The Causes of Long Covid

There are two really interesting papers that have come out that give us some very badly needed insights into “Long Covid”, which we can define as a constellation of symptoms that persist many weeks after a coronavirus infection. Most people recover quite well - I’ve had the damn virus more than once myself and haven’t noticed any particular long-term effects. But not everyone is so fortunate! Estimates are fuzzy, but there are millions of people worldwide who are dealing with long-Covid problems, and this has a real public health impact. But trying to figure out what’s going on has been difficult. One of the most likely guesses has been that this has something to do with the immune response, of course. That would fit with the individual nature of the response, since everyone’s immune system has its own fingerprint, and it would also fit with known immune-based sequelae to other infections. You can start with acute things like Guillaon-Barré syndrome and go on from there; there’s no doubt whatsoever that in some people particular viral or bacterial infections can go on to resonate for years while others don’t go though this at all. This sort of thing is particularly noted in respiratory viral infections, for various reasons that are still being worked out. Lyme disease may well be another example. There is no doubt that research in these areas has been hampered by years of assigning these problems as more of a matter for psychiatry than immunology Unfortunately, it has been very hard to shore up this very appealing autoimmune hypothesis with hard data, but that might have just changed. There have been many reports of autoantibodies (a key signature of autoimmune disease) in these patients, but the literature on these seems to be in a rather shaggy state and in need of a lot more validation than has been available. But here’s a paper from Cell Reports Medicine, and here’s another from Cell itself. Both of these groups have done painstaking searches for such autoantibodies - the first finding candidates targeting skin and epithelial tissue, the second (looking closely at patients with neurological and cognitive symptoms) targeting neural and endocrine tissues. It’s believed that the skin/epithelial autoantibodies may well be targeting nerve endings in those tissues, so there could be an overall neurological component to Long Covid in general.

Importantly, IgG fractions from the blood of these individuals cross-reacted with several types of mouse tissue in vitro, and transfer of this IgG to living mice reproduced symptoms such as pain, fatigue, coordination problems, temperature sensitivity and more. These effects were not seen with IGg transfer from unaffected patients. It hardly needs pointing out that you cannot transfer a nervous disposition or a persistent bad attitude by transfusing antibody fractions. Long Covid is a real a disease as lupus, MS, Hashimoto’s, or Type I diabetes, all of which are driven by production of antibodies to a person’s own tissues. Many will immediately think of fibromyalgia, another autoimmune syndrome that has also been taken to the point of identifying autoantibodies. It’s possible that what we’re calling Long Covid is a new variety of this, but it could also be its own distinct immunological problem. There’s an awful lot of work to be done to figure out what the exact protein targets are of the autoantibodies and what sets off their production in susceptible individuals. Ideally insights into that might help you identify such people prospectively.  It’s also going to be a hard road to treatment - you will note, for example, that there is no decent treatment for fibromyalgia itself. But it’s possible that the B-cell-targeting therapies that are being tested for diseases like lupus might provide a way forward, and the good news is that we are in general entering on what looks like a golden age for immunology. May it continue, and bring understanding with it.