By Maria Fernanda Ziegler | Agência FAPESP – Most patients who survive severe COVID-19 tend to experience symptoms or complications for weeks or months, in a syndrome known as long-hauler, post-acute, or simply long COVID. Preliminary studies have analyzed the clinical condition of these patients, their mental health, quality of life, and rehabilitation needs.
“We’ve been suffering from the pandemic for over a year, and we now realize that the disease can also have long-term consequences. These aren’t fully understood by scientists, so it’s very important for researchers everywhere to share data and knowledge about long COVID,” said Luiz Eugênio Mello, FAPESP’s Scientific Director, on welcoming participants to an online seminar on “Long and Post-Acute COVID-19”, held June 2 as part of a series of FAPESP COVID-19 Research Webinars, organized with the support of the Global Research Council (GRC).
The webinar featured presentations by scientists from Brazil and the United States on the results of these studies. In Brazil, for example, 882 patients treated at Hospital das Clínicas, the hospital complex run by the University of São Paulo’s Medical School (HC-FM-USP), are being followed in a study that focuses on symptoms of long COVID six months after discharge from hospital. All had the severe form of the disease, and two-thirds required treatment in the intensive care unit (ICU).
The results so far show that 89.3% had persistent symptoms more than six months after discharge, including fatigue, muscle and joint pain, and dyspnea (shortness of breath). In addition, 58.7% reported at least one emotional or cognitive symptom, such as memory loss (42%), insomnia (33%), poor concentration (31%), anxiety (28%) or depression (22%).
“These symptoms are all interrelated. In other words, we’re finding that a person who complains of memory loss also reports insomnia, anxiety and depression. It’s important to bear in mind that these frequencies were adjusted for the presence of such symptoms before the patients in question had COVID-19,” said Geraldo Busatto, principal investigator for the study. Busatto heads HC-FM-USP’s Psychiatry Neuroimaging Laboratory (LIM21).
Structured interviews with the patients enabled the researchers to diagnose neuropsychiatric disorders. “We detected an array of disorders, including post-traumatic stress disorder in 13.65%, similar to the frequency for the overall population. However, the frequency of psychotic symptoms such as hallucinations (8.71%) and delusions (6.35%) was higher for the age range in question,” Busatto said.
The participants were also asked to perform cognitive tasks. “In the sustained attention task, they performed worse than the norm for the Brazilian population, especially in the 60-75 age group, but in verbal fluency, a frontal lobe task, there was no material difference. This shows that the cognitive deficits caused by COVID-19 aren’t uniform. Some areas of cognition may present more deficits than others,” Busatto said.
Post-COVID quality of life
Another study that is being conducted in Brazil at more than 55 research centers is investigating quality of life and long-term outcomes for about 1,000 adult patients after hospitalization with COVID-19.
“Preliminary results show all-cause mortality of 6.9% six months after hospital discharge. The rehospitalization rate was 16%. After stratification, however, we found that 24% of subjects who required mechanical ventilation during hospitalization died six months after discharge, against only 2% who did not require intubation. Again, rehospitalization was significantly higher for patients who were intubated: 40% compared with 10% for patients who were not intubated. These differences are statistically significant even after adjusting for covariates such as age and comorbidities,” said Regis Goulart Rosa, a physician and researcher in the Department of Critical Care at Hospital Moinho de Vento in Porto Alegre, Rio Grande do Sul state, and one of the principal investigators for the study.
The study also detected a clinically and statistically significant loss of physical functions that are important for day-to-day activities. “There was a sharp decline in the first three months, followed by a relative improvement until the sixth month,” Rosa said. “However, patients who required ventilation had not recovered to their pre-COVID baseline even after six months.”
A similar study is under way in the US, following up on 1,500 survivors of the disease for six months after discharge in order to observe their cardiopulmonary and mental health, as well as financial strain. Data for 253 patients collected a month after discharge showed that 54.9% had a new cardiopulmonary symptom, while 15.9% continued to need supplemental oxygen at home. Significant percentages had new or worsened symptoms such as coughing (23%), breathlessness while trying to sleep (13.4%), rapid or irregular heartbeat (19.1%), and chest pain, tightness or angina (11.3%).
“It’s troubling to discover that many of the patients who experienced these difficulties returned home without any assistance to deal with the new problems. To this, we must add the finding that 55% of respondents reported a drain on their finances after hospitalization. Furthermore, 38% had to ask family members to take time off work to care for them, and 20% had to change their own work. These findings point to the socio-economic impact of the disease and also of long COVID,” said Catherine Hough, a professor at Oregon Health & Science University and one of the leaders of the study.
Recovery from COVID-19 can be slow for many patients. In the US study, 85% felt their health had not been fully restored one month after discharge from hospital, with 65% experiencing a disability and 63% a significant cognitive problem. “When we analyzed the same data three months after discharge, we found very little change: 75% still hadn’t recovered completely, 60% reported a disability, and 54% reported cognitive impairment,” Hough said.
Studies on long COVID must take into account diseases and other health problems that were already present before infection by SARS-CoV-2. The virus “can be a magnifier of prior problems”, Hough said.
The mechanisms that underlie the immune response to COVID-19 and may explain this variation in post-acute symptoms and complications are also being studied. “The defense mounted by the human immune system against this coronavirus varies considerably, and for this reason, we see a wide array of outcomes, from asymptomatic to mild, moderate and severe COVID-19. Similarly, some people suffer from acute disease while others have the long-hauler version, with symptoms or disabilities that last months and even years,” said Carolina Lucas, a research fellow in Akiko Iwasaki’s laboratory at Yale School of Medicine (USA).
In a study published in Nature, Lucas and colleagues identified four immune signatures that could be used to predict the trajectory of the disease in moderate and severe patients. The study involved 113 patients admitted to the Yale School’s hospital in March-May 2020, measuring levels of T cells, cytokines, leukocytes and other immune system proteins over a period of 51 days after the onset of symptoms. About 100 volunteer healthcare workers served as healthy controls.
The researchers found higher levels of proteins involved in tissue healing and repair among moderate patients who recovered. Mixed-type cytokines were more common among severe patients, appearing in combinations not usual for viral infections and constituting a maladapted immune response. A larger percentage of this group died.
Timing was also considered decisive. The analysis showed that severe patients were unable to control viral load over time and displayed higher levels of interferon, a protein produced by defense cells to combat pathogens. Another aspect identified by the researchers was a correlation between viral load and cytokine levels regardless of disease severity.
A recording of the complete webinar can be watched at: covid19.fapesp.br/covid-19-longa-e-sub-aguda/545.