Category: Outcome

Categories
Covid-19 Mortality Outcome

Obesity and Covid-19: the challenge is growing

That obesity is a risk factor for doing badly following infection with Covid-19 is well known.  Recent data has given some more precise estimates of the risks and also what the explanations might be. More relevant is the concern that health services should be doing more and, as I will explain at the end of this post, is that health services have not learned the lessons from Hurricane Katrina (and on which I made my first public contribution this week to this debate!)

How is obesity defined?

  • I am sure this is well known to readers of this blog!
  • There are accepted cut offs based on body mass index (BMI) which is calculated from weight (measured in kg) divided by height squared measured (in metres).
  • The following thresholds are used (which I have translated into the nearest stone equivalent) for a women of average height 5ft 3 inches and a man 5 ft 9 inches.
  • From this  a male of this height with a weight over 14 stone is considered obese

Waist hip ratio

  • Apart from BMI, epidemiologists also measure the ratio of waist to hip circumference (WHR)
  • The waist should be smaller than the hips but the cut off for normality varies between the genders-women have smaller waists.  
  • Excess weight around the waist is consider as ‘central obesity’ and is more hazardous for health
  • A report in the British Medical Journal this September reviewed all the major research and found importantly that a central obesity is a predictor of dying prematurely from all causes after allowing for BMI
  • In other words, both body weight and body shape are important   

Obesity and Covid-19: risk of becoming infected

  • The UK Biobank Study published this month data from a large population survey of over 500,000 people who had had different measures of obesity and linked these data to the national laboratory Covid-19 test database
  • The results show a 60% greater risk of catching infection in obese people compared to people of normal weight.
  • They found a similar increase in risk looking at waist circumference 
  • What was even more interesting was that the risk of Covid-19 from obesity was greater in people from black and other ethnic minorities (BME)
    • As an example an obese (BMI>30) person from the BME community will have twice the risk of being CoVid-19 positive than a white person with the same BMI
    • This is not due to the rate of infection in those from  BME groups being higher anyway: the rate of infection in non-obese (BMI<25) was the same in both white and BME groups

Obesity and risk of severe disease

  • On top of an increased risk of getting the infection there are loads of studies showing that people who are obese have a greater chance of being admitted to hospital,  and once admitted ending up in an intensive care unit
  • Below is the up to data information of Covid-19 admissions to all the ICU’s in the UK
  • As shown compared with the background population, more  obese and severe obese patients are admitted to intensive care 
  • Once admitted obese and severe obese patients are at a substantial increased risk of dying. A recent summary of several studies showed that mortality rates approached 70% in the most obese patients admitted to ICU’s
  • Having an unhealthy waist hip ratio, adds to those risks for example leading to a doubling of  the chances of needing hospitalisation

Why does obesity make Covid-19 worse?

There are many theories but these include a mixture of plausible explanations

  • Obese people have a constant low grade of inflammation in their bodies even when they are well, but this gets worse when they have an infection
  • The virus stays longer in the organs such as the lungs as the immune system struggles to get rid of the virus 
  • Obese people make more of a protein called ACE2 which stays on the surface of lung cells and it is that protein which is thought to be what the spikey bit of the Covid-19 virus sticks to
  • Obese people have fewer of the healthy bacteria, we all have, hanging around in their guts and lungs, and this interferes with our natural immunity 
  • Lung capacity is reduced, the more obese people cannot expand their lungs so well 
  • It can be more technically challenging to treat obese people in ICU’s
  • Obese people have greater problems with  diabetes and high blood pressure 

Why am I covering this topic now?

  • The data are overwhelming that obesity, and its disease partners diabetes and high blood pressure, increase the risk of Covid-19, of being admitted to hospital with Covid-19, of ending up in intensive care and of dying
  • We are also faced, as a result of the pressure of managing acute Covid-19,  with a major reduction in routine health care especially in primary care and the putting on hold the preventive health  care that identifies those who have these health issues and actively manages them.
  • Following Hurricane Katrina, general health deteriorated in the population because of diversion of health care to manage the acute problems
  • These recent data from a global survey of health care professionals highlight the great impact of Covid-19 on health care in general, and these easily managed problems in particular
  • The point is that unless there is a return to active prevention programmes, health screening and regular primary care contacts, obesity and its consequences will go unchecked making the outcomes of Covid-19 much worse.
  • I made these points at a workshop I attended this week!
  • Hopefully someone will listen!

