Medical Emergencies

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Avian influenza, and the medical emergencies it brings. :Avian influenza, and the medical emergencies it brings. Daniel R. Hinthorn, MD, FACP Division of Infectious Diseases University of Kansas Medical Center

Influenza virion structure :Influenza virion structure 16 types, H1-16 9 types, N1-9 8 RNA genes * * * * Allows escape from host cell response Internal gene virulence factor Kilbourne, Influenza, 1987. Pringle, IDN, 2004 Tamiflu works here Amantadine works here H gene 4 N gene 6

Slide 3:Fecal spreaders Virus mixers With both human And bird virus receptors Large numbers Assist in spread To humans Incidental hosts Incidental hosts Incidental hosts Swine receptors are both 2,3 and 2,6 receptors * Avian receptor is a 2,3 sialic acid receptor. * Human receptor is a 2,6 sialic acid receptor.

Can emergence of pandemic strains of influenza viruses be prevented? :Can emergence of pandemic strains of influenza viruses be prevented? A classic mistake made by chicken & turkey farmers is To raise a few domestic ducks on a pond near poultry barns These birds attract wild ducks. Solution: Raise domestic poultry in ecologically controlled houses with a high standard of security & limited access. Humans, pigs & aquatic birds are the principal variables associated with the emergence of new human pandemic influenza viruses. Pigs are probably the major mixing vessel for influenza viruses because the respiratory epithelial cells in pigs have receptors for both human & avian influenza viruses. Solution: Separate pigs from people & ducks. In live bird markets, separate chickens from other species, especially from aquatic birds.

Transmission of human influenza :Transmission of human influenza Influenza is highly infectious, easily and rapidly transmitted by Droplets with sneezing, coughing, talking especially among people in close proximity Incubation period is 1-2 days The virus grows quickly in the new cells over 4-6 hours releasing new virons to infect nearby cells When is someone “contagious?” From 1-2 days before onset of symptoms until 5-7 days after start of symptoms. High viral concentrations in the throat allows for rapid spread of influenza for 2 days before illness. Courtesy of Chien Liu, MD

Length of illness before resuming normal activities after influenza :Length of illness before resuming normal activities after influenza 0-24 hrs 14.5% 25-48 hrs 26% 49-72 hrs 24% >72 hrs 31% 60% return 72 hours Clin Drug Invest 2000: 19;111-121

Complications of influenza :Complications of influenza Exacerbation of COPD Prolonged cough even without COPD Pneumonia Primary viral Secondary bacterial pneumonia Newer concerns: CA-MRSA Increased mortality rates from pneumonia Reye’s syndrome CNS and fatty liver Other: myocarditis, neurologic syndrome

Clinical avian influenza: Index case of H5N1 in humans in Hong Kong 1997 :Clinical avian influenza: Index case of H5N1 in humans in Hong Kong 1997 May 21, 1997: a 3 y/o boy died in ICU on day 5 after admission with Reye syndrome, Acute influenza pneumonia & ARDS. Tracheal aspirate yielded influenza virus, no bacteria. The child’s illness & death was complicated by the use of aspirin causing Reye syndrome. The virus was H5N1 avian influenza. Each of the 8 RNA segments was of avian origin The virus was highly pathogenic for chickens.

Criteria needed for influenza to become pandemic :Criteria needed for influenza to become pandemic Characteristics needed for influenza virus to become pandemic Highly pathogenic to humans Readily transmissible between humans Global population with no immunity to the virus Mayo Clinic Proc 80:1552, 2005

Person to person spread of bird flu began in a family in 2004 :Person to person spread of bird flu began in a family in 2004 11 y/o Thai girl lived with her aunt, had contact with sick chickens Ill with fever, cough & sore throat on September 2, 2004. Admitted to hospital on 9-7-04 with temp of 38.5 C & dyspnea Findings were pneumonia, lymphopenia & low platelets. Condition worsened. Transferred to a tertiary hospital with Dx viral pneumonitis or dengue. Despite ventilation, broad-spectrum antibiotics & fluids Died on 9/8/04: 17 hours after onset of clinical influenza pneumonia.

