By Dr Irina Metzler
One of the puzzles in the Covid story is how different the effect of SARS-CoV-2 can be from person to person. If we accept the notion of ‘asymptomatic transmission’, then Covid is inconsequential for such a large number of apparently infected people that they notice no symptoms whatsoever, while others have symptoms so mild they are comparable to the common cold, yet a minority of infected people suffer very severe reactions and unfortunately sometimes lethal outcomes. This very wide variance in how individuals’ bodies react to the virus makes COVID-19 a most unusual illness. What follows are some speculative musings on potential factors influencing individual variance, in other words, asking the question: Have we missed something that could explain why some people fall very ill and even die, yet others don’t even know they’ve got it?
Besides individual disparity in reactions to the SARS-CoV-2 virus, there is of course the disparity in how regional variation affects mortality and severe illness. Contrary to most beliefs in an efficient health care system (including preventative care, hygiene, nutrition, immunisation programmes), whereby there should be less illness in those nations that have better and more accessible healthcare provisions, Covid actually seems to be less of a threat to poorer, economically weaker nations which had a lower case fatality rate (meaning fewer deaths per number of infected individuals) than economically stronger countries).
Demographics certainly play a role in this disparity, since older people are more likely to fall victim to Covid than younger, and economically wealthier countries have larger numbers of the old than poorer countries. But other factors, such as the former ‘hygiene hypothesis’, now refined as the ’Old Friends’ hypothesis, and the incidence of autoimmune disorders in higher-income countries have also been advanced. The hygiene hypothesis is well known and argues that the more ‘clean’ we have become, the less chance our immune systems have had to be ‘trained’ in how to ward off pathogens. Hyper-hygienic conditions, which have been advocated in most high-income countries, through things as basic as using anti-bacterial products for everything from chopping boards for food preparation to the now ubiquitous hand sanitisers, have in fact contributed to the lack of training in childhood for most Westerners’ immune systems. Lack of exposure to parasites and other pathogens, which would train the immune system, has been linked to impaired Type1 interferon activity, which in turn has been linked with susceptibility to the SARS-CoV-2 virus (see Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients). Paradoxically, then, the inhabitants of higher income countries are, despite enjoying overall better health outcomes, at greater risk of developing severe COVID-19 than those in lower-income nations.
With the ‘hygiene hypothesis’ in mind, let me now develop a related hypothesis further, namely the idea of hyper-medicalisation. Hyper-medicalisation describes the increasing use of medical services, medical treatments and medicines in a given society. In the Western world, we have seen an exponential growth in the use of pharmaceuticals, treatments and services. This has come about due to more and more diseases being treatable (which in ethical terms is good, obviously), but also due to more and more diseases being discovered and identified. In fact, there is a whole catalogue of conditions, mainly on the neurological and developmental disorder side, that apparently did simply not exist three or four decades ago, Asperger’s/Autism Spectrum Disorder being the one best known, but also more exotic conditions such as Brugada Syndrome (a very rare genetic heart condition first described in 1998). And just to emphasise how recent our knowledge on viral diseases actually is, two of the four coronaviruses that infect humans with usually mild symptoms, namely human coronaviruses HKU1 and NL63, were both only discovered in 2004. But discovery does not mean a virus or disease did not exist prior to discovery; NL63 is estimated to have diverged from another coronavirus HCoV-229E around a millenium ago, and therefore likely to have circulated in humans world-wide for centuries (see Mosaic Structure of Human Coronavirus NL63, One Thousand Years of Evolution). The date of that discovery in 2004 is probably connected with the fact that because of the much more serious outbreak of yet another coronavirus, the ‘original’ SARS in 2002, by 2003 scientists were actively hunting for similar viruses – a case of seek and thou shalt find. Or to put it another way, you can only ask the right questions from an informed standpoint, which implies that if you know (or think you know) what you are looking for you are much more likely to find it than by chance alone.
We know more as a society about diseases, as well as having higher expectations for our health, but we are also far more worried to the point of acting like collective valetudinarians. One side-effect of this is that, as many more people now compared to the past will seek medical advice and treatment, and receive such treatment, the number and variety of pharmaceuticals (‘drugs’) we take is also on the up. Yet again demography is a contributing factor. Older people are basically more likely to require (and want) medication to deal with the ‘niggles’ of getting older. This is all well and good for the more-or-less standard diabetes, hypertension and cholesterol drugs that most people over a certain age seem to be on simultaneously. But keep adding to the cocktail of pharmaceuticals, for more and more conditions and diseases and the chances of cross-reactivity increases. As they say in mechanics, the greater the number of moving parts, the greater the risk of breakdown.
Now consider what the mix of hyper-medicalisation, low levels of innate immunity and demographics may contribute to the susceptibility to COVID-19 and the severity of the disease in an individual. Here we need to turn to two pieces of observed reactions in COVID-19 patients: cytokine storm and antibody-dependent enhancement (ADE). ‘Cytokine storm’ has been the term used for an immune response that has gone into overdrive, when proteins in a person’s blood called cytokines reach such a high level that the body does not just fight off invading pathogens but starts to attack its own cells (see Cytokine Storms May Be Fueling Some COVID Deaths). Cytokine storms are known to be related to autoimmune disorders but also to inflammation more generally. Obesity is one of the leading causes for higher levels of cytokines, because body fat stores large quantities of cytokines, which when released leads to higher levels of inflammation. In Europe, around 30-70% of adults are overweight, with 10-30% in the obese category, and as has been noted time and again, being overweight let alone obese is one of the major risk factors in developing severe Covid (see Covid-19: Why are age and obesity risk factors for serious disease?).
