Saturday, 8 August 2020

Smoking and COVID-19 - the evidence gets stronger

I've found it impossible to keep up with all the research on smoking and COVID-19 recently. The tireless @phil_w888 has now catalogued over 700 studies of COVID-19 patients that have data on smoking prevalence. 

In the last week, the largest observational study yet conducted found that smokers (in Mexico) were 23 per cent less likely to test positive for COVID-19. This is in line with the results of an ongoing meta-analysis by some researchers who would clearly prefer the hypothesis to be disproved but who nevertheless have found a 26 per cent reduction in infection risk for current smokers. 

A study published in the Lancet a couple of weeks ago looked at the factors associated with COVID-19 caseloads at the national level. It found that countries with higher rates of smoking tended to have lower rates of Covid infection.

And a newly published prospective study of nearly 20,000 Covid cases tells a familiar story. Your chances of ending up in intensive care with the virus are increased if you are male, non-white, from a low income area, obese ... or a nonsmoker. 

Note the telltale dose-response relationship. The heaviest smokers are an incredible 88 per cent less likely to end up in ICU with COVID-19.

The same rules apply to your chances of testing positive for COVID-19. Indeed, it seems increasingly clear that smokers are less likely to end up in intensive care with COVID-19 because they are less likely to catch it in the first place.

Factors such as obesity, deprivation and being BAME are now universally acknowledged as risks for COVID-19. The UK government, in particular, has gone to town on the obesity finding. 

The smoking finding, by contrast, continues to be ignored, although the evidence for a protective effect is about as a strong as the evidence for obesity being a risk factor. 

And yet the association with smoking is not even mentioned in the abstract of the latest study (above), nor is it mentioned in the abstract of the Lancet study. The authors of the latter describe it as an 'unexpected finding' which 'requires further investigation'. The authors of the other study describe it as a 'counterintuitive finding' , although they do acknowledge that it is 'consistent with very low rates of smoking seen in patients presenting with COVID-19 in Wuhan and similar data from the USA and with the findings of a more limited analysis of patients with COVID-19 in France.

They also propose several possible causal mechanisms: 

This may reflect a general immunomodulatory effect, a mechanism that is thought to explain the lower incidence of sarcoidosis, extrinsic allergic alveolitis and ulcerative colitis in current smokers. Alternatively, smoking may cause increased ACE2 mRNA expression in human lung much as ACE inhibitors or ARBs are believed to, suggesting a possible common protective mechanism for severe COVID-19 disease. Additional possible mechanisms include a direct protective effect of nicotinic receptor stimulation or an association of smoking with another protective factor. This finding arose when including smoking status as a confounder and should be interpreted cautiously. Further studies are required to verify the apparent protective association, determine whether it is independent of other risk factors, and investigate potential mechanisms. 

The 'public health' lobby has done a good job of ignoring these findings so far, but how long can it continue? With the world economy crippled by lockdowns and social distancing - not to mention the human cost of the virus - is it ethical for them to overlook a possible solution? That solution may not involve smoking per se. It is likely to merely involve harmless nicotine. 

These findings get stronger by the day and are extremely interesting, and yet I do not see much interest in them from the people who are supposed to be protecting our health. It could be a fatal oversight.



Monday, 3 August 2020

Remain (Inside) vs. Leave (the House) - the faultline in British politics

It's not a novel observation to say that the debate about lockdown measures is a rerun of Brexi, with the same people lining up on each side. But why should that be? In this article for the Telegraph, I throw a few theories around...

On the face of it, the two issues have nothing in common. It may be that Brexiteers are less risk averse. No Deal Brexiteers, in particular, embrace risk almost by definition. Remainers, by contrast, feel safer with the status quo, and once lockdown became the status quo, any loosening of it felt like a risk.

Or it could be about settling old scores. Some pro-lockdown campaigners are more or less explicitly anti-Tory activists who oppose any relaxation so they can say ‘I told you so’ in the future when there is a second wave of (hello, ‘Independent SAGE’).

Others are still smarting from the referendum. I swear there are political journalists in this country who will go to their graves convinced that the biggest news story of 2020 was Dominic Cummings driving to Barnard Castle. It is difficult to imagine them getting quite so upset about a special adviser possibly committing a minor breach of a regulation if he had not run the Leave campaign. 

