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Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Laidback Al

Well-known member
A Summary of Worldwide Human H5N1 Cases in 2011
Laidback Al, Senior Moderator, www.FluTrackers.com
January 1, 2012

Abstract ? In 2011, 59 human cases of H5N1 were reported from around the world, a 23% increase over 2010. Five countries reported cases in 2011, Bangladesh, Cambodia, China, Egypt, and Indonesia. Almost half of the 59 cases (about 45%) were children under 10 years old. The fatality rate did not appreciably decline in 2011, about half of all the reported cases died. Four small family clusters were noted during the year. The source of exposure for all of the cluster cases has been reported as exposure to sick and dying poultry. None of these clusters resulted in sustained human to human transmission. Based on an analysis of the 2011 data, the potential for a virulent H5N1 pandemic has not diminished.

The big H5N1 news of 2011 was the bioethical debate surrounding the publication of the details of genetic research by two groups of scientists who were able to create a laboratory strain of H5N1 that maintained it virulence and was easily transmissible in aerosolized droplets. A few of the many media reports and commentaries are referenced in this FluTrackers thread. Equally as important, but without the accompanying media hype, is that there was a 23% increase in the number of worldwide H5N1 human cases over the number of cases in 2010. In 2011, at least 59 cases were recorded; in 2010 the total was only 48. The following summary of human cases from 2011 is generally organized according to the outlined presented last year in ?A Summary of Human H5N1 Cases in 2010? (link).

Background

Influenza A(H5N1) (often referred to ?bird flu? or avian influenza or HPAI) is a novel influenza virus. It first infected humans in Hong Kong in 1997, where 19 human cases were discovered over a period of several months. Most of the cases were infected from sick poultry, although one family cluster was noted. An extensive culling campaign was instituted and over 1.5 million poultry were eradicated in Hong Kong. No more human infections were discovered after the culling that year.

About 2002, avian influenza became an internationally reportable disease to the World Health Organization (WHO) under International Health Regulations (IHR). I believe the first WHO Disease Outbreak News report for human H5N1 cases was published in February of 2003 which reported several H5N1 infected family members from Hong Kong who travelled to Fujian Province where they were most likely infected. Three family members died. (initial link)

Since 2003 until December 31, 2011, the World Health Organization (WHO) has officially reported a total of 574 confirmed human cases of H5N1, 58 of these in 2011. The most recent WHO time line of significant events associated with the H5N1 virus was updated on November 7, 2011 (link).

The recent human case reported from Shenzhen, China (see this thread), has not yet been reported by WHO, but will be included in the 2011 count because onset was on December 21, 2011. This individual is included in the tallies and discussions below.

Number of Human H5N1 Cases in 2011

The tabulation for WHO-confirmed H5N1 cases in 2011 is 58, including the December-reported case from Egypt (link and link), but will most likely include the recent case from China (link) bringing the total to at least 59 in 2011. Compared to 2010, the number of worldwide H5N1 cases increased in 2011 by 23% (11 cases).

Since 2003, 15 countries from around the world have reported human H5N1 cases to WHO. In 2011, only 5 countries will have reported human cases of H5N1, Bangladesh, Cambodia, China, Egypt, and Indonesia. Each of these countries has previously reported human cases. Vietnam, which has reported a few cases each year between 2007 and 2010, did not report any cases in 2011.

1. Map of world H5N1 2011.jpg

Map of countries with H5N1 infections in 2011. Yellow highlighted countries have previously reported human H5N1 cases in prior years, but not in 2011.

Last year (2010), Egypt led the world?s countries with 29 confirmed H5N1 cases that year. This year, Egypt again leads with 37 cases. Indonesia is next with 11 cases, followed by Cambodia (8 cases), Bangladesh (2 cases), and China (1 cases). Prior to 2011, Cambodia had only reported 10 cases between 2005 and 2010, the 8 cases from 2011 represent a surge in cases in this country.

With 182 WHO reported cases, Indonesia continues to lead the world in cumulative number of human H5N1 cases. With the 37 newly reported cases in 2011, Egypt?s total number of cases is 156 and second only to Indonesia. Every year since 2009 Egypt has annually outpaced Indonesia in the number of officially reported H5N1 cases. At the current rate, Egypt will surpass Indonesia as the country with the most confirmed H5N1 infections some time in 2012.

