Bird Flu, (H5N1) Prof. Nassiri

Bird Flu, (H5N1) Prof. Nassiri Institute of International Health Michigan State University

Bird Flu Objectives: At the end of this lecture, the participants should be able to: 1. Understand the concepts of shift and drift in influenza A virus. 2. To understand the current transmission mode of avian flu. 3. To understand immunopathogenesis of avian flu.

Bird Flu Objectives: At the end of this lecture, the participants should be able to: 4. To examine about pharmacologic treatment of avian flu. 5. To know about avian flu pandemic preparedness. 6. To appreciate osteopathic approach in management of avian flu.

Bird Flu Crossing the Species Barrier 1,407 known human pathogens among viruses, bacteria, parasites, protozoa and fungi. 58% were transmitted from animals to human. 38 new illnesses have made the jump from animals to man in the last 25 years.

Bird Flu Avian flu has reached a cultural and media tipping point, a kind of celebrity as the premier biological menace to civilization. Joel Achenbach Washington Post December 11, 2005

Influenza Viruses Influenza viruses nomenclature: Types (A, B, and C) Subtype (eg( eg., H5N1; antigenic shift ) Strain (antigenic drift )

Influenza A Viruses Influenza type A viruses are divided into subtypes based on two proteins on the surface of the virus. These proteins are called: Hemagglutinin (HA) Neuraminidase (NA) 16 different HA subtypes 99 different NA subtypes

Influenza A Viruses Hemagglutinin (HA) Facilitates viral entry into the host cell. Protective antibodies are directed against HA making it the crucial element in current vaccines. Neuraminidase Releases new virus from infected cells

Influenza A Influenza viruses can genetically change in two different ways: Antigenic drift Antigenic shift

Influenza A Influenza viruses can change in two different ways: Antigenic drift Both Both A & B do it on a routine basis. Minor genetic changes occurring within the surface marker proteins: Caused by point mutation in gene May result in an epidemic Produces new virus strains (forces us to make a new vaccine every year).

Influenza A Antigenic Shift An abrupt, major change in the influenza A viruses,, resulting in a new influenza virus subtype that can infect humans Hemagglutinin Hemagglutinin and neuraminidase Has not been seen in humans for many years. Totally new surface markers appear on virus surface.

Influenza A Drift & Shift: Compare/Contrast Antigenic Drift Antigenic Shift Occurs during viral replication Trading off RNA segments between animal & human strains Frequent Infrequent

Influenza A Antigenic Shift Three conditions must emerge for a potential pandemic: (1) If a new subtype of influenza A virus is introduced into the human population. (2) If most people have little or no protection against the new virus. (3) If the virus can spread easily from person to person.

AVIAN INFLUENZA : BIRDS TO HUMANS Migratory water birds Domestic birds Humans Hong Kong 1997, H5N1 HK, China 1999, H9N2 Netherlands 2003, H7N7 Hong Kong 2003, H5N1 Vietnam & Thailand 2004, H5N1

(1918) Pigs can be infected with both avian and human strains, serving as a mixing bowl for viral reassortment. (1957, 1968) Generation of New Influenza A virus Subtypes with Pandemic Potential. Source: NEJM, 350 (12), March 18, 2004

CONSEQUENCES: ANTIGENIC SHIFT Population will have little or no immunity to new virus All or most people will not previously have had infection due to it Will not have been vaccinated against it Lack of immunity allows virus to spread more rapidly and more widely than ordinary flu virus Potential for a pandemic

Circulating influenza strains and pandemics in 20 th century 1918: Spanish Flu 20-40 million deaths 1957: Asian Flu 1 million deaths 1968: Hong Kong Flu 1 million deaths H1N1 H2N2 H3N2 1918 1940 1960 1980 2000 WHO

P = Poultry H = Human

Countries Reporting Avian Influenza during 2004. Information is from the World Organization of Animal Health.

Avian Flu: Human Cases WHO has confirmed 184 cases through 3/21/06 with 103 deaths (56% mortality rate). Cases have been reported from: Vietnam (93/42) Thailand (22/14) Cambodia (4/4) Indonesia (29/22) China (15/10) Turkey (12/4) Iraq (2/2) Azerbaijan (7/5)

Avian Flu: Global Spred Avian flu was reported from Quinghai Lake in China, then Siberia in July, 2005 and later Kazakhstan and Mongolia. October: cases in birds reported from Turkey, Romania, Croatia and Ukraine. February: Nigeria, Greece, Italy, Bulgaria, Egypt, India, France, Germany.