Similarly, it is hard to imagine Sir Ed Davey reporting someone to the police for going to the pub two weeks after travelling to America - and therefore possibly not having quite done the full fourteen day quarantine - if his name wasn’t Nigel Farage (or as Carole Cadwalladr dubbed him, in typically understated fashion, ‘Typhoid Nigel’). Farage’s response was to tell Davey, not unreasonably, to ‘get a life.’


Do read it all.


Saturday, 1 August 2020

Alcohol doesn't cause cancer?

There was much excitement in 'public health' circles last year when a study failed to find an association between moderate drinking and lower rates of heart disease. The study used conventional epidemiology and Mendelian Randomisation (MR) to look at a Chinese population in which a gene that is associated with alcohol avoidance is relatively common (it is very uncommon in the West). The authors found a protective effect for heart disease when they used epidemiology but not when they used MR. It was not the first MR study to come to this conclusion.

MR studies featured prominently in the Sheffield Alcohol Research Group's report for the Australian government last year (Australia has since lowered its drinking guidelines). They also feature prominently in the US Dietary Guideline Advisory Committee's report (the US is also pondering a lowering of the guidelines). You can see the appeal to the anti-alcohol lobby.

The hype around MR studies says that they are 'nature's RCTs' and can prove causation. Neither of these claims is true, at least as far as identifying behavioural risk factors is concerned. Observational epidemiology is far from perfect but MR studies have enormous problems of their own. Self-reported alcohol consumption data might not always entirely reliable, but MR often does not involve alcohol consumption being reported at all. It is merely assumed that people with certain genes will drink less than other people.

But just as someone whose genes make them more likely to smoke is not necessarily a smoker, someone who has genes that make them more prone to alcohol avoidance is not necessarily a non-drinker (or even a light drinker). A few genes have been identified, particularly in Asian populations, which make people react badly with alcohol, but this is no guarantee that they will not drink heavily. In situations and cultures in which drinking is expected - networking among Japanese businessmen, for example - any genetic predisposition towards light drinking or teetotallism may soon evaporate.

In a commentary in the European Journal of Epidemiology, Kenneth Mukamal and colleagues argue that MR “is subject to all of the limitations of instrumental variable analysis and to several limitations specific to its genetic underpinnings, including confounding, weak instrument bias, pleiotropy, adaptation, and failure of replication.” MR studies on alcohol consumption and cardiovascular disease, they write, “demonstrate that it must be treated with all of the circumspection that should accompany all forms of observational epidemiology”.

Two new MR studies were published recently, neither of which attracted much attention. In June, an MR study published in Cancer Genetics found no association between inferred alcohol consumption and breast cancer. It also found no association with ovarian cancer.

And then last week, an MR study published in PLOS Medicine failed to find an association between inferred alcohol consumption and any form of cancer except - using one of the two databases - lung cancer.

The PLOS study is particularly interesting because it also looks at smokers - or, more accurately, people with a genetic predisposition to smoking. If it hadn't found an association with lung cancer, it would have raised serious questions about MR's credibility in this area. Fortunately it did, but it only found a doubling in risk, whereas epidemiological studies suggest that risk increases by anything from five to fifty-fold depending on smoking intensity. The study also found associations with several other cancers, but the risk ratios were quite low. For most of the cancers studies, there was no statistically significant association.


The results for inferred smoking therefore point broadly in the right direction, but it seems that the risk has to be rather large for MR to show a statistically significant result.

The results for alcohol, however, would require the textbooks to be rewritten if they were true. The epidemiological evidence linking alcohol to several forms of cancer is nearly as strong as the evidence linking moderate drinking to lower rates of heart disease. Lung cancer isn't one of them, but that is the only cancer with which the MR study found a statistically significant elevation in risk, albeit in only one or the two datasets used.


What are we to conclude? That MR has 'proven' that moderate drinking does not reduce heart disease risk, but that drinking in general does not increase cancer risk? Or that MR studies are too crude to find the kind of associations identified by observational epidemiology - including the link with breast cancer which is the basis of the 'no safe level' meme?

If we are to allow MR studies to override epidemiological findings about alcohol, several babies will have to be thrown out with the bathwater.