H5N1 Case-Fatality Rate in 2011

Of the 59 cases in 2011, 32 died. The overall case-fatality rate (CFR) for H5N1 in 2011 was 54%, very similar to 2010 when the overall CFR was 50%. The highest CFR in 2011 was 100% for Cambodia, all 8 confirmed cases died and China - one case, one death. The lowest was Bangladesh at 0%, neither of the two cases from this country died.

Only six of the fifteen countries with human cases of H5N1 have 15 or more officially reported cases. For each of these six countries the cumulative CFR is, in descending order, 88% for Cambodia, followed by 82% for Indonesia, 68% for Thailand, 65% for China, 49% for Vietnam, and the country with the lowest CFR is Egypt at 36%. Together these six countries through 2011 have an overall CFR of 60%. The interesting statistic is that the CFR in Egypt dropped from 44% in 2010 to 36% in 2011. Although there is inter-year variability, the overall CFR for the 574 WHO reported cases is 59%.

Based on data available in 2007, some researchers have estimated that the real CFR for H5N1 should be between 14% and 33% (link). The authors of the study write ?Clearly, if such a CF rate were to be sustained in a pandemic, H5N1 would present a truly dreadful scenario. A concerted and dedicated effort by the international community to avert a pandemic through combating avian influenza in animals and humans in affected countries needs to be a global priority.? In light of the additional data since 2007 (including the more recent WHO reports) and the discussion of CFR above, there is no compelling reason to believe that the CFR for the H5N1 viruses should range between 14% and 33%.

Demographics of H5N1 Cases in 2011

For the 59 H5N1 cases from 2011 some limited demographic information is available in the WHO Disease Outbreak News. Also local media reports sometimes have additional demographic information that is presented in translated news reports here at FluTrackers and elsewhere.

Last year in 2010, the ratio of infections between males and females was highly skewed. About 33% of the cases were male while about 67% were females in 2010. In 2011, females still outpaced males, although at a lesser rate. Females represented about 59% of 2011 cases while males represented only 41% of the cases. Presumably the same factors that skew the sex ratio in regular influenza apply to H5N1 cases. A recent article, Mechanisms of sex disparities in influenza pathogenesis[FONT=&quot],[/FONT] suggests that females generate higher proinflammatory cytokine and chemokine responses to influenza resulting in greater morbidity and mortality than males. The authors also note that pregnancy is a risk factor for greater morbidity and mortality. Since 2007 there have been at least six pregnant women that have contracted H5N1. None survived.

Male Female Ratio 2011.jpg

Chart of Male/Female ratio of H5N1 infections, 2011 and 2003-2010


The ages of H5N1 cases from 2011 range from less than 1 to 55 years old, with a median age of 11. The median age of infection in 2011 is much lower than in 2010, although not as low as in 2009 when numerous H5N1 infections in children in Egypt lowered the median age to 4 years.

Age Group Table 2011.jpg

Table of 2011 H5N1 infections by age group.


Count by Age Group 2011.jpg

Graph of the Number of 2011 H5N1 cases by age group.

The table and graph above show that children under 4 years represent about 31% of all H5N1 infections in 2011. Notably, the CFR for this youngest age group was only 22%. Why a such a high percentage of these children are surviving is unclear, but it may reflect that concerned parents are taking their sick children to the hospital early after symptom onset and that early administration of antivirals were effective in saving the lives of some of these children.

H5N1 Clusters in 2011

In 2011 four human cluster of H5N1 were reported. In February a mother and son contracted H5N1 in Cambodia, both died. Also, in February, a mother and daughter from Bekasi in Indonesia became infected. The mother died and apparently the child survived. In September three family members, a mother and two children, contracted H5N1 on the island of Bali, Indonesia. None survived. Finally, In November, an adult brother and sister were infected, along with the woman?s child in Menyet El-Nasr, Egypt. Only the child survived. For all of these individuals, the reports suggest that these infections were the result of exposure to a common source, most likely poultry. No evidence of human-to-human transmission was reported.