Avian Flu: Global Spread More than 30 countries have reported cases. Spread has been in migratory birds, who often do not become ill when infected Concerns for spread to Alaska via migratory birds

Avian Flu Transmission Farm to Farm Bird droppings Contaminated dusts, soils, equipment Vehicles, feed, cages or clothing Mechanical vector Country to County Bird trade or migration of migratory birds infected with the virus Can be passed bird bird, or bird human when virus is inhaled, as it is an air-borne disease.

Avian Flu Symptoms of bird flu in humans Typical flu-like symptoms Fever Cough Sore throat Muscle aches Eye infections Pneumonia Severe respiratory diseases (such as acute respiratory distress)

H5N1 Low Pathogenic versus Highly Pathogenic Avian Influenza Viruses HPAI viruses can kill 90 to 100% of infected chickens (high mortality in poultry). LPAI viruses cause less severe or no illness if they infect chickens. Because LPAI viruses can evolve into HPAI viruses, outbreaks of H5 and H7 LPAI are closely monitored by animal health officials.

Chest Radiographs Radiographs of patients (panels A, B, and C) showing widespread consolidation, collapse, and interstitial shadowing. In Panels D, E, and F, three chest radiographs show the progression on days 5, 7, and 10 of illness, respectively. Source: NEJM, No 12, Vol 350, March 18, 2004

H5N1 Receptors K. Shinya. Nature 2006; 440: 435-6 Avian viruses preferentially recognize sialic acid linked to galactose, which predominant in alveolar and intestinal cells. Human adapted influenza viruses preferentially recognize sialic acid, which predominated on bronchial epithelial cells.

Pathogenesis of H5N1 H5N1: More Pathogenic? H5N1 viruses induce much higher gene transcription of proinflammatory cytokines in macrophages, in particular TNF, when compared to H3N2 and H1N1. Levels of TNF are similar to those induced by E. coli lipopolysaccharadie, resulting in a systemic inflammatory response (SIRS) similar to bacterial sepsis.

Pathogenesis of H5N1 Cytotoxic Therapy? Some patients with H5N1 infection have had reactive hemophagocytosis. Tx of EBV associated-hemphagocytic Lymphohistiocytosis (HLH) with apoptosis inducing therapy (etoposide and dexamethasone) has increased survival from 50% to 90%. Proposed consideration for avian influenza associated-reactive HLH. Henter JI. Lancet 2006; 367: 870-73 73

Pathogenesis of H5N1 Bird Flu is much more deadly than human flu viruses H5N1 promotes much more inflammation in human lung cells than the human flu virus H1N1. In a human cell line, the bird flu virus triggered more than 10-100 times the level of inflammatory proteins as human flu virus.

Pathogenesis H5N1 Why Bird Flu is much more deadly than human flu viruses? The hyper-response may upset the delicate balance that drives the immune system, making it more vulnerable to the infection. Malik Peiris,, Ph.D., University of Hong Kong: It is like nuclear power, if it is well controlled it can be very beneficial, but if it is out of control, there can be huge problems.

Pathogenesis of H5N1 Triggers of inflammation Protein messengers Chemokines & Cytokines as mediators of inflammation

Pathogenesis of H5N1 Cytokine Strom Unleashing a torrent of inflammatory cells & chemicals Triggers an overreaction by the immune system: Turning fried to foe.

Pathogenesis of H5N1 In a Strom: Overproliferation of immune cells & chemicals Killing not just virus-infected cells but healthy bystandard cells as well

Pathogenesis H5N1 Consequence of Storm The lining of blood vessels weakens, letting fluid leak out BP drops Organs start to fail Lungs fill with fluid

Pathogenesis of H5N1 Consequence of Storm The lining of blood vessels weakens, letting fluid leak out BP drops Overactive Sympathetic response Organs start to fail Lungs fill with fluid

Pathogenesis of H5N1 Consequence of Storm The lining of blood vessels weakens, letting fluid leak out Muscle contraction may further stimulate the already overactive sympathetic system. BP drops Organs start to fail OMT diminishes somatic inputs from contracted muscles. Lungs fill with fluid

1918: Reeve 42859- Lung. Influenza, Bronchopneumonia.

Bird Flu Pandemic H5N1 Three conditions must be met for a pandemic to start: 1. A new influenza subtype must emerge * 2. It must infect humans and cause serious illness * 3. It must spread easily and sustainly (continue without interruption) among humans * The H5N1 meets the first two criteria.

