The study did, however, identify a number of modifiable factors and potential treatment targets that may improve outcomes

COVID brain

The latest results from the Post-Hospitalisation COVID-19 (PHOSP-COVID) study, published as a preprint on 15 December 2021, point towards the possibility of personalised treatments for patients suffering from long COVID. Data show that there is no or minimal improvement in symptom severity and patient perception of recovery 12 months after discharge following hospitalisation for acute COVID-19. However, the study did identify a number of modifiable factors and potential treatment targets that may improve outcomes.

No or minimal improvement 

The prospective, longitudinal cohort study recruited adults hospitalised 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. Five-month data has now been collected from 2320 patients discharged between February 2020 and March 2021. Twelve-month data is available for 924 patients who were discharged between February and November 2020. Regarding these individuals, the mean age was 58.7 years, 35.6% were female, and 27.8% received invasive mechanical ventilation (IMV).

At 5 months only 25.5% of participants said that they were fully recovered. The data released today show that, unfortunately, this proportion remained largely unchanged at 12 months (28.9%).

There was a substantial deficit in median EQ5D-5L utility index from pre-COVID (0.88) to 5 months (0.74) and 1 year (0.74).

A number of factors were found to be associated with reduced odds of being recovered at 1 year: female sex (odds ratio [OR] 0.68; 95% confidence interval [CI] 0.46–0.99), obesity (OR 0.50; 95% CI 0.34–0.74), and IMV (OR 0.42; 95% CI 0.23–0.76).

Also, although steroids have proved life saving in the acute setting, they do not appear to have a significant benefit for patient-perceived recovery.

Overall, there was minimal or no improvement between the 5- and 12-month points in any of the 50 symptoms assessed in the study. At 1 year, one in four patients had self-reported symptoms of anxiety and depression, and one in 10 had symptoms of post-traumatic stress disorder (PTSD). There was also minimal change in any aspect of organ function.

There were marginal improvements in 6-minute walk distance and cognitive function, but these were not clinically significant.

Commenting on the findings, co-author Dr Rachael Evans, Clinical Associate Professor and Honorary Consultant Respiratory Physician at the University of Leicester, said: ‘While we are pleased to see that there is some improvement, it was small, and still one in 10 had clinically relevant cognitive impairment at 1 year. Unfortunately, we aren’t seeing improvement at 1 year from where people were at 5 months post discharge.’


The PHOSP-COVID study also included a cluster analysis. The team previously published results that identified four distinct clusters at 5 months in terms of the severity of physical, mental health, and cognitive impairments—very severe symptoms, severe symptoms, mild symptoms, and a subgroup of patients with moderate physical symptoms but much worse cognitive impairment.

In the latest report, the team sought to understand patient-perceived recovery, the associated risk factors for failure to recover at 1 year, and the association between these previously described clusters and multiple inflammatory mediators using a proteomics panel. The results released today show the trajectory of recovery across different health domains, and the differences in recovery trajectory by cluster.

‘We looked at the questionnaires on breathlessness, fatigue, anxiety, depression, PTSD, physical functioning, and cognitive impairment, because these all seem to track together. If you have severe breathlessness at 1 year, you were very likely to have the same severity these symptoms, but cognitive impairment did seem to separate for a subgroup of patients,’ Dr Evans explained.

‘We looked at this at the 5-months point initially, and there is now a larger data set, almost double the number, and we see the same four groups.’

There was a clear difference in the number of symptoms in each cluster, ranging from an average of 20 symptoms in the very severe group to four in the mild group. Dr Evans said that this is information that could be used in guiding clinical care.

‘For patients going to see their GP, if they have a lot of symptoms, it is highly likely that they are experiencing more severe impairments and perhaps need more support,’ she said.

The clustering analysis also identified a number of factors that influenced the severity of symptoms. There was a higher proportion of women in the very severe and severe clusters, and a higher proportion of men in the mild cluster and the moderate/cognitive cluster.

Obesity was significantly associated with the severity of symptoms. Approximately 48% of patients in the mild cluster had a body mass index over 30 mg/kg2 compared with 70% in the most severe cluster. Walking tests distance was lower in the very severe cluster (44%) compared with the mild cluster (72%).

This points to the involvement of a number of modifiable factors in the severity of long COVID. Further research will be needed to determine if interventions targeted at these factors can improve outcomes.

Systemic inflammation 

One of the most interesting findings of the PHOSP-COVID study is the association between markers of systemic inflammation and severity of the condition.

It has previously been hypothesised that hyperinflammation associated with acute COVID-19 leads to a persistent inflammatory state after COVID-19, and that this systemic inflammation leads to dysregulated immunity and multiorgan dysfunction. Several studies have found that elevated inflammatory markers, including interleukin-6, are associated with severity of acute illness, but there are no large studies investigating the relationship between systemic inflammation and ongoing health impairments after COVID-19.

The PHOSP-COVID study found that a higher proportion of patients in the most severe group had C-reactive protein levels in excess of 5 mg/l (38.4%) compared with the mild cluster (14.5%).

The team looked at almost 300 inflammatory proteins and found that the levels of 13 of these proteins were significantly higher in the very severe cluster compared with the mild cluster. Interestingly, two of these proteins were also elevated in the group with moderate physical symptoms but higher cognitive impairment.

‘That really is putting a potential biological explanation behind the severity of these clinical symptoms in clinical clusters,’ Dr Evans said.

Mental health effects 

Professor John Geddes, Head of the Department of Psychiatry at the University of Oxford and lead for the mental health component of the study, said that this same biological mechanism may be driving the mental health sequelae seen in long COVID.

‘What’s really intriguing about the PHOSP-COVID study is that it offers us opportunities to look at how the biological impairments play out across the mental health symptoms, which are often consigned to psychological reaction. Some of it might be that but, almost certainly I would say, not all. It’s likely to be related to the biological process as well,’ he said, ‘but clearly it’s complicated and we need to continue to try to elucidate the mechanisms that are leading to the different constellations of symptoms.’

‘In terms of meeting the needs of these patients, it’s very clear that we need a multipronged approach, which includes treatment for mental health symptoms and probably problems coping with this very slow recovery from this hideous illness. That needs to be provided alongside physical rehabilitative care,’ he added.

Going forward 

The PHOSP-COVID study has now produced robust data showing that symptoms of long COVID persist beyond 12 months and, unfortunately, there appears to be little or no improvement in the severity of symptoms over that time period. But it does offer some exciting opportunities to develop treatments and interventions that may benefit both the physical and mental sequelae of COVID-19. Studies could now examine the impact of weight loss interventions or individualised physical rehabilitation on symptom severity and quality of life. There is also the possibility of looking into the arsenal of anti-inflammatory medicines that are already licensed, and if they could play a crucial role in treating this debilitating condition.

This article originally appeared on Medscape, part of the Medscape Professional Network.


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