Cambodia Cluster 1.jpg

Bekasi cluster 2.jpg

Bali Cluster 3.jpg

Egypt Cluster 4.jpg

Timeline for each of the four H5N1 cluster in 2011.

Although not a 2011 human cluster, media reports in Indonesia in 2011 retrospectively reported a three person family cluster in 2009 (link). In 2009 Indonesia balked at IHR and failed to report H5N1 cases throughout the year. Indonesia reported 20 H5N1 cases on December 28, 2009 (link). Because WHO did not received any case-specific information on these individuals, these cases could only be counted in the aggregate for 2009. Throughout 2010, WHO provided a footnote, noting that these 20 cases were counted into the aggregate for Indonesia. In 2011, WHO cumulative tables no longer included this footnote. Also in 2011, WHO no longer provides the archives of the previous cumulative count-by-countries-by-year tables. To obtain the previous archive tables one must request them from WHO (?earlier tables are available upon request at WHOinfluenza@who.int?).

H5N1 Seasonality

Recently the authors of Seasonal Oscillation of Human Infection with Influenza A/H5N1 in Egypt and Indonesia state ?despite recent suggestions that H5N1 incidence in humans is seasonal with more cases occurring in cooler months, evidence for these claims has not been critically evaluated?. The authors of the study only found a weak correlation between weather and climate events and H5N1 infections in Egypt and Indonesia. The authors also state ?Seasonality of human H5N1 was observed but not statistically significant in Egypt, while in Indonesia H5N1 incidence did not correlate with changes in meteorological variables. Therefore, it remains possible that the observed correlation between weather and human H5N1 in Egypt can be explained by chance.?
Previously researchers have documented that H5N1 infections follow a seasonal infection pattern consistent with regular influenza infection patterns. The failure of these authors to find a seasonal pattern is probably a function of an inadequate sample of data. The graph below shows the incidence of onset for H5N1 cases by month from all countries between 2006 and 2011. Clearly, the number of H5N1 infections increases between December and May worldwide every year. Additional research is necessary to understand the mechanics of seasonal fluctuation of H5N1 infections.

Onset Dates 2006  2011.jpg

H5N1 Sequences

Last year Egypt released sequences from 14 H5N1 cases. This year, even though Egypt has reported the largest number of H5N1 cases (37) not one sequence has been publicly released. In contrast sequences for five of the eight infected individuals from Cambodia have been released.

DISCUSSION ISSUES

How Representative is the WHO Data on H5N1 Cases?

As noted last year and is still true this year, there is no framework to assess how representative these 59 cases are of the full range of human H5N1 infections that occurred throughout the world in 2011. The biases in the data could result from any number of factors, poor surveillance and case identification, inadequate reporting, economic expediency, political motivations, etc.

The biggest concern about data biases relates to the possibility that there are many cases of mild or subclinical infections. In one recent article Identification of H5N1-Specific T-Cell Responses in a High-risk Cohort in Vietnam Indicates the Existence of Potential Asymptomatic Infections, the authors found that 4 of 747 individual had antibodies to H5N1 and 24 of the 747 had H5-Specific T-cell responses suggesting there are asymptomatic cases of H5N1. These researchers studied a high risk population in Vietnam so it is not known if these results can be extrapolated to the larger general population. It should be a research priority to identify the parameters of mild or asymptomatic H5N1 cases.

Call For Open Access of Infectious Disease Data

The information presented here was derived from a number of public on line sources. However, there is no open source, publically available database human H5N1 cases. A preliminary line list was developed by the authors of Avian influenza A(H5N1) in humans: new insights from a line list of World Health Organization confirmed cases, September 2006 to August 2010 and is available in a spread sheet format (link). Echoing these authors, FluTrackers has made a Call for Open Data on All Influenza, Human & Animal, from Around the World

High H5N1 Infection Rates Among Small Children

Since 2009, there has been an observable trend of an increasing number of H5N1 infections among very young children. This should not be surprising since H5N1 is a novel influenza virus, and young children are more susceptible to influenza viruses in general. What is surprising is the recovery rate ( i.e. low CFR) for this age group. As virulent at H5N1 is, many of the infected children survive. The children survive at a much higher rate than their infected adult counterparts. These children would not have time to build up cross-protective immunity, so the recovery process for these young people is worthy of further study. Also, most of these child infections do not occur in family clusters so questions arise about the exposure source for these children. What is the nature of contact between exposed poultry and these young children? Is there a mild asymptomatic strain of H5N1 circulating in some countries?

