Thursday 26 March 2020

Covid-19 pandemic : The German Paradox

Deaths per million population seems to be the most robust and useful measure of the impact of the Covid-19 pandemic.

But not always – there are some countries in which deaths per million is surprisingly low. The most obvious one is Germany, deaths per million remaining much lower than its neighbours, only a tenth of the deaths per million in Belgium

We have seen that disease incidence, cases per million, can include well people testing positive, or on the other hand just sick or dead people testing positive. Understanding this is helped by a view of tests per million population.

Norway is top of the list of nations with population testing, with more than 8,000 tests per million population (UK 957). Norway has a relatively high level of cases per million (591.1, UK 141.2). This is likely to be the result of extensive testing of people who are not ill, and these are included as “cases”. 

Norway experiences a low death rate of “cases”, 0.4%. There is also a low number of deaths at 2.6 per million population, UK 6.9.

Germany also has a low number of deaths from Covid-19, 2.7 per million. Why is this? It cannot explained in the same way as Norway, as the testing rate in Germany is only 2000 per million, a quarter that of Norway.

Germany has a lot of “cases” 474.1 per million, with a low death rate of 0.5%. What is going on? The number of deaths from Covid-19 is low, compared to a high incidence rate (more than three times that of the UK). How can this be explained? This has been questioned in the media, but without an explanation, even in Germany.

This is not a mathematical aberration, but it is obvious that somehow the deaths from Covid-19 are being under-reported in Germany. It is not a deliberate conspiracy to hide deaths, but the reason lies in medical culture in Germany, and probably in a few other countries with relatively few deaths.

Certified Cause of Death

This has troubled me for a long time. 

The death certificate works on the basis of a single disease causing death.
This is usually straightforward in a younger or middle-aged person. It could be myocardial infarction (heart attack), cerebral infarction or haemorrhage (stroke), road traffic accident, shooting, meningitis, tuberculosis, lung or other cancers, for example. 

The layout of the UK Death Certificate is shown below.

Things became less clear in older people, especially those who die after their 80th birthday. They might have several conditions simultaneously, none being life-threatening on its own, but they add together to create a burden of illness that leads to death. Example are diabetes, hypertension (high blood pressure), heart failure (controlled), obesity, Parkinson’s disease, osteoarthritis, impaired mobility, COPD, dementia.

When the elderly person dies it is often difficult to identify the single disease responsible. In reality the main reason for death is “old age”, in that without disease we will all “conk out” at about the age of 100 (give or take ten years). But the coroner will not like “old age” as a certified cause of death, even though arguably the whole purpose of medicine to to enable people to die from old age rather from disease. It is interesting to note that in the obituaries in the British Medical Journal, “Old Age” is the most common of the given causes of death (in 2020 so far, 20 out of 63, cancers second with 14).

It is mainly the elderly with pre-existing chronic disease who are dying from Covid-19. If this happens in the UK, Covid-19 will be registered as the cause of death (Category I), with important pre-existing conditions being recorded in Category II (not entered into national statistics).

In Germany it appears that things are different. It is the chronic conditions (dementia, heart failure, COPD etc) that will be recorded as the cause of death. Covid-19 would be regarded as the final blow, “the straw that broke the camel’s back”. There is good reason for this if the final event were broncho-pneumonia, developing in the frail individual who is unable to cough. This is called “opportunistic” pneumonia. 

However whereas broncho-pneumonia would not have occurred without the patient being frail, weak, and perhaps bed-bound, we cannot say that about Covid-19. It is not “opportunistic” but it can attack anyone, whether weak or strong, whether old or young. The elderly tend to die following Covid-19 infection because being they (we) are intrinsically weak internally, with reduced vitality or physiological reserve. They have reduced immunity and weak body defence mechanisms in general.

Death statistics

If the average age at death in a population of a million is 100 years, it means that 10,000 people will die on average each year (one million divided by 100). If the average age at death is 80, approximately 12,000 will die each year. So we expect that in the UK with a population of 67.5 million there will be about 810,000 deaths per year, or 2220 per day.  National statistics should be able to display this day by day but I have been unable to identify such data presentation. 

During the month of March 2020 we would see an increase as 422 people have died from Covid-19. 

The graph show theoretical average deaths per day in February 2020, with real UK deaths from Covid-19 added for March. The increase is not clearly seen. However we are interested in excess deaths, those greater than expected. In early 1969 there were 80,000 excess deaths in the UK as a result of Hong Kong flu, but I cannot access day by day data.

The excess deaths become more visible if we adjust the baseline of the graph to just below the theoretical average. We can see the excess deaths and it is these that will identify the Covid-19 pandemic.

Germany has a population of 83.5 million, leading to a theoretic average death rate of 2745 per day. Once again, this could be plotted as a daily number by German national statistics. We would then need to look at the pattern during March 2020. Would it show a cumulative increase of just 157 deaths above what is expected (average 10 per day)?  Perhaps it would show more, indicating the true number deaths resulting from the Clovid-19 pandemic.

Retrospective analysis in various countries will be more informative.

Monday 23 March 2020

Covid-19 and Vitamin D – air pollution and mortality in Italy

Satellite image showing hot-spot of air pollution in northern Italy

The pandemic of Covid-19 is a serious world-wide problem at present. It is due to a coronavirus related to SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East acute Respiratory Syndrome), and like them it originated in animals.

