Understanding the mechanistic role of the carotid chemoreflex in patients with long COVID and unexplained breathing difficulties

Long-COVID is a condition in which people continue to have health problems for many months or years after a COVID-19 infection. It is a big health and economic problem in the UK, affecting nearly 2 million people and costing £8 billion each year. Many people with long-COVID experience ongoing breathing difficulties. They have a pattern of erratic breathing during exercise and even at rest, even though their lungs appear normal. We're not sure why this happens, but there is increasing evidence that this is due to disruption of the control of breathing, coordinated by the brain and nervous system, rather than a specific lung problem. A key part of this breathing control system is the carotid chemoreflex. This reflex is driven by small organs in the neck called the carotid bodies which monitor the chemical status of the blood, sending signals into the brain causing breathing and circulatory adjustments. The carotid chemoreflex, thus, controls breathing and feelings of breathlessness. When someone gets infected with the COVID-19 virus, the virus can get into the carotid bodies and disrupt their normal function. This could explain why some patients with long-COVID are breathless at rest and during exercise despite their lungs being normal. Our recent research shows that the carotid chemoreflex is more sensitive in people with long-COVID who don't have other health issues. This might be one of the reasons why they feel breathless and breathe too heavily during exercise. We propose to conduct 3 studies. In the first 2 studies, we will temporarily "switch off" the carotid chemoreflex with a medicine called dopamine. We know that temporary use of dopamine does not cause many side-effects in people because it has been used extensively in people with and without health problems. However, in study 1 we will test that dopamine does not lead to adverse effects in 6 patients with long-COVID. We will move to Study 2, in which we will use dopamine in 21 people with long-COVID and abnormal breathing and 21 people without long-COVID (controls). The results of the two groups will be compared to determine whether temporarily switching off the carotid chemoreflex improves breathing at rest and during exercise in people with long-COVID. If this works; we will know that the carotid chemoreflex is driving some of the breathing difficulties in patients with long-COVID. Dopamine however cannot be used long-term as a treatment because the body removes the drug too quickly. However, if dopamine works to improve breathing, we will explore a drug called gefapixant, which can help regulate the carotid chemoreflex. Gefapixant is currently used to treat people with chronic cough. We know that in animals, gefapixant works to calm the carotid chemoreflex, but we need to know whether this will work in people with long-COVID. We will therefore test in 41 people with long-COVID (Study 3) whether gefapixant can calm the carotid chemoreflex. If successful, this treatment could transform long-COVID therapy and potentially benefit people with similar symptoms from other post-viral illnesses or heart failure, for example. This research has been co-designed by people with long-COVID, doctors who look after them, experts in clinical trials and respiratory experts.