Probability of an H5N1 Pandemic

While the limited epidemiological data on 570+ cases of H5N1 infections cannot help predict the potential of a virulent H5N1 pandemic, recent research by two teams, one in the Netherlands and one at the University of Wisconsin, might shed some light on this important issue (see this FluTrackers thread). The research results demonstrated a ?proof of concept?. The researchers created a virulent and transmissible strain of the H5N1 influenza virus that can infect through aerosolized respiratory droplets. These experiments provide strong evidence that H5N1 has the potential to become a pandemic virus strain without losing its virulence.
While the details of the experiments have not yet been released, media reports and researcher interviews indicate that only a limited number of genetic changes were necessary to create this virulent strain. For virologists and genetic researchers with a background in statistics, I think it would be a trivial exercise to develop a probability estimate of how likely such genetic changes can occur in Nature without human intervention. While the threat of a release of a laboratory created virulent H5N1 strain is very real, we must not lose sight of the potential for such a strain to reassort or mutate in Nature and start the next high CFR pandemic.

Concluding Comments

Based on the comments from the researchers at the Erasmus Center in the Netherlands, the researchers from the University and Wisconsin, and other noted influenza researchers, a high fatality H5N1 pandemic scenario is a much more likely event today than it was this time last year. So, once more it is necessary to call on governments from around the world to develop comprehensive plans for managing serious infectious disease threats. There is a need for additional research and planning, not just for a potential H5N1 pandemic, but for any novel emerging infectious disease that could cause a serious pandemic.


Notes


1: The data used in this post have been derived from numerous publicly available online sources including WHO, various ministries of health reports, and other internet media reports. For some individual cases details such as age, sex, specific residence, etc. are lacking. Also news media reports sometime provide conflicting data about individual cases. The basic data and information presented here is believed to be reasonably accurate.

2: The information presented here is based on data reported through December 31, 2011. A review of the WHO GAR announcements shows that some H5N1 cases are only reported and confirmed weeks and sometimes months later. Because WHO uses the date of onset to assign a case to particular year, there could be some cases that will be retrospectively assigned to 2011 at a later date which will affect the data presented here.

Acknowledgements and Disclaimer


I would like to thank all of the posters and moderators at FluTrackers.com, internet bloggers, and other internet forum members for their efforts at online tracking of H5N1 and other emerging infectious diseases. Thanks are also due to open source journals and researchers who post full copies of their papers. The opinions expressed here are my own and do not necessarily represent those of FluTrackers.com.
 
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Re: A Summary of Worldwide Human H5N1 Cases in 2011

Re: A Summary of Worldwide Human H5N1 Cases in 2011

Thank you Al. Very informative.

I made a copy of your paper for this forum also.

:tiphat:
 
Re: A Summary of Worldwide Human H5N1 Cases in 2011

Re: A Summary of Worldwide Human H5N1 Cases in 2011

Is there a known reason why there are relatively few cases in people over 40?
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Somehow when I copied the thread to this forum the attachments changed their form. Can someone fix this?

Thanks!

:)
 
Re: A Summary of Worldwide Human H5N1 Cases in 2011

Re: A Summary of Worldwide Human H5N1 Cases in 2011

Is there a known reason why there are relatively few cases in people over 40?

The age distribution of officially reported H5N1 cases is very pronounced. Here is an approximate graph of most of the reported H5N1 cases by age group.

H5N1 cases by age group 2003-2011.jpg

As you can see more than half of all reported cases were 19 years old or younger.

The explanation for why so few older people are infected is unknown. Certainly older people are in contact with sick poultry too, at least as much as the 18 children under 4 years old who were infected in 2011. Could older people have some kind of cross-protective immunity? Maybe. But where would it come from, H5N1 is a novel virus.

