Thursday, 9 January 2020

Atmospheric Pollution – bad air & ultra-fine particles

Bad Air – Miasma 

During the nineteenth century the population of London, like the populations of many European cities, suffered from several epidemics of cholera. The cause of these epidemics was put down to “Miasma”, that is “bad air”. Miasma was the current paradigm in Europe, in that it was the explanation and assumed cause of all sorts of diseases including epidemics. The air was certainly bad, with a “stench” as well as smoke. The physicians of the day were impotent; they could hardly be expected to clean the air. There was no provision for the population at risk to be moved to a location of clean air. 
19th century representation of Miasma

There was no possibility of reducing or prohibiting the burning of coal, but it was the smell of the air ("the great stink") that was considered to be the main factor of miasma. Sir Edwin Chadwick, the first public health physician in England, took action by organising the construction of drains to take the foul-smelling waste into the River Thames and thus rid the populated parts of the city of “miasma”. Unfortunately the drains entered the Thames above the water intake.

Dr John Snow and the Broad Street pump

During the 1854 epidemic of cholera in London a thoughtful young physician Dr John Snow, unlike Sir Edwin Chadwick, was not content with the miasma paradigm. The paradigm was the result of the philosophical approach to medicine – thinking about the problems. Snow had a scientific approach – research. 

Dr John Snow, 1813–1858
His data collection identified the geography of the epidemic, its epidemiology. The cluster of cases of cholera pointed to a specific water pump, the one situated in Broad Street. His advice to stop using the pump went unheeded: everyone (including all other physicians) accepted that the disease was due to miasma, and of course the people wanted water from a convenient pump close to home. The story goes that Snow removed the handle of the Broad Street pump, thus making it unusable. Following this the epidemic came to an end.

Paradigm change

The miasma paradigm came to an end in the latter years of the 19th century but only because there was a new paradigm to take its place: transmission of disease, and specifically cholera, is due to water-borne micro-organisms.

The germ theory opened a new era of medical research, the new science of microbiology. Many new bacteria were to be identified and classified, and linked to a large number of human and animal diseases. Viral and fungal diseases were identified later. By the 1960s when I was a medical student it might have been thought that all of microbiology was known, but this was very far from reality.

Bad air again

The miasma concept did not completely disappear and it is now being revived. During the latter half of the 19th century and the first half of the 20th century “bad air” was a very serious problem in Europe. Whereas clean water was the priority in the 1880s, clean air became the priority in the 1950s. 

A major effect of air pollution by smoke was and still is the inhalation effect causing chronic lung disease, chronic bronchitis, later called chronic obstructive pulmonary (lung) disease (COPD). It was because of the large number of deaths from what was then called chronic bronchitis that the UK Government introduced the Clean Air Act in 1956, and it turned out to be the very effective

Sunlight and immunity

During the 19th and early 20th centuries, the other major health effect of air pollution was recognised as being a reduction of sunlight penetration to ground level, resulting in vitamin D deficiency and rickets. The knowledge of this seems to have been lost in recent years.

Robert Koch had demonstrated tuberculosis (called consumption, phthisis, or even Koch’s Disease) to be caused by a bacterium – Mycobacterium tuberculosis, or Koch’s bacillus. However here we find an interaction between bacterial infection and the susceptibility of individual people. 

Towards the end of the 20th century it became obvious that reduced immune competence (as in AIDS) makes tuberculosis more likely to occur, and this is also an effect of vitamin D deficiency. Blockage of sunlight by polluted air (or by staying indoors) has serious effects on immunity, and an increased risk of tuberculosis is just one of them. 

It had been demonstrated by Niels Fyberg Finsen in 1905 that tuberculosis of the skin (lupus vulgaris) could be healed by exposure to UV light.

Bad air today

I remember that when I was a young boy in Manchester, UK, it was possible in the winter months to look directly at the sun, which was often just a pale disk in the sky. 

