How long COVID depletes the body

Millions of people continue to suffer from exhaustion, cognitive problems and other long-lasting symptoms after coronavirus infection. The exact causes of the disease, known as long COVID, are not known. But new research is offering clues, describing the toll the disease has on the body and why it can be so debilitating.

Diagnosing the long COVID

Patients with severe COVID may end up in hospitals or on ventilators until their symptoms resolve. Body damage from severe COVID — pneumonia, low oxygen, inflammation — usually shows up on traditional diagnostic tests.

Long COVID is different: a chronic disease with a wide variety of symptoms, many of which cannot be explained using conventional laboratory tests. Difficulties in detecting the disease have led some physicians to dismiss patients or misdiagnose their symptoms as psychosomatic. But researchers who have been studying COVID patients more deeply for a long time have found visible dysfunction throughout the body.

Learn more about the COVID-19 pandemic

Studies estimate that perhaps 10% to 30% of people infected with the coronavirus may develop long-term symptoms. It’s unclear why some people develop long COVID and others don’t, but four factors appear to increase the risk: high levels of viral RNA early in an infection; the presence of certain auto-antibodies; reactivation of the Epstein-Barr virus; and having type 2 diabetes.

The immune system

Long-time COVID patients appear to have a disrupted immune system compared to post-COVID patients who fully recover. Many researchers believe that chronic immune dysfunction after coronavirus infection can trigger a chain of symptoms throughout the body.

One possibility is that the body is still fighting off remnants of the coronavirus. Researchers have found that the virus spreads widely during an initial infection and that viral genetic material can remain embedded in tissues – in the intestines, lymph nodes and elsewhere – for many months.

Ongoing studies are trying to determine if these viral reservoirs cause inflammation of surrounding tissues, which could lead to brain fog, gastrointestinal problems and other symptoms.

The researchers also found evidence that COVID can trigger a long-lasting and damaging autoimmune response. Studies have found surprisingly high levels of autoantibodies, which mistakenly attack a patient’s own tissue, several months after an initial infection.

A third possibility is that the initial viral infection triggers chronic inflammation, possibly by reactivating other viruses in the patient’s body that are normally dormant. Reactivation of the Epstein-Barr virus, which infects most people when young, could help predict whether a person will develop long COVID, a study has found.

In the complex world of the immune system, these explanations can coexist. And just as different long-term COVID patients may have different symptoms, they may also have different immune issues. Identifying the issues that are central to each patient’s disease will be key to guiding treatment, said Yale immunologist Dr. Akiko Iwasaki.

For example, a patient with autoantibodies could benefit from immunosuppressive drugs, while a patient with a viral reservoir of COVID should receive antivirals, Iwasaki said. “Depending on what each person has, the treatment would be quite different.”

The circulatory system

Many long-time COVID patients struggle with physical activity long after their initial infection and experience a relapse of symptoms if they exercise. Early studies suggest that a malfunction in the circulatory system could impair the flow of oxygen to muscles and other tissues, limiting aerobic capacity and causing severe fatigue.

In one study, patients with long-lasting COVID symptoms had unexpected responses to cycling. Although they had apparently normal hearts and lungs, their muscles could only extract a portion of the normal amount of oxygen from small blood vessels when they pedaled, which greatly reduced their exercise capacity.

One possible culprit: Chronic inflammation can damage nerve fibers that help control circulation, a condition called small fiber neuropathy. The damaged fibers, seen in skin biopsies, are associated with dysautonomia, a dysfunction of automatic functions – such as heart rate, breathing and digestion – which is very common in long COVID patients.

These findings demonstrate that people with long-term COVID have systemic physical problems, rather than just being anxious or out of shape, said Dr. David Systrom, an exercise physiologist at Brigham and Women’s Hospital who helped conduct the study on the bicycle.

“You can’t compensate for small fiber neuropathy with a skin biopsy. It’s not in anybody’s head,” Systrom said. “You can’t compensate for poor oxygen extraction to this degree. All of these are objective measures of disease.

South African researchers have discovered another circulation problem: microscopic blood clots. The tiny clots that form during an initial COVID infection usually break down naturally, but may persist in long COVID patients. These clots could block the tiny capillaries that carry oxygen to tissues throughout the body.

Inflammatory substances called cytokines, which are often elevated in long COVID patients, can damage the mitochondria that fuel body cells, making them less able to use oxygen. Blood vessel walls can also become inflamed, limiting oxygen uptake.

Whatever the cause, low oxygen levels can contribute to the most common symptom of COVID-19: severe fatigue. Researchers studying patients with chronic fatigue syndrome (also known as ME/CFS), which shares many characteristics with the long COVID, have found a similar pattern: a lack of oxygen triggered by circulatory problems puts tremendous strain on the body’s metabolism, making simple activities feel like strenuous exercise.

The brain

Even people with mild cases of COVID can experience long-lasting cognitive impairment, including reduced attention, memory, and word-finding. Possible long-term neurological problems due to COVID constitute “a major public health crisis”, according to Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke.

The researchers found a wide range of dysfunctions in the brains of long COVID patients. While it’s unclear how often COVID directly enters the brain, even mild infections appear to cause significant brain inflammation, according to the researchers, who included Stanford neurologist Nath, Iwasaki and Michelle Monje.

Infections can trigger the overactivation of immune cells called microglia in a way that appears similar to the process that can contribute to cognitive problems in aging and some neurodegenerative diseases.

Another research group found that long COVID can dramatically reduce the amount of oxygen reaching the brain, a finding that has also been seen in patients with a similar condition, chronic fatigue syndrome.


Shortness of breath is a common symptom of long COVIDs. But common lung tests — including chest X-rays, CT scans and functional tests — often come back normal.

Using specialized MRIs, a team of British researchers found preliminary evidence of lung damage in a small group of long-term COVID patients who had never been hospitalized. Detailed analyzes of their lung function indicated that most patients absorbed oxygen less efficiently than healthy people, even though their lung structure appeared normal.

The researchers warned that a larger group of patients will be needed to confirm the results. If the results hold, possible explanations for the observed shortness of breath include microclots in the lung tissues or thickening of the blood-air barrier that regulates oxygen uptake in the lungs.

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