Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study

Abstract

Background: No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.

Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.

Findings: 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7-9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46-0·99]), obesity (0·50 [0·34-0·74]) and invasive mechanical ventilation (0·42 [0·23-0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74-1·00]), at 5 months (0·74 [0·64-0·88]) to 1 year (0·75 [0·62-0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.

Interpretation: The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

Funding: UK Research and Innovation and National Institute for Health Research.

Figure 1

Study profile

Figure 2

Patient-perceived recovery at 1 year (A) Compared with patient-perceived recovery at 5 months. (B) Risk factors for being less likely to recover. (C) Compared according to the four clusters. (D) Compared with health-related quality of life (assessed by the EQ-5D-5L utility index). WHO clinical progression scale classes are as follows: 3–4 indicates no continuous supplemental oxygen needed; 5 indicates continuous supplemental oxygen only; 6 indicates continuous positive airway pressure or bi-level positive pressure ventilation or high-flow nasal oxygen; and 7–9 indicates invasive mechanical ventilation or other organ support. The forest plot of the patient and admission characteristics associated with patient-perceived recovery at 1 year used multivariable logistic regression and multiple imputation. EQ-5D-5L score before COVID-19 was retrospectively completed by participants. BMI=body-mass index.

Figure 3

Volcano plots representing multinomial regression association results for comparison of 296 proteins between the four clinical phenotypes Results corrected for age, body-mass index, and number of comorbidities, comparing 296 proteins between very severe physical and mental health impairment and mild physical and mental health impairment clusters (A), severe physical and mental health impairment and mild physical and mental health impairment clusters (B), and moderate physical health impairment with cognitive impairment and mild physical and mental health impairment clusters (C). The red horizontal line represents an unadjusted p<0·05 threshold. Proteins that were significantly differentially expressed (compared with the reference mild cluster) after FDR adjustment are indicated in red; FDR cutoff used was 0·1. FDR=false detection rate.

Figure 4

Characteristics associated with the four recovery clusters (A) Patient characteristics, CRP concentration, exercise performance, and symptom count across the four clusters (error bars indicate IQR). (B) Health-related quality of life across the four clusters assessed before hospitalisation (patient estimate), and at 5 months and 1 year after discharge. EQ-5D-5L utility index stratified by cluster and pre-hospital health status assessed retrospectively. Very severe indicates the very severe physical and mental health impairment cluster, severe indicates the severe physical and mental health impairment cluster, moderate with cognitive indicates the moderate physical health impairment with cognitive impairment cluster, and mild indicates the mild physical and mental health impairment cluster. BMI=body-mass index. CRP=mean C-reactive protein concentration assessed at 1 year. IMV=invasive mechanical ventilation. ISWT=incremental shuttle walk test distance percentage predicted assessed at 1 year. *Median number of symptoms at 1 year.