Avian Influenza - What is Happening and How Should We Prepare? - - - - - - - - -

Avian Influenza -

What is Happening and How Should We Prepare?

- - - - - - - - -John M. Matsen, M.D.

August 9, 2006

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Influenza Virology “There are three types of influenza

viruses, A, B, and C.

Only Influenza A viruses are further classified by subtype on the basis of the two main surface glycoproteins hemagglutinin (HA) and neuramininidase (NA). Dx by inhibition tests.

Influenza A subtypes and B viruses are further classified by strains.” (CDC 1/06)

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DEFINITION:

Avian influenza is an infectious disease caused by Type A influenza virus strains that commonly infect poultry and other avian species. The term is synonymous with “bird flu.”

The natural reservoir species for avian flu are ducks, shorebirds and gulls. (USDA)

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TUFTED DUCK

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They are genetically labile RNA viruses.

Other RNA viruses are, e.g., HIV, SARS, etc.

They lack the critical mechanisms for correcting replication errors.

The genetic composition of the viruses changes as they replicate.

All type A influenza viruses, including human

strains:

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Constant Mutation Now with a huge new amount of genetic

data, we have the ability to better understand multigenic traits for the first time. As they carry RNA instead of DNA, influenza viruses mutate constantly because the enzyme that generates RNA makes frequent mistakes during replication. (NatureMed 2006; 12(258))

“H5N1 mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species.”

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Avian Flu Virus Makeup

Only influenza A viruses infect birds, and all known subtypes of the A viruses can

infect birds. In the influenza A genetic makeup, there

are 6 internal genes plus the HA and NA genes.

A specific gene of these 8 in the 1918 H1N1 virus had the unexpected capacity for sending the body's immune system into overdrive, causing inflammation, hemorrhagic pneumonia and death.

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Pathotype Definition

There are two primary pathotypes of Avian Influenza virus:– the most common is low pathogenic AI

(LPAI) which is found in a few poultry flocks in the United States and elsewhere every year—usually spread from wild birds.

– the other is the highly pathogenic AI (HPAI), which is much less common and is associated with higher mortality in poultry.

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Pathotypes Can Change

•Avian flu viruses of low pathogenicity (LPAI) can, after circulation for just short periods of time, in a poultry population, mutate into HPAI.

During a 1983–1984 poultry epidemic in the US, the H5N2 virus was of low pathogenicity initially, but within 6 months mutated to become HPAI, with a mortality approaching 90%.

During a 1999–2001 poultry epidemic in Italy, the H7N1 virus, initially of low pathogenicity, mutated within 9 months to a HPAI form. (WHO)

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Influenza Viruses Continually Evolve

They continually manifest small changes or antigenic “drift.”

Can swap or “reassort” genetic materials and merge with other flu viruses

This occasional reassortment process is known as antigenic “shift.”

The resulting novel subtype is different from both parent viruses.

(WHO & CDC)

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Avian Flu Spread “Here, we report that genetically and

antigenically distinct sub lineages of H5N1 virus have become established in poultry in different geographical regions of Southeast Asia, indicating the long-term endemicity of the virus, and the isolation of H5N1 virus from apparently healthy migratory birds in southern China.” (PNAS 02/10/06)

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Avian Flu Spread The H5N1 bird flu in humans has

evolved into two separate strains, or “clades,” a development that will complicate the search for a vaccine and the prevention of a pandemic, US researchers reported.

(Garten RJ, et al. International Conference on Emerging Infectious Diseases. March 2006. Paper # 64)

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H5N1 Presence 2006.

