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.Blog: Sunday April 26th, 2020.The first volunteers in the Oxford Covid-19 project were enrolled on schedule last week. While this important study progresses over the next weeks and months, I’ll consider a related issue of immunity: why does the severity of Covid-19 show such enormous variation? At one extreme, devastating, sometimes fatal illness; at the other, infection that may even not be recognised because there are no signs or symptoms of an illness. Because of the latter, it is not known how many people have been infected with Covid-19, information that is crucial to making decisions on the duration and stringency of lockdown.Before considering immunity, could these differences in severity depend on the virus itself? We know that the amount of virus that is spread from one person to another varies. This affects the likelihood and number of new infections but there is no compelling evidence that it affects the severity of the disease in any one individual who becomes infected with Covid-19. (The biology of transmission, including the concept of basic reproductive rate [R] needs to be discussed on another occasion). What about variation in the virus itself, in other words are there some variants of Covid-19 that are more virulent than others? There is no evidence for this and through sequencing the genetic material of thousands of isolates of Covid-19, this seems vanishingly improbable.This leaves us with explanations that have to do with variation in how our immune systems respond to the virus; susceptibility and severity. Some people are intrinsically more likely to get infected than others, independent of exposure. So, two people who are subjected to the same amount of the same virus in precisely the same conditions may differ in the probability of becoming infected. They differ in susceptibility because they have different degrees of immunity to the virus, for example because of prior exposure or, as we hope in the future, immunisation. But if infection becomes established, there is the issue of the severity of the infection. Our immune systems are different depending on two major variables. Our genes and our life experiences - often referred to as nature and nurture. They are not independent of one another. They cannot and should not be teased apart. So, let’s think nature (genetics) via nurture (environment) The genetic basis of the immune system is a vast topic, one that would need a multi-volume book to do it justice. But it’s where I would expect to find the major reasons for the differences in severity of Covid-19 infections. We are programmed through nature and via nurture, but nobody has the key to unlock the code of these instructions. Scientists have made huge progress in understanding the intricacies of our immune responses in general, but we are only scratching the surface of how this knowledge can be applied to any one individual. Of course, the human genome project has been a huge advance, but using this information to predict complex determinants of health and disease are in their infancy. What we can say is that what we experience as disease – fever, aches and pains, tiredness, pneumonia even multi-organ failure – are mostly the result of our immune responses. The virus may kill off some of our cells but these direct effects pale into insignificance compared to what the virus triggers through our immune responses. I like the way in which this is described by Lewis Thomas, a pathologist from New York, in his delightful book of essays called the Lives of a Cell1 ‘The germs that seem to have it in for us in the worst way – ones that really appear to wish us ill – turn out on close examination to be rather more like bystanders, strays, strangers in from the cold. They will invade and replicate if give the chance, and some of them will get into our deepest tissues …….. but it is our response to their presence that makes the disease. Our arsenals for fighting them are so powerful, and involve so many different defence mechansims, that we are in more danger from them than from invaders. We live in the midst of explosive devices; we are mined’We do not have effective treatment to treat Covid-19 at present although there is a a huge research effort to develop new treatments. Efforts to develop vaccines are moving forward apace but, in my opinion, are not likely to be widely available until at least a year or more from now. Infusing plasma (blood from which the red and white blood cells have been removed) obtained from people who have recovered from Covid-19 infection is being studied as a promising possibility and may be available in the reasonably short term – for the lucky few.Living with uncertainty is no fun. Eleanor Roosevelt wrote: ‘You gain strength, courage and confidence by every experience in which you really stop to look fear in the face…… you must do the thing you think you cannot do.’ We are gaining knowledge and making rapid progress in understanding this new pandemic virus. It takes time. For example, men die more often from Covid-19 than women and a clue to this may be in the number of receptors (ACE-2) that are higher in men. Further work is needed, but overall I am optimistic that scientists will find answers in the form of new drugs, vaccines and public health interventions. cientists are only scratching the surface of understanding how our immune systems respond to microbes in general or to one germ in particular, such as Covid-19. What we can say is that what we experience as the illness - fever, aches and pains, tiredness, pneumonia, perhaps organ failure - are all the result of our immune responses. The virus may kill off some cells, but these direct effects pale into insignificance in comparison to what the virus triggers through our immune responses. I like the way in which this is described by Lewis Thomas, a pathologist from New York in his delightful book of essays called The Lives of a Cell1. ‘The germs that seem to have it in for us in the worst way – the ones that really appear to wish us ill – turn out on close examination to be rather more like bystanders, strays, strangers in from the cold. They will invade and replicate if given the chance, and some of them will get into our deepest tissues ….. …but it is our response to their presence that makes the disease. Our arsenals for fighting them are so powerful, and involve so many different defence mechanisms, that we are in more danger from them than from the invaders. We live in the midst of explosive devices; we are mined.’ But not all of us are subject to this havoc and there are only the smallest hints as to what determines the extremes between life-threatening infection and speedy recovery (with everything in between) even though we know some generalities – age being a conspicuous variable. But chronology itself is a blunt tool for predicting who is at risk of severe disease. Men seem more likely to be seriously affected than women. An important clue bearing on this is that men have a higher prevalence of the receptor to which the Covid-19 virus binds to human cells (through the spike protein that we mentioned previously). It is called ACE-2 and is a basis for exploring treatment possibilities for the future2. So, we do not yet have any effective drugs for treating Covid-19 and drenching your lungs with bleach is not a wise option. There are enormous efforts to develop a vaccine, but realistically this is not likely to be widely available until at least a year from now (in my opinion). Infusing plasma (blood from which red and white cells have been removed) obtained from people who have recovered from Covid-19 infection is being studied as a possibility and may be available in the reasonably short term - for the lucky few. Living with uncertainty is no fun, not at all, Eleanor Roosevelt wrote: “You gain strength, courage and confidence by every experience in which you really stop to look fear in the face…. you must do the thing you think you cannot do.” END ON POSITIVE NOTE. ................
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