Mother of the girl :Mother of the girl 26 y/o woman lived 4 h away by car Worked in a garment factory with no contact to chickens. She came to see the daughter Provided unprotected bedside care of her daughter for 16-18 hrs on September 7 and 8. Mother developed fever on Sept 11 Returned to Bangkok after the funeral. She was admitted to a hospital on Sept 17 Had pneumonia Died on Sept 20

Aunt of the little girl :Aunt of the little girl 32 y/o woman had sick chickens with deaths. Buried 5 dead chickens on Aug 29 & 30 Used plastic bags on her hands & no more contact with chickens. The aunt provided ~13 hrs of care for the girl on Sept 7. Aunt attended the child’s funeral - Sept 9. Aunt developed fever - Sept 16 Admitted to a hospital - Sept 23. Treated with oseltamivir (Tamiflu) & recovered. RT PCR - Sept 23 was positive for H5 hemagglutinin Serum day 8 was negative for antibody (Sept 23) Serum day 21 was positive for H5 antibody (Oct 7)

Slide 14:Ungchusak, K. et al. N Engl J Med 2005;352:333-340 Chest radiographs from the three patients with avian influenza A (H5N1)

Live bird markets spread avian influenza :Live bird markets spread avian influenza Live birds promote the spread of avian viruses. H5N2 & H5N1 viruses Isolated from live birds until in Hong Kong. Ducks in USA markets are currently harboring many influenza A viruses These include H2N2 viruses Related to the Asian/57 (H2N2) viruses that have disappeared from transmission among humans. Emerg Infect Dis 4:436, 1998

Reported exposures and OR likelihood of getting avian influenza :Reported exposures and OR likelihood of getting avian influenza Visiting a live poultry market 0 Touching an unexpectedly dead bird 29 Having such a bird around the house 6 Dressing a dead bird, plucking a bird 17 Being <3 feet away from a dead bird 13 Storing products of a sick or dead bird in 9 house Touching a sick bird or being <3 feet 4 from it Contact with someone with suspected 1 H5N illness

Avian influenza shows species spread :Avian influenza shows species spread 1997, H5N1 poultry sold live animal markets in Hong Kong 2003, poultry in 8 Asian countries contracted it. Human disease as poultry contacts increased Species transmission steadily increases Bengal Tigers Domestic cats affected 2004, Mongolia, Siberia, Croatia 2005, Europe poultry affected 2006, Africa poultry affected >30 countries worldwide now harbor H5N1. Mayo Clinic Proc 80:1552, 2005

Global bird flu has spread to >30 countries. :Global bird flu has spread to >30 countries. To Africa where veterinary medicine is sparse To Europe: France, Romania, Germany To Asia: India, Iran Recent acquisitions: Greece, Italy, Turkey, Croatia, Russia, Azerbaijan and Romania in Europe, Iraq and Iran in the Middle East and in Nigeria, Africa. April 15, 2006 surveillance shows 59 birds now positive for N5H1 in Germany. Increased from 1 bird two weeks ago.

Smuggling: predominant mechanism of transmission of bird flu today? :Smuggling: predominant mechanism of transmission of bird flu today? 3 million packages of chicken smuggled from China to Milan 260 tons of chicken meat shipped illegally into Italy just last year. Bags of duck feet found stacked on pizza in freezers Trafficking in illegal animals is a close second behind illegal drug trafficking Live poultry and prepared foods are believed to be the new mechanism of transmission worldwide of H5N1 H5N1 survives on meat, feathers, bones, and cages but dies with cooking Nigeria, Viet Nam chicken cases but no wild birds NYT April 15, 2006

How the 1918 pandemic flu is relevant to the current bird flu :How the 1918 pandemic flu is relevant to the current bird flu Virus gene sequence from tissue blocks kept at AFIP, studied by Taubenberger Influenza was recovered from a body frozen in the tundra in 1918 & never thawed. (Tumpey) All 3 pandemics of 20th century started from bird flu! 1918 H1N1 Spanish influenza 1957 H2N2 Asian influenza – reassortment 1968 H3N2 Hong Kong influenza – reassortment Belshe NEJM 353:2209, 2005

All 3 previous pandemics were caused by avian influenza! :All 3 previous pandemics were caused by avian influenza!

