LONDON – A U.K.-wide study has found that seven out of 10 patients hospitalized with COVID-19 infection were continuing to suffer physical and mental health problems five months after discharge.

Each of the participants with ongoing problems had an average of nine persistent symptoms. The magnitude of the health burden was substantial and only weakly related to the severity of illness suffered during the acute phase of the disease.

Unlike the acute phase of disease, when patients admitted to hospital are disproportionately male and from an ethnic minority background, those who experience more persistent symptoms of long COVID-19 tend to be middle-aged white women.

However, cognitive impairment – or brain fog – was a predominant symptom in a subset of older, male patients.

C-Reactive protein levels were elevated in all but the most mild cases of long COVID-19, indicating underlying systemic inflammation. Further research is taking place on patient samples to try and find specific causes.

The findings are based on 1,077 patients discharged between March and November 2020, who are taking part in the Post-Covid hospitalization (Phosp-Covid) study. This is the first cut of data from the £8.4 million (US$11.5 million) study, which is due to recruit 10,000 participants, making it the largest and most comprehensive attempt worldwide to characterize long COVID-19.

“Our results show a large burden of symptoms, mental and physical health problems and evidence of organ damage five months after discharge with COVID-19,” said Rachael Evans, respiratory consultant and associate professor at Leicester University, co-lead of Phosp-Covid.

Patients who required mechanical ventilation and were admitted to intensive care took longer to recover. However, much of the wide variety of persistent problems was not explained by the severity of the acute illness, which was largely driven by lung injury. That indicates “other, possibly more systemic, underlying mechanisms,” Evans said. “The main reason people needed hospitalization was acute lung injury, but what we are seeing is whole system involvement.”

One of the aims of the study is to assess the effect of drugs given during the acute phase of infection, to see if there is any impact on longer-term recovery. Standard-of-care treatment with dexamethasone only started in the U.K. in June 2020, after the Recovery trial demonstrated it reduced mortality of mechanically ventilated patients by one-third, and only 31% of the patients covered in this first analysis of Phosp-Covid data were given the steroid.

The early indicators from the study are that while dexamethasone reduces mortality, it does not appear to have an impact on longer-term recovery.

The prevalence of more than 40 different symptoms was assessed by patient questionnaires and participants were given a full physical and mental assessment, and breathing and blood tests to check organ function.

The 10 most common symptoms reported were muscle pain, fatigue, physical slowing down, impaired sleep quality, joint pain or swelling, limb weakness, breathlessness, pain, short-term memory loss and slowed thinking.

Still seeking specific causes

Of 450,000 people admitted to the hospital with COVID-19 in the U.K. 300,000 survived. The assortment of problems seen in Phosp-Covid points to a significant burden of disease and the need for multidisciplinary care, said Chris Brightling, professor of respiratory medicine at Leicester University, who is leading the study.

“Our findings support the need for a proactive approach to clinical follow-up, with a holistic assessment to include symptoms, mental and physical health, but also an objective assessment for cognition,” Brightling said.

While beginning to size up the scale of the problem, the research is yet to pinpoint any specific causes. In addition to continued follow-up to assess the trajectory of recovery, more work is needed to build understanding of the biology underpinning post-COVID-19 symptoms, said Brightling.

One starting point for investigating why middle-aged women suffer more persistent symptoms could be that they are more prone to autoimmune diseases. “This may explain why post-COVID syndrome seems to be more prevalent in this group,” said Louise Wain, professor of respiratory research at Leicester University. Evidence of ongoing inflammation is an important signpost to guide research into biological mechanisms involved in long COVID-19, she said.

Among other factors associated with failure to recover, age mattered, but there was not a linear relationship. “Younger people of less than 30, and older people, seemed to recover better than those of middle age,” Evans said. Immunotyping and profiling of how immune responses to COVID-19 infection varied with age form part of the investigation to get to the root of why this is the case.

Being obese, with a body mass index of more than 30, was associated with failure to recover, but did not reach statistical significance.

Of all the patients, one-quarter had survived after treatment in intensive care, which is known to be associated with significant problems post discharge. However, other patients had significant ongoing symptoms as well. “Twenty percent were only in hospital for a short time and didn’t need oxygen, but still had symptoms,” said Evans.

Cognitive impairment

Brightling said it was “unexpected” to see a distinct subgroup of participants with cognitive impairment. “What was more surprising was the disconnect between the brain fog signal; it was independent of other symptoms,” he said.

John Geddes, head of the department of psychiatry at Oxford University, said it was “a very intriguing find,” which will be looked at more intensely during the rest of the study. “The next phase will involve more granular testing, so we are hoping for greater insights into the mechanism,” he said. That will involve brain imaging studies.

It also is planned to introduce control groups of patients admitted to hospital and to intensive care for other conditions, and to link back to participants’ full medical records, in order to tease out specific factors leading to slow recovery from COVID-19.