Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

[Laidback Al]

Advances needed in bird flu reaction

Thursday, 14 Aug 2008 00:01

Health officials have been urged to do more to speed up the identification of bird flu cases in humans.

Research conducted in Indonesia has shown the benefit of improved diagnostic methods and improved case management to diagnose patients with H5N1 influenza.

And UK experts are recommending the advice be taken on board now, rather than in "the teeth of a pandemic".

H5N1 can be fatal to humans, with Indonesia having one of the highest bird flu mortality rates.

Research published in health journal the Lancet hails the combined effect of antiviral drugs ? oseltamivir ? and better case management.

Dr Toni Wandra of the Indonesian ministry of health and colleagues analysed the factors associated with bird flu fatality in the south-east Asian country.

Between June 2005 and February 2008 127 confirmed bird flu infections were recorded.

Investigation teams were deployed to investigate and manage each confirmed case; they obtained epidemiological and clinical data from case-investigation reports when possible and through interviews with patients, family members and key individuals.

The researchers found that 81 per cent of infected patients died, with patients taking an average of six days to be taken to hospital.

On reaching hospital the vast majority had a fever and nine in ten had breathing problems.

However, for the first two days after onset, most patients had non-specific symptoms; only 31 had both fever and cough, and nine had fever and breathing problems.

The average time taken from the beginning of treatment with the antiviral drug oseltamivir was seven days; treatment started within two days for one patient, who survived.

One third of patients receiving treatment within six days survived compared to one fifth for treatment after seven days.

Starting treatment within two days was associated with significantly lower mortality than was starting treatment at days five to six or later.

"Early case identification and treatment with oseltamivir is key to addressing the high case-fatality rate in Indonesian cases. There is a clear need to identify definite causes for high-case fatality," the authors write.

Dr Wandra is also advocating greater poultry surveillance and for healthcare workers to be trained in case management of early H5N1 influenza.

Professor Sheila Bird from the Medical Research Council and Oxford University professor of tropical medicine Jeremy Farrar said:

"Consideration needs to be given now - not in the teeth of a pandemic, and not deflected by either proprietary defensiveness or opportunistic profiteering - to gauging the comprehensiveness of national surveillance for human H5N1 cases.

"The world also needs to find a more equitable way to ensure that all share in the benefits of such important research. Indonesia could give the lead here."

http://www.inthenews.co.uk/news/int...nces-needed-in-bird-flu-reaction-$1236323.htm

credits to Helblindi

 

[Giuseppe]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

But, overall what's new in the statement that more than 80 per cent of Indonesian H5N1 human cases had fatal outcome?

It was reported earlier even in peer-review papers...

 

[Vibrant62]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

For me, this poses major questions on UK Pandemic strategy.

QUOTE: However, for the first two days after onset, most patients had non-specific symptoms; only 31 had both fever and cough, and nine had fever and breathing problems.

The UK pandemic strategy includes sufficient Tamiflu for 25% of the population. The algorithm that is being developed to indicate initiation with Tamiflu includes a requirement for presentation of high fever and cough. From this statement, it is clear that this only occurs in a relatively small proportion of patients within the treatment window. So what are GP's to do in a practical setting, and how could the algorithm be modified to ensure that the majority can have therapy in sufficient time for it to be effective?

With the above statement, how would a GP distinguish between a pandemic flu strain or one of the host of other respiratory viruses that always is circulating, to decide that Tamiflu allocation was indicated? How could you ensure that the stockpile was being used wisely, and for greatest effect? If you wait until fever and cough has onset, then this data suggests that @70% of patients would initiate Tamiflu too late for it to be given within the maximally effective time window, and, again, extrapolating this data, approximately 60 patients out of every 100 who waited for fever and cough onset before initation of Tamiflu treatment would, ultimately, die.

To me this suggests that the UK urgently needs to revise its strategy for Tamiflu allocation in a pandemic, and that it should perhaps be restricted to contacts of known cases who go on to develop early symptoms, much as Indonesia appears to have done within its containment strategies. Use of prophylactic Tamiflu amongst contacts is widespread in Indonesia, and we have no way of knowing how many contacts may have gone on to develop full blown H5N1 infection without such interventions. The fact that larger and more widespread clusters have not emerged, may be solely down to this strategy; as such, mimicking this pattern may be a far more effective use of the UK (or any other country that holds one) Tamiflu stockpile.

