With case numbers falling, Ruth Gilbert tests some COVID-19 theories
Donald Trump has excelled at stand-out advice to head off major disasters. Anyone remember his sage exhortation for avoiding worldwide arboreal conflagrations? Yes, rake your forest floors. Last month he surpassed himself much more dangerously with an astonishing suggestion for curing COVID-19 victims - inject them with disinfectant.
As the world races to find answers to the disease, we are still deep in the realms of speculation. Some theories seem more feasible than others, but by comparison with the above, the smorgasbord of theories explored below should seem far less unlikely than they might otherwise appear.
The main COVID-19 risks
In the previous article to this one, several groups were mentioned as being at higher risk.
It's now become more well established that:
- UK men are more likely to die of COVID-19, outpacing women by nearly 100% amongst 45-64 year olds, and 30% over age 65.
- Older people account for the majority of COVID-19 deaths: 88% (probably an understatement) of deaths registered in England and Wales by 24/4 were amongst over 65s
- Death rates associated with deprivation are twice as high.
- There's a large over-representation of non-white patients compared to the population
We also know that compared to viral pneumonia, higher levels of co-morbidities are involved amongst ICU COVID-19 patients, with high blood pressure, high BMI and diabetes featuring strongly. However, co-morbidities are not the whole answer to why certain people are worse affected.
A study of 28% of all UK hospitalised COVID-19 patients (16,749) found 47% had no documented comorbidity. Among the rest, the most common noted at admission were chronic cardiac disease (29%), uncomplicated diabetes (19%), chronic pulmonary disease excluding asthma (19%) and asthma (14%). (Hypertension was not one of the criteria searched on, but is often mentioned elsewhere.)
The tricky thing about all these associations with the disease is working out which of them actually tell us anything useful. It's very easy to look at each one in isolation and jump to conclusions. It's also difficult to separate differences between the rates of infection (differentiating exposure vs susceptibility), severe symptoms and mortality, which don't always match between groups.
Why are men harder hit?
Contrary to what their partners might suggest, it's not to do with differences in hand-washing. Men and women are equally likely to contract the virus. That's where equality ends. Men are in the majority to be hospitalised with COVID-19 (60%), and to end up in ICU (72%) and, once there, are less likely to survive (51% of the men died, while only 43% of the women did). In the ONS statistics, this translates to men accounting for nearly two thirds of COVID-19 related deaths in the 45-64 and 65-74 age groups. (The proportion lowers with increasing age, as there are more older women.)
An intriguing fact comes out of the Continuous Mortality Investigation's analysis of excess death rates. In week 17, for over 75s, men and women had pretty much the same percentage increase of death rates (+129% to +138%). But whilst younger men were also dying twice as fast as expected, for women rates were up by relatively lower rates: 73% vs expected amongst 45-64 year-olds and 59% if 65-74.
Thoughts so far about the role of testosterone and oestrogen have proved inconclusive, although the latter is being looked at more closely. Female immune systems certainly give general improved protection, producing higher levels of antibodies and preventing as much viral load and inflammation as suffered by men. One of the explanations offered is to do with the X-chromosome, of which female DNA has two. However, none of this explains why the male disadvantage is so pronounced for this type of infection compared to others.
Smoke and mirrors
One suggested explanation for the gender split has been that men more likely to be smokers than women and tend to smoke more heavily. This is especially true in China. However, conflicting data there makes a link look less likely than you'd guess. Although some smokers fared less well with severe symptoms, smokers were very much under-represented amongst patients.
In the UK, the link is also tenuous, as we have now have low numbers of smokers to start with and the ratio of male smokers to female is only 1.3 vs their ratio of arrival for COVID-19 in ICU, being 2.5.
The high rate of severe COVID-19 amongst Asian and Black ethnicities is also a confounder for smoking as a top risk factor. Smoking prevalence in these groups in the UK is about 2/3 of that for whites.
Even more surprisingly, whilst no-one's suggesting taking up smoking, a French study appeared to show that people who smoke are 80% less likely to catch COVID-19 than non-smokers of the same age and sex. This seems counter to other findings that smokers fare less well when it comes to worse symptoms and the fact that smokers have more ACE2 receptors, which are the route in that the virus uses.
A possible explanation is in the difference between incidence and severity. Inhalation of nitric oxide could help prevent infection, whereas once the virus manages to get a grip, the damage already done by smoking makes patients more vulnerable.
The King's College Twins study team using the ZOE COVID-19 symptom study app, now with about three million UK users, found from analysing 2,633 twin users of the app that roughly half of the difference in symptoms between people can be explained by underlying variations in their genes, while the rest is due to other factors such as amount of viral exposure (viral load), underlying health conditions, environment and lifestyle.
This lends credence to the idea that genetic differences could explain part of the differences in severity of symptoms and in mortality between the sexes and different races.
The BAME concern
Concerns have been raised about the disproportionately high numbers of people of Black, Asian and mixed ethnicity (BAME) vs White COVID-19 patients. For example, ONS data just out shows Black males are 4.2 times more likely to die from a COVID-19-related death and Black females are 4.3 times more likely than White ethnicity males and females.
As you'd expect, wide differences within ethnic sub-groups exist, making analysis difficult.
Higher levels of diabetes among some groups has been thought to be one potential factor.
Early high level indications had suggested that case fatality rates are no worse than for Whites, after controlling for other factors. This suggested the main problem is exposure in the first place. This can be related to location, occupations in the front line whether in healthcare or service roles, and also factors to do with relative poverty and overcrowded housing.
However, the new ONS data counters that as the whole answer. Controlling for socio-economic background as well as age and sex, all groups, except for Chinese women, showed a higher risk than Whites, with Blacks still being at almost double the risk.
Solutions ruled out or being tested
Apart from those New Yorkers discovering ingestion of disinfectant results in internal burns, many other more plausible things have been tried and don't seem to help much or are being tested but results aren't out yet. Among the don't help list are:
- Remdesivir, an antiviral drug getting the FDA all clear, seems to have minimal effect
- ACE inhibitors seem to make no difference, whilst fortunately doing no harm
- Antimalarial hydroxychloroquine, another Trump favourite, has shown no particular benefits, but with increased risks, although Novartis hasn't given up hope
- Systemic corticosteroid treatment has been found to have no significant benefits in China
- Treatment for altitude sickness rather than acute respiratory distress syndrome (ARDS) has been confirmed to be wrong and dangerous
Among the longshots being tested for symptomatic relief or immunity are:
- Monoclonal antibodies - the guided missile version of plasma taken from convalescents
- Vitamin C taken intravenously is the subject of a trial of 140 patients being recruited in China, but is not due to report until the end of September
- Nicotine patches are to be tried in Paris, as potential ACE2 binders
- Inhaled nitric oxide
- Llama antibodies are being investigated by a Belgian / US team for vaccine potential
Rays of hope
Despite the horrifying numbers we've been seeing, we can at least be heartened by the falls in case numbers of late and the speed at which researchers of all sorts are throwing light on the facts which will ultimately help us better defend ourselves against this horrible virus.
On a lighter note, we could find that Trump is right for once, when it comes to the benefits of sunlight. Not only is UV light a known disinfectant, but the race is on to determine the correlations between COVID-19 experience and exposure to the sun. It's hypothesized that benefits of sunlight on the skin - vitamin D and nitric oxide production - act to reduce vulnerability due to factors such as hypertension, obesity, blood clotting problems and immune dysfunction.
Release of lockdown into the sunny weather could be just what the doctor ordered.
Ruth Gilbert heads up insuringchange.co.uk
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