COVID-19 can lead immune system to exhaustion even in young people with mild to moderate symptoms

Researchers in Brazil and Portugal have been following patients under 40 who had the disease before being vaccinated. Alterations found in immune cells up to 180 days after infection resemble those found in patients with chronic diseases.

By Maria Fernanda Ziegler  |  Agência FAPESP – Preliminary results of a study conducted at São Paulo State University (UNESP) in Brazil suggest that infection by SARS-CoV-2 can cause severe immune system alterations even in healthy young people with mild to moderate COVID-19. In the study, Brazilian and Portuguese researchers analyzed defense cells collected from unvaccinated individuals between 30 and 180 days after they were infected.

“The immune cells from patients infected by the virus were exhausted, resembling cells from people with second- or third-degree obesity, or patients with chronic diseases, or much older people. It’s completely unexpected for young people without health problems,” Fábio Santos de Lira, a professor at UNESP’s School of Science and Technology (FCT) in Presidente Prudente, told Agência FAPESP.

The findings were presented at a conference held by the International Society of Exercise and Immunology (ISEI) in the United States. The study is part of a broader project known as the Fit-COVID Study and supported by FAPESP. It is being conducted by researchers affiliated with institutions in São Paulo state and the University of Coimbra in Portugal. 

The main aim is to investigate the effects of COVID-19 on the immune, vascular and autonomic nervous systems in people under 40 with mild to moderate COVID-19, for up to two years after they were infected.

“Our project aims to find out how COVID-19 affects healthy young people, a segment of the population that was completely neglected at the start of the pandemic. They went to hospital and were diagnosed but weren’t given treatment because their symptoms were mild or moderate. They went home and isolated themselves without any follow-up. However, our studies have shown that even these people may have suffered significant damage to the systems analyzed as a result of the infection,” Lira said.

The main sign of immune system alterations in these cases is extreme fatigue, he added. The group compared the immune systems of 20 infected and 20 uninfected subjects, observing alterations in the former that included impaired lung function, low levels of physical activity and, in contrast with severe COVID-19 patients, low levels of cytokines (pro-inflammatory molecules produced to tell the immune system to send more defense cells to the infection site).

“This is self-regulation by the immune system. They didn’t have severe COVID-19, as shown by the low levels of cytokines. It’s a mechanism that counterbalances the effects of the virus, reducing levels of interleukin-6 [IL-6, an important mediator of the inflammatory response known as the cytokine storm] and raising IL-10 and soluble TNF-alpha receptor levels [anti-inflammatory cytokines]. In addition, we observed a rise in levels of prostaglandin, an inflammatory molecule, and an alteration of the lipid profile with high triglycerides and more leptin [a hormone that helps regulate appetite],” Lira said.

Samples were collected in May 2021, when this part of the population had not yet been vaccinated. In addition to the data measured shortly after infection, the researchers took blood samples from these patients after they had all been vaccinated and will do so again one year on.

Exhaustion

Healthy young people would not normally be expected to display major immune system alterations. “However, when we analyzed the energy metabolism of their immune cells, we found it to have been completely altered. The virus had reprogrammed the immune cells and pushed them to a totally inflammatory state. It’s a very aggressive virus, even for healthy young people demonstrably without clinical problems of any kind,” Lira said.

Another finding was that physical activity can act as partial protection against the harmful effects of SARS-CoV-2 on the immune system. When the researchers analyzed monocytes, T lymphocytes and other defense cells, they found that the infected subjects exhibited a reduced anti-inflammatory profile of regulatory T cells, while levels of PD1 – a protein that acts to prevent T cells from attacking other cells in the body – were increased in both CD4 and CD8 T cells.

“Curiously, their level of physical activity partially protected these patients against immune system alterations. The higher the level of physical activity, the greater the protection against alterations in CD8, but not CD4,” Lira said.

The researchers also analyzed muscular condition in terms of grip strength, sitting and standing up, six-minute walk distance and quadriceps force, among other tests.