In either event, whilst much of the data presented is not new to us, it may be new to planners and other medics who are less informed. I hope it prompts a rethink, at least until such time as some form of sensitive and accurate rapid test is available to GPs within a surgery setting.

 

[JJackson]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

While there is certainly no news value to the Indonesian <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-comffice:smarttags" /><st1:stockticker>CFR</st1:stockticker> remaining at about 80% this is still an important paper in that it helps highlight a key problem ? namely timing.
<?xml:namespace prefix = o ns = "urn:schemas-microsoft-comfficeffice" /><o> </o>
Trawling through some of the current posts I find a number of interrelated issues with timing as a common theme. We have Randy Kruger?s open letter to ProMed calling on them to go with the first hand anecdotal evidence rather than wait for confirmed Indonesian Government stats (We have another ProMed extract with Indonesia trying to spot a downward trend in their version of - as opposed to the WHO?s ? of the <st1:stockticker>CFR</st1:stockticker> stats). We have the Lancet adding further evidence to the giant pile that points to the fact that a drug the says ?to be taken within 48 hrs of symptom onset? on the box is less effective if it is generally administered nearer the 148 hr mark. The corollary to this is if you try and bring this down by administering earlier, to undiagnosed patients with Flu Like Illness, then you are likely to increase the prevalence of Ostelamivir resistance in seasonal flu ready to feed back into H5N1 if it goes epidemic. The BBC had another story on a new quick (2 hrs) flu test (EU funded at <st1lace><st1laceName>Nottingham</st1laceName> <st1laceName>Trent</st1laceName> <st1laceName>University</st1laceName></st1lace>) but again this is at the development stage not waiting to ship.
<o> </o>
The WHO developed an AI pandemic plan based on the <st1:stockticker>IHR</st1:stockticker> system working. This requires countries to set up a network to collect data on suspected communicable disease cases, funnel it to a central collection point and then forward it on to WHO (48hrs). WHO would use this data to spot clusters and swoop in with its Tamiflu blanket in an attempt to contain the outbreak. Obviously all this is not working quite as planned. Firstly (and this is my chance to say I-told-you-so) the <st1:stockticker>IHR</st1:stockticker>(2005) is working exactly as its signatories designed, they did not put any meaningful sanctions into it for non-compliance so they could ignore it if it suited them to do so. It is inconvenient to <st1:country-region><st1lace>Indonesia</st1lace></st1:country-region> at present so they are ignoring some provisions. Secondly it is impossible without a cheap & quick test on the ground to sort the handful of H5N1 patients ? from the hoards with the generalised symptoms found in the first 24hrs. In most cases the patient will not seek medical help until they have spent 48hrs at home without any sign of improvement, they then present to the local hospital who either ship them on, if very ill, or give them a bed. The HCWs treat the symptoms and unless the patient fails to respond ? or dies ? they are unlikely to proceed to a lab confirmed diagnosis. Retrospective analysis of clusters shows it common for the index case to have died and been cremated before testing and it is only because further contacts become ill that these were tested and circumstantial evidence made the index case known. This of course begs the question how many other deaths (or recoveries) were H5N1 but without either a lab test or attendant cluster to prove it?
<o> </o>
The <st1:stockticker>IHR</st1:stockticker>(2005) was also careful not to give the WHO the right to enter any country without being invited. This naturally means that the host of case zero is responsible for identifying the cluster, confirming & admitting that it is AI, forwarding it on to the WHO and then requesting WHO send in help - all in time to prevent any infected carriers leaving the containment area. As the system currently operates the chances seem good that an infectious carrier will have reached all the worlds major transport hubs before a WHO team is invited into ground zero and probably before anyone is willing to confirm that there is an epidemic. I can not think of a single cluster case to date that ? with the benefit of hindsight ? would have led to containment; in all cases identification of the cluster and the infectious agent was after the event and had sustained h2h been achieved a run away chain reaction would have ensued.
<o> </o>
We need a new plan ? or at the very least a major revamp of the ones we have - based on the current realities not aspirational dreams.