1918 influenza virus has unique qualities vs usual human influenza :1918 influenza virus has unique qualities vs usual human influenza It does not need protease to activate H but it can activate H by neuraminidase It grows faster, reaches higher titers. It is 100 times more lethal in mice than any other human influenza virus. It replicates rapidly to high titers in lungs of mice quickly killing. Kills ALL mice in 3 days with 39,000X more virus in lungs vs usual influenza that kills NO mice. It quickly kills developing egg embryos in which it is grown. (Difficult to make vaccines!) NB: H5N1 gives higher lung concentrations of virus & may be receptor based. Did 1918 cause more pneumonia for same reason? Belshe NEJM 353:2209, 2005

Our attitudes and public health infrastructures. :Our attitudes and public health infrastructures. More people are alive today because of health care & public health measures. We treat diabetics, AIDS, neoplasms, do organ transplants. We immunize for all sorts of previously lethal diseases. In the 2/3 world, people are now surviving because of better nutrition and infrastructure though they have a long way to go. Influenza preparedness is like the New Orleans levees: Are we doing all the right things or just doing a partial job? The levees may be there but will not protect as needed in a real pandemic. To support that concept, look at the large numbers of influenza deaths each yr. Have we accepted 36,000 flu deaths each year as “just the way things are.” If our influenza Katrina comes in the future, we’ll be glad we prepared.

Seasonal and pandemic influenza preparedness: a global threat :Seasonal and pandemic influenza preparedness: a global threat 1918 pandemic was the worst plague of the past century. ~50-100 million deaths, mostly under age 65 y. Extraordinarily high replication of virus in lungs. Vigorous cytokine cascade caused ARDS. World population now 3X more than in 1918. Estimated deaths now 180-360 million if ~ lethality then. The US has 36,000 deaths every year from influenza, and 200,000 hospitalizations. Globally, there are 500,000 deaths every year from influenza Again if we can learn to control seasonal influenza, not accepting it as the inevitable, we may be able to make progress toward controlling a future influenza pandemic. If we can’t control the annual flu, why do we think we can control a pandemic?

Pandemic influenza occurs when 3 factors occur at once. :Pandemic influenza occurs when 3 factors occur at once. When 3 things come together for a pandemic Antigenic shift or a substantial change in viral antigens Human population is immunologically naïve to the new virus. We don’t have antibody so the new strain of virus. Highly pathogenic organism for humans doing lots of damage. This has occurred 3 times in the past century H1N1 in 1918, H2N2 in 1957, H3N2 in 1968 H5N1 concerns are via migratory birds in traditional flyways Legal and illegal transport of live birds and bird meats. Fauci, JID 2006:194;S74

The Great Pandemic of 1918 :The Great Pandemic of 1918 By the Honorable Mike Leavitt, Secretary of Health and Human Services That great pandemic touched Kansas. In fact, it is likely to have begun here. In January to February, 1918, a physician in Haskell County noticed an outbreak of severe influenza. The local newspaper, “Santa Fe Monitor” reported on it as follows. Mrs. Eva Van Alstine is sick with pneumonia. Her little son, Roy, is now able to get up. . . . Ralph Linderman is still quite sick. . . . Goldie Wolgehagen is working at the Beeman store during her sister Eva's sickness. An infected soldier from Haskell County is thought to have carried the influenza with him to Camp Funston, now Fort Riley

Historical details of the great influenza of 1918 :Historical details of the great influenza of 1918 March 11, 1918 - Albert Gitchell, an army cook Became ill with high fever, headache, myalgia, sore throat & cough. By noon, 107 persons in the Camp had similar symptoms. By the end of the first week, 500 soldiers were ill, and many had died. Mr Gitchell survived. In mid-March the outbreak affected more than 1,100 soldiers, killing 38. The disease disappeared, then returned with a vengeance in the fall. The first official report of the disease came on September 27th.