The more intriguing question is why young children under the age of 10 have such a high survival rate. It seems that about 2 out of every 3 children under the age of 10 infected with H5N1 survive. I think these cases deserve more scrutiny and may hold the key for lowering the CFR in the event of an H5N1 pandemic.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Al,

It took me a while to realize that you are the author of the paper presented above. Outstanding work! Thanks.

Given this consistent age distribution, one question that comes to mind is - Could there be many mild unreported cases among older people that would greatly reduce the actual CFR? Also, there has to be some immunological explanation. Have there been studies of antibodies present in older people who are contacts of the severe cases and who might have had a similar exposure without contracting a severe case?

Survival among younger patients could be related to immune response rather than prior exposure and cross immunity. Perhaps, like smallpox and vaccinia, -there is a milder virus that gives partial immunity to H5N1. If so, it must have still been around as late as the latter part of the 20th Century and perhaps could still be isolated and used to produce a vaccine. Pardon my naivete, and I'm sure much smarter people than me have evaluated this, but it's worth mentioning.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Al,

It took me a while to realize that you are the author of the paper presented above. Outstanding work! Thanks.

Given this consistent age distribution, one question that comes to mind is - Could there be many mild unreported cases among older people that would greatly reduce the actual CFR? Also, there has to be some immunological explanation. Have there been studies of antibodies present in older people who are contacts of the severe cases and who might have had a similar exposure without contracting a severe case?

Survival among younger patients could be related to immune response rather than prior exposure and cross immunity. Perhaps, like smallpox and vaccinia, -there is a milder virus that gives partial immunity to H5N1. If so, it must have still been around as late as the latter part of the 20th Century and perhaps could still be isolated and used to produce a vaccine. Pardon my naivete, and I'm sure much smarter people than me have evaluated this, but it's worth mentioning.


Yes, all of you comments are valid. There are some antibody studies, but I don't think anyone has pulled together a meta-analysis yet. Certainly young children can not have developed any cross-protective immunity to H5N1, yet they survive at a higher rate than healthy individuals in there 20s and 30s.

Perhaps those people who are "much smarter than you or me" will jump in here and provide some observations and suggestions. :)
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

This is a very impressive and helpful summary, Al. :) I wish I had a theory to add here about the age distribution of vulnerability, but don't have one.

I'm wondering about Jim's theory about older people having some immunity to H5N1 from exposure to milder bird flu viruses. If that's true, I wonder if people over 55 leading lifestyles without any contact with live poultry might be just as susceptible as younger adults?
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

This is excellent.

Was it send to ProMEDmail ?

I have sent it via email to many, now also ProMED. Thanks Gert.


Subject A FluTrackers Original Paper: A Summary of Worldwide Human H5N1 Cases in 2011
Sender flutrackers@flutrackers.com
Recipient promed
Date Today 03:45

Submitted by FluTrackers:

Please see an original work by FluTrackers that is fully sourced including charts, graphs, maps:


A Summary of Worldwide Human H5N1 Cases in 2011

http://www.flutrackers.com/forum/showthread.php?t=179069


All or part may be freely reproduced.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Here are some comments from around the net:


January 02, 2012

Human H5N1 cases in 2011

Thanks to Mike Coston at Avian Flu Diary for providing the link to this impressive work by Laidback Al at FluTrackers: A Summary of Worldwide Human H5N1 Cases in 2011. This is the kind of detailed analysis we should be getting from WHO and every hot-zone country's health department.

http://crofsblogs.typepad.com/h5n1/2012/01/human-h5n1-cases-in-2011.html


-------------------------------


MONDAY, JANUARY 02, 2012
Referral: A Summary Of Worldwide H5N1 Cases in 2011






# 6048




One of the senior moderators at FluTrackers, who goes by the moniker Laidback Al, has put together an impressive overview of human H5N1 cases reported during the year just past.



Al, who is well known at FluTrackers for his skill with maps and charts, uses visual representations of the data to good effect here.



I?ve posted just a snippet from the abstract and smaller versions of a couple of his graphics below, but I encourage everyone to go to the thread and read it in its entirety.


This is as fine of an overview of the situation as you are apt to find anywhere, and I?ve already downloaded a copy and put in into the reference folder on my desktop.



