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H5N1 Meeting Rome H5N1 Risks To Human Health

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    Posted: July 11 2007 at 4:01am
1

2.1 c Highly Pathogenic Avian Influenza A (H5N1) & Risks to Human Health

Alice Croisier, Elizabeth Mumford and Keiji Fukuda, WHO

1. Introduction

Human infection with highly pathogenic avian influenza A(H5N1) virus was first described in

Hong Kong (1997), with 18 laboratory confirmed cases (6 fatal) reported from the H5N1-

affected area. Almost four years after the re-emergence of H5N1 infections in poultry populations

in South East Asia1, the virus is still circulating and threatening human health in two separate,

yet related ways : firstly, as a zoonotic human threat posed by the highly pathogenic avian

influenza A(H5N1) virus itself, and secondly, in the possibility that an influenza virus with

pandemic potential may emerge from either the H5N1 strain or from any other influenza virus.

WHO has developed a strategic plan for pandemic influenza in relation with the specific H5N1

threat 2. The following five public health actions remain of high priority to WHO for continuous

prevention and control of human H5N1 infection and for limiting opportunity for H5N1 virus

mutation or reassortment into a pandemic strain, as well as for containing at source a potential

pandemic virus and building national capacities to cope with a pandemic.

Strategic action Goal

1. Reduce human exposure to the

H5N1 virus

Reduce opportunities for human infection and, in so

doing, reduce opportunities for a pandemic virus to

emerge

2. Strengthen the early warning

system

Ensure that affected countries, WHO, and the

international community have all data and clinical

specimens needed for an accurate risk assessment

3. Intensify rapid containment

operations

Prevent the H5N1 virus from further increasing its

transmissibility among humans or delay its

international spread

4. Build capacity to cope with a

pandemic

Ensure that all countries have formulated and tested

pandemic response plans and that WHO is fully able

to perform its leadership role during a pandemic

5. Coordinate global scientific

research and development

Ensure that pandemic vaccines and antiviral drugs

are rapidly and widely available shortly after the start

of a pandemic and that scientific understanding of the

virus evolves quickly

From: WHO strategic action plan for pandemic influenza, 2007,

http://www.who.int/csr/resources/publications/influenza/StregPlanEPR_GIP_2006_2.pdf

FAO of the UN, WHO and OIE with the collaboration of UNSIC and UNICEF

Ba

2

2. The Zoonotic threat3

Pathogenicity in humans

Highly pathogenic avian influenza A(H5N1) virus is able to cross the species barrier and cause

infection and illness in humans. From November 2003 to 14 June 2007, a total of 312 laboratory

confirmed cases of human H5N1 infection (190 fatal) were reported from 12 countries4. Most of

the cases were reported from South East Asia5. Laboratory confirmed cases of human infection

continue to be reported6, and documentation of the incidence of human disease and of the

characteristics of laboratory confirmed cases is on-going7,8.

The pathogenesis of the disease is not completely understood. The main clinical feature of the

disease is, still, severe pneumonia often complicated by Acute Respiratory Distress Syndrome

(ARDS). Although mild cases and sub-clinical illness have been reported9 , 10 , most patients

experience severe illness, and overall the case fatality rate among laboratory confirmed cases

remains as high as sixty percent. An optimal treatment regimen has not yet been established.

Early recognition of patients and timely administration of an influenza-specific antiviral agent

using standard protocols are essential for further evaluation of the effectiveness of antivirals11.

Identifying the source of human H5N1 infection during outbreak investigation

Human infection with H5N1 virus seems to be associated with contact with infected birds. The

incidence of cases seems to be higher in countries where established cultural practices (including

live animal markets and keeping/slaughtering/preparing poultry in households) promotes

frequent and intense interactions between humans and poultry12.

It remains unclear which specific activities (e.g. slaughtering, de-feathering, butchering, meat

preparation, collecting eggs, playing with poultry, engaging in cock-fighting activities, having

poultry within the household) place individuals at a higher risk of infection and whether people

get infected through aerosolization of the virus during these activities, by self inoculation (e.g.

through contaminated hands), and/or via other exposure routes.

Another question is, why those exposed in the same way, or at the same time, as confirmed

cases do not get infected and ill. Is a blood relationship important?

Childhood infections following contact with birds while playing have been reported, but the

importance of this particular exposure pathway is difficult to analyze in settings where humans

and animals closely share the same living spaces.

For some confirmed cases no indication of direct contact with birds has been found, and only the

presence of sick or dying poultry in the neighbourhood or visiting of a live animal market was

reported. If sufficient supportive data were available, such findings on exposure might suggest

indirect transmission of the virus. For example, considering the virus' ability to survive in the

environment, exposure might occur through self inoculation with contaminated hands after

contact with contaminated environments or fomites.