Influenza and how a recruit wrote about it :Influenza and how a recruit wrote about it A soldier from Camp Funston followed the effects of the pandemic in his letters sent home. On September 29, he wrote: we are held up because "influenza," or some such a name, is in the camp. It is some such a thing as pneumonia, and they seem to think it is pretty bad. It is at least bad enough to beat us out of our passes. A week later, on October 6th, he wrote, “Lots of them go to the base hospital every day and quite a number of them are 'checking in.' There are between 6 and 7,000 cases in the camp.”

Two days later he wrote: I am still playing the part of a "dry nurse," ha-ha. :Two days later he wrote: I am still playing the part of a "dry nurse," ha-ha. This is the name us boys have invented for a gentleman nurse. The roof of our hospital has been leaking in several places and we have been having some time keeping the poor devils dry. They are keeping our beds all filled with new patients as fast as we send the old ones "home well" or to the hospital, half-dead. There haven't been so many cases the last 48 hours. I sure hope that they all get well soon, for I am sure getting tired of the job. I don't like to stay up every night in the world. We put six more of our boys in bed today. We are getting real short-handed.

A physician wrote about the 1918 influenza :A physician wrote about the 1918 influenza It starts with what appears to be an attack of ordinary influenza. When brought to the hospital, they very rapidly develop the most vicious type of pneumonia that has ever been seen. Two hours after admission they have mahogany spots over the cheek bones. A few hours later you can begin to see cyanosis extend from the ears all over the face. It is hard to distinguish the colored man from the white. It is only a matter of a few hours then until death comes, and it is simply a struggle for air until they suffocate. It is horrible. We have an average of 100 deaths per day. Kilbourne, Influenza 1987

A nurse wrote about the 1918 influenza :A nurse wrote about the 1918 influenza It happened so suddenly. In the morning we received an order to open a unit for flu. By night we’d moved into a converted convent. Almost before the desks were out, the stretchers were in, 60 to 80 to a classroom. We could hardly squeeze between the cots and oh, they were so sick. They all had pneumonia. We knew those whose feet were black wouldn’t live. Kilbourne, Influenza 1987

The epidemic raged :The epidemic raged In Topeka, the hospitals overflowed. Emergency hospitals were opened at the Garfield School and the Reid Hotel. Two infirmaries connected to Washburn College were opened. The college gym was transformed into an observation hospital. The Secretary of the State Board of Health did all he could to contain the disease He closed schools, churches and theaters. He quarantined homes with ill patients. He limited the numbers of people in stores and passengers on streetcars. Yet, the pandemic still took a terrible toll. The final cost will never be known.

The epidemic spread in 1918: pandemic influenza :The epidemic spread in 1918: pandemic influenza U.S. soldiers were sent overseas causing spread to England, France, Russia and Germany. In May, an estimated 8 million people died of it in Spain. The virus was brought back to the US and as the Spanish flu.

The Spanish flu was devastating back in the US :The Spanish flu was devastating back in the US Initially confined to military installations. First civilian case was in Boston, September 1918, and spread throughout the country. 33,387 died in New York 15,785 died in Philadelphia 14,014 died in Chicago 6,225 died in Boston 2,302 died in Kansas City Mortality was high in young people (W shape curve). Deaths worldwide: 20,000,000 (Revised upwards to 50 M) USA: 500,000 or more

Pneumonia and influenza mortality curves of 1892, 1918, 1957 pandemics :Pneumonia and influenza mortality curves of 1892, 1918, 1957 pandemics Monto et al, JID 2006:194;S92 Note the W shaped curves for 1918 compared with the U or J shaped curves of other pandemics. Mortality was far lower during pandemics of 1957, 1968 vs 1918. Possible reasons: Lower virulence of viral strains New medical interventions Vaccine, antibiotics

Slide 37:H5N1 deaths

CDC on pandemic deaths :CDC on pandemic deaths Little is known about clinical events that contributed to deaths in pandemic influenza Review of 1918-1919 clinical data shows that bacterial superinfection was NOT the cause of death for most people. It is not clear what the most likely mechanisms were If we knew these, could some provide opportunity for future interventions in a pandemic. Even a moderate pandemic would exceed the surge capacity of US hospitals, ICUs, supply chains, & domestic production systems. Thus stockpiling of antivirals and vaccines and to address the whole production cycle. CDC questions would washing masks for reuse provide protection? Gerberding, JID 2006:194;S77