Covid-19 started in the Chinese city of Wuhan. The spread of the virus in Wuhan was extremely rapid, but effective closure of the city minimised spread elsewhere in China. Air transport enabled the virus to spread rapidly world-wide.

The virus has caused major problems in Iran and in Europe, and within Europe Italy has suffered most in terms of disease and deaths.

It is deaths that are most important. It is easy to forget that in 1968-69, during period of only about two months, 80,000 people died in the UK alone as the result of the pandemic of what we call Hong Kong flu. I was working as a young doctor in the front line at that time. We were taken by surprise by the pandemic, and of course there were no intensive care units in those days.

In the present pandemic "cases" can include people who are ill and test positive for Covid-19, and people who are perfectly well and test positive. As testing becomes more widespread the number of "cases" will increase as more well people are tested.  The numbers of deaths will change more slowly.

Its is considered that:

Death rate (%) = Total deaths x 100 / Total cases

When the denominator (total cases) increases at a greater rate than the numerator (total deaths), the death rate will appear to reduce. This will be a misleading health indicator, and it is a mathematical aberration.

It is much better to use as a health indicator the total number of deaths as proportion of the total population, that is total deaths per million. This is generally robust, but in some nations, for example Switzerland, the resident population might be significantly higher than the official population.

I have constructed a spreadsheet to collect and analyse the data concerning Covid-19 in a number of countries. The data, up-to-date on March 23rd 2020, can be seen below.

The variations within Europe are particularly interesting. 

The death rate as proportion of "cases" who die is remarkable low in Ireland (0.4%), Germany, (0.4%) and Norway (0.3%). Is this due to a large number of well people who have tested positive? If not is it the result of exceptionally good medical services? Or perhaps a common factor that cannot yet be identified.

The same countries have a low number of deaths per million population, Ireland 0.8, Germany 1.3, Norway 1.3. The numbers are greater but still comparatively low. There seems to be a real factor in these countries responsible for the low mortality. 

The low mortality in Germany in particular has been discussed widely in the media but no explanation is forthcoming.

The UK is experiencing 4.9 deaths per million, and 84.2 cases per million, relatively low. Cases per million are much higher in Ireland (184.9), Germany (313.3). and Norway (441.7), but this could be a result of extensive testing of the well population. 

Numbers tested in different countries are available:

It can be seen that Norway has conducted far more tests per million population than other European countries. This will explain the high cases per million (441.7) with few deaths per million (0.3). The testing rates in Germany and Ireland are not exceptional.

The testing rate in Italy is second to Norway in the European countries shown, but Italy has an exceptional problem. The Italian people and the health services are struggling. To date there have been almost 60,000 cases and 5,500 deaths. This represents a 9.3% mortality of cases, and an astonishingly high 90.5 deaths per million population.

Many people in Italy have thought long and hard about why this is, as indicated to me by my friend Dr Luca Mascitelli. No explanation is at hand.

However, it is on the Lombardy plain in northern Italy that the epidemic has been most serious and with the highest fatality. The major city of Bergamo has been identified as the epicentre of the epidemic. An inspection of a pre-epidemic image of Europe identifies the Lombardy plain as the area of Europe with greatest air pollution.

Copernicus satellite image showing northern Italy, February 2020.

The Lombardy plain sits at the foot of the Alps, which rise very steeply on the south side. The River Po runs through the plain. The main cities are Bergamo and Milan. Turin is a short distance to the west, in Piedmont. It is a place of motor cars, and restrictions have been suggested in Milan in recent months. It is one of the areas in the world with the least wind.

Lombardy, Italy
The man pollutant detected by the Copernicus satellite has been nitrogen dioxide, but in general air pollution blocks the transmission of sunlight through the atmosphere to ground level. The sunlight is essential for the synthesis in the skin of Vitamin D from 7-dehydrocholesterol. After its activation in the liver and kidneys to Calcitriol, Vitamin D combines with and activates the Vitamin D Receptor enzymes in the cells, in turn switching on a chain of genetic events, stimulated at the DNA level by Vitamin D Response Elements that enhance T-cell activation and the defensive inflammatory cascade.

Activation of intracellular and genetic processes by vitamin D

Enhancement of defensive T-cell activation by vitamin D following micro-organism invasion

It is was established in the early years of the 20th century that vitamin D is essential not just for bone health but for defensive immunity. At that time it was the disease tuberculosis that was particularly important, and for which air quality was so critical. The immune suppression caused by lack of sunlight and vitamin D in the activation of tuberculosis, so obvious in industrial cities, was met again in the late 20th century during the epidemic of AIDS. This was another acquired immunodeficiency syndrome that led to activation of tuberculosis and other conditions.

It is no coincidence that Wuhan, China, also experienced very serious air pollution before the epidemic. Also, it is now the time of the year when immunity and body stores of vitamin D are at their lowest, and it has been noted that this is the time when tuberculosis is most likely to present as an illness. 

And so perhaps this is the explanation as to why northern Italy is suffering so badly at present.

A public health initiative should be to supply vitamin D in large bolus doses to the people of Italy, and other countries where death rates are high. In fact, it is what we all need to help with protection against Covid-19.

The pandemic in Germany is causing surprisingly few deaths. This, the German paradox, is the subject of the next Blog post: