Scientists in the UK and US have discovered a previously overlooked Covid-related syndrome which has now resulted in a paper in eBioMedicine, a journal published by The Lancet.
It started with an email to Dr Pradipta Ghosh, professor in the Departments of Medicine and Cellular and Molecular Medicine at the University of California-San Diego School of Medicine, from Dennis McGonagle, PhD, professor of investigative rheumatology at the University of Leeds, UK, which triggered an international collaboration that uncovered the Covid-related syndrome.
McGonagle had asked Ghosh if she were interested in collaborating on a Covid-related mystery.
“He told me they were seeing mild Covid cases,” Ghosh said. “They had vaccinated around 90% of the Yorkshire population, but were seeing this very rare autoimmune disease called MDA5 – autoantibody associated dermatomyositis (DM) – in patients who may or may not have contracted Covid, or could not even remember being exposed to it.”
McGonagle described patients with severe lung scarring, some of whom presented rheumatologic symptoms like rashes, arthritis and muscle pain, which often accompany interstitial lung disease. He was curious to know if there were a connection between MDA5-positive dermatomyositis and Covid-19.
DM is more common in individuals of Asian descent, particularly Japanese and Chinese, reports News-Medical.net. However, McGonagle was noting this explosive trend of cases in Caucasians.
But that was the least of the problem, Ghosh added. Because he said: “Oh, and some of these patients are progressing rapidly to death.”
Ghosh is the founding director of the Institute for Network Medicine at UC San Diego School of Medicine, home to the Centre for Precision Computational Systems Network (PreCSN – the computational pillar within the Institute for Network Medicine). PreCSN’s signature asset is BoNE (the Boolean Network Explorer), a powerful computational framework for extracting actionable insights from any form of big-data.
“BoNE is designed to ignore factors that differentiate patients in a group while selectively identifying what is common across everybody in the group,” Ghosh said. Previous applications of BoNE allowed her and her team to identify other Covid-related lung and heart-afflicting syndromes in adults and children.
As a rheumatologist, McGonagle specialises in inflammatory and autoimmune conditions. His expertise, combined with the computational power of the Institute for Network Medicine, proved to be an excellent collaboration for probing the post-pandemic upsurge in inflammatory and autoimmune diagnoses.
Ghosh said McGonagle’s roster of patients, all within the UK’s National Health System (NHS), helped to facilitate the investigation.
The NHS has a centralised health care database with comprehensive medical records for a large population, making it easier to access and analyse data for research purposes.
The two experts pulled together a team to probe what they found was indeed an entirely new syndrome.
The study began with the British lab’s detection of autoantibodies to MDA5 – an RNA-sensing enzyme whose functions include detecting Covid-19 and other RNA viruses. A total of 25 patients from the group of 60 developed lung scarring, also known as interstitial lung disease.
Ghosh noted that the lung scarring was bad enough to cause eight people in the group to die from progressive fibrosis. She said there are established clinical profiles of MDA5 autoimmune diseases.
“But this was different. It was different in behaviour and rate of progression, and in the number of deaths.”
Ghosh and the UC San Diego team explored McGonagle’s data with BoNE. They found that the patients who showed the highest level of MDA5 response also showed high levels of interleukin-15.
“Interleukin-15 is a cytokine that can cause two major immune cell types,” Ghosh said. “These can push cells to the brink of exhaustion and create an immunologic phenotype that is very, very often seen as a hallmark of progressive interstitial lung disease, or fibrosis of the lung.”
BoNE allowed the team to establish the cause of the Yorkshire syndrome, and pinpoint a specific single nucleotide polymorphism that is protective.
By right of discovery, the group was able to give the condition a name: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with Covid-19. It is called MIP-C for short, “pronounced mipsy”, Ghosh said, adding that the name was coined to make a connection with MIS-C, a separate Covid-related condition of children.
Ghosh said it was extremely unlikely that MIP-C was confined to the United Kingdom. Reports of MIP-C symptoms are coming from all over the world, and she said she hoped the team’s identification of interleukin-15 as a causative link would jump start research into treatment.
Study details
MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the Covid-19 pandemic
Paula David, Saptarshi Sinha, Ella McLaren et al.
Published in eBioMedicine on 8 May 2024
Summary
Background
Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus.
Methods
This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between January 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in Covid-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak.
Findings
Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed Covid-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in Covid-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response.
Interpretation
A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during Covid-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.
News-Medical.net article – A previously unknown post-COVID syndrome found (Open access
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