8/fulltext

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 study 6 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.

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