Taj Mahal in polluted air

This is now a feature in the newly industrialising countries, particularly China and India. On a "cloudless" day in many cities such as Beijing and other industrial cities of China it is not possible to see the sun due to the high level of pollution, and things are similar in Delhi and other Indian cities. In fact most heavily polluted atmospheres are in Indian cities. The health consequences of this are yet to emerge, but vitamin D deficiency can be predicted.

This is no longer the case in the UK and other European cities today and the air quality is very much improved compared to what it was in the 1950s. The carbon particles are now different. The pollution today is with ultra-fine particles and these cannot be seen. They do not seem to block the sun and the air appears to be clean.

London 2018

In London and other European cities in the mid-20th century, the main pollutant was the industrial and domestic burning of coal. Coal had a high content of sulphur, and major pollutants were sulphur dioxide and sulphurous acid, both very toxic to the lungs.

Motor car fuels, with petrol and diesel, have also been responsible for the release of toxic sulphur gases into the atmosphere, mainly in the cities. However legislation has resulted in the the purification of fuels for road vehicles to virtually eliminate the sulphur content. 

Decline of sulphur content of road traffic fuel in UK since legislation

January 1st 2020 will see the introduction of rules by the International Maritime Organisation to allow shipping to use only low sulphur fuels.

"Toxic air" – Ultra-fine particles

In the EU the air has become much cleaner since the mid-20th century, but despite this obvious change we are told that our air is "toxic" and is causing enormous damage to us in a large number of ways. Ultra-fine particles apparently pass through the bronchial tree and into the depths of the lungs, then entering the body. However undesirable this might be, it cannot be assumed that they are causing disease. The fact is that in the UK and the EU in general, life expectancy continues to rise. We are healthier than ever before.

PM – Particle Matter
Ultra-fine particles cannot be seen with the naked eye but they can be measured in a laboratory. A detailed summary was produced by a UK government working group in 2018. Ultra-fine particles have a diameter less than 100 nanometers, or <0.1 microns. With the improvement of fuel quality and combustion processes there has been a significant reduction during the early years of the 21st century and a further reduction is anticipated, especially if there is a major reduction in the use of carboniferous fuels.

Decline of ultra fine particles

I am not proposing that we should be complacent. There is a serious problem of too many cars on our roads, but like everyone else I want to keep mine! It will be many years before we change to electric vehicles and domestic heating by electricity. Even though more than half of electricity generated in the UK in 2019 was from non-carbon sources, the source of additional generation of electricity in the future remains uncertain. 

Microplastic pollution 

There is also concern about plastics. The effect of large plastic waste products on sea life is obvious and very tragic. However there is also a problem with microplastic pollution. It has been observed that these are present in the seas and in sea life, but recent studies have detected microplastic particles in the air. They are present in many cities with London having the highest recorded levels. 

Once again it is not clear whether they are toxic or inert, and whether or not they have a detrimental effect on human health. A study in 1998 demonstrated microplastics in cancerous human tissue, but a causative role cannot be assumed. Apparently we consume about 50,000 microplastic particles per year. They decompose extremely slowly, and if they are toxic the effects will be with us for a long time.

Disease attributed to air pollution

I cannot help thinking of the miasmic theory when I read assertions that present-day diseases "are the result of" atmospheric pollution. I find it perfectly reasonable to accept that 41% of global deaths from chronic obstructive pulmonary disease (COPD) are the result of the inhalation of toxic air pollution. However to state that 20% of Type 2 Diabetes deaths are the result of air pollution stretches credibility. 

Similarly it is stated that 19% of deaths from lung cancer are due to air pollution. We know that most lung cancer has been caused by cigarette smoking, but atmospheric pollution has not been an accepted cause. At present, at least in the UK, there seems to be a significant epidemic of lung cancer in "never-smokers", and 80% of cases are in women. This is a great worry but there has been no good evidence that it is the result of atmospheric pollution. The possible role of microplastics requires further evaluation.

