Study: The Female Predominant Persistent Immune Dysregulation of the Post COVID Syndrome: A Cohort Study. Image Credit: CHOTE BKK / Shutterstock

Are women more likely to develop long COVID?


Researchers found different groups of symptoms persisting after coronavirus disease 2019 (COVID-19), with fatigue and higher IL-6 levels common in women. About 75% of the patients they treated were women, indicating a link between sex hormones and immune response.

A large proportion of people who recover from COVID-19 suffer from persistent symptoms even six months after recovery. People have reported fatigue, joint pain, and shortness of breath several months after recovery. Studies estimate about 10-30% of the patients who recover have persistent symptoms months after recovering from acute illness.

Direct organ damage, including loss of smell, cardiomyopathy, neuropathy, and interstitial lung disease, has also been observed. Apart from organ damage, pain all over the body and cognitive brain impairment, or “brain fog,” have also been reported. Such chronic symptoms are similar to those observed after other viral infections such as Zika, SARS-CoV, and chikungunya.

Central sensitization syndrome is a group of chronic disorders like chronic headache, irritable bowel syndrome, and fibromyalgia. They are believed to have shared physiological processes with brain inflammation and changing of the brain and spinal cord pathways. An increase in cytokines and chemokines levels has been seen, similar to that seen in COVID-19.

Study: The Female Predominant Persistent Immune Dysregulation of the Post COVID Syndrome: A Cohort Study. Image Credit: CHOTE BKK / Shutterstock

Researchers from Mayo Clinic have been seeing patients with persistent symptoms after COVID-19. In a study published on the medRxiv* preprint server, they report their initial findings on 107 patients they have treated for persistent symptoms after recovering from COVID-19.

Categories of persistent symptoms

The study included patients seen between January and April 2021. Acute symptoms, those occurring within four weeks of COVID-19 onset and those persisting beyond four weeks, were recorded. All the patients completed a standard questionnaire regarding symptoms, treatment, and ongoing symptoms. About 75% of the patients were women.

The team identified six categories of predominant persistent symptoms: fatigue, shortness of breath, myalgia, chest pain, headache, and orthostatis (a decrease in blood pressure upon sitting or standing up). More women had fatigue, orthostatis, and chest pain, while more men had headaches and shortness of breath.

Interleukin-6 (IL-6), an anti-inflammatory cytokine, was elevated in 69% of the women (compared to 39% men), which corresponded to increased fatigue, myalgia, and orthostatis. These three characteristics were grouped under the central sensitization characteristic. This characteristic was predominant in women (80% vs. 27% in men).

Differences based on sex

The study of patients shows there is a predominance of women seeking care for persistent symptoms after COVID-19. They usually have higher IL-6 levels than males and reported fatigue as the most common symptom. As is known for central sensitization, more women had symptoms similar to central sensitization.

Most of the patients had elevated IL-6 levels more than three months after the infection, something not reported before. Higher cytokine levels are believed to be the primary cause of adverse outcomes in COVID-19. IL-6 has also been associated with death in COVID-19 patients.

The higher IL-6 levels may be partially responsible for the sex differences seen in chronic COVID-19 symptoms. One of the factors affecting the overall immune response to COVID-19 is sex. Men seem to have higher rates of hospitalization and death. Studies have shown men have higher IL-8 and IL-18 levels than women, but when women had a higher high immune response, it positively correlated with disease progression.

Changes in immune response also vary throughout the lifecycle of a person, with post-puberty/premenopausal women having higher levels of inflammatory cytokines compared to men. Such effects may be because of sex hormones.

Symptoms seen in patients with central sensitization are similar to the symptoms seen after other infections such as Lyme disease and post ICU syndrome. In all these cases, there are increased IL-6 levels. IL-6 is associated with fatigue and sleep disturbance.

Treatment of these symptoms has usually been frustrating, as patients have several such disabling symptoms but almost no abnormalities in lab tests. The most compelling explanation is believed to be that the brain and spinal cord become more sensitive to stimuli, reducing the threshold for perception and magnifying existing stimuli. There is also believed to be a genetic component to central sensitization as well a having a certain type of personality, like being detail-oriented.

Based on these considerations, the authors hypothesize that the right genes, the right personality, and an event that causes system distress, like a viral infection or other forms of trauma like surgery and life events, can lead to central sensitization. The symptoms often last beyond the event, and there may also be the development of new symptoms. Understanding the different characteristics of persistent symptoms may help better define treatment options.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.



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