Avian Flu Risk Reduction (avoid emergence of a new virus) Public Health Measures Elimination of animal reservoir Culling, movement control, vaccination Protection and immunization of at-risk individuals Cullers, healthcare personnel

MANAGEMENT Vaccine Social measures Antiviral Medicines Adamantanes Neuraminidase inhibitors Amantadine Rimantadine Oseltamavir (Tamiflu) Zanamavir (Relenza)

NEURAMINIDASE vs ADAMANTANES Newer, more potent class of antiviral Older class of antiviral Associated with less toxicity Less likely to promote resistance Associated with several toxic effects Effective against all subtypes of type A Leads to rapid development of resistance; including few cases of H5N1 Have great potential for diminishing the effects of influenza infection Resistant strains are easily transmissible to susceptible contacts NEJM 2005; 353: 1363-73

Antiviral Medications for Influenza CDC Recommendations: Influenza A virus resistance to amantadine and rimantadine can emerge rapidly during treatment. On the basis of antiviral testing results conducted at CDC and in Canada indicating high levels of resistance, CDC recommends that neither amantadine nor rimantadine be used for the treatment or chemoprophylaxis of influenza A in the United States.

Antiviral Medications for Influenza CDC Recommendations: Oseltamivir or zanamivir can be prescribed if antiviral treatment of influenza is indicated. Oseltamivir is approved for treatment of persons aged >1 1 year. Zanamivir is approved for treatment of persons aged >7 7 years. Oseltamivir and zanamivir can be used for chemoprophylaxis of influenza.

Avian Flu Pandemic Preparedness Federal policy State policy County policy US Department of Health and Human Service s Pandemic Influenza Plan http://www.hhs.gov/pandemicflu/plan As the document notes, in the case of a true pandemic, hospital capacity may be overwhelmed, and healthcare workers may themselves become ill! Currently, U.S. has 965,000 staffed hospital beds.

Stages of a Pandemic WHO/CDC (national measures before and during a pandemic): Interpandemic period Pandemic alert period Pandemic period

Stages of a Pandemic Interpandemic period Phase 1 No new subtype in humans. Infection may be present in animals. If present in animals, the risk of infection or disease is considered to be low. Phase 2 A circulating animal influenza virus subtype poses a substantial risk of human disease.

Stages of a Pandemic Pandemic alert period Phase 3 Human infection(s) ) with a new subtype, but no human-to to-human spread, or at most rare instances of spread to a close contact. Phase 4 Small clusters with limited human-to to-human transmission. Phase 5 Large cluster(s) ) but human-to to-human spread still localized (substantial pandemic risk).

Stages of a Pandemic Pandemic period Phase 6 Increased and substantial transmission in general population.

Osteopathic Approach OMT and Flu OMT has been shown to: Improve motion Enhance blood and lymph flow associated with thoracic cage motion, More rapid clearing of airway secretions Maintaining proper lung function Ultimately enhancing healing. Source: American College of Osteopathic Family Physicians (ACOFP)

Osteopathic Approach OMT and Flu Treatment should be directed to the entire body in a holistic approach, and should not be limited to the cervical, upper and lower thoracic regions, lumbar, and sacral regions in addition to the thoracic cage. Source: American College of Osteopathic Family Physicians (ACOFP)

Osteopathic Approach In the bird flu pandemic of 1918, six percent of patients in the care of allopathic physicians (M.D.) died, compared to only one quarter of one percent (0.025%) of those treated by osteopathic physicians (D.O.). Source: News Release, A.T. Still University (5/11/2006)

Osteopathic Approach Michael M. Patterson, Ph.D., JAOA, Vol 105, No 11, November 2005: The Coming Influenza Pandemic: Lessons From the Past for the Future Fatality rates in diagnosed H5N1 victims are running about 50%. Even if that fell to 5% as the virus traded virulence for transmissibility among people, [Frederick G. Hayden, a University of Virginia virologist and an advisor to the WHO] warns, it would still represent a death rate double [that of] 1918, and that s s despite modern technologies like antibiotics and ventilators.

Osteopathic Approach Michael M. Patterson, Ph.D., JAOA, Vol 105, No 11, November 2005: The Coming Influenza Pandemic: Lessons From the Past for the Future The The osteopathic medical profession can well be a potent force in the next influenza epidemic if it remembers the lessons of its heritage and has the courage to prepare itself to teach those lessons to others.

Osteopathic Approach Global OMT Awareness for a Potential Flu Pandemic Osteopathic preparedness should also be included in the following websites: WHO CDC NIH State Health Departments County Health Departments

Osteopathic Approach 2006 OIA Conference in Germany Panel discussion on Avian Flu & OMT Recommendations: Global awareness on the early benefits of OMT The role of profession The role of COMs Higher risk of transmission to osteopathic healthcare provider via OMT Experimental model of flu and OMT

OMT Approach Miller Thoracic Pump Technique

At this point, if you re a bird, it s s a pandemic. If you re a human being, it is not. Mike Leavitt, HHS Secretary