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Are We DONE Here??

by: SusanC

Sat Nov 14, 2009 at 00:02:48 AM EST


Has the pandemic in the UK gone past its peak?  There are signs that the worst may be over... Or, I must be dreaming...
SusanC :: Are We DONE Here??
Sometimes I'm just slow.  I've been copying and posting the ILI charts for England and Wales on the news diary every week, but it didn't occur to me to do a comparison, with other countries like the US.  Until just now in the heat ;-D of a debate on the justification, or lack thereof, for the use of adjuvants in the UK for the current pandemic, when 2 pieces of information came together and a lightbulb went up in my head!

The first is the seropositive rate among clinical trials subjects in Germany earlier this summer, for the H1N1 vaccine, by GSK.  The following table is from their EMEA file:

At the time, I wondered whether there was something wrong with their test, that the seropositive rate was so high.  I should have had more faith.  Testing for antibodies is the bread and butter of the laboratory part of vaccine companies like GSK, and they have, well, substantial budgets.  In any case, after vaccination, the seroprotection rates were 98.4% and 97% for adjuvanted and unadjuvanted groups respectively, which are exceptionally high numbers.  So the initial seroprevalence was probably correct, or close enough to be correct.

The second piece is just lining up the dates and weeks of the ILI charts from the UK (England and Wales to be precise, but 'UK' is shorter and easier!) and the US, which produced the following composite picture (top panel: US, bottom panel: UK).  The dates are lined up so that if you drop a vertical line from the top to the bottom chart, you're looking at the same point on the calendar dates.

One hint for looking at these charts is, if you want to know the number of people infected in one wave relative to another, just compare the size of the area under the curve.  So, as you can see, the US had a small first wave which happened earlier, and which was just a fraction of the previous seasonal flu wave.  Now they are having a very big second wave.

In comparison, the UK had a very big first wave which happened later (makes sense, since it originated from across the Atlantic).  This first wave was, by my rough 'eyeballing' estimate, about 2-3 times the size of the previous seasonal wave.  And now in the second 'wave', we have these wavelets bumping along the bottom, with the exception of Wales (broken green line) which had the smallest first wave that started last, compared to other regions.  And now Wales is having somewhat bigger waves than the rest.  

So, I'm thinking, does this mean that we are already running out of susceptible subjects?  If you have a significant proportion of population already immune, then transmission is much slower, more sporadic, and you don't see that huge rising wave like in the US.

Also, seasonal flu in the UK starts and ends earlier than in the US, as you can see for 08/09.  So we are getting into the flu season here, and if we are not seeing huge numbers, it might mean something, you know.

Just to be (more) sure, I did a couple more checks.  I looked around the various UK sites, and found this page with this bit of news:

Latest news - 12 November 2009

There were 64,000 new cases of swine flu in England last week, down nearly 25 per cent on the week before when there were 84,000 new cases.

Hmmm, down nearly 25%.  That's not exactly how a rising pandemic wave would behave, is it?

I also looked at the NHS Direct syndromic surveillance data, for fever and cough, downloaded from the HPA site.  NHS Direct operates a 24 hour phone service for people to call if they get sick and need advice or care.  The number or percentage of calls for a particular symptom can be used for surveillance analysis.  

So I downloaded it, and the document says this on the first page:

Please note: The NHS Direct system change that was introduced on Saturday 4th July to deal with the increased call volumes experienced due to swine flu has been discontinued over the weekend of 3-4 October.

Apparently, in July the volume of calls was such that they had to do a system change.  The signficant part, for me, is that that change was reverted back to their previous service, on Oct 4.  I don't know if we can interpret the data during that period, but we can look at what happened after they changed back to their previous system.  I highlighted (pale yellow) the corresponding periods from Oct 4 to now, and in 2008, for comparison.  

The difference between 2009 and 2008 is very small.  It could be that lots of people are getting their tamiflu directly by calling or answering a list of questions online, and so bypassing these different surveillance systems.  However, when I looked at the Weekly National Influenza Report, I found this chart.

Nope, that hypothesis was incorrect.  The fall in cases is real.  (But I did scratch my head a little, over the regular bumps up and down.  I don't know, maybe that is due to variations on different days of the week?...)

Anyway, I also tried looking for hospitalisation data, in the off chance that many people were so sick they went straight to the hospital, but unfortunately, I was unable to find it.  I then tried looking for some mortality data.  I said tried because even though I found those, the information is a little, well, incredible, so I don't know if I'm missing something.  I'm just going to show you these 2 charts, showing all deaths registered by week, and respiratory deaths respectively.  The big peaks in the middle (blue and green) are the seasonal flu deaths.  The period since the beginning of this pandemic, is represented by the later part of the blue line, and the red line just starting.  

So I'm looking at them and thinking, am I seeing things?  Or, more accurately, NOT seeing things?!  Where are the excess deaths due to the pandemic?  We had this huge wave in the summer, and it didn't make a noticeable difference in the mortality curves??

Somebody help me out here.  I'm just so confused.  Either we've done exceptionally well, and the pandemic has come and gone and we'd hardly registered substantial numbers of deaths, or... what?  I have no idea.

In any case, the original question that started this quest, namely, what is the point of giving millions of people adjuvanted vaccines of uncertain safety in a mild pandemic, has now acquired a new dimension, namely, what is the point, of giving millions of people adjuvanted vaccines of uncertain safety in a mild pandemic, when the worst may be over?? The HPA (or whoever is supposed to do this stuff) should conduct some seroprevalence studies, as a matter of priority urgency, to see how many people are still seronegative, because it may well give us some insight as to how best to move forward with the vaccination saga - um, sorry, programme - that will protect the most people with the least possible adverse effects!!

