Long COVID: What factors contribute to the risk?

Only a minority of patients are considered fully recovered 1 year after being discharged from hospital due to COVID-19, with women and obese individuals at increased risk of long COVID, according to results of the prospective PHOSP-COVID* study presented at ECCMID 2022 and published in The Lancet.

“[O]ur study highlights an urgent need for healthcare services to support this large and rapidly increasing patient population in whom a substantial burden of symptoms exists,” said the researchers.

Participants were 2,320 adults who were admitted to hospital for COVID-19 in the UK and discharged between March 7, 2020 and April 18, 2021. Post-hospitalization recovery was assessed 5 months and 1 year post-discharge. All patients completed the 5-month assessment. A total of 807 patients (32.7 percent) completed both assessments (mean age 58.7 years, 35.6 percent female). About 28 percent had received invasive mechanical ventilation.

Full recovery, based on patient-reported outcome measures, physical performance, and organ function, occurred in a minority of patients and was comparable at 5 months and 1 year (25.5 and 28.9 percent of patients, respectively). [ECCMID 2022, session SY114; Lancet Respir Med 2022;doi:10.1016/S2213-2600(22)00127-8]

At 1 year, women were less likely to report full recovery (odds ratio [OR], 0.68, 95 percent confidence interval [CI], 0.46–0.99), as were individuals who were obese (BMI ≥30 kg/m²; OR, 0.50, 95 percent CI, 0.34–0.70) and those who required invasive mechanical ventilation (OR, 0.42, 95 percent CI, 0.23–0.76). Receipt of systemic corticosteroids at acute admission had no bearing on patient-perceived recovery at 1 year (OR, 1.05).

At 1 year post-discharge, the most common persistent symptoms were fatigue (60.1 percent), aching muscles (54.6 percent), physically slowing down (52.9 percent), poor sleep (52.3 percent), breathlessness (51.4 percent), joint pain or swelling (47.6 percent), slowing down in thinking (46.7 percent), pain (46.6 percent), short-term memory loss (44.6 percent), and limb weakness (41.9 percent). Symptom prevalence was generally unchanged between the 5-month and 1-year assessments, with minor decreases in limb weakness, paraesthesia, and balance issues.

Recovery by severity

Clinical recovery was previously categorized according to four clusters – mild, moderate with cognitive impairment, severe, and very severe – based on severity of physical and mental health and cognitive impairment at 5 months post-hospitalization.

There were more women in the very severe compared with the mild cluster (53.9 percent vs 28.4 percent) and more obese patients (70.8 percent vs 50.2 percent).

“[This result highlights] a group that might need higher-intensity interventions such as supervised rehabilitation,” said the researchers.

At 1 year, there were fewer patients who reported full recovery in the very severe compared with mild cluster (4.7 percent vs 49.1 percent). There was also a higher number of symptoms (20 vs 4), reduced exercise capacity (as per incremental shuttle walk test; 44.4 percent vs 72.4 percent [predicted]), and more patients with C-reactive protein (CRP) levels >5 mg/L (38.4 percent vs 14.5 percent) in the very severe cluster.

Compared with patients in the mild cluster, inflammatory mediators of tissue damage and repair were increased in patients in the very severe and moderate with cognitive impairment clusters. The 13 proteins increased in the very severe vs mild cluster 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). IL-6 and CD70 molecule were increased in the moderate with cognitive impairment vs the mild cluster.

Health-related quality of life, as per EQ-5D-5L utility index, was decreased at both 5 months and 1 year compared with pre–COVID-19 (median 0.74 and 0.75 vs 0.88). Anxiety, depression, breathlessness, and fatigue improved between 5 months and 1 year among patients in the very severe cluster, but there was minimal change in physical performance and no overall change in systemic inflammation as per CRP levels. Cognitive impairment was improved at 1 year in the moderate with cognitive impairment cluster, with no change in the other clusters.

“[There were] minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters,” the researchers said.

How does this data help manage long COVID?

“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,” said the researchers. “We therefore highlight traits to identify individuals at high risk of non-recovery and potential targetable pathways for interventions.”

“[W]e 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.”

“[W]e 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 individualized,” they continued.

The researchers noted that the results may not apply to patients who were infected with newer COVID variants. The cohort also included patients who were unvaccinated prior to infection.  

There are currently no available treatments for long COVID. Evidence of persistent systemic inflammation in some patients in this study highlights the potential use of anti-inflammatory strategies in this population, the researchers concluded.