It?s a keeper, and highly recommended.

http://afludiary.blogspot.com/


--------------------------------------


:applause: :tiphat:
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Well done and thanks Al for a very good paper.

I have a couple of theories that could potentially explain the age distribution and fatality graphs.

The age distribution /fatality pattern we see here is very similar to that seen for pH1N1.

The argument has been that older people were largely unaffected to pH1N1 due to evidence showing that residual cross immunity to previously circulating H1 viruses provided some protection see http://www.flutrackers.com/forum/showthread.php?t=176274&highlight=pH1N1+severity+abstract

However this may not be the entire explanation for this phenomena

Another potential explanation (which could have contributed to this age distribution) could lie in the recent research that identifed that children infected with H1N1 had the highest antibody titre when infection was severe; the potential implication here is that severe infections are directly correlated to the strength of the immune response, or the degree of immune system over-response (aka cytokine storm or malfunctions in the Th1/Th2 modulation systems).

http://www.flutrackers.com/forum/showthread.php?t=178893&highlight=severity+infection

Children have immune systems that are still poorly formed, and perhaps less able to launch a massive innate over-response which could account for the higher infection rates with lower mortality rates; the paper above shows that the stronger the immune response, the more severe the disease.

People over the age of 40 enter a life phase where metabolic efficiency starts to decline, and immune system responses are known to be sub-optimal older age groups. This is evidenced by the large body of immune system research in aging adults and studies investigating reduced efficacy of vaccines in the elderly. Vaccines have been shown to decline in efficacy from 40+. What kills the 40 - 65+ age group is primarily secondary infections.

The age distribution curve for both H5N1 symptomatic infection, hospitalisations and deaths appear to reflect this data and could be resposnible for the patterns we see,

If this outline explanation were to be responsible for the distribution curves, then it would suggest that the most likely place to look for asymptomatic H5 infections would be in persons aged 40+ ... and a reduced death rate in children would not necessarily mean that the causative strain is less virulent (thinking of Egypt here).
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Thought the group would be interested to know that this paper has been picked up by a couple of the `Twitter Daily' newspapers.


Tuesday, Jan. 03, 2012 edition of The Microbiology Daily published by Cesar Sanchez has it on the front page (link will change when today's paper is archived)

http://paper.li/TwistedBacteria/microbiology


And the Emergency Management Daily published by AllHandsDotNet has it in today's headlines section.

http://paper.li/AllHandsDotNet/em/


I suspect it will be picked up by others.

I've taken the liberty of placing a link at the top of the sidebar on my blog as well.




Once again, congratulations Al on a terrific paper.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Thanks Al. It is obvious a great deal of time and thought went into this and I greatly appreciate it.

Re the discussion issues.

On over and under reporting.
It must be extremely difficult for a physician to pick out a disease with an ILI symptom set which is so rare most doctors will never see a case (long may that continue to be true) against a background of Dengue, Chikungunya et al. It is akin to my going to the doctor with a headache and expecting him to realise this headache is due to a brain tumour rather than all the other much more common causes. Looking back through the threads on this site you will find instances where it is the second member of a family who is seriously ill and gets tested while the first fatality has already been buried with some other cause of death. How many times have isolated cases of H5N1 been buried with Dengue as the cause and conversely how many recovered Dengue cases actually had H5N1? If you cast your mind back to the start of the 2009 pandemic there were absurdly high CFRs being calculated based no the confirmed fatalities to confirmed cases ratios. The worrying thing with H5N1 is when you look at the family clusters where everyone is being tested, treated and scrutinised the high CFR does seem real.

On the call for open access
Absolutely and you have to go no further than Al's résumé to see that it is not only the WHO accredited labs and pay-per-view peer reviewed journals that can make a valuable contribution, given the data.

Re the small children
Only anecdotal I know but I have seen in many countries that toddlers love to chase around and pick-up and carry the chickens which double as food and family pets.
Children's immune systems spend their formative years adjusting to their environments setting the boundaries which in latter life will trigger immune responses and I had assumed this had some bearing without any detail knowledge as to how. Would love to have the opinion of someone who understood the early development of the immune system.