What may we learn from the 1918 bird flu pandemic for today? :What may we learn from the 1918 bird flu pandemic for today? Nothing else—no infection, no war, no famine—has ever killed so many in so short a period. (CFR in 1918 was 10%. SARS CFR was 8%.) Single handedly, flu thrust the year of the 1918 back into the previous century. Not since the 1890s had the mortality rate in New Orleans, Chicago, and San Francisco been as high. The 1918 death rate in Philadelphia was higher than at any time since the typhoid and smallpox epidemics of 1876. Kilbourne, Influenza 1987

Potential for impact in Kansas of a future pandemic of influenza :Potential for impact in Kansas of a future pandemic of influenza The USA estimates 89,000 to 207,000 dead 314,000 - 734,000 hosp 18 to 42 million OP visits 20 to 47 million ill The economic impact $71.3 to $166.5 billion Kansas estimates 2,500 deaths 5,000 hospitalizations 500,000 outpatient visits 1 million ill www.pandemicflu.gov

How to control the pandemic in Kansas, non-hospital isolation & quaratine :How to control the pandemic in Kansas, non-hospital isolation & quaratine Influenza is now among the list of communicable diseases with federal authorization for isolation and quarantine (Amendment to EO 13295) State have the authority to declare and enforce quarantine in their borders. Quarantine is very effective in protecting the public from disease. People in isolation may be cared for in their homes, in hospitals, or in designated healthcare facilities. The Governor of Kansas may choose to use “snow days” as a means of disease prevention. Non-hospital isolation and quarantine is a non-issue in pandemic influenza due to a novel virus. www.pandemicflu.gov

Strategies to contain the spread of contagious illnesses :Strategies to contain the spread of contagious illnesses Control of infected or potentially infected. These may be voluntary or controlled by public health authorities Isolation refers to people who have an illness Separation of people Restriction of movement Now common for tuberculosis Federal, state, and local authorities all have this power to isolate the ill Quarantine refers to people exposed but who may or may not become ill. Focused delivery of specialized health care Protects health people from exposure May be in homes, hospitals, or other designated sites

Special powers at the federal level :Special powers at the federal level The CDC has powers that states do not have Community Containment measures Applies to groups or communities where there is extensive transmission Designation is to reduce social interactions, prevent inadvertent exposures. Increase social distance between people Community wide quarantine The “snow day” to stay at home. Schools, work place, public gatherings, and transportations are halted or scaled back. Requires fewer resources than community wide quarantine

Community wide quarantine :Community wide quarantine Quarantine is resource intensive Requires mechanism to enforce it Requires provision for necessities Snow days are preferred Quarantine is reserved for times when drastic measures are a must and when snow days have not contained an outbreak.

What we can help the media emphasize during an outbreak :What we can help the media emphasize during an outbreak Simple steps to reduce transmission of respiratory viruses like influenza Avoid close contact with people who are sick. Wash hands hourly. If staying at home, keep >3 feet away from others (ill or not). Cover mouth and nose when coughing or sneezing and wash hands after each time.

How to care for someone at home during a respiratory pandemic :How to care for someone at home during a respiratory pandemic Get plenty of rest. Drink lots of fluids. Avoid using alcohol or tobacco Use OTC medications to treat symptoms But NEVER give aspirin to children or teenagers with possible flu. Reyes syndrome. Cover nose and mouth with a tissue when coughing or sneezing. Don’t touch eyes, nose or mouth without washing hands before and after.