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Are We DONE Here?? | 62 comments
in the meantime
across the pond in Canada, the sudden increase in number of deaths this week is causing concern.

http://www.theglobeandmail.com/life/health/h1n1-swine-flu/second-h1n1-wave-takes-lethal-toll-on-canadians/article1361766/

Second H1N1 wave takes lethal toll on Canadians

A sudden spike in H1N1 deaths over the past week reveals that the pandemic virus is taking a far greater toll on Canadians during the second wave, raising fears that it is just as severe, if not worse, than seasonal flu.

Ontario's confirmed tally of fatalities jumped to 61 from 37 last week; five more people died in Alberta since Tuesday; Quebec confirmed four deaths in the past 24 hours; and British Columbia recorded eight more deaths over the past week.

More than 190 Canadians have died from H1N1 - and with additional deaths expected, health officials say there is a heightened urgency to get more people vaccinated quickly, especially the young who have been so badly affected.

The death tally, which in the spring averaged two to four a week, is at least three times higher during this second wave as the virus spreads. "We haven't seen the peak yet, in my view," David Butler-Jones, Canada's chief public health officer, said yesterday. "We will continue to see, unfortunately, more people in ICUs and hospitals, and, unfortunately, more deaths as well."

My little 2 cents is, this is compatible with the classical exponential growth (see the UK first wave!!) of pandemic flu that really spooks people.  That said, the biggest lesson about influenza, still, is that it is unpredictable.  So, maybe it's still too early to tell, for the UK, US, Canada, or any other country.  It's one of those things that you can only be 'sure' in hindsight...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


something else, about Canada and the UK
if Canada didn't have such a big first wave even though physically it sits right next door to the US, while we here on the other side of an ocean got hit big and hard and early, it only shows that epidemiology works.  

The concept of connectedness being more important for disease transmission than physical proximity is well illustrated by the different experiences in the 2 countries.  The UK is one of the most highly connected countries in the world, so it should come as no surprise if, in the end, it does turn out that the biggest number of infections has already happened in the first wave, and now the virus is just sporadically scraping up whoever got left out the first time round...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
stable virus is a big help
you can't predict that,but it seems that's what we have.

is there a third wave to come? Will it be  a mutated virus?

Stay tuned, but that's part of the rationalization for vax of any kind, taking out the adjuvant question.


[ Parent ]
so far, fingers crossed n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
The Third Wave - A Prediction and Possible Explanations
I believe that the second wave is (or will ) end because of herd immunity but I suspect there will be a third wave in the US in January-February. I believe that it will be a much smaller wave then the second US wave. After all the historical novel influenza strains have had a third wave http://www.cdc.gov/ncidod/eid/...

So why could we get a third wave if herd immunity terminates the second wave?

One possibility is that that viral interference whether from interferon or other innate immunity secondary to other recent viral infections (for example  as rhino viruses see http://www.eurosurveillance.or... )is a real phenomenon and that it effectively increases the herd immunity during and helps terminate the second wave. However,these individuals who recently had other viruses and are therefore able to fight off H1N1 with enhanced innate immunity may not develop humeral immunity (H1N1 specific antibodies).  As their enhanced innate immunity decreases these individuals become susceptible to H1N1 infection.  

A second possibility is that the very dry indoor environment in January  (see http://www.pnas.org/content/10...  and  http://www.pnas.org/content/10... )leads to increased indoor survival of virus and infections of individuals in indoor settings such as stores etc who under October indoor conditions would not be exposed to H1N1 and therefore never develop immunity. (I think the 2nd surge - at least in the Northeast was due to optimal outdoor temperatures for airborne survival and transmission- temperatures just above freezing when people are still out and about and cloudy with no UV to kill the virus.)

If these two groups of non-immune people are large enough than a critical mass of non- immune individuals may develop to generate a third smaller wave even in the absence of viral mutation. (Unless everyone gets vaccinated before then!) Please note that these are just ideas and may be wrong. I would love to hear other thoughts on these or other possibilities.  


[ Parent ]
Lack of Herd Immunity
I have serious doubts about whether herd immunity can be established in the near future.  The lack of vaccine availability - and the public disinterest in some areas when it comes to being vaccinated - may combine to contribute to a definite lack of herd immunity.

In my local area, a vaccine clinic was held last week with 1000 doses free for the asking - no one turned away who requested the vaccine.  At the end of the day, even after relatively heavy advertising, more than 1/3 of the available vaccine still remained.  This was the first opportunity this area had had to be vaccinated, other than the doses that had come in that went directly to schools.

Over at PFI, much discussion involved NY City vaccine clinics, where only a small fraction of the available doses were actually given.

In some places, there have been long lines of people trying to obtain the vax, only to be turned away when the vaccine allotted to the clinic was gone before everyone who wanted a dose had been given one.  Entirely different problem, but also no help towards herd immunity.

Herd immunity can also come about thru enough people having been infected that they then gain immunity - but the problem with that might be the multitude of anecdotal reports we've seen regarding re-infection with the virus.
Apparently, one episode of the illness doesn't necessarily provide immunity.

I personally am not convinced at this point that we're even in wave 2 - the downtrend in cases over the summer in the US could be a statistical artifact brought about by the fact that most schools in the US were closed during the summer; however, when schools reopened in the fall, the case numbers rose dramatically.  Was this a reflection of a 2nd wave formation, or simply an artifact caused by the mitigating effect of school closures?

I don't know how to tell the difference - and I'm not convinced that anyone else does, either.

I think in hindsight all this will become crystal clear - but in the present time it is all seen as thru the glass darkly.  We can make assumptions to support any theory - but the cold hard reality of the situation may still lay in wait for us to discover at a later time.


