Infectious Disease

It is ‘not only a respiratory disease’

January 05, 2023

4 min read



Healio Interviews

Frontera reports NIH funding. Al-Aly and Koroshetz report no relevant financial disclosures.


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As the world continues to grapple with effects of the COVID-19 pandemic, individuals around the globe are still dealing with symptoms of SARS-CoV-2 infection for months, even years, after their initial infection.

Post-acute sequelae of COVID-19, more commonly referred to as long COVID, are defined by the CDC as a wide range of new, returning or ongoing health issues that people experience after being infected with SARS-CoV-2, the virus that causes COVID-19.

While there currently is no definite reason as to why long COVID occurs in those who are infected with SARS-CoV-2, researchers throughout the United States have been studying its effects for more than a year. On Sept. 16, 2021, the NIH announced it was allocating nearly $470 million for the study of long COVID.

Jennifer A Frontera

“Honestly, there are multiple reasons why people might have long-term symptoms, and it depends in part on how severe their initial COVID-19 course was,” Jennifer A Frontera, MD, a neuro-critical care specialist at New York University Langone Health, told Healio. “People who were hospitalized or had low oxygen levels may have had very different pathologies from folks who did not require hospitalization.”

Headache, fatigue most common symptoms

In October 2022, in a study published in Brain, Behavior, & Immunity, researchers reported fatigue and headache were the most common long COVID symptoms. In addition, at least one neurological symptom was self-reported by 80% of patients included in the study.

Although the SARS-CoV-2 virus has been circulating for almost 2 full calendar years, experts are still researching how and why symptoms continue to linger, as well as the different areas of the body the virus affects. While COVID-19 is a respiratory infection, long COVID has prominently affected the central nervous system — and specifically the brain.

“Clearly, [long COVID] is not only a respiratory disease,” Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center and chief of research and education services at Veterans Affairs St. Louis Health Care System, told Healio. “It is a systemic disease that affects nearly every organ system, including the brain.”

All organs affected

In August 2021, in eClinicalMedicine, researchers published data from an international study that included thousands of patients from 56 countries who were infected with COVID-19. The authors reported more than 200 symptoms in every organ system that were associated with long COVID. Al-Aly reported similar findings in a study he co-authored in October.

According to Al-Aly, people who contract COVID-19 have a much higher risk for several prolonged symptoms, not only headaches and brain fog. He and researchers found increased risk for all types of strokes; cognition and memory conditions, such as Alzheimer’s disease; episodic disorders; sensory disorders; hearing and vision problems; loss of smell and taste; and conditions involving inflammation in the brain, such as encephalitis.

Al-Aly said he and colleagues approached the study thinking data would confirm suspicions that brain fog and fatigue were primary effects of long COVID on the brain. “But what we found is really much more profound than that,” he said. “There really are various neurologic abnormalities in people with SARS-CoV-2 infection. It is really spanning different domains of the neurologic system. That was quite the finding.”

Al-Aly, who has been on the forefront of long COVID research since the initial days of the pandemic in the US, said there are many hypotheses as to why COVID-19 can affect different organ systems in the body and ultimately create prolonged symptoms.

Vascular vs. inflammatory hypotheses

“The vascular hypothesis suggests that SARS-CoV-2 can interact with the endothelial lining of the blood vessels, which are actually present everywhere,” Al-Aly said. “[The virus can] irritate the endothelial lining, making that lining more prone to form clots or microclots.”

While this was one of several hypotheses Al-Aly spoke of, it is currently unknown whether any of them are true. Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke, Healio told it may not be because COVID-19 is affecting the brain, but rather the body’s immune system.

“If you get the flu, the symptoms will appear and they are due to the fact that it is not the virus infecting the [body]but the virus and your immune system’s response to the virus that creates the circulating chemicals called inflammatory mediators, and they affect brain function,” Koroshetz said.

Koroshetz compared long COVID’s effects to that of individuals with rheumatoid arthritis, a chronic inflammatory condition. He said most people with rheumatoid arthritis also report similar fatigue symptoms.

“It’s some of the autoimmune disorders where your immune system is overactive,” Koroshetz said. “You will get these same symptoms of fatigue and these problems, in terms of processing speed. These conditions are thought to be that the inflammatory mediators are affecting brain function.”

Mental problems also occur

An additional concern surrounding long COVID is not a physical problem, but a mental one. With symptoms lasting for months at a time, to even more than a year, there are reported increases in depression and anxiety among individuals with lasting symptoms, Frontera said.

“Depression is probably bidirectional,” she said. “We know that people who have brain injury, like stroke or Parkinson’s disease or seizures, have high risks for depression. We know depression is driven by neurochemical imbalances or neurotransmitter imbalances in the brain, and that can be triggered by a primary brain injury. The neurochemical imbalances that manifest as depression can exacerbate certain symptoms.”

Frontera, who recently co-authored a study on stressors and their impact on recuperation from COVID-19, said common problems in life can add to the burden of long COVID and the recovery process from infection.

“Things like financial insecurity, food insecurity, social isolation, grappling with new disability, death of a loved one — these things all can impact a lot of the neurological symptoms and the ability for folks to recover after hospitalization,” she said.

Frontera noted it is important for clinicians to look at all aspects of a patient’s life because some personal factors may affect the severity of specific symptoms.

“If there are environmental or socioeconomic structures that could be addressed by a social worker, or someone else who could offer the patient resources, that is important to keep in mind,” she said. “There are opportunities to help some of these people out, and treating some of the issues — like food insecurity or financial insecurity — can really go a long way towards ameliorating some of symptom pathology we see.”


Chen AK, et al. Brain Behavior Immune Health. 2022;doi:10.1016/j.bbih.2022.100491.

Davis HE, et al. EClinicalMedicine. 2021;doi:10.1016/j.eclinm.2021.101019.

XuE, et al. Nat Med. 2022;doi:10.1038/s41591-022-02001-z.


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