To state that 16% of deaths from coronary heart disease (CHD) are the result of atmospheric pollution is very suspect. Which 16% ?Are these deaths in countries that experience a high level of air pollution? Is there really a link? The reality is that deaths from coronary heart disease have shown a major epidemic of the latter half of the 20th century, and the epidemic is now effectively at an end. To link atmospheric pollution to the major decline in coronary heart disease deaths at the present time would not be realistic. I have expressed my conclusion that coronary heart disease must be due to micro-organisms.

On November 18th 2019 we read in the UK press that: "Air pollution from homes, industry and cars kills five people a week in Bristol", and  up to 36,000 per year in the UK. Who are these people? What was the precise cause of death, remembering of course that "air pollution" is not a recognised cause of death. This is poor quality research that adds very little but as a scare story, it creates headlines. Once again there is the proposal that air pollution contributes to asthma, lung cancer, heart disease, stroke and diabetes. Of these only a link to asthma has plausibility. The others are purely speculation without any direct plausible mechanism.

Earlier in the year a delightful 9 year-old girl in Lewisham, south London, died as a result of asthma. It was claimed by her mother that the cause of death was air pollution, and this has received a great deal of attention by the national press. Air pollution is not a recognised cause of death, and the reality is that the child died in a severe attack of asthma. She had experienced 24 admissions to hospital on account of asthma during the previous 3 years. I can understand the concern of the mother as the family lived 25 metres from the notoriously busy South Circular Road. Asthma is not due to air pollution, but inhalation of smoke and other chemicals can precipitate a severe attack. It would not have been possible stop traffic movement outside the house, but perhaps there could have been assistance to the family moving into a rural environment.

On Thursday November 28th 2019, the national press reported that the "Impact of air pollution on health may be far worse than thought.... almost every cell in the body may be affected by dirty air". It suggested that atmospheric pollution might have a causative role in heart failure, urinary tract infections, strokes, brain cancer, miscarriage, and mental health problems

This newsfeed is based on a recent British Medical Journal paper, which draws on USA Medicare data concerning hospital admissions and discharges. There is no reason to suspect that the findings cannot be applied to other countries. 

At the same time we learned that 90% of the world's population are exposed to air pollution above the WHO recommended upper limit.  We are told that air pollution increases the risk of glaucoma, a condition in which the pressure inside the eye increases and this can lead to loss of vision if not treated.

A press release on December 19th 2019 informs us that depression and suicide are linked to air pollution, and that "cutting the air pollution around the world to the EU's legal limit could prevent millions of people becoming depressed." It was pointed out that intermediary mechanisms are unknown, and thus only conjectural.

City life

Life is much more pleasant in a rural environment: the contrasting health between the citizens of Manchester and Salford, UK, and those of surrounding villages was first investigated and publicised almost 300 years ago, as I described in an earlier Post. As it was then, so it is now and employment tends to be concentrated in growing cities and not in the countryside. For those in employment, rural living usually means a long commute, mainly by car.

Stalybridge, Manchester in 1950

Stalybridge, Manchester in 2018

There is clearly a health advantage to rural rather than inner city living but the health issues and reasons for this are complex. Can the visible air pollution in major cities in India and China be equated to the invisible ultra-fine particle pollution in London and other similar cities in Europe and North America?

Is the air in London "toxic" or are there other reasons for health disadvantages? The wide range of illnesses associated with air pollution suggests common susceptibility rather than true cause.

If it the result of atmospheric pollution, could the susceptibility be the result of reduction of sunlight penetration to ground level?  This will certainly be the case very in the major cities of India and China in which there is very obvious visible air pollution. 

It is strange that in the many recent articles that I have read on the subject of the  detrimental health effects of air pollution, I have not seen any mention of the interference of penetration of sunlight to ground level. It is as though there is a conspiracy to ignore the obvious great importance of the sun to human health and the role of the sun and vitamin D in maintaining good immunity and good health.

The importance of the sun.