[ Parent ]
NYC had low turnout last week
high turnout this week (advertising helps!)

Long Lines Wait For H1N1 Vaccines At Weekend Clinics

http://ny1.com/5-manhattan-new...


[ Parent ]
And it looks like cases
are ramping up a bit in the area which probably also helped motivate more people.  

[ Parent ]
Paradox of Vaccination: Is Vaccination Really Effective against Avian Flu Epidemics?
Interesting to read: Paradox of Vaccination: Is Vaccination Really Effective against Avian Flu Epidemics?

http://www.plosone.org/article...
" Furthermore, vaccines might provide immunological pressure on the circulating strains, which might engender the emergence of drifted or shifted variants with enhanced potential for pathogenicity in humans [1]. Therefore, although vaccination programs have been recommended recently, some field evidence indicates that vaccination alone will not achieve eradication. Moreover, if not used appropriately, vaccination might result in the infection becoming endemic [11], [17].

An important issue related to influenza epidemics is the potential for the emergence of vaccine-resistant influenza viruses. The vaccine-resistant strain, in general, causes a loss of the protection effectiveness of vaccination [19], [20], [21], [22] (there is experimental evidence of the loss of the protection effectiveness for antiviral-resistant strains [23]). Consequently, a vaccination program that engenders the emergence of the resistant strain might promote the spread of the resistant strain and undermine the control of the infectious disease, even if the vaccination protects against the transmission of a vaccine-sensitive strain [20], [21], [22]."  


[ Parent ]
yes that is so true
We don't have any country that has achieved very high vaccination rates among the general population, so we have actually no data on the evolutionary pressure such vaccination would impose on the virus.  We know that flu viruses are infinitely adaptable, certainly much faster than we can come up with new ideas.  So if we vaccinate sufficient people to achieve some type of herd immunity, in ways that can affect the transmission of the virus, would we see new strains happen faster?  Nobody knows the answer to that.  

What about the use of adjuvanted vaccines with theoretically enhanced cross-protection?  Remember the protection offered by the vaccine, any vaccine, is only or mostly against the HA.  We do not know the degree to which changes in the NA or even 'internal' genes (which do have surface epitopes and may affect the conformation or shape of the surface antigens) alters host susceptibility.  History tells us the flu virus, particularly the descendants of the 1918 pandemic, is very adaptable, so by creating a high level of immunity against existing epitopes, are we setting ourselves up for new viruses that have evaded such immunity in novel ways?  No one knows the answer to that.  

It's again a 'theoretical risk', but only because we have not encountered it.  Same way that we had not encountered the problem of H5N1 in humans before 1997.  If you look back at the literature, very few people before 1995 believed an avian flu virus can jump species directly without an intermediate host and cause such significant and persistent problems as we are seeing now!!  We are the victims of our own (lack of) imagination!!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
also victims of our own success n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Since only 124 people have died so far from swine flu in England
and about 180 deaths for the whole of the UK, you wouldn't expect to see a spike on the graphs of deaths that doesn't go below a minimum of 8000 per week. In fact if this flu is dominant by the winter proper you might expect the normal flu death spike in the elderly to be greatly diminished. Which would mean that 'mild' is not an inappropriate term for this virus.

Not clear at this stage.
It could be that the UK cases are at peak but you have to remember that it was half term (2 weeks given different schools) so it may be temporary dip. I've marvelled in previous years that the UK has had practically no flu season at all for the last 9 years. They've even had to reduce the baseline activity bar, which is why you have to be a bit careful comparing the US to the UK graph. They also show different measurements and scales.

There will be lots of reasons why the US and UK charts don't match. School terms, paid sick leave, geographic spread, availability of Tamiflu, past exposure, etc. There was a point in the summer while flu raged in the US, where I was beginning to think the UK wasn't going to get a peak and then boom, it took off. Was it the Tamiflu?

I'm fairly sure that huge amounts of international and national travel has made us all much more robust when it comes to flu but I also think that air temperature has a something to do with it too. Can the UK thank global warming for lower flu rates? Flu in the UK bears an uncanny inverse relationship to global temperature.
http://www.hpa.org.uk/web/HPAw...
And currently it's fairly mild.

Will there be more peaks, bigger peaks? Don't know. What I do know is that influenza is unpredictable. A(H1N1) might be stable now but this IS influenza.

What I do think the various national peaks and troughs show very clearly, is how much school kids drive the waves.

As for vaccination - there's also an argument for not vaccinating anyone.


And comparing stats
From latest figures
http://www.google.com/hostedne...

US
Population - 304,059,724
Infected - 22,000,000
Dead - 3900

http://www.hpa.org.uk/webw/HPA...

England
Population - 49,138,831
Infected  - 668,000
Dead - 124

So compared to the US the UK/England has a distance to go before catching up. Of course there's always the problems of over/under estimation. nb I think they are counting the packs of Tamiflu issued as positive cases (with reservations).



[ Parent ]
you can also say
looking at previous pandemics, in every one of them where we have some data, the severity and pattern varied a great deal.  Even within one country, there are pockets of high death rates and places that are hardly affected.  So, for me the mortality figure is not a good measure of cumulative AR because of such a big variation.  That's what you need to look at to know how many people are still susceptible.  R0 tends to vary a whole lot less, and incubation period varies the least, in different places.  Seroprevalence, especially done serially, would give us the best idea.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Moisture
Here in the Nordics, (Sweden) they say we are usully hit harder by flu's because of the low moisture levels in the air during winter season (it has something todo with that virus particles travels longer during wintertime through coughing and similar). UK has more moisture all the time.