Re probability of pandemic
This bit I have my doubts about
For virologists and genetic researchers with a background in statistics, I think it would be a trivial exercise to develop a probability estimate of how likely such genetic changes can occur in Nature without human intervention.
I suspect this is far from trivial as there are far too many variables we can not assign values to with any degree of certainty.
How many sequences produce viable transmissible viruses?
What conformational changes do sequence changes cause to key sites?
What are the fitness penalties associated with each change?
What are the relative probabilities of different AA substitutions?
How much of a role does recombination play vs point mutation?
Those are a few off the top of my head but I am sure a researcher in the field could find many more.

Looking forward to next years review - I trust you realise we all hope this is going to be an annual event.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

If immune over-response is largely to blame for severe and fatal cases, regardless of the underlying cause of the more moderate immune responses in children and older people, then perhaps more effort should be placed on developing treatments that moderate the immune response and prevent cytokine storms, rather than attempting to create isolate-specific vaccines for every flu strain. This wouldn't prevent the flu, but it would reduce its severity.
The age distribution /fatality pattern we see here is very similar to that seen for pH1N1.

The argument has been that older people were largely unaffected to pH1N1 due to evidence showing that residual cross immunity to previously circulating H1 viruses provided some protection...

However this may not be the entire explanation for this phenomena

Another potential explanation (which could have contributed to this age distribution) could lie in the recent research that identifed that children infected with H1N1 had the highest antibody titre when infection was severe; the potential implication here is that severe infections are directly correlated to the strength of the immune response, or the degree of immune system over-response (aka cytokine storm or malfunctions in the Th1/Th2 modulation systems).

http://www.flutrackers.com/forum/showthread.php?t=178893&highlight=severity+infection

Children have immune systems that are still poorly formed, and perhaps less able to launch a massive innate over-response which could account for the higher infection rates with lower mortality rates; the paper above shows that the stronger the immune response, the more severe the disease.

People over the age of 40 enter a life phase where metabolic efficiency starts to decline, and immune system responses are known to be sub-optimal older age groups. This is evidenced by the large body of immune system research in aging adults and studies investigating reduced efficacy of vaccines in the elderly. Vaccines have been shown to decline in efficacy from 40+. What kills the 40 - 65+ age group is primarily secondary infections.

The age distribution curve for both H5N1 symptomatic infection, hospitalisations and deaths appear to reflect this data and could be resposnible for the patterns we see...
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

As I said, I forwarded Al's paper to many. One is Vincent Racanciello. He has recently agreed to be an adviser to FluTrackers and we thank him!

He weighs in with this blog and I agree with him 100%. One of the problems in discussing H5N1 is that we simply do not have enough information. Also something Al mentions. In this 2008 NEJM paper, the authors documented that frequently other diseases are diagnosed before an H5N1 case is confirmed via blood test. How many dozens or even thousands of cases have never been tabulated?

Should we fear avian H5N1 influenza?
3 JANUARY 2012


The only thing we have to fear is fear itself – Franklin D. Roosevelt

Why is there such widespread fear of avian H5N1 influenza virus?

Why did Paul Keim, chair of the National Science Advisory Board for Biosecurity (NSABB) say “I can’t think of another pathogenic organism that is as scary as this one”. What lead Donald McNeil, writing about H5N1 in the New York Times, to conclude that “In its natural form, it is known to have infected only about 600 people since its discovery in 1997, but it killed more than half of them.”

McNeil’s statement is incorrect. Yet it summarizes why Paul Keim, the NSABB, and many others fear the virus.

The problem is that we cannot say with any certainty that the virus has infected only about 600 people. What we do know is that among the 600 seriously ill individuals infected with influenza H5N1 who are admitted to hospital, over half of them die.

To know the fatality rate of avian H5N1 influenza virus in humans, we need to divide the number of fatalities by the number of infections. We do not know that last number – but there are hints that it could be quite large. In a recent study of rural Thai villagers, sera from 800 individuals were collected and analyzed for antibodies against several avian influenza viruses, including H5N1, by hemagglutination-inhibition and neutralization assays. The results indicate that 73 participants (9.1%) had antibody titers against one of two different H5N1 strains. The authors conclude that ‘people in rural central Thailand may have experienced subclinical avian influenza virus infections’. A subclinical infection is one without apparent signs of illness.

