A recent observational and retrospective study published in is causing discussion eBioMedicine (scientific journal of the group The Lancet). A team of Anglo-American researchers, led by Dennis McGonagle and Pradipta Ghosh, analyzed a group of Yorkshire patients positive for an autoimmune disease linked to the enzyme MDA5 (Melanoma differentiation-associated protein-5). An increase in cases has therefore been observed in connection with the Covid-19 pandemic. This led the authors to distinguish a new form: the MIP-C (MDA5-autoimmunity and Interstitial Pneumonitis Contemporary with the COVID-19 Pandemic).
Neither the first nor the last illness linked to Covid-19
This inflammatory, chronic disease manifests itself not only in the lungs but also in the skin and muscles. The progression is rapid and potentially deadly. It is explained by the action of antibodies that attack MDA5. Cases increased until 2022, when they began to decline. Symptoms include lung scarring, arthritis, myalgia, and skin rashes.
«We don’t have to worry about this MIP-C – he explained to Adnkronos Professor Matteo Bassetti -, it is an autoimmune disease that can be induced by Sars-CoV-2, it is the first time I have heard of it in four years of Covid. These are interesting works carried out during the pandemic, but I have never seen a case since I have been doing this job. Sars-CoV-2 may certainly have exacerbated some diseases, it may have “turned on” some already known autoimmune lung diseases, but – he concludes – I don’t think this is a big problem”.
We are talking about a «very interesting topic because after 4 years of work on Sars-CoV-2, new links with various autoimmune diseases are being discovered. The cause of dermatomyositis was hypothesized to be a virus – continues Professor Massimo Andreoni interviewed by Adnkronos – and today we know that Covid most likely plays a role. […] Many discoveries come precisely because as a scientific community we are studying this respiratory virus in great depth, so in the near future we will find other diseases linked to this infection.”
How MIP-C emerged
According to the reconstruction of Professor Ghosh of the San Diego School of Medicine in California, it all started when his overseas colleague McGonagle «told me that they were finding mild cases of COVID despite having vaccinated around 90% of the Yorkshire population, and they were encountering this very rare autoimmune disease called MDA5.” We would like to point out that mild forms of Covid, despite the vaccine alone, should not be a surprise; in fact, let us remember that Covid vaccines especially prevent severe forms of Covid-19.
During the Covid-19 pandemic, several cases of autoimmune dermatomyositis linked to the action of MDA-5+ proteins (this is an enzyme that allows the recognition of various mRNA viruses, including SARS-CoV-2). We are talking about a rare interstitial lung disease, which progresses rapidly and consequently has a high mortality rate.
The researchers studied a large cohort of patients where there was a plausible link between the autoimmune disease and Covid-19. They then defined similarities and differences compared to the Covid-related form, namely the MIP-C. This “new version” manifested itself “during or following a high community circulation of SARS-CoV-2 – explain the authors of the study – and only 58% of cases had had a previous vaccination against SARS-CoV2”.
Compared to the pre-pandemic form, MIP-C presented with a interstitial lung disease (ILD) in 40% fewer of the cases analyzed, even though the basic conditions that make this development possible existed. «Despite these differences – the researchers continue -, bio-informatics analyzes confirmed the shared immunophenotypes between the two as determining factors of ILD». However, we are talking about a rare pathology. At least this is what we know at the moment: “awareness and follow-up of MIP-C are essential to ascertain whether it will evolve into the typical adult form of MDA5 with much higher rates of lung disease”, hope the authors of the research.
The most probable correlation with Covid-19 (and not with vaccines)
The researchers suggest that this increase in interstitial lung diseases – contemporary with the pandemic waves – can be explained by “aberrant” responses of type 1 Interferon. Taking any future anti-vax readings off guard, we would like to point out that this work shows “good evidence of a link between SARS-CoV-2 infection and vaccination and perhaps both.” In short, it is precisely the existence of the pandemic that appears to be the determining factor. Let’s examine some passages that may appear ambiguous:
«Given that almost 42% of new cases were not vaccinated before MDA5+ disease – the researchers continue -, this suggests that a milder COVID-19 disease, both manifest and hidden [Ricordiamo che molti casi sono asintomatici, Nda] may be sufficient to cause autoimmunity to MDA5. Given that the peak of MDA5 positivity tests followed the peak of COVID-19 cases in 2021 and coincided with the peak of vaccination, these findings suggest an immune reaction or autoimmunity against MDA5 following exposure to SARS-CoV-2 and/or the vaccine; could represent a novel immunogenicity in non-immune subjects following the involvement of RNA with MDA5, causing an increase in cytokine response and thus triggering an autoimmune disease. The development of herd immunity and lower respiratory exposure to SARS-CoV2 could theoretically contribute to the milder phenotype at the population level in the MIP-C entity we propose.”
Although the study authors suggest a link between activation of the MDA5 protein with either natural infection or vaccination “or potentially both,” leading to MIP-C; the first thing that emerges is how «the severity of COVID-19 can dictate the risk of progression towards [la malattia polmonare interstiziale, Nda]; a risk that Covid vaccines significantly reduce. Moreover, their conclusions speak of “a plausible and potentially causal link between the increase in anti-MDA5 positivity, autoimmune ILD and COVID-19”, while vaccines are not mentioned.
The limitations of the study
The study also has limitations. Despite the importance of texts of this nature which allow us to contextualize diseases and their extent, we often tend to forget that we are never faced with sacred and inviolable texts. It is no coincidence that we specified right from the introduction that we are talking about observational and retrospective research. We are therefore talking about work carried out by collecting data regarding phenomena that have already occurred, therefore without the researchers having been able to carry out further checks.
For example, the authors of the study point out that “the majority of patients were not systematically tested”, which is why in several patients there is uncertainty about the “Covid-19 infection status”. Not to mention that we are talking about 25 patients with lung scarring characteristic of interstitial lung disease (eight of whom died due to the related progressive fibrosis), out of a total of 60 people. The same uncertainty is also found on the analysis of antibodies:
«Another limitation is the lack of data on the serology of Covid-19 – the authors report -, i.e. antibodies against the spike, binding domain of the spike receptor and nucleoprotein. This limits any extrapolation in relation to MIP-C disease and the precise link between SARS-CoV-2 circulation, infection and vaccination.”
We noted in the article that there is also an “asymptomatic dimension” of Covid-19, which further contributed to limiting the study results. «We do not have data on asymptomatic infection or prolonged carrier status as potential factors in some of these cases – the researchers continue -; nor did we have patient-derived samples to analyze the transcriptomic datasets of our cohort.” We are certainly not talking about a poorly done job, nevertheless all these limitations also played a role in the statistical rigor, which by the authors’ own admission “was not possible in some cases”.