I was thinking if people in nordic countries or primary the northern parts of europe might experience more flu's then the southern parts of for example europe, there must be studies made that consider this, I will look for them. If so ... could it be that as you also suggests that we are in general "used" to flu's ... and mayby I don't if it is not related to phsyiology it might be related to behaviours ... also not so much in uk but we have very good systems in nordic countries for example longer vacations, a lot of paternity leave and you will get paid even though you are home sic or with sic kids, this is VERY different from US and also UK. This might result in that people are home earlier when experience sickness and also perhaps even for longer periods.

So unfortunatley I to think it is difficult todo these types of comparisions due to differences in population, behaviour and also cliamte (even though us is big). Maybe you can break down the statistics of US and compare similar climates ... but you also need do consider behaviours but ...  


[ Parent ]
oups
sorry for the bad english ... I where about to preview but pressed the wrong button.

[ Parent ]
I don't know
As for vaccination - there's also an argument for not vaccinating anyone.

It's a spectrum of risk vs benefits.  Let's say immunocompromised people, people on chemotherapy, transplants, kidney dialysis, kids with severe neurological disorders.  Just to name a few.  These are really high risk.  They come down with it and there's no telling that antivirals will save them, so you have to do something to protect them



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
"here" makes me think of "there and everywhere"
http://www.eiss.org

select week 45

look at "charts" from each place

pity we can't aggregate/select better, or can we? or not yet? with weight per population? age groups? should be doable

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


more comparisons
For those of you who said you can't compare across different countries, let me explain something.  The above comparisons are based on each country's epidemic size as compared to the previous flu season (ie 2008-9) of that particular country.  You can compare it that way, with one caveat, that the last flu season may be substantially different across different countries.  For example, if the UK had a particularly mild flu season in 2008-9, then it would give an illusion of a very big first wave if you compare it to one seasonal flu.  So I looked up the charts for the UK and the US, and reconfigured them to show the pattern of seasonal flu for the past 3 years.  

Here's the one for the UK, taken from the HPA archives.

And here's the one for the US.

As you can see, the 2008-9 season in the UK was in fact not particularly mild - it wasn't very severe, but more severe than the previous 2 years.  Whereas for the US, the 2008-9 season was about the same as 2006-7, but much milder than 2007-8.

In other words, the first wave in the US was only a fraction of the preceding seasonal flu, which in turn was a relatively mild season, which to me says that it was a genuinely small wave.  Whereas the first wave in the UK is several times bigger than the preceding seasonal flu, which was in turn slightly more severe than the previous 2 years.

As I said, none of this is definitive, but this serves as another verification, that the big first wave in the UK was real, and not an artefact due to comparison with seasonal activity.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


You can't say that either first wave in the UK and the US was entirely natural
They were exacerbated by panic and changes in policy.

Part of the reason the UK wave was larger than a normal seasonal flu wave because normally very few people go to the doctor with flu. That may be the real reason we've had low flu seasons for the past 9 years. For the first time ever, people in this country are being routinely offered an aid to flu. There won't be many who turn down free drugs, even if they don't take them. After all, that was what you predicted.

Add to them, those who thought their case of a cold was flu and you get a lot of people turning up to collect their Tamiflu. Wasn't there testing that showed only a third of cases were actually swine flu?

The US had a damping system on that. Firstly they had to pay for the drug and secondly they were much less likely to get it.

Once the people realised that the flu wasn't killing loads of victims the drive to aquire Tamiflu abated somehwat. The summer holidays added to that, in part because people were probably unwilling to interrupt their holiday plans.

None of this means that the UK wave isn't peaking but it's still too early to tell.


[ Parent ]
true, but I don't think
Part of the reason the UK wave was larger than a normal seasonal flu wave because normally very few people go to the doctor with flu. That may be the real reason we've had low flu seasons for the past 9 years. For the first time ever, people in this country are being routinely offered an aid to flu. There won't be many who turn down free drugs, even if they don't take them. After all, that was what you predicted.

it can account for THAT much difference.

Wasn't there testing that showed only a third of cases were actually swine flu?

Actually, see my comment below, on the investigation of the outbreak at Eton.  There 100% of cases who were still symptomatic tested positive with PCR.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
also, this was not flu season.
Wasn't there testing that showed only a third of cases were actually swine flu?

The charts for the previous years, that I've looked at, generally do not show much activity except for the seasonal flu period.  So, again, the key is to compare like for like.  If a substantial proportion of cases in that huge wave was not H1N1, the question is, what was it?  It's not the kind of thing that happens at that time of the year.

What I'm learning, is that epidemiology consists of a collection of incomplete and imperfect data, any single one of which may not mean anything, but one needs to look at the sum total of all these bits of information in order to draw any findings from them..  Very interestinig.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
the point that I'm making
with this additional piece of information, is to make sure the comparison with the seasonal flu is not skewed because of a milder preceding season in the UK.  That's ALL I'm saying, in that comment.  I spent hours tracking down the information and then reformatting the graphics just to make this one point, just in case the data was skewed...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
looking at it from a different perspective
The ILI surveillance tracks healthcare seeking behavior.  There's a threshold of severity below which cases would not show up in such surveillance data.  To get an idea of how many people might be infected for each person seeking medical care, here's an interesting study An outbreak of influenza A(H1N1)v in a boarding school in South East England, May-June 2009.

Eton College is a boarding school for boys aged 13-18, and the biggest full-boarding school in terms of population size (1,307 students).  The school is not named in the paper but the events around the outbreak and school closure have been widely reported in the media.  

Here's a brief summary of the outbreak.  The index case was a 14-year old student who sought medical care for flu-like illness on May 27.  He had no history of travel to an affected area nor contact with known confirmed cases, and thus, would not have been tested under HPA guidelines at the time.  However, he was seen by a private healthcare provider at the school, and a swab was taken, which came back positive for H1N1.  