We know that the sun has at least four metabolic effects on our bodies, three of which will have a protective effect on the cardiovascular system. They are as follows.
  • Vitamin D is synthesised in the skin from 7-dehydrocholesterol  by the action of the sun. Vitamin D in its twice-activated form calcitriol activates (via the intracellular vitamin D receptor) specific genes that are involved in turn in activating immune defensive processes. Immunity is very important in the control of infection and in the prevention of CHD.
  • It has become clear that there is a cardiovascular benefit from sunlight acting on the skin that is independent of vitamin D synthesis. The action of the sun on the skin synthesises nitric oxide from nitrates circulating in the blood and passing through the skin. The role of nitric oxide is not completely understood but it appears to have a significant role in control of arterial health and blood pressure.
  • It also appears that skin cells (keratinocytes) are activated by sunlight to in turn activate immune mechanisms within the body. Once again this will be of benefit in CHD.
  • Finally, the sun, acting through the eyes  stimulates the pineal gland within the brain to secrete melatonin. This is of importance to brain activity but it does not at present appear to be of direct cardiovascular benefit.

Intermediary mechanisms

However I emphasise the point that understanding the link between air pollution and disease is essential, as without it we have no plausibility. We have great experience of the effects of air pollution in the UK in the 19th and 20th centuries, and the benefits of pollution controls. The major problem was obstruction to sunlight with vitamin D deficiency: this will indeed affect "almost every cell in the body".

The insistence that bad air causes so much premature death without  any clear intervening mechanism effectively brings us back to the miasma theory, which was replaced by the germ theory more than a century ago. But the germ theory is being ignored by those who are understandably concerned about the effects of air pollution. This is at the time of a huge expansion of the germ theory. The identification of the immune-enhancing effects of the sun would bring together air pollution and the germ theory.

New analytical techniques have demonstrated many more varieties of micro-organisms that are part of the human microbiome. Many have be linked to a variety of human diseases, most chronic, but “proof” will be very difficult in the absence of transmission studies and long-term follow-up. 

However it is looking as though a large number of human diseases are the result of changes to our microbiome. This must be linked to immune mechanisms, and acknowledge the importance of air pollution and the importance of sun exposure.

Sunset – Conwy Estuary, North Wales

Saturday, 12 October 2019

Microbes that cause Coronary Heart Disease

Micro-organisms and Coronary Heart Disease

Today on the coast of North Wales
I have suggested previously that coronary heart disease is due to  micro-organisms, several causing the endemic form of the disease, and this might have been a feature of life since the beginning of Homo Sapiens. There is a suggestion of this from embalmed Egyptian mummies, but otherwise there has been no preservation of human soft tissues, only bones. The well-described 20th century pandemic of coronary heart disease must have been the result of one specific micro-organism.

The basis for this is that coronary heart disease clearly has an environmental cause. A possible chemical cause occurring simultaneously in all continents in temperate zones would be unlikely. A dietary factor (effectively chemical) has been assumed, but despite half a century of investigation, no robust evidence has been identified. We must conclude that coronary heart disease is not due to diet.

The epidemic

The epidemic nature of coronary heart disease in the 20th century clearly indicates that it is not genetic: it is not possible for a genetic disease to create an epidemic because genetic factors within a society change extremely slowly. However coronary heart disease has a strong familial pattern, but it is not Mendelian; it would appear to be non-genetic inheritance. 

It is important to appreciate that we inherit 
from our parents more than our genes. We also inherit place of residence, type of housing, money, religion, culture, education, and also micro-organisms. It is important to appreciate that microbial diseases can spread within a household, within and between generations. We also inherit immunity to disease, and this appears to be a dominant genetic pattern, being acquired by all offspring (except those with very rare disorders of immunity).

In the 1960s the UK cardiologist Dr Maurice Campbell, studying national statistics,  recognised that coronary heart disease appeared after 1924 as an apparently new disease with an exponential increase in death rate. This suggested an epidemic, but it was only with the decline of the death rate after 1970 that the true pattern of an epidemic could be confirmed. 

Campbell M. Death rate from diseases of the heart: 1876 to 1959. British Medical Journal 1963: August 31st.p 528.
Campbell M. The main cause of increased death rate from diseases of the heart: 1920 to 1959. British Medical Journal 1963: September 21st. page 712.
A similar pattern emerged in the USA and elsewhere. The USA data source was mainly from health insurance companies, the information being compiled by Professor William G Rothstein.