Nations With Confirmed Cases (070706)

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Confirmed Human H5N1 Cases

COUNTRY

2004 2005 2006 TOTALS

cases

deaths

cases

deaths

cases

deaths

cases

deaths

Azerbaijan 0 0 0 0 8 5 8 5

Cambodia 0 0 4 4 2 2 6 6

China 0 0 8 5 11 7 19 12

Indonesia 0 0 17 11 37 31 54 42

Iraq 0 0 0 0 2 2 2 2

Thailand 17 12 5 2 1 1 23 15

Turkey 0 0 0 0 12 4 12 4

Vietnam 29 20 61 19 0 0 93 42

TOTAL 46 32 95 41 40 27 23

2 134 7/20/2006

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Highly Pathogenic Avian Influenza

The H5N1 strain has now (4/06) been reported in over 50 countries, and governments throughout the world have slaughtered the enormous number of well over 200 million chickens, ducks, other poultry and wild birds in an effort to keep the H5N1 virus from spreading.

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PNAS 2/10/06 “Our data show that H5N1 influenza

virus has continued to spread from its established source in southern China to other regions through transport of poultry and bird migration. The identification of regionally distinct sub lineages contributes to the understanding of the mechanism for the perpetuation and spread of H5N1…”

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Nature 442, 37(6 July 2006) “As the avian influenza virus H5N1

swept from Asia across Russia to Europe, Nigeria was the first country in Africa to report the emergence of this highly pathogenic virus. Here we analyze H5N1 sequences in poultry from two different farms in Lagos state and find that three H5N1 lineages were independently introduced through routes that coincide with the flight paths of migratory birds, although independent trade imports cannot be excluded.”

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Avian Influenza A Viruses

Human-to-human transmission of the H5N1 avian influenza would be cause for great concern, but WHO investigations have in the past identified only one “likely” / “probable” instance of human-to-human spread, in 2004, with one additional possible case in 2005. The increasing number of reported family clusters of H5N1 in Asia may mean human-to-human transmission. Some suspect there have been other human-to-human transmissions.

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Critical Gene a Suspect in Lethal 1918-1919 Epidemic

(1) By recreating the influenza virus that killed 50

or more million people in 1918-19, Kobasa, et al. may have identified the gene that turned it into one of the most lethal in human history. The gene, one of eight in the virus, seems to have an unexpected capacity for sending the body's immune system into overdrive, causing inflammation, hemorrhagic pneumonia and death.

(From Kobasa, et al. Nature. 10/07/04)

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(2) Using reverse genetics, they synthesized

the hemagglutinin antigen and the neuraminidase genes based on the genetic sequences of the 1918-1919 influenza pandemic strain, and in recreating the virus, they have shown that the resulting virus is significantly more virulent than the wild-type strain in a mouse model.

(From Kobasa, et al. Nature. 10/07/04; Hoft, et al. NEJM. 12/9/04)

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(3) “Different strains of influenza virus have different pathologic effects... These events were associated with more severe pathological features and higher mortality, suggesting that overactive host immune response...may trigger severe disease.

“Death rates in the 1918 pandemic were highest among young to middle aged adults, and lower in the elderly.”

(Hoft, et al. NEJM. 12/9/04)

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Resurrected 1918 Flu Virus

The team resurrected the 1918 pandemic virus by using gene sequences obtained from formalin-preserved specimens and from preserved tissue from a 1918 Inuit flu victim exhumed from the Alaskan permafrost. The virus is as lethal as expected, killing mice more quickly than any other human flu virus known. Recreating the 1918 strain “had to be done, and it's produced some extremely interesting results.”(Tumpey, et al. Science.

2005;310(77)).

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Chemokine Storm In 1997, avian influenza virus H5N1 was

transmitted directly from chicken to human and resulted in a severe disease that had a higher mortality rate in adults than in children. The characteristic mononuclear leukocyte infiltration in the lung and the high inflammatory response in H5N1 infection prompted comparison of the chemokine responses between influenza virus–infected adult and neonatal monocyte-derived macrophages (MDMs). The demonstrated strong induction of chemokines and their receptors by avian influenza viruses, particularly in adult MDMs, may account for the severity of H5N1 disease. (Zhou, et al. J. Inf. Dis. July1, 06; 194.)

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Pathogenicity Change•Avian flu viruses of low pathogenicity (LPAI) can,

after circulation for just short periods of time, in a poultry population, mutate into HPAI.