At the time, the policy in the UK was containment (ie contact tracing and prophylactic tamiflu).  Contact tracing revealed that he had very limited contact (only 15 students) with others while symptomatic.  Upon further enquiry, it turned out that there has been an outbreak of ILI in the school, and 39 students had sought medical care at the school in the 4 weeks prior to identification of this case.  

By this time in the investigation, the school had already closed for a short break, and students were dispersed all over the country.  A decision was made to contact all students and staff, and those who were symptomatic were asked to call for telephone assessment.  As a result of this, more cases were discovered.  

In total, there were 102 symptomatic cases.  Apart from the 39 who by that point were no longer symptomatic, PCR tests on the rest, ie 63 people (62 students and 1 staff) all came back positive.  Those who were positive were treated with tamiflu, and the rest of the students and staff were offered prophylaxis (with 48% uptake, in the end).  

So, what do we learn from this outbreak?

  • The outbreak happened in week 18-22, when there was only a small increase in the ILI surveillance chart, before the actual big first wave (shaded area on chart)


  • The attack rate among students was 8%, within that 4-week period.
  • All cases were mild.  No one was hospitalized.
  • 38% (39/102) of symptomatic cases sought medical care.
  • It is striking that 100% of those still symptomatic tested positive with PCR.

So, if we look back at this from where we are now, what can we infer?  I'd say, it is true that most cases are mild, and almost 2/3 of cases did not seek medical care.  In a more severe pandemic, the proportion would be much less, so ILI surveillance is actually a marker for both AR and severity.  

Secondly, the 8% AR is actually pretty high.  Eton College is not like a city school.  The school is spread over some 400 acres with 400 buildings source, so the number of contacts per student is much lower than regular schools.  Given that, and given it was so early in the pandemic (ie with very little seeding), an 8% AR within a 4 week period tells me it was very easily transmissible right from the beginning.

All that happened before the big first wave.  Which is another bit of indirect indication, that probably a lot of people are immune by now.  I think....  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


for a teenager
Contact tracing revealed that he had very limited contact (only 15 students) with others while symptomatic.

such a low number of contacts within (I assume) 2-3 days is really striking.  I don't know how exactly they defined close contact, but it's still very low.  Can you imagine the number of contacts a student would have, if this was a city high school with 3000 students??



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Not comparable
Eton is a residential school. While the number of connections made might be smaller (at least for this lad) they probably spend more time togther. And some will have more contact than others.

At 1294 pupils it's not a huge school but it's bigger than any I went to. Average school size is about 1000.

When I mentioned that only a third of cases were positive, I didn't mean from known outbreaks but individual families contacting their doctors.

The number of people seeking help varies with concern. Even the government's statistics include a huge margin of error because they're not convinced that the number who reported flu actually had it. 313,000 to 1,382,000 is a big spread.

Despite some major school outbreaks during that first wave I didn't get the impression that it encompassed the majority of schools. In the main, it seemed to be concentrated in some of the bigger cities - London, Birmingham, Sheffield. That's also where you'll find most of the huge schools. The only cases in my local schools were very quickly quashed by closure and Tamiflu. Reports of any cases were very low.

I'm not saying that there wasn't a summer peak but I'm not sure that it was genuinely bigger than our normal winter peak. I'm not saying that we haven't reached our winter peak, I just think it's too early to tell.


[ Parent ]
that I disagree
I'm not saying that there wasn't a summer peak but I'm not sure that it was genuinely bigger than our normal winter peak

It's very hard to have something that is about 3 times bigger, and think it's all an artefact.  10% bigger, maybe 30% bigger, possible.  But this is a LOT bigger.

I'm not saying that we haven't reached our winter peak, I just think it's too early to tell.

That I agree.  Flu is unpredictable, so time will tell



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
what's the difference?
When I mentioned that only a third of cases were positive, I didn't mean from known outbreaks but individual families contacting their doctors.

If people were symptomatic that's a clinical case, whether it was in Eton, Wales, or Nottingham.

2/3 of the people at Eton didn't feel sick enough to see a doctor.  But when they were actively traced, the ones who were still symptomatic (which the families contacting their doctors will also be) all tested positive.  I find it very amazing, and I'm still trying to figure out what it means.  It's a very unusual finding.  The only explanation I come up with, is that because this was an active outbreak investigation, the people who were taking swabs were probably much more competent and able to do it right.

It's hard to get a false positive with PCR (short of contamination, but these samples were taken in different parts of the country, 9 different centers, I believe), but it's very easy to get a false negative, because the swab was not done right, the samples got dried out, they sat on the shelf for too long, whatever.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Really?
"If people were symptomatic that's a clinical case, whether it was in Eton, Wales, or Nottingham."

Gee and here I thought that there were other diseases that could be confused with swine flu ;-)

Not everyone with mild symptoms is free from flu. not everyone with flu symptoms have it. I'm not saying the Eton cases didn't have flu, I'm saying that not all of the cases across the country were swine flu. The government is currently guessing about half.



[ Parent ]
that is the definition of a 'clinical case'
for ILI.  Someone who has symptoms in the middle of this pandemic.  If they are confirmed, they are a confirmed case.  If there is any reason to think it's probably H1N1, such as contact with known confirmed case, it's a probable case.

I didn't make it up.  It's the definition.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
I believe you, but it doesn't make it true.
It also doesn't give you any idea how many people normally go to the doctor with seasonal flu. The bulk would be made up of the elderly I suppose.

One question, are the graphs made up of medical diagnoses or are the flu line cases included?


[ Parent ]
ILI just means
flu-like illness.  There's a definition, but it's not a medical diagnosis.

