A Deadly Post COVID Syndrome Doctors Never Saw Coming

10 January 2024
by: Juicing For Health
in Lifestyle & Wellness

Last updated on

Professor Dennis McGonagle sat in his office at the University of Leeds, staring at medical charts that made no sense. Patients were arriving with a rare autoimmune disease he had studied for years, but something was different. Alarmingly different. MDA5-positive dermatomyositis has always been a condition of Asian populations, particularly among Japanese and Chinese patients. Yet here in Yorkshire, England, white British patients were flooding into his clinic with the same telltale antibodies. Some developed severe lung scarring. Eight would die. Between 2020 and 2022, McGonagle and his colleagues documented 60 new cases of Anti-MDA5 positive dermatomyositis in a region where the disease was virtually unknown before the pandemic. Even stranger, many patients had no memory of being sick with COVID-19. Some had experienced nothing more than mild symptoms or perhaps felt nothing at all. McGonagle needed help solving a medical mystery that was claiming lives.

When Numbers Tell a Disturbing Story

Before 2019, MDA5 autoimmunity represented just 0.4% of muscle-specific autoantibody tests in Yorkshire. By 2021, that figure had exploded to 4.8%, a twelvefold increase that coincided precisely with major waves of SARS-CoV-2 infections sweeping through the region. No other autoantibodies showed similar patterns. Just MDA5. McGonagle reached across the Atlantic to Professor Pradipta Ghosh at the University of California San Diego School of Medicine. Ghosh directs the Institute for Network Medicine, home to computational tools powerful enough to extract patterns from massive datasets. Her team had already identified other COVID-related syndromes affecting hearts and lungs in adults and children. “He told me they were seeing mild COVID cases,” Ghosh recalled. “They had vaccinated around 90 percent of the Yorkshire population, but now they were seeing this very rare autoimmune disease.” What happened next would give this mysterious condition both a name and a potential explanation.

An Enzyme Turns Against Itself

MDA5, or melanoma differentiation-associated protein 5, serves as one of your body’s frontline defenders against viral invaders. When SARS-CoV-2 enters your system, MDA5 acts as an RNA sensor, recognizing the virus and triggering immune responses to fight it off. But in these Yorkshire patients, something went wrong. Rather than simply detecting the virus, their immune systems began producing antibodies against MDA5 itself. Antibodies that attack an enzyme designed to protect you create a cascade of destruction. Triggered by these rogue antibodies, patients developed progressive interstitial lung disease. Lung tissue begins scarring, thickening, and losing its ability to transfer oxygen into the bloodstream. In severe cases, breathing becomes labored, then desperate, then impossible. Among the 60 patients McGonagle identified, 25 developed interstitial lung disease. Half of those cases progressed with frightening speed. Eight patients died despite aggressive medical intervention.

Cracking the Code with Computational Power

Ghosh assembled her team, including computational scientist Saptarshi Sinha and undergraduate researcher Ella McLaren. Armed with comprehensive medical records from the UK’s National Health System, they deployed their signature tool called BoNE, the Boolean Network Explorer. BoNE operates differently from traditional statistical analysis. Rather than looking for differences between patients, it searches for commonalities, ignoring factors that vary while identifying what every patient in a group shares. Feeding McGonagle’s patient data into BoNE, the UC San Diego team discovered a striking pattern. Patients showing the highest MDA5 response also exhibited elevated levels of interleukin-15, an inflammatory cytokine with a dark reputation. Ghosh explained that IL-15 “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.” Pieces of the puzzle were falling into place. By right of discovery, the international team earned the privilege of naming their finding. They called it MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID-19. Mercifully, they shortened it to MIP-C, pronounced “mipsy,” deliberately echoing MIS-C, a separate COVID-related syndrome affecting children.

Patients Without Known Infections

Among the most puzzling aspects of MIP-C remains its apparent trigger. Only 8 of the 60 patients had previously tested positive for COVID-19. Yet the surge in cases tracked perfectly with regional SARS-CoV-2 circulation during 2021. Several explanations emerged from the data. Many patients likely contracted asymptomatic infections they never knew about. Others may have experienced such mild symptoms that they dismissed them as ordinary colds. Still others might have been exposed to the virus without developing full infections. Vaccination history added another layer of complexity. Among the 60 patients, 58% had received anti-SARS-CoV-2 vaccines before developing MDA5 autoimmunity. However, 42% had not been vaccinated at all, suggesting infection alone could trigger the syndrome. Peak MDA5 positivity followed peak COVID-19 cases in 2021 and overlapped with peak vaccination rates. Researchers concluded that “an immune reaction or autoimmunity against MDA5 upon SARS-CoV-2 and/or vaccine exposure” appeared responsible, though the exact mechanisms remained unclear. Recent research may offer clues. Modified RNA in vaccines can be sensed by MDA5 in lymph nodes, resulting in type I interferon production. These interferons then induce antigen-specific CD8+ T cell responses. Because RNA recognition by MDA5 depends on sequence and structure, the resulting immune activation varies by cell type, tissue, and biological context.