During a 1983–1984 poultry epidemic in the US., the H5N2 virus was of low pathogenicity initially, but within 6 months mutated to become HPAI, with a mortality approaching 90%.

During a 1999–2001 poultry epidemic in Italy, the H7N1 virus, initially of low pathogenicity, mutated within 9 months to a HPAI form. (WHO)

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“Of the 16 avian influenza virus subtypes,

H5N1 is of particular concern for several reasons.

“H5N1 mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species.

“H5N1’s ability to cause severe disease in humans has now been documented. In addition, laboratory studies have demonstrated that isolates from this virus have a high pathogenicity for humans.” (WHO)

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HOW DEADLY THE PANDEMIC ?

“Even in the best-case scenarios of the next pandemic, 2 to 7 million

people will die and tens of millions will require medical attention.

“If the next pandemic virus is a very virulent strain, deaths could be

dramatically higher. “The global spread of a pandemic cannot

be stopped, but preparedness will reduce its impact.” (WHO)

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Human-to-human transmission raises

demand for DNA data. A strain of avian flu that spread through a

family in Indonesia, killing seven of the eight people infected, was accumulating mutations as it spread from person to person, according to confidential sequence data seen by Nature.

The cluster of cases of the deadly H5N1 strain, which occurred earlier this year, is the first in which the World Health Organization (WHO) has admitted that human-to-human transmission was the most likely cause of spread.

(See Nature 441, 554–555 and 442, 114-115; 2006).

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Human-to-Human

TransmissionSequence data show

that mutations were accumulating as it spread from person to person.

(Nature 442, 114-115; 2006)

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“Something in the Airway”

“The existences of a molecular barrier that may contribute to [transmissability] has now been confirmed in patients. The key is the distribution in the human airway of the different receptors preferred by avian and human derived viruses. The [H5N1] virus binds preferentially to binding molecules that are common in the lower respiratory tract but are less well represented in the upper respiratory tract. As a result, the [current H5N1] virus is not readily spread by droplet infection or cough.” (Editor’s Comment. Nature. 2006;440:436)

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Needs Better Transmissibility

“The H5 strain of avian flu has so far failed to develop a pandemic form. Some virologists fear it may need only better transmissibility. The new findings suggest that the virus could acquire such a property by switching its preference from the cell receptor found in the lower lung, known as alpha 2-3, to the receptor found on cells in the upper airways, known as alpha 2-6.” (Ibid)

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2-step Mutation “A team of scientists at the Scripps

Research Institute reported in Science (March 17, 2006) that only a couple of mutations might be needed to enable the H5 virus to make this switch to the alpha 2-6 receptor. This is the about same number of mutations made by the H1, H2 and H3 (pandemic) viruses when they adapted to infect people. Since (RNA) viruses can mutate fast, a two-mutation step is not such a big hurdle.”

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Dr. Anthony Fauci - 4/11/06

“It is entirely conceivable that this virus is inherently programmed that it will never be able to go efficiently from human to human,'' Fauci said. ''Hopefully the epidemic (in birds) will burn itself out, which epidemics do, before the virus evolves the capability of being more efficient in going from human to human.'‘ (NYT 4/12/06)

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BMJ 4/15/06 David King, the UK government's

chief scientific adviser, states that the chances of the virus mutating into a form that could spread between humans were "very low," and it was "totally misleading" to say that such a mutation was inevitable.

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Current Vaccine Status

The US already has several million doses of a bird flu vaccine based on a sample of a virus taken in 2004 from Vietnam.

But researchers have noted the emergence of a second strain or clade of bird flu.

US-HHS plans to create a new vaccine targeted at the second variety. "In order to be prepared, we need to continue to develop new vaccines," HHS’s Mike Leavitt said at an immunization conference in Atlanta.