“We found differences in muscular strength only in the results of the six-minute walk. The distance was shorter for the COVID group than for the controls. However, respiratory function, both absolute and relative, and forced volume were statistically impaired in the infected group. All values were lower. This confirms the damage done to lung function as well as diminished exercise tolerance,” Lira said. 

The analysis of immune cell energy metabolism showed a predominance of glycolysis – the breakdown of glucose to produce energy. “Predominance of the glycolytic metabolism points to inflammation. The cells are exhausted, producing cytokines in abundance even at rest, and don’t respond to stimuli. All these factors show that the immune system is seriously deficient,” he explained.

Nervous system alterations

In addition to monitoring the immune systems of young people who had COVID-19 before they were vaccinated, the Fit-COVID study is analyzing the damage done to the autonomic nervous system – the part of the central nervous system that controls involuntary functions such as breathing, heartbeat, digestion and so on.

Based on the data, the researchers have concluded that any damage to the autonomic nervous system is repaired about five months after patients recover from the disease.

The results of this part of the study are reported in two articles published in Environmental Research and Public Health in February 2022 and January 2023 (read more at: agencia.fapesp.br/38132). 

The autonomic nervous system has two divisions: the sympathetic and the parasympathetic. The sympathetic nervous system helps the body activate its “fight or flight” response to danger or a threat. Energy expenditure increases as it raises the heart rate and blood pressure, releases adrenalin, contracts and relaxes muscles, dilates the bronchi and pupils, accelerates respiration, and activates the sweat glands. The parasympathetic nervous system normalizes the internal organs once the threat has passed.

In this part of the study, analysis of heart rate up to 180 days after infection showed heightened activity of the sympathetic nervous system while at rest. “Resting parasympathetic activity is expected to be higher than resting sympathetic activity because the sympathetic nervous system is associated with physical activity. If a person needs to start running all of sudden for whatever reason, the sympathetic nervous system controls the body’s responses to this stress, such as heart rate acceleration. Resting parasympathetic activity ought therefore to be stronger than resting sympathetic activity, especially in healthy young people,” said Ana Paula Coelho Figueira Freire, a professor at the University of Western São Paulo (UNOESTE) and first author of the articles.

The imbalance detected in the autonomic nervous systems of healthy young people infected by SARS-CoV-2 may be associated with higher inflammatory levels. “One factor that could be associated with this imbalance in the autonomic nervous system and its recovery five months later is control of the pro-inflammatory cytokine storm over time,” Freire said. “The immune system lowers the level of inflammation as it recovers, and this may affect the autonomic nervous system, reaching an eventual resolution of the inflammation.” 

Although the autonomic nervous system recovered after five months in these patients, Freire added, heart rate variability suggests higher sympathetic activity could be related to possible cardiovascular comorbidity and even sudden death. Healthcare professionals as well as researchers can use the findings to deepen their understanding of the course of this disease. “Even young adults can find their health has been compromised by COVID-19,” she said. “The autonomic nervous system recovers over time, but we need to increase our understanding of how the disease behaves, especially in this younger part of the population.” 

The Fit-COVID Study will also analyze immune cells from Olympic athletes who were not infected by the virus before they were vaccinated. “We want to observe in the laboratory how immune cells from Olympic athletes, which are clearly very efficient, react to blood serum from the healthy young individuals tracked by our study. We want to find out whether these cells can attenuate the pro-inflammatory effects of the serum from infected subjects before the vaccine and after the vaccine,” Lira said.

The article “Role of body mass and physical activity in autonomic function modulation on post-COVID-19 condition: An observational subanalysis of Fit-COVID Study” is at: www.mdpi.com/1660-4601/19/4/2457. 

The article “Autonomic function recovery and physical activity levels in post-COVID-19 young adults after immunization: an observational follow-up case-control study” is at:  www.mdpi.com/1660-4601/20/3/2251.