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Categories
Anti-viral drugs Immunity Outcome transmission

Genetic mutations in the virus and in humans: Do they offer a way out?

As the pandemic progresses the virus mutates. Mutations in us result in differences in how our immune system fights the infection. In this post I review how recent research on the impacts of these mutations could change the way we control and treat the disease – I found the results really interesting and even hopeful!

What is a mutation?

  • The different genes in every organism, from virus to man, consist of chains of different sequences of 4 building blocks, called nucleotides
  • The 4 – referred to as ‘A’, ‘C’ ‘G’ and ‘T’- can form very long sequences with up to 2 million in  any one gene 
  • You can think of genes as very long necklaces made up of Lego blocks in the 4 main colours
  • The exact sequence of the nucleotides in each individual gene does vary:
    • no two humans have identical sequences in any of our genes: there are many points of difference
    • even though a virus has far fewer and much shorter genes, there can be many differences in the genes (these are then referred to as different ‘strains’)
  • Such differences in the sequence of nucleotides are referred to as mutations. Mutations continually occur in all species
  • In some mutations, there is a substitution of one nucleotide for another
    • In the example below a  ‘red’ T was substituted by a ‘blue’ ‘C’
source: http://biology4alevel.blogspot.com/2016/06/133-genetic-mutations.html
  • In other mutations, sequences can be missing from one gene to another: this is called deletion
  • In yet other mutations, extra sequences can be added, often copies of short sequences, this is called duplication

How common are mutations in the Covid-19 virus?

  • This virus just has one strand of the genetic material RNA
  • This strand though has 30,000 nucleotides
  • Already scientists have identified 13,000 separate mutations 
  • Although this might seem very high, the level of mutations is 6 times lower than in the influenza virus 

What are the potential consequences of Covid-19 mutations?

  • Most mutations will have no consequences in terms of the infection
  • Even so, identifying such individual mutations can be very helpful in tracking the spread of infection between people
  • Of those that do make a difference, some mutations can affect the transmissibility of the virus (ie how easily it spreads) and others the severity of the infection
  • Early on in the pandemic, one mutation (OK it’s called D614G) was thought to be responsible for altering the spike protein on the surface of the virus that causes it to stick to human cells (and is the bit that most vaccines are directed against)
  • This mutation is now present in 80% of Covid-19 virus samples studied
  • The Chilean outbreak is thought to be due to further mutations in the spike protein gene making it even more sticky to human cells
  • There are other mutations, associated with a deletion of some of the virus’s genetic sequence, that make it less infectious
  • A study from Singapore in the Lancet in August suggested that that country’s lower death rate may be due to a deletion which produces less severe disease

The results were impressive-Singapore has lowest fatality rate in the world:

  • What is interesting is that mutations in the virus are likely to occur in response to how humans combat the infection.  There could be both beneficial and harmful consequences:
    • Beneficial: Consider for example there are two mutations: the one that causes very serious infections and the other that causes mild infection.  People carrying the latter are more likely to spread the infection and thus that version of the virus will become more prevalent.
    • Harmful: There are several examples of  viruses mutating to try and overcome our body’s immune response
  • We should not forget that significant (but what significant means is difficult to be precise) mutations in the virus could affect the success or otherwise of any new vaccine
  • Although at the moment most vaccine researchers believe their vaccines should be resilient against the types of mutation currently recognised  

How common are mutations in humans?