 

[gsgs]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

no mention of the reassortment and almost identical
sequences for two people 25km apart in early 2007 ?

 

[JJackson]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

My first post was (due to getting sidetracked) written before reading Vibrant62's. As a fellow Brit I am also concerned by the diagnosis/distribution section of the the UK plan. If - as seems likely - patient zero is outside the UK I am not overly concerned by misdiagnosis but by the speed of diagnosis and the breaking of social distancing that the diagnosis and distribution may cause.

At present finding H5N1 patients in amongst background illnesses prevalent in a tropical developing nation environment is like looking for a needle in a haystack but in a high CAR flu epidemic in the UK the situation would be reversed, very few people with flu symptoms would have anything but flu. In this case self certification should be adequate and delivery should not be by collection but by courier/post. My preferred solution is for the UK Government to order 6 tablet Tamiflu sample packs now and post one to each residential address on the declaration of phase 6. If you think you are ill you confirm by phone and are told to take a table immediately. A full course is then posted out and should arrive within the 3 days the starter pack buys you.

Tamiflu in the system very early, no contact by the patient or their family/friends (who may well be infectious & not yet symptomatic) as part of the process. If other family members become ill they should also use tablets from the starter pack or any courses already shipped. This plan requires forward planning in Tamiflu ordering, resilience in the call center (preferably virtual) and postal/carrier services. A collect from pharmacy system breaks quarantine and requires a high level of stockpile regional and local distribution, which may cause local shortages as waves pass through different locals. It has the further disadvantage of requiring mobility on the the part of the patient which may be unrealistic in rural areas, single occupier homes, homes without cars that use public transport, the elderly or infirm etc. Even if all these problems were solved any solution that cause even a short delay in getting the first tablet into the patient will have two effects firstly it will reduce the effectiveness of the Tamiflu stockpile and secondly it will increase the incidence of Tamiflu resistance.

Better to get the pills to the people and risk some being taken inappropriately than to delay their arrival and have them just not work.

 

[HenryN]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

no mention of the reassortment and almost identical
sequences for two people 25km apart in early 2007 ?

Please.

 

[HenryN]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

But, overall what's new in the statement that more than 80 per cent of Indonesian H5N1 human cases had fatal outcome?

It was reported earlier even in peer-review papers...

The papers focus on why the CFR is above 80%, which is VERY high.

 

[Vibrant62]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

JJ

My concern over the current strategy and misdiagnosis is simply this. The stockpile is currently only sufficient for 25% of the popualtion, but there is an 'in prinicple' acceptance that this needs to be expanded - not necessarily with Tamiflu - to cover 50% of the population.

Under present proposals and plans, each individual has the right to only ONE course. So use your allocated anti-viral drugs badly - i.e for a cold or other RSV or similar, and that's it - you have shot your bolt, and can get no more. To access your Tamiflu or other antiviral drug within the 48 hour window, you would have to start being treated when symptoms may be very mild, and when they would be indestinguishable from any other respiratory type virus or illness, and testing will be an impossibility.

How many people experience respiratory infection symptoms of one form or another in the winter season? Most of us I think. So the stockpile could very, very rapidly get fully used in its entirety within a first pandemic wave. What then for a second? Or third? There will be inadequate time to restock, and - depending on how rapidly a second wave follows - vaccines are unlikley to be widely available. Remember that at the moment, at best an entire years worth of 24/7 vaccine production will only produce iro 600million doses ..... globally. That is slightly less than is sufficient for 10% of the worlds population, and if distribution policies are adopted that are 'fair and equitable', that should just about cover health workers, essential service workers, police, army etc - and this assumes that we have a grace period of a year's worth of manufacturing before wave 2 hits. Add the 6 months required for full vaccine production to get cranking, and the chances are that the worst will have passed (i.e the first TWO waves) before there is much vaccine to give anybody. We may be able to improve on this given time and technologies that are currently in development - but even if we say we can cut the lead time to get to this state to 12 months in total, we still wont have enough vaccine for more than 10% of the population one year after the initial outbreak. There is still a lot of potential vaccine rationing in store with an empty anti-viral cupboard, and if wave 2 is more severe than wave 1 (as was the case in 1918) we are in for a world of trouble.

