Pain Mechanisms in long-Covid
Lead Research Organisation:
King's College London
Department Name: Wolfson Centre for Age Related Diseases
Abstract
The COVID-19 pandemic has affected hundreds of millions of people and while many individuals recover fully about 1 in 10 suffer from long term symptoms known as long-COVID. We know already that some patients still experience symptoms after more than one year. Muscle and joint pain and fatigue are common symptoms of long-COVID along with breathing problems and loss of smell. Some patients also suffer from abnormal sensations (pins and needles and burning pain) which could be due to damage to some sensory nerves. The mechanisms underlying pain and abnormal sensations in long-COVID are unknown and there are no effective therapies. Also there is currently no laboratory method to diagnose long-COVID.
Our research combines patient and lab-based studies to understand why long-COVID patients suffer from pain To do this, we will characterise the qualities, intensities and location of pain in long-COVID patients, test whether there is damage to pain-sensing nerves, and measure the impact of pain and fatigue on daily life.
The pain and fatigue seen in long-COVID resembles the symptoms found in patients with fibromyalgia, and we have very recently shown that the body's normal defence mechanism, the immune system, is responsible for pain in fibromyalgia patients. Immune cells produce antibodies which normally help us to fight infections. Our results showed that fibromyalgia patients produce antibodies that attack their own bodies and stimulate pain sensing nerves. We will therefore test to see whether antibodies are also responsible for pain and fatigue in long-COVID. To do this we will purify antibodies from people with long-COVID, inject them into mice and measure if the mice develop symptoms of pain and fatigue. We will also examine if long-COVID antibodies obtained from people who have sensory nerve damage, targets the similar sensory nerves in the mice. We will find out at a molecular level what part of the nerves are being targeted and begin to understand how the antibodies have their effects. Our work will improve management of long-COVID and potentially provide a laboratory method for diagnosing this condition.
Our research combines patient and lab-based studies to understand why long-COVID patients suffer from pain To do this, we will characterise the qualities, intensities and location of pain in long-COVID patients, test whether there is damage to pain-sensing nerves, and measure the impact of pain and fatigue on daily life.
The pain and fatigue seen in long-COVID resembles the symptoms found in patients with fibromyalgia, and we have very recently shown that the body's normal defence mechanism, the immune system, is responsible for pain in fibromyalgia patients. Immune cells produce antibodies which normally help us to fight infections. Our results showed that fibromyalgia patients produce antibodies that attack their own bodies and stimulate pain sensing nerves. We will therefore test to see whether antibodies are also responsible for pain and fatigue in long-COVID. To do this we will purify antibodies from people with long-COVID, inject them into mice and measure if the mice develop symptoms of pain and fatigue. We will also examine if long-COVID antibodies obtained from people who have sensory nerve damage, targets the similar sensory nerves in the mice. We will find out at a molecular level what part of the nerves are being targeted and begin to understand how the antibodies have their effects. Our work will improve management of long-COVID and potentially provide a laboratory method for diagnosing this condition.
Technical Summary
About 10% of patients infected with COVID-19 have persistent symptoms (long-COVID) that can last for over a year. These include musculoskeletal pain and fatigue as well as paresthesias (tingling, burning pain) and symptoms of dysautonomia (e.g. breathlessness, chest pain). Our proposal will investigate if small fibre neuropathy (SFN) and autommunity are responsible for these neurological symptoms.
We will recruit patients who have A) pain and fatigue, B) fatigue but no pain, C) symptoms resolved after COVID, and D) asymptomatic with no COVID infection. Validated questionnaires will be used to characterise the location, quality and intensity of pain and to identify patients whose pain and symptoms suggest (SFN). A diagnosis of SFN will be ascertained by quantitative sensory testing and by histological analysis of intraepidermal nerve fibre density (IENFD) in skin biopsy samples. In addition, we will assess the presence of dysautonomia by measuring cardiovascular parameters in the laboratory at baseline and under provocative testing. We will assess the impact of pain on physical activity during daily life using wearable sensors which capture movement, posture and autonomic data. Blood will be collected from patients for antibody studies.
IgG from patient blood will be isolated and administered to mice by intraperitoneal injection. Mice will be tested for their sensitivity to mechanical and thermal stimulation before and then daily after antibody administration. Effects on spontaneous activity will also be assessed as this may be affected by pain/fatigue. The presence of SFN in antibody treated mice will be assessed by measurements of skin IENFD. Fatigue will be assessed by performance on treadmill and rotarod tests. These experiments will show if we can passively transfer symptoms of pain from patients to mice. Immunohistochemistry and Western blotting will be used to identify the cellular binding sites and likely epitopes for patient IgG.
We will recruit patients who have A) pain and fatigue, B) fatigue but no pain, C) symptoms resolved after COVID, and D) asymptomatic with no COVID infection. Validated questionnaires will be used to characterise the location, quality and intensity of pain and to identify patients whose pain and symptoms suggest (SFN). A diagnosis of SFN will be ascertained by quantitative sensory testing and by histological analysis of intraepidermal nerve fibre density (IENFD) in skin biopsy samples. In addition, we will assess the presence of dysautonomia by measuring cardiovascular parameters in the laboratory at baseline and under provocative testing. We will assess the impact of pain on physical activity during daily life using wearable sensors which capture movement, posture and autonomic data. Blood will be collected from patients for antibody studies.
IgG from patient blood will be isolated and administered to mice by intraperitoneal injection. Mice will be tested for their sensitivity to mechanical and thermal stimulation before and then daily after antibody administration. Effects on spontaneous activity will also be assessed as this may be affected by pain/fatigue. The presence of SFN in antibody treated mice will be assessed by measurements of skin IENFD. Fatigue will be assessed by performance on treadmill and rotarod tests. These experiments will show if we can passively transfer symptoms of pain from patients to mice. Immunohistochemistry and Western blotting will be used to identify the cellular binding sites and likely epitopes for patient IgG.