At home, persons may develop problems: what to look for in children :At home, persons may develop problems: what to look for in children Take the person to the ED, or call physician. Tell the receptionist or nurse about symptoms This will allow triage, and monitoring in a separate area. Signs to seek medical care in children High or prolonged fever Rapid breathing or trouble breathing Bluish skin color Not drinking enough fluids Changes in somnolence, irritability Seizure Influenza symptoms that improve then worse cough, fever Worse underlying illnesses as heart, lungs, or diabetes

At home, persons may develop complications: look for these in adults :At home, persons may develop complications: look for these in adults High or prolonged fever Difficulty in breathing, rapid breathing or trouble breathing Pain or pressure in chest Not drinking enough fluids Near fainting or actual passing out Confusion Persistent or severe vomiting, or passing blood Worse underlying illnesses as heart, lungs, or diabetes

What to tell students & staff in schools. Include teachers, janitors. :What to tell students & staff in schools. Include teachers, janitors. Frequently cleanse hands and be sure there are supplies to do so. Wash hands 15 sec, (time to sing birthday song 2X) Alcohol based is OK but rub hands until dry. Cover mouth and noses when coughing or sneezing and be sure there are tissues available. Discard in containers and cleanse hands. Be sure supplies are everywhere, lunchroom, library, playgrounds. Encourage sick students to stay at home until afebrile 24 hrs Work closely with local health department if there are plans to close the school. It is unknown if school closure helps control influenza.

Slide 50:April 2007

Areas of planning for a pandemic in Kansas (see also the handouts) :Areas of planning for a pandemic in Kansas (see also the handouts) Plan for an impact on businesses How it will impact travelers Establish policies and procedures to implement during a pandemic Include how to keep the business running How to prevent employees from getting the illness Allocate resources to make the above happen Educate and communicate with your employees, suppliers, and customers Coordinate with people external to your organization to learn from and mutually support your community during such events. www.pandemicflu.gov

Epidemics and pandemics in the 21st century :Epidemics and pandemics in the 21st century The history of humanity is replete with deaths due to epidemics and pandemics. But we are so advanced, we are tempted to believe that we can now control epidemics so that we have nothing to worry about today. Is this assumption correct? A resounding no. Plagues can and will strike humanity again. Could we really be at risk for an influenza pandemic? Most scientists believe we have great potential risk.

Anti-influenza viral studies :Anti-influenza viral studies Two major targets for antiviral drugs: M2 inhibitors Amantadine, Rimantadine Neuraminadase inhibitors Oseltamavir, Zanamavir Clade 1 (Vietnam & Thailand) versus Clade 2 (China) Clade 2, unlike clade 1, appears to be susceptible to both classes Shows differences in antigenic shift and drift in clades, and the need to do susceptibility studies on isolates to properly treat pts. Unlikely antivirals will contain a pandemic, but could help in local areas.

What current influenza research is focused on :What current influenza research is focused on New drugs and new classes Peramivir, neuraminidase inhibitor Use of oseltamivir in children under age 1 Dose ranging studies Screening for other new antivirals Looking for new influenza targets for drugs Viral entry, replication, and HA maturation. Current goal of national stockpile is to have 81 million doses of drugs available for use nationally.

Pandemic preparedness: antivirals :Pandemic preparedness: antivirals Major targets for influenza viruses #2 now Neuraminidase (zanamavir, oseltamivir) M2 inhibitors (amantadine, rifantadine) Clade 1 SE Asia (Vietnam, Thailand) 2004, some R to M2 Clade 2 China susceptible to both classes Susceptibility studies are needed as these data show. Planned studies: Use in ages <1yr Varying dose regimens Combination regimens of the two targets New neuraminidase inhibitors (eg. peramivir) Screening new antiviral drugs Evaluating novel drug targets (entry, replication, HA maturation) Attempt to have 81 million doses for initial containment then use in 25% population. JID 194:2006;S74

Benefits of oseltamavir in 2004 insurance records :Benefits of oseltamavir in 2004 insurance records Influenza like illness, treated with oseltamavir in outpatient offices Total of 39,202 pts were treated Less likely to develop pneumonia Less required hospitalization Fewer died in the 30 days after 32% fewer CAP, 67% fewer MI, 91% fewer all cause deaths. Control group not prescribed the drug Total of 136,799 pts. Canadian study compared osel vs either (aman or no therapy) Osel Rx needed fewer Rx antibiotics afterward, Osel Rx were less likely to be hospitalized soon afterwards. Hayden and Pavia, JID 2006:194:S120