There are also cases for whom no putative source of infection has been identified. In these

situations, fear of reprisals for owning, selling or consuming sick poultry, fear of income loss

consequent to the culling of the flock, and the stigma associated with owning an infected flock,

might have led to non-reporting poultry disease or death, even when official reporting systems

are in place. Illegal actions such as organizing cock-fights, smuggling pet birds or poultry, or

hunting protected wild birds could also have played a role in information bias during the

investigation of cases13. Still other hypothetical sources of H5N1 virus infection need to be more

closely studied, including consumption of undercooked poultry meat and eggs, handling of

fertilizers made from bird feces, exposure to other contaminated environments including surface

water14,15, general lack of hygiene, the role of exposure to infected species other than birds, and

the role played by asymptomatically infected but nevertheless infectious birds, need to be

studied further16. However, it has been established that there is no risk of infection from properly

cooked poultry meat or eggs if cross contamination is controlled17.

Background Paper

3

In a few clusters, limited human-to-human transmission of H5N1 virus has been the most likely

mode of transmission, as was documented in Thailand18. This was suspected for a few cases

when very close and unprotected contact with a case occurred at a critical phase of illness. In all

these situations the transmission chain ended spontaneously. Disentangling human-to-human

transmission from bird-to-human and from contaminated environment-to-human transmission

data is challenging given the living conditions that often exist within the affected households,

where all these different possible exposure pathways might have occurred concomitantly.

Improving documentation of exposure and infection source for every case is crucial for a better

understanding of the transmission from animals to humans and for a more accurate estimation of

the incubation period in humans.

Research on the risk factors for infection and illness

As described above, no specific risk factors for human infection, beyond unprotected handling of

sick and unexpectedly dead poultry or sharing living areas with them in the few days prior to

disease19,20,21, have yet been identified with certainty nor validated through research.

Further research is needed to understand the distribution of illness and to better identify groups

at risk of infection. In particular, it remains unclear why, despite their potentially high exposure

to infection 22, professional poultry industry workers in H5N1-infected areas have over the past 3

years only on very rare occasions developed the disease.

The observation of disease in blood-relatives in the same cluster23,24,25 may well be due to

common behaviors or shared contaminated environment, rather than linked to genetic predisposition,

although both hypotheses need to be studied26.

The true incidence of human H5N1 infection remains unclear. Unfortunately, systematic testing

of asymptomatic close contacts of laboratory confirmed cases during outbreak investigation is

often hampered not only by testing constraints a , logistic problems of contact tracing, legal

restrictions related to international shipment of biological specimens, and ethical considerations

(e.g. the need for an agreed research protocol), but also by refusal of contacts to participate in

studiesb, limiting our understanding of the real spread of infection. Research activities could also

play a key role in understanding how infection is spread and why H5N1 disease incidence is still

low compared to the possible level of exposure to infected animals. Some sero-prevalence

studies have been carried out amongst social contacts of cases27 , cullers 28 and among the

population in H5N1-affected areas 29 and recently in groups at occupational risk of exposure to

avian viruses in non-H5N1-affected countries 30,31 to try to answer these questions, but research

remains largely insufficient.

The current risk of nosocomial transmission of H5N1 virus exists but was assessed as very low

32,33,34,35 compared to human seasonal influenza viruses36 . However, these findings are based on

a small number of studies and continuous assessment is needed.

Early case detection and surveillance

Human avian influenza symptoms are not specific and may lead to delayed diagnosis, especially

in countries or areas where H5N1 infections have not been reported in poultry. The diagnosis

might sometimes only be suspected when the patient severely deteriorates (i.e. 5-6 days after

symptom onset) or after learning that a close contact of the patient has recently died from or

developed a similar disease.

a Testing of asymptomatic contacts is done on paired serum specimens collected 2 weeks and using microneutralisation, a

technique available only in few reference laboratories and requiring a higher bio-safety level (BSL3+).

b E.g. for fear of being identified as H5N1 case or being tested without consent for HIV infection.

4

Surveillance and early warning systems for human disease have been introduced or strengthened

in many countries affected with avian influenza outbreaks and in some other high risk and/or

neighboring countries. The performance of these systems remains largely sub-optimal and

unpredictable, especially in countries with competing health priorities and which are resource

poor environments, and/or where no human cases of infection have yet been reported.

Sero-surveillance is needed in groups with occupational exposure (including health care workers,

poultry and pig farm workers, veterinarians, cullers, live animal market vendors) for

documentation of the incidence of infection and of the clinical spectrum of illness, and should be

carried out in the frame of comprehensive study protocols

Virus evolution

Virological surveillance to date has allowed the identification and categorization of H5N1 viruses

affecting birds into 10 clades. Several of these viruses variants - so far all of pure avian originhave

been responsible for human infection and illness, as seen in Cambodia, Viet Nam and

Thailand (clade 1), Indonesia (clade 2.1), Azerbaijan, Egypt, Iraq, Turkey, and Nigeria (clade 2.2)

and China and Laos (clade 2.3).

The rapid evolution of the H5N1 viruses has important implications. Reagents used for laboratory

confirmation of human cases need to be up-dated regularly, and selection of representative

strains for research and development of human H5N1 vaccine prototype needs to be carried out

regularly 37 . As well, evolution of viruses isolated from animals must be considered when

reagents and vaccines are being developed.