Your idea, whilst good depends on an antiviral supply sufficient to cover 100% of the population at the start of the pandemic. It also accepts that antiviral drugs will be inadvertantly used against lesser infections, as pandemic influenza and other respiratory infections cannot be distinguished from each other.

This is my concern with current strategic planning, before we get into the mechanics of distribution, phone lines etc.

 

[gsgs]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

the hope is, that not so many people become infected,
when the mitigation strategy is effective.
So with a very rigorous strategy they might succeed with
25% * population courses .

 

[Vibrant62]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

School closures and other social distancing measures are planned to be reactive rather tahn proactive, so I would not hold out too much hope there based on current strategies - and the inappropriate use issue is a big one. Much will be wasted ... or used too late to be effective

 

[JJackson]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

I am not sure that I would agree my plan calls for 100% coverage but it does call for 6 tabs (actually 5 packs would be better because then another 5 pack could be sent out to complete the course) per domestic household (rather than person) and addition 5 packs or 10 packs for further infections. The only additional stock requirement is those 5 packs that are in households that never had anyone fall ill. Even if stocks were distributed to pharmacies, as originally envisaged in most local plans, you would still have dead stock in areas that were not as badly hit as expected with the danger of shortages in areas that had a sudden peak. Either way, due to the way Tamiflu works (blocks the exit of newly created virons from infected cells), every generational cycle of the virus (measured in minutes) that you can interfere with by having ostelamivir in the system is worth attacking so the key is to get something into your system as early in the infection as possible. My guess is half a course started at 24hrs is probably as good as full course at 72hrs. Tamiflu slows the spread of the infection buying time for the host’s defences to get on top of the infection, it can’t completely stop infection it just buys time.
<?xml:namespace prefix = o ns = "urn:schemas-microsoft-comfficeffice" /><o></o>
With the existing plans I foresee the primary weapon (Tamiflu) being squandered because it was only half as effective as it should have been due to not being taken early enough. To compound this the later application – even if it is within 48hrs – will mean it is coping with far more infected cells in the host and far more virons each of which has a chance of being resistant, hit it earlier and the virus has fewer opportunities to develop resistance.

 

[Giuseppe]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

The papers focus on why the CFR is above 80%, which is VERY high.

Yes. But we at FT know well this... This paper is at least untempestive...

 

[gsgs]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

I think you can always easily move medicine around - even in a pandemic.

 

[Vibrant62]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

GSGS - you are a numbers man so you may be able to do this better than I.

JJ - I think the idea is a sound one JJ to overcome delays in getting medication to people in time. The 100% figure is based on the following assumptions, which are very approximate/ rough indeed.

1. UK Population 60m
2. Current stockpile iro 15million courses
3. Projected stockpile iro 30 million courses (planned)
4. Average household size @ 2.3 persons or 26million households
5. Initial allocation 5 tablets per household equivalent to 13 million packs
6. 50% CAR so 50 million packs required if everyone is to be treated - however, 50% will already have a hallf treatment course, so this can be reduced by 12.5million packs
7. Assume 30% of usage is misdirected (ie used to treat other infections) but that 50% of these individuals do go on to contact pandemic flu and need treatment. This is equivalent to 9 million treatment courses. I need to verify what the actual population incidence is of respiratory illnesses in the course of a year, but I am pretty sure it is quite close to this.

So far (on the very generalised assumptions above) we have a requirement for 60 million treatment courses to cover everyone who contracts the disease over the course of a pandemic, or sufficient for 100% of the UK population. This does not allow for the possibility that people may be infected in successive waves (this did happen in 1918) and therefore require further antiviral allocations, not is there any allowance for 2x dosage for seven days for late presenters and those hospitalised as goes on in Indo presently.