Suggestions of infection

It was suggested in 1983 that the epidemic pattern of coronary heart disease was very suggestive of a viral epidemic, leading to the suggestion that it could be the result of a micro-organism. The authors were EP Benditt, T Barrett and JK McDougall, writing in the Proceedings of the National Academy of Science, USA. They stated:

‘The rise and fall of coronary heart disease (CHD) in a number of Western countries in this century has been dramatic….The shape of the CHD mortality curve reminds one of the rise and fall of epidemic diseases due to microbial agents.’

They also stated:

‘If we accept that aberrations in cholesterol metabolism provide the whole etiological basis for coronary and other vascular occlusive disease, we need hunt no further. On the other hand, we think there is still a great deal to be explained and that viruses may well hold some, if not all, of the missing pieces of the puzzle.’ 

Benditt EP, Barrett T, McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci USA. 1983; 80: 6386-9.

36 years later we know very well that there are indeed serious aberrations in the cholesterol story. A microbiological causation of coronary heart disease seems to provide a much more plausible explanation. But is it plausible that coronary heart disease might be due to a microbe? To answer this question it is not essential to identify a microbe, but it is the principle that needs to be clarified. Firstly, is there a better explanation? The answer to this is ‘No’, but conventional wisdom is unfortunately still firmly entrenched in the diet-cholesterol-heart theory.

Figure 1. The epidemic of coronary heart disease in USA men
Observations of infection

In 1977 it was noticed that: ‘A considerable proportion of the patients admitted to the coronary-care unit of the King Edward VII Hospital, Midhurst, Kent, gave an unsolicited history of an influenza-like illness before admission.”

Nicholls AC, Thomas M. Coxsackie virus infection in acute myocardial infarction. Lancet 1977; 309: 883-884. 

This led to a structured research project, the result of which was the observation that 10 out of 38 patients admitted with an acute myocardial infarction had positive antibodies indicating recent infection with Coxsackie virus. It was already known that Coxsackie B virus could cause myocarditis, an infection of the heart muscle. Myocardial infarction is a different disease, although there can be some clinical confusion between the two in individual cases. 

Griffiths PD, Hannington G, Booth JC. Coxsackie B virus infections and myocardial infarction. Lancet 1980; 315: 1387-1389.

Houston, Texas, has been a pioneering centre of vascular surgery, led by the charismatic surgeon Michael DeBakey. A study from his department found high levels of antibodies to Cytomegalovirus in 57% of his surgical patients, compared to 26% in a control group.

Adam E, Melnick JL, Probtsfield JL, et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet 1987; 330: 291-293.

Coronary heart disease is a particular problem in a transplanted heart, for reasons that are not clear but which are likely to be the result of therapeutic suppression of immunity. Cytomegalovirus has been detected in 62% of patients with coronary artery disease developing after heart transplantation compared to its detection in only 25% of those without coronary heart disease. 

McDonald K, Rector TS, Braunlin EA, et al. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection. Am J Cardiol 1989; 64: 359-362.

A study from Helsinki investigated 54 consecutive patients with stroke, all aged less than 50 years, and compared them with 54 community-based age and sex-matched controls. 19 patients had evidence of a febrile illness during the previous month compared with just 3 controls. In 80% of cases, the infection was respiratory, and mainly bacterial. This study again indicates an infection preceding an atherosclerotic event.

Syrjänen J, Valtonen V, Iivavainen M, et al. Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients. BMJ 1988; 296: 1156-1160.

It is interesting to note that there has also been an association identified between Helicobacter pylori and coronary heart disease. The plausibility of a significant direct causative effect is uncertain, even though it has been detected in atheromatous tissue. However it is important to remember how readily Helicobacter pylori  became accepted as the cause of peptic ulcer. Previously diet and stress were considered to be the cause.