The important thing is again comparing like for like, within the same system of surveillance, over time, where whatever the definition and criteria for reporting is, it's the same over time, but it may not be the same when you compare across different systems.

In other words, you can't compare cases per population between UK and US, because the reporting criteria may be different.  But you can compare US pandemic vs US seasonal, and then UK pandemic vs UK seasonal, and then see the difference between the 2 sets of results.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
there are 3 sources
One question, are the graphs made up of medical diagnoses or are the flu line cases included?

for the stuff I posted on the top diary.  One is the RCGP chart, which is just ILI.  Second is NHS Direct, and the chart I used tracked fever and cough.  Third is the tamiflu distribution system, NPFS, whatever that stands for.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
ie, the RCGP tracks GP consultations n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
one thing
(and I'm kinda slow to think of that) is that with the upgraded NHS Direct between July and October AND with the NPFS where people can just get tamiflu, both of those would have reduced the need for GP consultations, so without those, the wave would probably have been even bigger, by the RCGP reporting system.  

The NHS Direct system change happened on Week 27, which is just at the beginning of the big wave.  The NPFS thing started 3 weeks later, ie week 30, which is about the peak of that big wave.

OK, I really have to go.  That's it for now.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Immunity
All that happened before the big first wave.  Which is another bit of indirect indication, that probably a lot of people are immune by now.  I think....  

I'm not a big believer in infection = immunity any more. There have been many, many anecdotal and a few confirmed cases of multiple infections from this virus over the period of a few months (which incidently corresponds to my own experience - I've written here previously of my first bout of the flu in August and a second in October).

I think this virus is going to be present for another go 'round or two or three in the next year or so. And if it acquires the ability to increase viral load (as I believe it has in Eastern Europe) the next wave will be more contagious and more virulent.


[ Parent ]
oh, sure it's going to go round again
next year or so.  I'm just talking about this particular period, right now, the so called 'second wave', that doesn't seem to take off in any region except Wales, and even there it's not too big.  

Also, Wales demonstrates that the virus IS capable of causing significant sickness at this time of year for the UK.  The only thing I can see to account for the difference between Wales and other regions, is that they had a smaller first wave.  That is an indication (not conclusive, but indicative) that the size of the second wave is inversely proportional to the size of the first wave, roughly speaking



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
which is reminiscent of this
Spain in 1918 http://www.newfluwiki2.com/dia...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
And Northern Ireland
they are still very much on the rise and they did have a comparable peak with ours. Northern Ireland do regularly have a bigger peak than England and Wales. Scotland is usually somehwere in between.

http://www.hpa.org.uk/web/HPAw...

Scotland did have an initla peak (slightly ahead of ours) but it was titchy.

AFAIK none of the UK regions other than England are using the telephone Tamiflu distribution.


[ Parent ]
sorry, I'm lost with finding these pages
where is the parent page for that link?  I can't understand just one single pdf page with one chart.  I'd like to see the context.  This information is scattered over so many places it's ridiculous.  

Thanks!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
ok, I'm scratching my head over that chart
N Ireland looks like it's a different pattern, but the graph for Wales shows a higher peak in the first than a second wave, whilst that's not what the RCGP charts show, for Wales.  The source of info is different, so I don't know if it's a sampling issue?  The darn thing doesn't tell you (or at least I can't find it) what is the source of the info, how it's collected and reported, ie how accurate is their reporting?  

What I'm saying is, if the pattern for the known places, like Wales, is consistent across the 2 reporting systems, then it's easier to interpret that data.  It's weird...

And, as for issuing tamiflu by phone, I did think of that, but that's dropped as well, apart from the initial high (chart at top diary).



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
and with that
I'm going to have to leave it for now, cos I need to get back to other urgent stuff.  I'll post if I can think of an explanation, but right now that question, about N Ireland, is open.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Does Infection = Immunity?
I too am no longer certain that all infection equals long term immunity.  In my spare time I have been pulling some of the old literature on viral interference and innate immunity.  This literature is very mixed and inconclusive since it has always been impossible in the past to know if there were definite 2nd infections and how different virus interfered with each other. The technology just didn't exist.  So what are the possible reasons for 2nd infections.  

A) The first infection was cleared through innate immunity http://www.medscape.com/viewar... and specific humeral immunity never develops. In this case the innate immunity may have been enhanced (or at peak virus catching capacity because of a simultaneous or recent infection with another RNA virus.)  

B) An antiviral agent aborts the infection before humeral immunity can develop.

C) The virus mutates sufficiently that the humoral immunity is no longer adequate.

Please keep in mind that I am not certain of any of this, however, right now it makes the most sense to me personally given what we know.  


[ Parent ]
several issues here
a) There is a difference between short term and long term immunity.  Let's take seasonal flu.  We all have some immunity to it, but since the virus drifts, we still get infected, but the infection is not anywhere near as severe as when the virus is totally novel.

So that's 2 different kinds here.  One is general immunity to that subtype, eg H3N2, which is not strong enough to offer specific and total protection to a drifted strain, or when a new subclade appears, as in the 2003/04 season, which caused a lot of illness and more deaths than usual.  

In general, I'd say, since we are talking about a novel virus, H1N1, then infection would result in some immunity such that a second infection would be less severe, but it may not be enough to prevent re-infection altogether.  Which is compatible with findings from 1918 - infection in the first wave did not protect against infection in the fall, but protected against death.  Further explanation in this diary, Spanish Influenza in Spain, also Crosby's observation on reduced mortality in sailors, http://www.newfluwiki2.com/sho...

b) no, antivirals like tamiflu do not interfere with development of immunity, whether short term or long term.  Here's the reason: tamiflu is a neuraminidase inhibitor.  The virus enters a host cell and replicates, then the host cell dies and lots of virus particles are released to infect other cells.  NA inhibitors act on the back end of that process, as the virus EXITS the cells, so it's not terribly efficient in stopping the virus.