(AP 3/6/06)

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Current Vaccine Status

“The second vaccine will be based on a virus sample taken from Indonesia last year, said Ruben Donis, leader of the molecular genetics team at the CDC's influenza branch. The virus circulating in Indonesia is related to the Vietnamese virus, but it is not a descendant and it causes a different immune system response, he said.” (AP 3/6/06)

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WHO Proposed Immediate Prevention

Actions Because of uncertainties about

the disease situation in poultry and the potentially severe consequences for human health, WHO has defined the following proposed actions:

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WHO Proposed Immediate Prevention

Actions 1. Continue to work towards elimination of H5N1 in all poultry populations: small holdings as well as commercial flocks.

2. Promptly report to relevant authorities and organizations new outbreaks in poultry.

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WHO Proposed Immediate Prevention Actions

3. Put in place mechanisms to verify control progress and eventually monitor freedom from the disease.

4. Ensure close collaboration between public health and agricultural sectors and veterinary services.

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WHO Proposed Immediate Prevention Actions

5. Strengthen communicable disease surveillance in humans and collect

and provide the data needed for an accurate assessment of risks to human health.

6. Share viruses with laboratories in the WHO Global Influenza Surveillance Network.

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WHO Phase of Pandemic Alert

‘

April 8, 2006

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PANDEMIC PREPAREDNESS

“Given the current threat, WHO has urged all countries to develop or update their influenza pandemic preparedness plans for responding to the widespread socioeconomic disruptions that would result from having large numbers of people unwell or dying.”

(WHO)

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CDC, DOS, FDA, NGA, USDA, WHO and all 50 States

The Web sites of these and other resource and administrative units all have pertinent pandemic planning and preparation documents. Units within our purview, and, indeed, all of our family units should have copies of these. We have distributed these widely. All state governments also have such for distribution.

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HHS and State Governors Holding Pandemic

Summits

‘

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Advanced Planning Importance

"A pandemic flu outbreak in any part of the world would potentially cripple supply chains, and dramatically reduce available labor pools," the Deloite report said. "In a world where the global supply chain and real-time inventories determine most everything we do, down to the food available for purchase in our grocery stores, one begins to understand the importance of advanced planning.” (NYT 3/16/06)

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Worst-case Scenario SYDNEY, Feb 16/06 (Reuters)—A worst-

case scenario bird flu pandemic could wipe US$4.4 trillion off global economic output and kill more than 140 million people, according to an Australian Lowry Institute for International Policy report which detailed four scenarios—mild, moderate, severe and ultra pandemics—using historical data on previous influenza pandemics and the economic fallout from the SARS crisis in Asia in 2003.

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“A Nightmare Scenario”

“The havoc that would be wrought by an avian-flu pandemic is so awful that we must act now to be able to prevent such a disaster.”

“. . . A pandemic could well bring global, national and regional economies to an abrupt halt. . . Imagine the chaos.”

(M. Zuckerman, Editor-in-Chief. US News & World Report. June 27, 2005)

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“On a Wing and a Prayer.” (Edit.) Nature.

May 26, 2005 “This issue's focus on avian flu highlights

progress and incoherence in the world's response to a potential human pandemic. But the threat is enormous, and some priorities are clear enough. Millions of people killed in highly developed countries within months, and tens of millions worldwide. The global economy in tatters. A Hollywood fantasy? No—it's now a plausible scenario.”

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Effect and Survival The effect of an influenza pandemic

on individual communities will be relatively severe and prolonged when compared to other natural disasters, as it is expected that outbreaks will reoccur in waves.

Life or death (survival) for many will be determined by how well they and their communities are prepared.

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What Can Happen—

TRANSPORTATION:

Planes don’t fly Trains are halted Buses don’t run Travel curtailed Gasoline supplies

dwindle Mobility crisis Travelers stranded

COMMERCE:

Services unavailable Food scarce Medicines rationed Household goods

gone Supplies in general are in short supply Inventories shrink Banks are closed

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What Can Happen—

CIVIL:

Safety Law enforcement Civil compromise Desperation Criminal element Utilities Water, etc. Communication

PEOPLE:

Social distancing 40% + could be ill Personal resources Failure to cope The sick, dying & dead Grief The vulnerable “Being alone”

concerns

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What Can Happen—

HEALTH CARE:

Medical facilities will be overwhelmed

Vaccines & antivirals in short supply and unevenly available

Nursing supplies ?? Rx & Medicines—

Need to “stock up” 2o infections Rx

EMPLOYMENT:

Offices closed Transit problems Work from home Loss of jobs/wages Business failures Urge prior planning

where it is lacking Inability to make

payments

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“Hunkering down...”

