Long COVID: Causes and Effects

Soon after COVID-19 stormed into our lives, the term "Long COVID" began to circulate. Many who contracted COVID and recovered officially continue to feel long-lasting symptoms such as fatigue, lack of concentration, breathlessness, and more. As time passed and more information gathered, studies estimate that 10-30% of those infected with COVID will develop "Long COVID" symptoms. Besides the troublesome symptoms, patients face another issue: improper diagnosis. Regular tests indicate everything is normal: the heart functions correctly, lungs work normally, and blood tests show no apparent problems. Yet, symptoms persist.

Today, research identifies various factors influencing the development of Long COVID. Additionally, studies highlight four key risk factors increasing the likelihood of developing Long COVID after a COVID infection:

• High levels of viral RNA in the early days of the illness
• Presence of certain types of autoantibodies
• Reactivation of the Epstein-Barr virus (EBV), which causes mononucleosis
• Type 2 diabetes

How is Long COVID diagnosed?

Diagnosing the active coronavirus of any strain is straightforward—it appears in various swab tests, and its symptoms are easy to identify and detect in various tests. People experiencing breathing difficulties due to the virus will show damages in tests, such as low oxygen levels in the blood, different inflammations like pneumonia, etc. However, diagnosing Long COVID is more complex. Standard lab tests don’t identify the problem’s source—yet the symptoms persist and linger. Early in the COVID pandemic, many doctors released patients with incorrect diagnoses or defined their symptoms as psychosomatic. Later, research defined the phenomenon of Long COVID.

How does Long COVID develop?

While some people infected with the coronavirus recover completely, others develop what appears to be a chronic disruption in the body's immune system, leading to Long COVID. But what exactly is this disruption? It seems to be various types, and for each Long COVID sufferer, the specific cause must be diagnosed to provide appropriate treatment.

Research found that upon first contracting coronavirus, the viral genetic material spreads extensively throughout the body. In Long COVID sufferers, this viral material can remain in different body tissues—such as lymph nodes, intestines, etc. Some studies estimate these viral remnants cause inflammation in their residing tissues, leading to a range of symptoms reported by Long COVID patients—such as intestinal issues, brain fog, and more.

Other studies found evidence that even though the virus is no longer active, certain individuals' bodies keep fighting viral remnants in tissues. These people showed very high antibodies levels in tests, even many months after the initial infection, seemingly without necessity.

Dr. Akiko Iwasaki, an immunologist at Yale University School of Medicine, states that it should be assumed that Long COVID's various phenomena are due to different reasons, and precise identification of the cause is critical for treatment. For instance, people with significant viral load and tissue inflammation will need antiviral medications, while those with high antibody levels without a clear reason will require immune-suppressing medications.

Why is it hard for me to exercise?

Many Long COVID sufferers report difficulty engaging in physical activity and tire quickly—despite simple tests showing normal heart rate and blood oxygen levels. So why does this happen?

One study examined individuals cycling. Long COVID patients whose standard tests showed normal heart and lung function still felt fatigue, exhaustion, and inability to continue cycling shortly after starting. Their muscles extracted only a portion of the oxygen needed from the blood vessels during cycling, making the activity difficult to impossible.

Researchers are investigating possible reasons for this phenomenon. One hypothesis is chronic inflammation in the body, harming nerve fibers that help control blood circulation—or, medically termed: small fiber neuropathy. A skin biopsy can identify these damaged fibers, and studies indicate they are linked to impaired autonomic nervous system, affecting digestion, heart rate, and respiration. These damaged fibers, found in Long COVID sufferers, prove a medical issue, not a psychosomatic one.

A study in South Africa identified another problem in Long COVID patients' circulation. Researchers found microscopic blood clots, usually formed at the disease's onset but typically broken down and absorbed into the bloodstream post-recovery. In Long COVID patients, these clots may remain for a long time, potentially blocking tiny blood vessels responsible for delivering oxygen to tissues throughout the body.

Another common phenomenon among Long COVID sufferers is the presence of cytokines in the body—substances appearing when there is inflammation in the body. Cytokines can damage mitochondria responsible for transferring energy to cells, making oxygen use in cells difficult. Blood vessel walls can also suffer inflammation due to cytokines, further limiting oxygen absorption.

Another study using suitable MRI scans found that in a small group of Long COVID patients, lung damage occurred—despite not being hospitalized before or experiencing respiratory issues. These patients underwent standard lung tests—chest x-rays, lung function tests, CT scans, etc.—but results always appeared normal. Only in adapted MRI scans was damage detected, with unclear origin, leading to less efficient oxygen absorption.

These phenomena may appear separately or together in different patients, yet all contribute to Long COVID's most common symptom—extreme fatigue, exhaustion, and difficulty in physical activities. Research found that in most cases, the reason is lack of oxygen in cells, making any simple activity feel like strenuous exercise.

The cognitive challenges of Long COVID

This oxygen deficiency may also cause the cognitive impairments many Long COVID patients experience—such as reduced attention and concentration, memory decline, and word retrieval difficulty. These phenomena occur even in initially mild COVID cases. Researchers don't know exactly how or how often the coronavirus reaches the brain directly, but field findings suggest that even mild viral infection in the brain can cause significant inflammation and cognitive difficulty. In some patients, such infection can also trigger excessive microglia activity—certain cells in the immune system, a process similar to cognitive issues in the elderly or those with degenerative nervous system diseases.