However, the H5N1 virus isolates and sequences available publicly for research and evaluation

are limited in geographic, temporal, and species coverage, complicating the ability of the

scientific and public health communities to make timely assessments of viral evolution and its

epidemiological significance. As well, for many of the available sequences, basic temporo-spatial

data are unavailable, further limiting the capacity for assessment of geographical spread.

Development of vaccines and testing reagents is challenged by continuous virus evolution, a

characteristic of influenza viruses, and the work of each of the laboratory of the Global Influenza

Surveillance Network38 will be key in carrying out this assessment at all stage of a pandemic39.

3. The pandemic threat

Influenza pandemics are unpredictable, in timing and in their consequences. They can be

responsible for a high death toll, and for major social disruption 40 . However, variability in

morbidity and mortality have been seen over the last century not only from one pandemic to the

other but also between waves of a same pandemic. The pattern of spread can also vary in a

single place during the same pandemic.

With circulation of highly pathogenic avian influenza A(H5N1) virus in avian, mammalian

41,42,43,4445,46, 47 and human populations, two of the three prerequisites for the start of a pandemic

have been met i.e. (1) the general population has no immunity to the virus, and (2) the virus is

able to replicate in humans and cause serious illness48. However, sustained human-to-human

transmission, the third prerequisite, has not been observed to date, and, according to WHO

Global Influenza Preparedness Plan49, the world is still in phase 3 of the pandemic alert period as

of June 2007, a phase where no or very limited human-to-human transmission has been

observed50.

The widespread distribution of H5N1 virus not only increases the chances of mutation of this

virus into a readily human-to-human-transmissible strain, but also provides more opportunities

for H5N1 virus to reassort with another influenza A virus subtype in a susceptible species (e.g.

humans, pigs) during dual infection. Both mechanisms - avian virus mutation and virus

reassortment - are known to have been at the origin of the latest influenza pandemics,

respectively in 1918 and in 1957/1968 51,52,53,54.

5

Some scientists also suggest that an increase in the range of mammals susceptible to H5N1

infection would represent an increase risk for further adaptation to humans.

Apart from H5N1 virus, other avian influenza A viruses such as H7 and H9 types are also

potential zoonotic and pandemic threats to human health 55 , 56 through the same virus

modification mechanisms. Infection by these subtypes is currently even less frequently

documented in humans than those by H5N1 virus57,58, and they show different pathogenicity and

transmission patterns. Some of these virus subtypes, such as H7N7, have been more easily

transmitted from person-to-person than H5N1 virus59,60,61, whereas for others, such as H9N2

virus, no to human-to-human transmission has been observed62. Swine influenza viruses may

also be a threat to human health63,64.

Finally, re-circulation of human influenza A(H2N2) virus in partly naive populations after several

decades also represents a potential influenza pandemic threat.

4. Conclusion

Both zoonotic and pandemic threats due to influenza viruses will remain as long as the viruses

circulate in animal populations.

Although highly pathogenic avian influenza A(H5N1) virus is not the only influenza virus threat to

human health, the pandemic threat is higher than ever since 1968 given its wide and continuous

circulation.

The epidemiology, clinical spectrum of human infection with this pure avian virus, and

transmission patterns to- and between-humans are still not fully understood.

Risk groups for infection, illness, and death also need to be better documented so as to improve

prevention and control policies.

Close monitoring of characteristics of cases in time, place, person and of H5N1 virus distribution

and genetic and antigenic characteristics are key to early detection of the emergence of a

potential pandemic strain.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Guests Quote  Post ReplyReply Direct Link To This Post Posted: July 11 2007 at 7:34am
Originally posted by fluPrepper2 fluPrepper2 wrote:


4. Conclusion

Both zoonotic and pandemic threats due to influenza viruses will remain as long as the viruses circulate in animal populations.

Although highly pathogenic avian influenza A(H5N1) virus is not the only influenza virus threat to human health, the pandemic threat is higher than ever since 1968 given its wide and continuous circulation.

The epidemiology, clinical spectrum of human infection with this pure avian virus, and transmission patterns to-and between-humans are still not fully understood.

FluPrepper2, yesterday AFT had articles posted revealing the common housefly could be a vector of avian flu. Testing of the housefly revealed bits of avian flu virus. Your article and this information on the housefly being a carrier is scaring me. I see the flies fly from one horse to another to a cow to the dog and then bites me, *&&^#$ Horse Fly. Should I be concerned about catching the virus from a fly?
Originally posted by FluPrepper2 FluPrepper2 wrote:

Risk groups for infection, illness, and death also need to be better documented so as to improve prevention and control policies.
We've had a 100 year rainfall in East Texas, puddles everywhere, Is the mosquito possibly going to be the pandemic switch?

Originally posted by FluPrepper2 FluPrepper2 wrote:

Close monitoring of characteristics of cases in time, place, person and of H5N1 virus distribution and genetic and antigenic characteristics are key to early detection of the emergence of a potential pandemic strain.
Seems like the virus is beginning to emerge much more quickly this past month.
    
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