“I’ll just camp down, probably in the secretariat, and stay there for 6 to 10 weeks . . . and my family will have to hunker down where they are (Switzerland).” (David Navarro, UN. NYT 3/28/06)

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Dr. Anthony Fauci - 4/11/06

The government still must prepare for the worst - ''it would be unconscionable not to'' – Dr. Fauci added. He recommended families stock up on supplies, including canned food and water, as they would anyway for a hurricane or winter storm. People who require regular medication for diabetes or other chronic illnesses should have an extra . . . supply, like they would for a vacation. (NYT 4/12/06)

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Support “in Place”RESOURCES:

Water Food necessities Personal

hygiene Cleaning items Sanitation Fuel, lighting Cash Etc.

FUNCTION:

Guidelines, manuals, etc.

Computer (Work from home) Cell phone Bicycles, motor bikes Equipment and tools Reading materials Entertainment items Radio, batteries, etc.

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U.S. State Department DVD“Being Prepared for Pandemic

Influenza”

In June, 2006, the U.S. State Department produced a DVD entitled “Being Prepared for Pandemic Influenza”. This is potentially a most helpful study and resource guide, particularly for individuals in distant locations. It is a video presentation of key preparation “musts”.

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“When Influenza Takes Flight”

“The governments concerned and the international community (and individuals) need to act now to find solutions to the challenges posed by these outbreaks. The threat of an influenza pandemic transcends the capacities of any individual nation or region. For the tsunami, the world had no warning. For avian influenza, the warning is there.”

(Troedsson & Rychener. NYT. 2/5/05)

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What Do We Need to Do—NOW

“Preparing for a potential pandemic is tremendously challenging, given the potential scope and the large number of unknowns,” said NIH Director Elias A. Zerhouni, M.D.

(http://www.nigms.nih.gov/News/Results/FluModel040306)

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What Do We Need to Do—NOW

Our challenge as Missionary Health Services is also “tremendously challenging, given the potential scope and the large number of unknowns” for thousands of missionaries in many distant, diverse and often underdeveloped locations.

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Personal and Public Health

Our responsibilities are defined as relating to personal, physical, dental, mental, safety, nutritional and public health matters.

MHS advises in security matters when that advice is sought, but ultimate circumstance security decisions are in the hands of Priesthood leadership and Church Security.

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Personal Health of Missionaries

A Caveat: The Church has accepted legal

responsibility and liability for missionaries, we are told . . .

Parents and grandparents assume, and rightly so, that all

necessary precautions, oversight and appropriate preparations will be

implemented and in place.

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Personal and Public Health

We need to provide general guidelines about health maintenance, preparations for possible “supporting in-place” and treatment of disease in those stranded by potential precipitous border closures, quarantines, and transportation absence.

If a pandemic occurs, civil chaos will be variable, and health systems will be overwhelmed. Food will be lacking.

Personal safety reality will be variable.

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Decision Makers Up-to-Speed

Because timing will likely be critical:

We need the mechanism to keep key decision makers in SLC and area

offices up-to-speed and ready to act. To be appropriately ready they need to

understand the workings of avian flu. We need the guidance of the Spirit and

the unanimity stated in D&C 107:27. We need prophetic inspiration.

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MissionaryMedical.org

More and more this Web site has become a key informational resource.

Our compliments to our colleagues.

It now needs a sophisticated, user-friendly up-to-date section on Pandemic Influenza Understanding and Planning for use by AMAs and mission presidents, their spouses, and other key mission personnel.