Mendall MA, Goggin PM, Molineaux N, et al. Relation of Helicobacter pylori infection and coronary Heart disease. Br Heart J 1994; 71: 437-439.

Ameriso SF, Fridman EA, Leiguarda RC, Sevlever GE. Detection of Helicobacter pylori in human carotid atherosclerotic plaques. Stroke 2001; 32: 385-391.

Earlier this year it has been reported that there is a significant association between coronary heart disease and Hepatitis C Virus (HCV). The nature of this association is uncertain, but the main significance is the fact that HCV is so widespread worldwide.

Lee KK, Stella D, Bing R, Anwar M et al. Global burden of atherosclerotic cardiovascular disease in people with hepatitis C virus infection: a systematic review, meta-analysis, and modelling study. Lancet Gastroenterolog/Hepatology 2019. Published Online  July 31, 2019 S2468-1253(19)30227-4

The discovery of Chlamydia pneumoniae

Chlamydia pneumoniae 
Chlamydia pneumoniae was first identified in 1950 in Taiwan, in a man with conjunctivitis. A previously unidentified micro-organism, it initially became known as Taiwan Acute Respiratory agent (TWAR). It has since been noted to be a common respiratory pathogen. There are no reports of it being detected in retrospective investigations from patients from before 1950.

The association between coronary heart disease and preceding respiratory infection stimulated a further study from Helsinki. It was published in 1988 and it looked at 40 men who survived acute myocardial infarction, 30 with previous coronary heart disease and 41 matched controls. They were all tested for antibody evidence of infection with the newly-discovered organism Chlamydia TWAR, subsequently reclassified as Chlamydia pneumoniae.

Generally, bacteria are identified by microscopy and culture, whereas viruses are identified by the appearance of antibodies in the blood. Chlamydia pneumoniae is a tiny bacterium that grows only within host cells and it can be cultured only with great difficulty. It can be detected by rising antibody titres and now by specific DNA detection using PCR techniques. The organism has been isolated in recent years and cultured from atherosclerotic tissue.

Figure 2. Positive serology to Chlamydia pneumoniae

Saikku P, Leinonen M, Mattila K, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and myocardial infarction. Lancet 1988; 332: 983-985.

We can see in Figure 2 that in the 1988 Helsinki study, 68% of the sample with recent myocardial infarction had positive antibodies (serology) to Chlamydia pneumoniae (TWAR). 50% of those with known coronary heart disease had positive antibodies.  A lower proportion of 17% of controls had positive antibodies. 

Infection with this organism appeared to be quite common. It is not known if the 17% of controls had coronary heart disease, just that so far in their lives they had no clinical manifestations of it.  If Chlamydia pneumoniae does have a causative role in coronary heart disease, then progression from the initial respiratory infection to myocardial infarction does not always occur. This might depend on susceptibility of individuals to the infection., or it might depend on repeated low-grade infection.

A group from Johannesburg, South Africa, looked at atherosclerotic tissue obtained at autopsy and in about half the cases they were able to identify Chlamydia pneumoniae by the technologically advanced methods of immuno-histochemistry and polymerase chain reaction (PCR). Many similar studies have been undertaken since then, a total of 27 by 1998. These studies have been undertaken in a number of countries and in only one study, in Brooklyn, New York, was there a failure to detective presence of Chlamydia pneumoniae in atheromatous tissue. 

Kuo C, Shor A, Campbell LA, et al. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infectious Dis 1993; 167: 841-849.

Chlamydia pneumoniae has been detected in atherosclerotic coronary arteries and also in carotid, femoral, popliteal arteries and in the aorta. It has not been detected in normal arterial tissue. 

Antibiotic therapy

If coronary heart disease is due a bacterium it might be anticipated that antibiotic therapy would help. This has never been extensive tested, as an infective cause has been considered only by a few individuals. But there is some suggestion of benefit, mainly by the antibiotic azithromycin. In Figure 3 we can see a positive benefit in those with coronary heart disease treated with a short course of azithromycin. Follow up was for just one month following a coronary event, and azithromycin appeared to give a significant advantage.