If 9% of the rural Asian population has been subclinically infected with avian H5N1 influenza virus strains, it would dramatically change our view of the pathogenicity of the virus. Extensive serological studies must be done to determine the extent of human infection with avian H5N1 influenza viruses.

Until we know how many individuals are infected with avian influenza H5N1, we must refrain from making dire conclusions about the pathogenicity of the virus. Doing so has only lead us down a dangerous path of fearing that H5N1 influenza virus might be used as a weapon of bioterrorism, and restricting the publication of scientific papers on the virus.

Khuntirat, B., Yoon, I., Blair, P., Krueger, W., Chittaganpitch, M., Putnam, S., Supawat, K., Gibbons, R., Pattamadilok, S., Sawanpanyalert, P., Heil, G., Friary, J., Capuano, A., & Gray, G. (2011). Evidence for Subclinical Avian Influenza Virus Infections Among Rural Thai Villagers Clinical Infectious Diseases, 53 (8) DOI: 10.1093/cid/cir525

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I think we should "fear" it but I also think we need to also understand it better.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Very impressive Al.

I agree with Jackson re. the higher infection rates in children and women.

The preponderance of infections comes from domestic chickens. In developing countries children and wives are responsible for the care of domestic fowl. Commercial chicken producion, even in developing countries, is done using modern methods. If chickens get sick in a huge chicken house all of the chickens are immediately killed and burned or buried. This is not the case in home production. Children and wives attempt to nurse a sick chicken back to health as even one dead chicken may have a big impact on a families ability to feed itself. There is also the lack of knowledge of good hygiene.

Ignorance, lack of funds and often transportation to a first rate medical facility interferes with getting a child or wife to medical care fast enough to save a life. Combining childhood and young adult cytokine production with social practicies in countries where H5N1 is high will result in skewed infection rates and mortality. Higher recovery rates in Egypt for children may be due to better education and closer medical facilities.

Something else to bear in mind was during the pandemic of 1918 children fared better than did their young parents. Healthy, well-fed and housed in close quarters the military suffered unimaginable losses during the Spanish flu. They too were the ones most likely to show 'hyacinth' coloration which inevitably led to death. Cytokine storms in both healthy pregnant women and young men were, and are, what kills, not the virus itself.
 
Re: Discussion - A Summary of Worldwide Human H5N1 Cases in 2011

Thanks for all positive comments.

I think that Vibrant62?s point about ?cytokine storm? response is a good one. Changing immune response as one ages may be an important component of H5N1 mortality.

JJackson makes an excellent point about H5N1 clusters. Often they are only recognized after the index case dies, and the second or third individual becomes ill. Of course, the initial cases are often not tested so those cases are not reported by WHO, and the number of individuals in the cluster is officially underreported.

I was using ?dramatic license? in my comments about the trivial exercise of estimating an H5N1 pandemic. There are many naysayers who believe that because H5N1 has been circulating so widely in animal populations and it has not yet cause a pandemic, it will not become pandemic in the future. I think the H5N1 experiments in the Netherlands minimally showed that, in the laboratory, an H5N1 virus could easily become a pandemic strain. Just how easy for it to occur in Nature is a probability question. We now have to assume that probability is greater than 0.0%.

Now that we believe it is greater than 0.0% we ought to be making preparations for such a pandemic. We learned an important lesson from the H1N1 pandemic in 2009. In our modern world, containment of a novel pandemic virus is not possible. Vaccination is currently the most effective weapon. Throughout FluTrackers, JJackson has numerous posts discussing the pros and cons of current vaccine production strategies and future options, e.g. the future of flu vaccine and anti-viral usage . Readers are urged to search for some of his other posts.

Also, now that we know such a pandemic could occur, we need to understand the potential parameters of such a pandemic. Surveillance and antibody testing would be greatly beneficial in this regard. I agree with V. Rancanciello that we don't known the extent of mild or asymptomatic cases of H5N1. It could greatly depress the CFR if we had some accurate numbers.
 
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