In mitigation of these numbers there will be a reduction of incidence through vaccination. If we assume a pandemic of 18 months duration (as per 1918) along with 'fair and equitable' global distribution of vaccine production, and that (at present) it remains at 600m doses per annum, we can reduce that anitviral course requirement by (at best) 18 million or at worst 12million (10% population coverage) after 18months. Good use of the prepandemic vaccine can further reduce this requirement by another 2 million or so, assuming it is fully effective. However this saving will be balanced out by twice infected and severe cases.

Additionaly, pandemic modeling does not show that good mitigations strategies reduce the number of infections overall over the course of a pandemic - just the timing of them. If you flatten the curve, the numbers are more manageable, so that the best resources for health care, hopsitalisation etc can be provided to more people, reducing mortality overall.

I believe that ths swiss have it right, and that 100% population coverage should be the target. That or a better usage strategy, or both.

 

[JJackson]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

I had originally done the math based on the UK plans 25% CAR - which actually makes it look worse as there would be more wasted tabs - and had hoped for a less than 30% misdiagnosis due to the fact you needed to call and get authorisation/confirmation of diagnosis before the second half of the pack was shipped would cut down the number of people dropping tabs at the first sign of a cold. But regardless of the exact numbers the point I am keen to hammer home is 'this drug needs to be taken as early as possible' with each passing hour it becomes a little less effective and a little more prone to resistance. The exact mechanics of diagnosis and distribution aside, any plan should start from this point and and adapt itself to accommodate this basic constraint. If it trades off speed for accuracy in diagnosis it needs to show that the trade off is worth it. Given that medical professionals able to do better than just derive a score off a flow chart or check list are going to be too busy to diagnose my cough I can not see any way the time trade off could be worth it.
This of course is only addressing the Pharmaceutical side of the problem and where the UK plan falls down badly is in not asking its citizens to make even basic preparations for disruptions to the supply chain or the need to be able to social distance by having stores on hand that allow you to avoid going out to look for essentials in mid-wave. As Vibrant62 so correctly points out, if the next pandemic follows the wave model, anything we can do to lower the peaks and widen the base of waves greatly increases the chances of medical help being available - especially access to scarce items like ventilators and ICU beds.

 

[tropical]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

Well, I carefully typed 20 min. of re-post, and than, inesplicably, because of the auto-logout, after reloging, I'd got a blank. It's so boring to type elsewhere first.

So now, I'm summing only.

JJ, Vibrant, are right (as we knows), but as Ironore. pointed, the creators/providers are the ones on the ball.

Needed:

100% gov. citizen coveradge on:
- urgent cheap fast bf/pand. virus hand tests at individual home (several stocks), or min. at the local bus/transport. field mash, or GP center (weak link)
- pre-pand. multistrains, old and last, vacc.
- antiviral box courses (1-2 per person), to be taken after the fast test demonstrate positiveness (test used first day of suspect).

Suspected situation for starting simptome testing would be signalized from local health authorities at the one pandemic case insurgence at town/rural region level.

If the govs don't pay the above courses, tests, expens. the singular citizens will, on their own, who don't want's must be awared mediaticaly of a biohazard event.


For further waves would prep the survivors (better if that are also resolved).

 

[gsgs]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

> Additionaly, pandemic modeling does not show that good
> mitigations strategies reduce the number of infections overall
> over the course of a pandemic - just the timing of them.

uhh, then I wouldn't call that a good mitigation strategy.
I think we/they assume a reduction in the total number
of infections.

As for antivirals - one package per treatment could be too few,
considering the H5N1-cases.
Also HCWs,doctors,essential workers will probably
get it prophylactically, upto 4 packages required for one wave.

 

[tropical]

Re: Lancet Article - Analysis of Human Bird Flu Cases from Indonesia

Vibrant62:
"I believe that ths swiss have it right, and that 100% population coverage should be the target. That or a better usage strategy, or both."
JJ:
"With the existing plans I foresee the primary weapon (Tamiflu) being squandered because it was only half as effective as it should have been due to not being taken early enough. To compound this the later application – even if it is within 48hrs – will mean it is coping with far more infected cells in the host and far more virons each of which has a chance of being resistant, hit it earlier and the virus has fewer opportunities to develop resistance."<!-- / message --><!-- edit note -->