Figure 3. The effect of azithromycin on coronary heart disease

Gurfinkel E, Bozowich G, Daroca A, et al, for the ROXIS study group. Randomised trial of roxithromycin in non-q-wave coronary syndromes: ROXIS pilot study. Lancet 1997; 350: 404-407.

This was a preliminary study, but subsequent experience did not confirm these findings.

Cercek B, Shah PK, Noc M, et al, for AZACS investigators. Effect of short-term treatment with azithromycin on recurrent ischaemic events if patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003; 361: 809-813.

However, before abandoning the prospect of antibiotics having a role in the treatment of coronary heart disease, we must remember from a previous Blog Post that statin drugs were initially developed as antibiotics. In 1971 the microbiologist Professor Akira Endo in Japan discovered a natural inhibitor of the pathway in a broth of the mould of Penicillium citrinum. The compound, which was named compactin or mevastatin, inhibited the enzyme HMG-CoA reductase. The first statin had been identified, but it had a significant unexpected effect: it reduced blood levels of cholesterol. Serendipity led to the highly successful marketing of statins as cholesterol-lowering agents rather than as antibiotics. 

But as I have pointed out previously, it is clear that the benefit of statins is not related to the cholesterol-lowering property. The observation that statins are of the greatest benefit at the moment of a myocardial infarction, when the infective inflammatory process is at it greatest, indicates an immediate antibacterial effect.

Plausibility of an infective cause of coronary heart disease

Clearly the story is not yet complete. Unfortunately the diet-cholesterol-heart story has monopolised research into coronary heart disease, and as the epidemic is now effectively over, the opportunities to investigate and explain the epidemic are very much constrained. How many people with coronary heart disease have had a micro-biological investigation?

We know that the three major heart diseases in the early years of the 20th century were due to micro-organisms. The first is the sexually transmitted disease syphilis. It damages in particular the aorta and the aortic valve. The causative micro-organism Treponema palladium (identified 400 years after the disease was recognised) invades the arterial wall, as happens in coronary heart disease. The second is rheumatic fever. This is due to a throat infection with Streptococcus pyogenes, and resulting damage to the the valves of the heart, mainly the mitral valve. The third is endocarditis. This is due to a variety of micro-organisms, mainly the Streptococcus viridans group of bacteria, which enter the blood circulation via diseased gums, or tooth sockets following dental extraction. The infection further damages already abnormal heart valves. Heart valves are liable to damage as the result of poor blood supply.

The most plausible explanation of the cause of atherosclerosis and coronary heart disease is that they are due to bacterial invasion of the arterial wall. Cholesterol is present in the tissues as part of the body’s defence mechanism. What we should regard as endemic disease with low mortality has probably always been present and will continue in the future. A variety of micro-organisms will be responsible.

On the other hand, the epidemic form of the 20th century with a very high mortality rate and onset of sub-clinical disease at an early age must have been the result of a new micro-organism to which humankind had no immunity at the time of its appearance at the beginning of the 20th century. 

The rapid rise of death rate was followed by an equally rapid fall due to the development of immunity during three generations. The new micro-organism was most likely to have been Chlamydia pneumoniae, although no substantial study has been undertaken (in contrast to the search for a new micro-organism following the appearance of AIDS toward the end of the 20th century).

Saturday, 31 August 2019

The Polypill - statistical spin and amplification of benefit

Many people in the world are taking medications of various sorts to improve their health and duration of life, most of these "medications" being futile. Life is at present longer and healthier than has ever been known. We are increasingly free of disease and as a result old age is the expectation for most of us.

But food enthusiasts of various sorts try to persuade us that changing diet can make our lives even better and longer. And there are of course many others who can make money out of our almost universal health pessimism, and our remarkable optimism in the power of medicines and special diets. Although the 20th century epidemic of high mortality coronary heart disease has now come to an end, we are still under pressure to take medications to prevent it.

Many people who are well and disease-free take statins. Many take aspirin. High blood pressure is constantly redefined so as to make more of us have hypertension. Pharmaceutical consumption without need increases, although of course it is necessary for economic growth. 