In addition, we know that when someone has symptoms, viral replication has already started.  If they take tamiflu say at 24 hours after symptom onset, the virus has head >24 hours headstart, in replication.  Then, drug absorption and distribution to the lung takes some hours, which is why I said, it's pretty inefficient, from that POV.

Now, the innate immune response starts minutes after the virus is detected.  Certainly we know that by the time someone is symptomatic, if you measure serum cytokines, just for example, you can see lots of changes already.  So, the innate immune system is already there, long before your antivirals can act on the virus.  

The development of adaptive immunity starts with phagocytosis of pathogens by innate immune cells, which then carry these pathogens/antigens and migrate to the regional lymph nodes to activate T-lymphocytes, as described in this diary.  When tamiflu starts to work, the innate immune system has probably done at least 2 days of work!!

c) It's true that an infection in a totally immunologically naive host may take some time before adaptive immunity happens, with antibodies etc.  The immune memory generated is really useful in subsequent infections when antibody levels rise quickly to meet the challenge.  That said, even in the first infection, adaptive immunity in the form of antigen-specific cytotoxic T-lymphocytes (CTLs), start around 5-7 days after onset.  

See Dawson 2000

In general, the pathogenesis of lytic viral infections, such as influenza infections, can be divided into two phases, the cellular events that precede T cell invasion and those that follow it. The initial attack of influenza A on respiratory epithelial cells causes the extravasation of small numbers of blood-derived neutrophils, followed by larger numbers of blood monocytes/macrophages into the infected lung. During this period, viral replication continues in the epithelial cells and infection spreads to the collecting macrophages.16-18 These processes alone are not able to clear the virus from the lung. By day 7, CD8+ cytotoxic T cells (CTLs) from nearby mediastinal lymph nodes (MLNs) begin to accumulate in the infected lungs and the efficient process of T-cell mediated viral clearance begins.

This response is required for viral clearance.  Although the innate immune system can keep the virus at bay, for a while, it's not enough for clearance, and the adaptive immune cells like CTL are responsible for that job.

Whether or not they develop measurable antibodies during that process, the fact that an adaptive immune response happened still leaves the person with antigen-specific memory cells, so the next infection will be more efficiently dealt with.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
in other words, immunity is a continuum
not an all-or-none phenomenon.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
That link didn't work!!
sorry, http://ajp.amjpathol.org/cgi/c...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Google Flu Data
It will be interesting at some later date to see how Google's Flu Tracker data compares with the various official sources. So far the early correlation seems fairly good but it's too early to really say.

effect of half-term break
(btw There's even a handy website for you to look them up, bless the internet.  http://www.halftermdates.co.uk/  I still remember the days when the school calendar that came as a booklet at the beginning of the school year was all you get to remind you of the dates.  That handbook was an 'important document' in the household. if you lost it, you'd be in trouble...  LOL!!)

Anyway, I looked up the dates.  They were surprisingly uniform.  Initially I thought they were different, but on closer look, "schools close on Oct 23" actually means the same thing as "half term starts on Oct 26", since the 23rd was a Friday and 26th was a Monday!!

With a few exceptions, in most counties (and I did look at most of them) schools closed on Oct 23rd and re-opened on Nov 2, ie a 1 week break with a weekend tagged on either end.  So I made a little chart here.

The number of regions where cases were falling vs rising, in the week before, during, and after half-term, are as follows:

  • before - 6 falling, 5 rising
  • during - 7 falling, 4 rising
  • after - 6 falling, 5 rising

It's too early to see any trend.  We'll need to wait a couple of weeks to see what happens, but I did want to put the little chart up so it's easier to compare, later.

One interesting thing is Wales (broken green line) had already peaked before half-term, but reversed and went back up again during!!  This of course is because Wales is a vacation spot.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


I know that my area had a mix over two weeks
because there were a lot of kids at the supermarket for both weeks. I remember thinking 'haven't the little plague carriers gone back yet' ;-)

[ Parent ]
BBC - More children 'than expected have had swine flu'
http://news.bbc.co.uk/1/hi/hea...

Up to a third of children in some areas may have had swine flu, but many will not have been ill, analysis shows.

The Health Protection Agency has reviewed blood tests which showed higher levels of infection among children than originally thought.

In hotspot areas, such as London and the West Midlands, a third of school-aged children may have had the virus, but only one in 10 or less got ill.

Across the UK, the figure is probably about a fifth, the HPA said.

The findings reinforce the fact the pandemic is a mild strain of flu.

[snip]

The agency has been carrying out blood tests on sample groups as part of its on-going surveillance programme to look for signs that individuals had come into contact with swine flu.

These have revealed high levels of infections without symptoms among children - between three to fives times as many have had the virus than have fallen ill.

COMMENT: Good for them, for doing the seroprevalence studies and releasing the findings.  It restores, somewhat, my faith in some professionals...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


also this
The HPA admitted this could explain why the virus had not really taken off this autumn - the number of new cases is currently half of what they were in the summer.

Quite.  



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
so, how much fuel left?
In hotspot areas, such as London and the West Midlands, a third of school-aged children may have had the virus, but only one in 10 or less got ill.

So, out of 10, 3 were infected: 1 ill, 2 not ill.  7 still to be infected, so there's fuel ahead, right?  Mostly "mild" fuel.

Across the UK, the figure is probably about a fifth, the HPA said.

Here I get a bit lost.  "A fifth" of what?  This doesn't help in trying to get an idea of how much "fuel" is left.