Two Faces of One Disease

MIP-C patients fell into two distinct groups with markedly different outcomes. Among the 25 who developed interstitial lung disease, symptoms centered on breathing difficulties. Chest CT scans revealed fibrosis, ground glass changes in lung tissue, or both. The average age hovered around 60 years, and 48% were women. Prognosis varied wildly. Twelve patients stabilized with or without specific therapy. Four developed progressive lung disease but survived. Eight died from pulmonary complications despite intensive treatment. By contrast, the 35 patients without severe lung involvement tended to be younger, around 53 years old, and 68.6% were women. Rather than respiratory distress, they presented with connective tissue symptoms. Cutaneous rashes appeared in 28.6% of cases. Raynaud’s phenomenon, where fingers and toes turn white or blue in response to cold or stress, affected 48.6%. Proximal muscle weakness troubled 40%. Some patients developed multiple symptoms simultaneously. Blood tests told an interesting story. Only 60% tested positive for antinuclear antibodies, a common marker in autoimmune diseases. Many patients carried additional autoantibodies beyond anti-MDA5, with anti-SAE1 and anti-Ro52 appearing most frequently. Creatine kinase levels, which typically spike when muscle tissue breaks down, remained surprisingly normal in most patients. Median levels were 90.5 units per liter, suggesting minimal muscle damage despite other symptoms.

Genetic Protection and Vulnerability

Genetic analysis revealed a protective variant that changes everything. Patients carrying the rs1990760 TT genotype in their IFIH1 gene, which encodes MDA5, showed reduced susceptibility to severe disease. Multivariate analysis demonstrated that rs1990760 TT emerged as the strongest determinant of IFIH1 transcript induction. Among those with this protective variant, younger age correlated with higher protection levels. Among patients lacking the protective genotype, being female and having moderate rather than severe disease increased IFIH1 surge. Steroids offered protection, but only in specific genetic contexts. Systemic corticosteroid treatment proved effective exclusively in subjects with rs1990760 CT/CC variants, not in those with the protective TT variant. Two distinct subgroups emerged among TT variant carriers. High inducers of the IFIH1 transcript showed 26 upregulated genes enriched for type 1 interferon signals. These genes included markers of progressive autoimmune lung disease like CXCL10, interferon-induced genes associated with systemic autoimmune rheumatic diseases, and adaptive immune hallmarks specific to MDA5+ dermatomyositis.

How MIP-C Differs from Classic Disease

Comparing MIP-C to classic MDA5-positive dermatomyositis reveals important distinctions. Classic disease strikes predominantly Asian populations, affects women at rates around 66%, and causes lung involvement in nearly all cases. Mortality rates run high, with rapidly progressive fibrosis being the norm. MIP-C presents differently. Ethnic distribution shifts to predominantly Caucasian patients. Gender balance tilts slightly toward women at 60%, but less dramatically than classic disease. Lung involvement drops to 42% of cases, at least in the first two years following diagnosis. While eight deaths occurred among 60 patients, representing a 13.3% fatality rate, many more patients experienced stable or slowly progressive disease. Nearly 60% of MIP-C patients showed manifestations of connective tissue diseases without severe pulmonary complications. Cutaneous rashes, Raynaud’s phenomenon, and mechanic’s hands appeared more frequently than in classic presentations.

What Doctors Still Don’t Know Could Matter

Ghosh stressed that MIP-C likely extends far beyond Yorkshire. Reports matching the syndrome’s clinical profile are emerging worldwide, suggesting a global phenomenon that may have gone unrecognized during the chaos of the pandemic. Awareness among clinicians remains limited. Many physicians have never encountered MDA5 autoimmunity, particularly outside Asian populations. Patients with unexplained breathlessness following COVID exposure, dermatomyositis symptoms in unexpected ethnic groups, or rapid lung function decline after vaccination may represent undiagnosed MIP-C cases. Research continues on several fronts. Scientists are investigating why some patients develop severe lung disease while others remain stable. Treatment protocols are being refined, with JAK inhibitors like tofacitinib showing promise for cases that don’t progress to severe fibrosis. Medical mysteries like MIP-C remind us that pandemics leave long shadows. Even mild infections carry hidden risks, triggering autoimmune cascades months after the original virus has cleared. As the world moves beyond acute COVID-19 crisis mode, vigilance for these delayed consequences becomes paramount. Somewhere right now, a patient may be developing unexplained breathlessness or mysterious rashes following a COVID infection they barely noticed. Understanding MIP-C could save their life.

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