Let me recap: we have, in high income countries generally, but especially in the UK, quite a few sections of a population with a reservoir of highly susceptible people for developing more severe reactions to SARS-CoV-2: relatively low innate immunity due to lifestyle and lack of exposure to microbial pathogens, a weighting toward an elderly demographic which in addition to age as a risk-factor is also a demographic commonly taking a cocktail of potentially counter-indicative medications, and a large proportion of the population who are overweight or obese and thereby at risk of a cytokine storm reaction.
And so to the final consideration: antibody-dependent enhancement (ADE). ADE occurs when so-called non-neutralising antibodies are present in a person, rather than neutralising antibodies, which actually make the susceptibility to some viral diseases worse. The immune system works by producing a neutralising antibody which can recognise and bind to the correct epitope of a virus, which then either stops the virus entering the body’s cells or stops it replicating in those cells. A non-neutralising antibody still binds to a virus, but fails to ‘neutralise’ the effect of the virus, in other words leaves the virus still capable of infecting body cells. If an individual has non-neutralising antibodies, derived perhaps from initial immunity after a previous infection or a vaccine, but whose immune efficiency is wearing off, then a subsequent infection by the virus can lead to a more severe reaction. It is important to note here that this ADE reaction is not a behaviour typical of all viruses, but only particular ‘families’ of viruses, of which, no surprises, coronaviruses are a part (dengue, ebola, HIV and RSV are others). It seems that the presence of non-neutralising antibodies actually enables the virus to gain easier access to infect immune cells, which then in turn elicits a hyper-inflammatory response, namely the cytokine storm mentioned above. To repeat, this is not the case for all viruses, but it does seem to be a persistent problem for coronaviruses generally and in particular with SARS-related viruses (see Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus). The genetic and structural similarities between SARS-CoV-2, causing Covid, and the other coronaviruses suggest strongly that ADE is a real risk.
Unfortunately this connection between coronaviruses and ADE has also been observed in a study looking at influenza vaccination and respiratory virus interference. The research wanted to establish if receiving the seasonal influenza vaccination might increase the risk of other respiratory viruses, a phenomenon known as virus interference. The conclusions of this piece of research showed very mixed results and were rather interesting, since they indicated that while virus interference was absent for most respiratory viruses, vaccine derived virus interference was significantly associated with coronavirus and human metapneumovirus.
While influenza vaccination offers protection against influenza, natural influenza infection may reduce the risk of non-influenza respiratory viruses by providing temporary, non-specific immunity against these viruses. On the other hand, recently published studies have described the phenomenon of vaccine-associated virus interference; that is, vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection.
This seems to have been the case with the coronavirus investigated in this study – which was published in January 2020, so before the SARS-CoV-2 virus had been identified.
Therefore I return to my original question: Have we missed something that could explain why some people fall very ill and even die, yet others don’t even know they’ve got it? If one takes a possible link between influenza vaccination and respiratory virus interference seriously, as well as considers the high-risk factors of much of the Western, never mind UK population (older demographic, low innate immunity, hyper-medicalised, obese) then the following questions need to be asked:
1. Is there a possibility that those people who received the seasonal influenza vaccine in autumn 2019 were then in spring 2020 more disposed to respiratory virus interference from one of the coronaviruses (which obviously includes the novel SARS-CoV-2)? And could the same be the situation now, with individuals having received the ‘flu vaccine in autumn 2020 suffering virus interference in January 2021? A simple trawl through medical records cross-referenced with individual fatality or severe illness requiring hospitalisation should provide the answer.
2. If there is a correlation between receipt of ‘flu vaccine and developing severe Covid, what mitigating factors could be considered? Should there be a more nuanced application of vaccination programmes? Would it be beneficial to look at individually-tailored risk assessments, given that Covid is presumed to be ‘far worse than the flu’, so that the cost of susceptibility to Covid (age, low innate immunity, obesity, multi-medicine reliant) is weighed up against the benefits of influenza vaccination?
These are not questions that can be dismissed out of hand. Certainly the potential linkage between flu vaccination and respiratory virus interference from SARS-CoV-2 needs to be looked at as a matter of urgency. What actions are then taken is a debate to be held when the results come in. For the time being I can only conclude, taking the ‘long view’ of a medical historian, that while in many ways our collective health has improved vastly over the past century, improvements come at the cost of hyper-medicalisation. The more we medicalise, the more illness we have. Build a better mouse trap and the mice get smarter. Medical history is replete with iatrogenic illness, caused by the well-intentioned but hasty and over-zealous actions of physicians in an attempt to cure. One may think of the mercury poisoning resulting from curative regimes for syphilis applied by eighteenth-century doctors, or the infamous Thalidomide-related birth defects resulting in the mid-twentieth century from something as innocuous as a pill prescribed against ‘morning sickness’, to cite just two of the better known instances. History will tell if the current approaches taken toward SARS-CoV-2 were justified.
Dr Irina Metzler FRHistS is a medical historian and former lecturer at the University of Swansea, as well as a Wellcome Trust University Award Fellow