These have revealed high levels of infections without symptoms among children - between three to fives times as many have had the virus than have fallen ill.

So this means 1 ill, 2-4 not ill.  Without knowing how many fell ill, we can't see how much fuel is left.  But the data is there somewhere, so it can be calculated.

the 1m figure for the overall number of cases seen so far is likely to be an underestimate by some way

So, not 1 million but what?  2-3 M?

Coupled with this, between 30% to 40% of over 50s are thought to have some immunity from previous strains they have come into contact with.

Again, some numbers as to how much herd immunity there is already in the UK.  Cos now we can look at how many people over 50s there are, and calculate the figure of how many among them "have some immunity", and add that to the number of kids who are believed to be now immune too.

In short, we might possibly calculate how much herd immunity there is already, in the UK.

---

IMHO, this could possibly be used as a point against using novel adjuvants if one is a healthy individual in the UK.  Just 'cos the need is not as high as thought, both because the infection is even milder than previously thought, and because my personal chances to have been infected already are higher than previously thought.

It will be good to have a look at the full document.  And also see similar studies in other places, which are probably underway.  And even if not, we must wonder, how much can we assume to be similar in other places?

This is interesting.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


[ Parent ]
one further thought
If we can compute the number of "already infected" individuals, and we look at the fact that the wave hasn't been great, then we could perhaps guess what level of obvious infection is needed in other countries, until they too will reach a "nationally protective" level.

Ok, this is just an admittedly fuzzy thought.

The concept, if I can call it that, is that maybe countries that are behind the UK in number of infections, are about to reach the same level of herd immunity, maybe with a "much less than 30%" level of clinical disease.

In fact, this is not a novel idea, and it would simply be consistent with what the ECDC says about expecting a cumulative attack rate (CAR) of "up to 20%" in the first year of the pandemic (which would be between now and April-June, depending on how you count.  Here (pages 10 and 11 on "2.2.3 Clinical attack rate*").

"Up to 20%" is "less than 20%" so, unless there are unpleasant surprises, and we should always be ready for that anyway, then maybe, just maybe, this particular outbreak is on its way out in some places of the world, in a few more months at least?  Or is that an optimistic opinion not supported by data?

I'd love to see more seroepidemiological studies, that's for sure.  And the specific numbers for this one.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


[ Parent ]
Too many guesstimates . . .
Nothing really to go on - too many "may have had" and "probably" to get anything concrete on which to base predictions.

Interesting maybe . . . useful is another matter.


[ Parent ]
not really predictions of course
Just a range of possibilities.  There will be less and less uncertainty towards the end.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
A fifth may have had the virus,
but in hotspots like London, a third have had it?  

"May have had" doesn't give any guarantees, though.  Here, with one documented case of a doctor having had it twice, and others who feel as if they've had it twice, also.... how much surety is there in counting cases that have gone by?  I hope someone is keeping track of those who've tested positive once, so they can be checked out if they get sick again.

"The truth does not change according to our ability to stomach it."  Flannery O'Connor


[ Parent ]
guarantees?
"May have had" doesn't give any guarantees, though.

I'd be happy with ANY kind of information. LOL!!  

It's called 'the fog of war'.  We probably won't know the full story till many years from now.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Here's the latest RCGP chart
as of Nov 22





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


which parallels what's said in this video
http://www.bbc.co.uk/blogs/the...

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
European assumption re Cumulative Attack Rate
Planning Assumptions for European countries (updated 091111) (page 2)

(My emphasis.)

Attack rates

The experience in the Southern Hemisphere epidemics and modelling based on this suggests overall infection rates in the range of 10-40% when both symptomatic and asymptomatic infections are combined. Taking the conventional figure of 50% of influenza infections being asymptomatic suggests clinical attack rates in the range of 5-20% [2]. Detailed analysis of the multiple wave epidemic in the United Kingdom is consistent with these assumptions. These relatively low attack rates are consistent with significant background levels of immunity in the adult population that increase with age. Hence clinical attack rates can be expected to be twice as high in people under 16 years than it is in older people. This is consistent with serological information from Australia and (unpublished) surveys in the UK [8]. The limited immunity in younger adults is considered to arise from multiple exposures to the seasonal H1N1 virus, while the higher levels in older adults due to exposure to the pre-1957 seasonal H1N1 virus (which was replaced by the 1957 pandemic virus). Experience in the Southern Hemisphere is that, in most countries where there is good preparation, overall absenteeism is no higher than in the other winters.

So, to recap.  A pandemic is 3D: disease, death and disruption.  This one, so far, is "not much disease", "not much death", and "not much disruption".

We'll get rid of the "so far" caveat in a few months, of course.

But for the time being, personal risk assessment can take these figures into account.

And these:

People seeking care - Primary care consultations

This is the most difficult parameter to estimate at European level, not least because of the variability across European countries of the arrangements for delivering primary care. An estimate previously cited is that around 15% of those with clinical symptoms will seek primary care [5]. However, the relatively mild nature of infection in many individuals may reduce this proportion. Conversely, a number of countries are expecting primary care to deliver antivirals, which will tend to increase the proportion of people seeking care - although some countries are using call lines or pharmacies to provide antivirals to reduce pressure on primary care. Additionally, a number of countries are providing pandemic vaccines via primary care. For these reasons, no useful EU/EEA figure can be given and countries may seek to estimate their own values. However, the crucial point is that it is important to have primary care and hospitals working together to ensure that hospitals and emergency services are not suddenly overloaded, as has happened in some settings outside Europe. The risk of this rises especially during weekends and holidays, when primary care may reduce the services available. Countries may need to make special provisions for this.

So, whatever figures are being given about CAR so far, they are uncertain, meaning in some cases they might be higher.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


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