Persistent COVID-19, an inexplicable tiredness

Months after SARS-CoV-2 infection, many people still have symptoms. The most frequent is a constant exhaustion that makes it difficult to return to daily life.


Some of the people who become infected with SARS-CoV-2 later develop profound exhaustion. Sometimes this prevents them from going about their daily routine.

The virus causes various neuropsychiatric manifestations. These not only affect seriously ill people with COVID-19, but also people with asymptomatic or mild symptoms.

There is not enough data yet on whether medications can relieve fatigue. A combination of targeted training and psychotherapy can help you cope.

In November 2020, a young man of athletic bearing came to my office. He was 28 years old, slim and, at first glance, in good health. In February of that same year, he had gone skiing and in March, he had felt ill. He developed a slight cough and had some fever. He also suddenly lost his senses of smell and taste. But her discomfort subsided within two weeks. In addition, his sense of smell gradually improved, until it recovered completely after four weeks. However, he was unable to return to his demanding IT job. He was constantly feeling tired and down. He lacked the concentration to work for an hour or more in front of the computer screen. In addition, he had headaches and muscle aches. Before the first confinement, I trained every week in the gym, he played tennis regularly and jogged frequently. Now he complained that he was not able to participate in any sporting activities.

About four weeks after the first symptoms, a blood test revealed the presence of antibodies against SARS-CoV-2, which showed that he had been infected with the new coronavirus and his immune system had developed defenses against this pathogen. Since he was no longer suffering from the acute phase of COVID-19, a nasopharyngeal PCR could no longer detect the virus. More than half a year later, he was still on leave and was unable to return to work. How could you help him? What was behind the abnormal exhaustion that kept him out of the game?

In 2019, no one knew that one of the greatest pandemics in history threatened the world. By the end of 2020, more than 84 million people had been infected with the SARS-CoV-2 virus, which claimed the lives of more than 1.8 million of them. In record time, researchers around the world studied the virus and its symptoms. They found that it is not a simple lung disease, but that the new coronavirus can affect a large number of organs, including the brain.

In the acute phase of the disease, neurological symptoms can be seen mainly in people in intensive care units. Sudden onset of confusion, or delirium, is one of the most common complications. According to a 2021 study carried out by the international team for the investigation of COVID-19 in intensive care, this symptom affected more than half of the 2,088 patients studied. In addition, critically ill people sometimes develop memory and orientation problems, seizures, or a stroke.

Persistent COVID-19 symptoms

Many of those affected who have presented a mild picture of the disease complain of alterations of smell and taste, headaches and muscles and abnormal fatigue. Many others have not even realized that they had been infected. An analysis published in September 2020 by the team of Nicola Low, from the University of Bern, estimates that this was the case for one in five infected. The researchers reviewed 79 previously published studies with data from 6,616 people who tested positive for SARS-CoV-2; of these, 1278 had had an asymptomatic infection.

In general, a large part of patients continue to have long-term discomfort after the disease has passed. It is what is known as persistent COVID-19. Among those with mild symptoms, about one in three complain of persistent problems; among severe cases, four out of five are affected. Late neurological consequences are increasingly seen in hitherto healthy young people. Often, a strong fatigue appears that persists even after having had enough sleep. Those affected perceive it as unbearable. This syndrome, called “fatigue,” makes tasks that require concentration, sports, and even reading almost impossible. Frequently,

Several studies provide preliminary data on the onset of fatigue after COVID-19. In the Faroe Islands in Norway, a team led by Maria Skaalum Petersen asked patients about persistent symptoms 125 days after disease onset. More than 50 percent said they had at least one of them; one in three, two of the symptoms, and almost one in five interviewed, three of them. The most common long-term symptoms were fatigue, taste and smell disturbances, and joint pain. A study conducted in Israel by Barak Mizrahi and his collaborators showed similar results. The team analyzed the symptoms of nearly 2,500 people before, during and after COVID-19. In many cases they detected fatigue, muscle pain and respiratory problems,

In England, David Arnold’s team examined 110 COVID-19 patients treated at Bristol City hospital three months earlier. According to their  study , fatigue and respiratory problems (39 percent in both cases) were the most frequent symptoms. Also, sleep disorders (more than 24 percent) and muscle pain (20 percent) appeared often. A group led by Mayssam Mehne and Olivia Braillard, from the Geneva University Hospital, studied mildly ill patients with SARS-CoV-2. As they found in their  research , a third of the 669 people with an average age of about 43 years had persistent symptoms after the disease. The most frequent complaint was fatigue.