  • The answer of course is immensely common, each one of us probably has millions of mutations
  • Many of these mutations affect how our immune systems fight infections
  • The interesting question is therefore to ask if mutations in these immune genes explain why some people have more serious infections than others
  • The short answer from a vast number of research studies is yes:  differences in these genes between people are linked to various dimensions of the outcome, including mortality
  • An example of a recent study is the one referred to below from the USA that showed that some people have a mutation that reduces the body’s production of interferon, which is our natural anti-viral drug. 
  • Indeed, other studies have shown that an effective interferon response is necessary to fight this virus
  • To be honest, at first sight knowing that people who have more severe disease than others have a genetic basis for this might seem not that helpful, as we cannot change our genes
  • But what this kind of research can do is to help suggest new drug possibilities.  Just yesterday came a press release from the biotech company ILC Therapeutics for an inhaled version of interferon that might be a useful new drug
  • This follow from another small UK study in July of the use of another type of  interferon which showed an 80% reduction in the likelihood of severe complications
  • These are early days and more evidence is needed

Conclusions

  • There has been a massive amount of research into the genes that:
    • allow Covid-19 to invade and cause such mayhem
    • impact on our immune response 
  • None of the research findings individually will be a game changer, there is a very complex jigsaw of how all the pieces fit together 
  • A better understanding of the mutations in the virus can help in tracking the infection both over time and between regions and local outbreaks
  • More importantly these insights from genetic mutations can help focus attention on novel approaches to treating the infection    

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Categories
Covid-19 Outcome

Getting over Covid-19: What are the data?

Patients admitted to hospital, especially those seriously ill enough to be admitted to an intensive care unit, not surprisingly frequently continue with ill health and take several months to recover back to their pre-Covid-19 fitness.  But what about the possible long term health problems following the much more frequent but less serious infections.  In this post I examine the data to answer this question.

What long term complications have been described following Covid-19 infection?

  • Although fortunately rarely, some hospitalised patients continue to be at risk of  serious heart, brain, lung, blood clotting and other complications of Covid-19  
  • Some of these problems are direct complications from the virus itself
  • Others come from an over-reaction by the body’s immune system: the so-called cytokine storm
  • Others result from being on a ventilator for many weeks
  • Further, anyone in a hospital bed for weeks loses muscle and their fitness plummets
  • All of these can obviously take some months to achieve full recovery

How large is the proportion of non-hospitalised (community) patients? .

  • This is a pyramid of the best estimates of the numbers with different grades of Covid-19 in the entire UK population, from March to September
  • Similar data apply to the other badly affected Western countries.
    • About 5% of the population have had the virus
    • Of those about half were ill
    • Of those about 1 in 10 were admitted to hospital (data correct to end September)
  •  Obviously in the elderly the picture is different.  However, the prevalence with infection is still around 5% and the overwhelming majority of cases are not admitted to hospital
  • What happens to the 1 in 40 (approximately 1.5 million people in the UK) who had symptoms of Covid-19 but were not ill enough to be admitted to hospital?

“Long-CoVid” in community cases 

  • Widespread surveys published  in the scientific journals and presented in all forms of media have emphasised the persistence of symptoms and ill health in many otherwise recovered Covid-19 patients
  • (The quality of the reports in the scientific press is not that much greater than in the lay media!) 
  • These reports have led to the prolonged ill health following infection being referred to as “long CoVid”
  • To bring about a consistency in labelling, the following definitions have been proposed:
  • There is not a single pattern as to what symptoms are still present at these time points
    • Some just have a persistent single symptom such as cough or loss of sense of taste and smell
    • Others have non-specific symptoms such as fatigue
    • Others have as many as 15 separate symptoms

An epidemiologist’s perspective: what do I want to know?

As an epidemiologist, I acknowledge that some people do have long term problems but I want to know

  • What is the actual proportion of those who had  Covid-19 who:
    • have continuing health problems?
    • have specific complications?
  • What is the time course in terms of:
    • how long to full recovery?
    • if there are new complications, over what time period do they occur?
  • Are there factors that will predict who is going to have problems?

There are also some very specific challenges to answering these questions!