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We need “Fact Sheets.” We need circumstance FAQs. We need key URLs for emergency. We need list of supplies to be on

hand in mission offices. We need a list of tools that may

be needed in the field.

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AMAs and MPs need to be brought up to speed and kept there, and

their understanding needs to be continually assessed and validated.

Preferably the Web site should be interactive, in order to respond to unique circumstances and individual questions.

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An effort, conducted with public relations help, needs to be mounted to

convince and train our remote colleagues to use this Web site.

Its value as a message center needs to be explored, the “kinks” worked out and its use and utility continually

enhanced.

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A section in this Web site, and also printed copies, needs to be

prepared outlining the care of a seriously ill flu victim unable to access professional help due to health system overload.

Lists of supplies, medications, etc., for the care of ill missionaries, need to

be carefully assembled and shipped with the help of the PBO to Area or

mission offices.

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Satellite service connectivity needs to be explored as an assured linkage service for computers and phones

in the event of an emergency / pandemic.

In the event of a pandemic, with communication failures and infrastructure challenges, we need to be able to connect, for many reasons.

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Missionary Health

We need to obviate and preclude a panic mentality, but at the same time we and they need to realize we are talking about missionary lives and suffering.

Life or death (survival) for many will be determined by how well they and their missions and their geographic communities are prepared and respond.

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We Need to Practice / Drill

In order to ensure the highest likelihood of success for whatever is to happen, plans for evacuation, “stay in place,” or other responses need to be carefully outlined, formatted, distributed, and “run throughs” or practice drills need to be carefully carried out and reviewed / assessed. Adjustments need to be made where advisable. AMAs should be involved. We need a tight ship ! ! ! !

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We need Mission Contingency Plans

Specific for a Pandemic Geography and mission physical

facilities will play a role in what a mission should do.

If the ultimate reality is a “stay in place” result, some prior planning is imperative in light of potential food and supply shortages.

If we will look to members, don’t we need to help them prepare ???

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District Conference Instruction Specific for a

Pandemic We need district conference and

mission-specific presentations for a variety of geographic locations.

These should also be available on our Web site, with appropriate updates.

Missionaries need to understand the seriousness, and the need for

optimal compliance.

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Missionaries Need to be Ready to Act

• To move in a very rapid fashion to a defined assembly location.

• To already know what can be taken and what is left behind.

• To understand critical timing factors.• To have “ready to go” the key carry

items.• To have a cash reserve. • Recommended food / survival items.• Social distancing.

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U.S. Embassy Relations

Maintain consistent and close contact with the U.S. embassy or consulate and the embassies of other non-US missionaries. Know the embassy URL.

Get to know the personnel. Don’t send a different person each time. Establish regular contacts using “savvy” persons.

Make certain the various embassies know of their citizens and their locations.

Assess embassies capacity for help.

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U.S. Embassy Relations

Have someone in each mission / area obtain information about what each embassy / consulate is planning with respect to their own employees and families in the event of a pandemic.

Obtain copies of the DOS Avian Flu Fact sheet and FAQs.

Learn about the “warden system.”

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US Embassy “Warden System”

A U.S. Embassy’s primary means of communication with U.S. citizens during an emergency is the warden system. The warden system is used to communicate both emergency and non-emergency information of interest to known U.S. citizens. The embassy can also distribute this information directly via e-mail or fax to any U.S. citizen who asks to be included in the warden notification network.

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Consular Response to A.I. Scenarios

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Embassy Reality in a Pandemic

Likely limit Phase 6 air evacuations to “official Americans”.

“A drawdown or ‘stay in place’ response would limit overall consular services.”

“In the event of deaths, Embassy will work with NOK on disposition of

remains, in accordance with local regulations and feasible options.”

What Should We Be Doing?

Knowledgeable awareness Up-to-date information and instruction Appropriate preparedness Validate understanding Agreed-upon compliance & readiness Savvy linkages and connectivity Optimal communication Create the spiritual environment to go with prayerful seeking for inspiration

Documents

Avian Influenza - What is Happening and How Should We Prepare? - - - - - - - - -