Thus, the appearance of fatigue does not appear to depend on the severity of the disease. The tendency to exhaustion can persist for weeks or even months after infection and significantly affect quality of life. In this context, doctors already speak of a “post-COVID-19 syndrome.” In addition to fatigue, other discomforts may occur, such as pain, breathing problems or mental disorders.

The many causes of fatigue

In general, fatigue is a typical side effect of debilitating illnesses. These include, for example, cancer and other chronic infections, such as tuberculosis. Sometimes it is even the first sign of a serious health problem. In addition, it is often accompanied by loss of appetite and weight and a general feeling of malaise. In some mental disorders, including depression, exhaustion is also a central symptom. During the COVID-19 pandemic, psychiatrists have observed an increase in cases of anxiety disorders, sleep disorders, depression, and post-traumatic stress disorder.

The cause could depend on different factors. The conditions of the pandemic reinforce the fears of some people. The social pressures and economic effects of confinement, as well as isolation, can also have a negative impact on mental health. Despite the many people suffering from the pandemic and its consequences, post-COVID-19 fatigue is unlikely to be a purely psychological problem. Many patients develop extreme fatigue, but do not meet the clinical criteria for depression. After a SARS-CoV-2 infection, along with exhaustion, concomitant cognitive problems sometimes appear. Those affected often complain of forgetfulness, difficulty concentrating, and loss of attention.

Some research has concluded that SARS-CoV-2 can penetrate directly from the nasal mucosa to the brain and there trigger inflammation. However, according to current data, this only happens rarely. In severely ill people, most neurological problems are likely to arise for other reasons. The body of some affected reacts to the virus with strong inflammation or by over-activating the blood clotting system. Lung damage can also have effects on the brain, since it makes it difficult for oxygen to reach the brain. By means of resonance images, diffuse lesions in the white matter, related to inflammation or circulation problems, have been observed in seriously ill patients. A team led by Avindra Nath, from the Bethesda National Institute of Neurological Disorders and Stroke, used a particularly powerful MRI scanner to examine the brains of 13 people who had died from COVID-19. In ten of them, they found small brain lesions. However, in most patients, standard MRI scans are normal.

The fact that fatigue appears even after mild COVID-19 symptoms and is not clearly correlated with severe cases, suggests that it is not a direct effect of the disease. On the other hand, many indications suggest that immune system disorders due to SARS-CoV-2 could cause neurological symptoms. Thus, as a defense against the virus, antibodies are formed that can cause inflammation in the brain, spinal cord, and peripheral nerves.

Some of the problems that remain after the acute phase could be due to these processes. In many infections, the body’s defenses produce proteins that promote the inflammatory process. The release of these cytokines is associated with fatigue and low mood. In severe COVID-19 cases, an excess of such molecules is sometimes generated and what is known as a ‘cytokine storm’ forms. This leads to many, sometimes life-threatening problems. In moderate conditions, fewer cytokines are secreted. But there are also clinically important effects.

What role does the immune system play?

Multiple teams have detected antibodies in the cerebrospinal fluid of people with severe COVID-19. These immune system molecules target structures in the body itself. They may interfere with brain function, causing extreme fatigue and cognitive problems. To date, such data is scarce in people with post-COVID-19 syndrome, and autoantibodies have not been shown to be present in the blood of those affected. However, from a neuroimmune point of view, it seems plausible that they play a role in fatigue. If this theory is confirmed, it could become the basis for future therapies. Perhaps exhaustion could be controlled with medications that influence the immune system.

Until the relevant data are available, the source of exhaustion cannot be tackled, but some drugs could alleviate it. Drugs such as modafinil (used to treat narcolepsy) or amantadine (used for Parkinson’s and fatigue in people with multiple sclerosis) would be possible candidates. However, controlled studies are required to show whether they are adequate.

In the coming months, more systematic studies will have to be carried out in people who have suffered from COVID-19 and continue to suffer its consequences. Magnetic resonance neuroimaging, as well as the analysis of antibodies in blood and cerebrospinal fluid, could shed light on the deterioration of bodily functions. They would have to be supplemented by clinical drug trials.

Last November I decided to pursue a combination treatment with my young and athletic patient. Thus, I prescribed specific physical and cognitive training, guided and accompanied by experts. I also prescribed a performance-enhancing drug used to treat people with depression. Thanks to the support of professionals for occupational reintegration, little by little he is returning to working life.