  • Anyone in the general population can have health problems similar to the symptoms discussed above.  Hence the key question: Is the rate of symptoms higher, and if so by how much, than in the general population (in that age group)?
  • Left are listed complications from ‘normal’ flu*
  • An extension of that argument is that recovery from other  common  viral illnesses,  especially influenza, can be marked by persistence of symptoms and development of complications

*https://www.researchgate.net/figure/Symptoms-and-complications-of-influenza-Complicated-influenza-is-defined-as-an-infection_fig1_311499723

  • It is not therefore a given that the persistence of problems following Covid-19  is more likely than that following other viral illnesses. However
    • The extent of the anecdotal  reports should not be ignored 
    • There are some seemingly very specific issues such as “Covid-19 toe” (see below) 
  • A second major challenge is knowing how representative are the patients who are being studied and whether there are any potential sources of bias in the data collection
    • Using  social media, a widely used  approach to recruitment, is unlikely to lead to a sample which is representative of the total population affected by Covid-19.
    • Further those who respond to such surveys are more likely to take part if they have symptoms

What do we know about the persistence of Covid-19 symptoms?  

https://covid.joinzoe.com/post/covid-long-term?fbclid=IwAR1RxIcmmdL-EFjh_aI-
  • The best data, allowing for recruitment bias, comes from the King’s College London symptom app (my ex PhD student Tim Spector again!)
    • The graph above shows the proportion at different time points after onset who are still poorly; and the very slow in improvement to complete health.
    • From the graph, just under 10% are  still poorly after 1 month (30 days)
  • In a telephone survey in the USA of 292 people who had tested positive 25% were still not back to their pre-Covid-19 health by 3 months
  • In another social media based study there was a steady fall in the proportion still feeling unwell after 4 months 

What symptoms persist?

  • A recent Dutch study, recruiting 2159 patients, mean age 47, from Facebook identified a large number of symptoms that were still present at an average of 11 weeks after the start of the infection
https://openres.ersjournals.com/content/erjor/early/2020/09/01/23120541.00542-2020.full.pdf
  • Interestingly in that group there were no symptoms that were more common on follow up
  • The prevalence of all the symptoms surveyed  (there were over 30 in that survey) reduced  during the 3 months but the most common ones were slower to disappear
  • As indicated above many of the symptoms like cough, fatigue, breathlessness are seen after influenza

What do we know about risk factors for persistence?

It is still early days in terms of having robust data on these questions but there is a consensus that any or all of the following might be important in predicting who will have continuing problems:

  • Poor antibody response to fight the infection (perhaps due to age or general immune problem)
  • The opposite of the above ie a greater immune response with the virus leading to an increased level of inflammation (a high temperature is part of the body’s inflammatory response to a virus)
  • Relapse or reinfection (at the moment the latter is thought to be very rare)
  • Losing cardiovascular and muscular fitness from prolonged inactivity 
  • Mental health factors in recovering from an infection – some have likened this to a post-traumatic stress syndrome.  In some patients the symptoms are similar 

Conclusions

  • As far as is known, and maybe studies will change that conclusion, people who have tested positive but who had no symptoms whilst infected do not then develop problems later 
  • On the one hand there is a high level of persistent problems in people who have been ill, but on the other there is no unique pattern of symptoms to such continuing problems
  • It seems that the rates of symptoms, 3 months after Covid-19, are greater than following a bad attack of flu, but how much greater we don’t know.
  • The positive news is that over time most people will recover completely
  • The more problematic issue is given we don’t know any specific cause for the persistence of symptoms, then there is no Covid-19  specific treatment.  Each problem will have to be managed symptomatically  

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Categories
Mortality Outcome transmission

Is there any evidence to suggest that Covid-19 is becoming less severe ?

Although in the USA and many other countries deaths from Covid-19 are not showing any major decline, deaths in Europe including the UK have been falling steadily since the peak of the epidemic in April.  In contrast to this positive news about falling death rates, there is no sustained slowing in the number of new cases detected.  This raises the question that possibly the infection may be becoming less serious as time passes.  In this post, I take a detailed look into the available data, and consider whether there is any support for such a possibility.

How large is the decline in deaths? 