The polypill
If vast numbers of people are taking four tablets per day (statin, aspirin and two to lower blood pressure) it might make life easier for these medications to be combined into just one tablet. This “polypill” has been developed, containing aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan. Even though the component medications might have been approved, combinations require a separate approval by the pharmaceutical regulating authority, and this requires additional clinical trials. 

The polypill trial
The clinical trial of the polypill has now been undertaken in Iran, and it has rather cleverly been called  the PolyIran study. The results were reported very recently in The Lancet, which appears to give special priority to articles promoting cholesterol and statins.  

The study involved 3417 subjects allocated to advice care only,  and 3421 subjects advice plus polypill. The subjects were aged between 50 and 75 years and the duration of follow-up was five years. 

There were 222 total deaths in the advice only group, this being  6.5% of the 3417 subjects.

There were 202 total deaths in the advice plus polypill group, this being 5.9% of the 3421 subjects

The difference is 0.6%, meaning that almost 200 (precisely 167) people would need to take a daily polypill for five years to prevent one death during this time. The polypill was effective in preventing death, but it is doubtful that a person prescribed it for five years for the purpose of preventing death would take it knowing that there is a 99.4% chance of it not preventing death.

Cardiovascular events
During follow-up, there were: 

301 (8.8%) non-fatal major cardiovascular events in those who received advice only, and 

202 (5.9%) non-fatal major cardiovascular events in those receiving advice plus polypill. 

The difference is 2.9%, the absolute reduction of event rates, meaning that the polypill was effective in the prevention of major cardiovascular events.

The spin
The absolute reduction of events by 2.9% does not sound to be very dramatic, and so statistical manipulation follows. 2.9% must be expressed as a proportion of 8.8%.

Once again we can see statistical spin, using the dubious method of taking percentages of percentages. 

(8.8-5.9)/8.8 expressed as a percentage = 33%. This sounds much better and this is what was appeared in the press, for example in The Guardian August 22nd 2019.

This spin amplifies the benefit of the polypill from 2.9% to 33%, by a factor of more than ten.

A useful expression of effectiveness is the NNT, the Number Needed to Treat in order to achieve one clinical benefit, We see in respect of the polypill that for death this is 167.

The paper expressed the NNT for the prevention of cardiovascular events as being 34.5 (100/2.9). This is correct and it means that if 34.5 people take the polypill for five years, one will not experience a major cardiovascular event. The value of this in clinical practice requires an informed discussion between doctor and patient, in this case a disease-free normal person.

Primary prevention only: 
By this is meant subjects without a history of cardiovascular disease. Within the discussion section we find: 

“The PolyIran study showed that the use of polypill resulted in around a 40% reduction in the risk of major cardiovascular events in individuals without a history of cardiovascular disease”.

It is not easy to identify the origin of the 40%, but it can be obtained from Table 2. 

737 of the subjects had a history of pre-existing cardiovascular disease, but the majority 6101 did not have. 

Of those without a history of cardiovascular disease (primary prevention) and receiving advice only, 229 out of 3068 experienced a cardiovascular event during the study, that is 7.5 %. 

Of those without a history of cardiovascular disease and receiving advice plus polypill, 136 out of 3033 experienced a cardiovascular event, 4.5%.

Thus the absolute benefit was a reduction of 7.5-4.5 = 3% in cardiovascular events in those receding the polypill.

More spin
A 3% reduction in events is not very dramatic. How can this number be increased?

The statistical manipulation becomes the expression of 3% as proportion of 7.5%. This is (7.5-4.5)/7.5 expressed as a percentage = 40%. 

40% reduction sound much better than 3%, amplification of effect by a factor of 13.

As I have expressed in a previous Blog post, statistical spin of this sort is disgraceful manipulation designed to mislead the general public and their medical advisors. The expression of proportionate over absolute benefit should be stopped.

Gholamreza Roshandel, Masoud Khoshnia, Hossein Poustchi et al.  Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.  Lancet 2019; 394: 672–83.