Rare health condition cases surge during COVID-19 pandemic

The condition is a type of autoimmune response linked to the body immune system mistakenly attacking itself. Intriguingly, the system being attacked normally works as a sentinel or guard, whose job it is to detect invading viruses. It is mainly seen in East Asian women and girls and was very uncommon in the UK. But researchers at the University of Leeds and Leeds Teaching Hospitals NHS trust, who were examining data on MDA5 autoimmunity in Yorkshire during the pandemic, noted an unprecedented 60 cases among mainly white men and women.

Researchers investigating the increase in cases believe that exposure to the COVID-19 virus may trigger the condition, which causes distinctive skin rashes, pneumonia and interstitial lung disease, a rapidly progressing lung inflammation with damage which is often fatal.

Principal Investigator Dennis McGonagle, Professor of Investigative Rheumatology in the University of Leeds' School of Medicine and Leeds Teaching Hospitals NHS Trust, said: "Whilst we very occasionally see this disease in the UK, this surge in cases was completely new and very different.

"It is important that physicians understand the symptoms so that patients can be quickly referred for treatment and have the best chance of a rapid and full recovery. Lives could undoubtedly be saved but there is a great need for research to try and slow or stop the rapid lung progression that occurs in some patients."

The research paper is published in The Lancet eBioMedicine.

Viruses and autoimmune response

The immune system contains a protein called MDA5, which helps detect RNA viruses like COVID-19. Normally, this protein helps trigger an immune response in the body, where more of the protein is produced to help fight off the virus. However, sometimes the immune system releases antibodies which mistakenly attack this protein, leading to MDA5 autoimmune diseases such as the rare disease described in this study. The exact cause is not well understood, but scientists believe the virus itself could trigger the response.

Autoimmune diseases seen after viral infections have similar features, such as fatigue, joint pain and swelling, skin rashes and digestive issues. During the COVID-19 pandemic, physicians saw a rare condition in children called multisystem inflammatory syndrome in children (MIS-C) where there was no evidence of active viral infection of the lungs. This MIS-C syndrome affected multiple systems in the body, including the heart, kidneys, brain, skin, eyes, and digestive organs, but usually spared the lungs. The disease seen in Yorkshire was dubbed MIP-C (pronounced "mipsy") because of its similarities to MIS-C in that it occurred around the time of the pandemic but where active infection was usually absent.

The 60 patients in the study presented at their GPs or to A&E with a range of symptoms including shortness of breath, muscle pain, rashes, and reduced blood flow to the fingers, known as Raynaud's disease. These symptoms are associated with autoimmune disease.

The patients were referred to rheumatology specialists for further testing and all were diagnosed with the condition. Of the 60 patients, 35 had received COVID-19 vaccinations, and 15 had previously tested positive for COVID-19. However, patients were not systematically tested for COVID-19, and some may have been infected, but were asymptomatic at the time. Such cases could have developed MDA5 disease due to an overreaction of their immune system to minimal exposure to the virus.

Twenty-five out of the 60 patients (41.7%) developed interstitial lung disease, and despite treatment with immunosuppressant medication, eight of those patients died. A ninth patient, who did not have interstitial lung disease, died from sepsis.

To understand the increase in cases of this rare condition, researchers collected data on the number of these tests between January 2018 and December 2022, alongside data on COVID-19 infections and vaccination, and information about each patient's symptoms. Analysis showed that just six cases of the rare condition had been diagnosed between 2018 and 2019. However, in the 3 years after 60 new cases appeared, eight cases were diagnosed in 2020; 35 cases were diagnosed in 2021 and 17 cases were diagnosed in 2022. Very few cases have occurred since then.

Patient demographics

Patients were aged between 43 and 71 years, with 36 of them being female.

Ethnicity:

• White: 32
• South Asian: 3
• Black Caribbean: 2
• Black African: 1
• Any other ethnic group: 4
• Asian (not Chinese): 4
• There was no ethnicity data for 14 patients.

Researchers noted that there was a strong overlap in 2021 between vaccination rates in Yorkshire and the surge in MDA5 disease cases. This peak, though, also occurred shortly after a community wave of coronavirus infection occurred in late 2021. A smaller overlap was seen between confirmed COVID-19 infection and MDA5. However, it was interesting to note that almost half (42%) of patients were not documented to have been vaccinated against COVID-19 before they tested positive for MDA5. Four children who tested positive for MDA5 were unvaccinated, pointing to the idea of an overreacting immune response after exposure to a virus.

Professor McGonagle said: "We know that vaccines can trigger an immune overreaction, but given that not all of these patients were vaccinated against COVID-19, and the increase in cases occurred when the COVID-19 virus was circulating in significant numbers, the evidence strongly suggests that the increase in cases of this rare disease is linked to exposure to the virus."

The data was generated by Dr Paula David and Dr Gabriele DeMarco from the University of Leeds' School of Medicine and the Leeds Teaching Hospitals NHS Trust, with their Trust colleague Dr Khizer Iqbal. This work was done in collaboration with Dr Pradipta Ghosh and her team at the University of California, San Diego, who showed that the MDA5 protein was found in higher amounts in patients with COVID-19 and in patients with other diseases involving MDA5. They discovered that this increase was linked to an abnormal immune response that slows the virus's ability to multiply and spread. Additionally, they found that higher levels of the MDA5 protein were associated with increased levels of Interleukin-15, a protein that activates T-cells, or immune cells. This interaction could be contributing to the autoimmune response.

The investigators say that doctors should be aware of their findings so that patients can be more quickly diagnosed and referred for treatment, which could help lessen lung damage and save lives. This is especially so in subjects with suspected pneumonia not getting better on therapy and where the rashes, muscle involvement and other disease features are absent.

Dr Paula David, the first author of the paper, said: "We think that this large, unprecedented outbreak of MDA5 disease in Yorkshire will help advance the field to better appreciate the role between viruses and autoimmunity."

Dr Saptarshi Sinha, the co-first author of the paper and the interim director of PreCSN, added: "Here at PreCSN, we enjoy the ability to help researchers such as the McGonagle group dive into big data and find patterns rapidly with precision that allows us to connect the dots. In this case, we are glad we could find a connection between a clinical presentation of autoimmune disease in the backdrop of COVID-19 at a molecular level."