The graph below shows the decline in total reported deaths from Covid-19 in Europe, which has occurred  since the peak in late March/early April (the blip in June was probably due to changes in recording deaths)

 
Source: https://www.statista.com/statistics/1102288/coronavirus-deaths-development-europe/

How does the  decline in deaths compare with the rates of infection?

  • The decline in number of deaths could, of course,  be explained by a similar drop in the numbers who are infected.
  • I have used the official UK data to show the patterns of  decline in both deaths and number of cases. 
  • To make the comparison easier, the figures in the graph below are the percent of deaths and cases  at each of the 4-week periods relative to the peak (which I called 100%).  Thus a figure of 50% percent for any 4-week period means that the number was half that of the peak
  • The graph shows that relative to the peak, deaths are falling at a greater rate than the fall in the number of cases.
  • However before concluding that the virus is becoming less severe, there are a number of other explanations that should be considered first.

What information do we need?

  • What is really needed is the ‘case fatality’ rate.  This is the proportion of people who develop the disease who then die.
  • Thus, a case fatality rate of 50% means that half of the people who develop Covid-19 are dying from the disease 
  • In order to calculate the case fatality rate, we need accurate data on the number of new cases. I have discussed this in my last post*. On one estimate, only about 1 in 10 cases in England are actually diagnosed and recorded
  • The impact of the under-reporting on the case fatality rate is large. For example, in the UK today (6th August) there have been 308134 cases and 46413 deaths.  At face value this suggests a case fatality rate of 15%.  That is ludicrously high.  We do not know what the true figure is, with the best available data being from China suggesting a rate of under 1%

*https://makingsenseofcovid19withs.com/2020/08/03/recent-peak-of-cases-in-manchester-neither-new-nor-unexpected/

Could the trends still be accurate?

  • The trends might be accurate even if the absolute numbers of cases are not
  • However, there is a problem given that at the beginning of the epidemic fewer people got tested, so more cases would have been missed 

What about other approaches to measuring severity?

  • Of course, death is not the only marker of how bad the infection is.  How many are admitted to intensive care is also a useful measure. 
  • That number though depends on how many intensive care beds are available and the threshold for admitting a person
  • Data from the UK indeed show a steady decline in the number of admissions to ICUs

Source: https://www.cebm.net/covid-19/covid-19-declining-admissions-to-intensive-care-units/

If the decline in deaths and ICU admissions is real, what are the explanations?

There are a number of possible explanations for the decline in the severity profile and deaths.  These are:

  • Relatively fewer older people, and relatively more younger people, are getting the infection, probably because of greater protective behaviours in the older age groups
  • Similarly, those with underlying health problems will also be avoiding risk more than those without
  • The treatment for those most seriously affected is improving.  This is indeed the case.  At the beginning of the epidemic only around 50% of cases admitted to ICUs survived in the UK.  By the end of May this had increased to 70% and is probably higher today.

Is there any possibility that the virus itself is becoming less deadly?

  • All of the above explanations are reassuring; in part suggesting our preventive measures and improvements in health care are working 
  • What would be really exciting would be if the virus itself was changing to become less severe!
  • As they spread in the population, viruses can change their genetic structure, or ‘mutate’.  This particular virus seems to be mutating approximately twice a month 
  • Indeed, one of the early changes was to generate a form of virus that would more easily transmit to humans.
  • Covid-19 is not mutating as much, though, as  is seen with many other viruses.  This is good news insofar as it might mean that those working to develop a vaccine would not need to worry about entirely new strains 
  • It can be argued that for the virus to survive, it would not do itself any favours if it killed everyone: the argument being that the milder the disease, the more likely that the virus gets passed on.  This is a possibility, but there is no evidence yet that this is happening with Covid-19 
  • Interestingly, the SARS epidemic in 2002 died out after about 8 months, for reasons that are not totally clear 

Conclusions

  • There are no definitive data that show the virus is causing less severe infections 
  • We are probably succeeding in reducing the spread in those most at risk and in the treatment of those with the most severe forms
  • It is not impossible that over time the virus itself may change to become less severe