Oseltamavir :Oseltamavir Aoki studied time between onset of symptoms and treatment. Controls started therapy 48h after onset Started in 6 h dec impaired activity by 6 days Duration of impaired health by 3.5 days Duration of fever reduced by 2.5 days The benefits of treatment are maximized when early treatment is provided. But no data on treatment infancts <1 y, compromised hosts, effect on encephalopathy, myositis, cardiomyopathy, myocarditis and risk for bacterial complications. In murine model, osel dec extent of pneumonia, prevents death, and decreases pneumococcal adherence. Hayden and Pavia, JID 2006:194:S120

Oseltamavir in a murine model vs avian influenza isolates from different years :Oseltamavir in a murine model vs avian influenza isolates from different years But murine models showed difference in the current H5N1 vs the 1997 H5N1 there were major differences in responses 1997 strain, oseltamavir given 36 hr after the virus was protective from death. 2004 strain, osel given even 4 hrs before flu inoculation and given at the highest doses was only partly protective. Treatment had to be extended to 8 days from 5 days for 75% to survive. There was no difference in susceptibility and no emergence of resistance. Hayden and Pavia, JID 2006:194:S120

Oseltamavir in the treatment of H5N1 influenza patients :Oseltamavir in the treatment of H5N1 influenza patients Development of resistance during therapy has been reported in Vietnam Level of pharyngeal virus were followed daily in influenza patients Oseltamavir 75 mg BID for 5 days after onset of pneumonia 4 had prompt decrease in the levels of pharyngeal virus All survived! In contrast, 4 that did not clear pharyngeal influenza virus by the end of the 5 day course did not survive One pt developed resistance after receiving treatment 4 days This patient had increased influenza throat viral loads. Death followed several days after oseltamavir was stopped. Implication is that development of resistance promotes treatment failure. Hayden and Pavia, JID 2006:194:S120

Antiviral resistance :Antiviral resistance Amantadine res viruses are infectious, virulent, fit and transmit. Rapid resistance has just occurred from 1-14% in 2003 to 92% in 2004. Mechanism is single serine to asparagine substitution in amino acid 31 (S31N). All were susceptible to neuraminidase inhibitors So we can’t depend on M2 ion channel inhibitors this year. Oseltamavir, resistance dev in clinical trials Adults ~1%, children 5%. In Japan where lower doses used, ~16-18% dev resistance. Hayden and Pavia, JID 2006:194:S120

Antiviral resistance mechanism neuraminidase inhibitors :Antiviral resistance mechanism neuraminidase inhibitors Mutations emerge during treatment at predominantly 3 amino acid sites in NA Arginine for lysine at 292 (R292K) Glutamate for valine at 119 (E119V) Histidine for tyrosine at 274 (H274Y) Leads to high level resistance >400 fold Also dec replication, and dec pathogenicity in ferrets. Japanese Rx 6 million courses, ~5% population Isolates collected from across Japan, #1180 isolates Only 3, 0.3% were resistant, 2 E119V and 1 R292K. Reassuring that only low level of resistance is seen clinically when these drugs are used widely. Hayden and Pavia, JID 2006:194:S120

Antiviral resistance mechanism neuraminidase inhibitors :Antiviral resistance mechanism neuraminidase inhibitors Not all neuraminidase inhibitors are alike Resistant mutants to osel still suscept to zanamivir, to A-315675, and partially to peramavir Combinations H9N2, rimantadine and osel improved survival in mice challenged vs either drug alone. Dual NA need to be tried Ribavirin with NA look good in animal studies New mechanisms being investigated Transcriptase inhibitors (ribavirin), long acting NA, conjugated sialidase, hemagglutinin inhibitors, small interfering RNA, polymerase inhibitors, protease inhibitors. Hayden and Pavia, JID 2006:194:S120

Neuraminidase inhibitors: Tamiflu (oseltamavir) & Relenza (zanamivir) :Neuraminidase inhibitors: Tamiflu (oseltamavir) & Relenza (zanamivir) Tamiflu given orally. ADE HA, Mild nausea. 75 mg BID for 5 days. For avian flu, 2X75mg for 2X5 days may be needed? Spectrum and potency similar to that of zanamivir against influenza A & B. Zanamivir (Relenza) is used by inhalation Relieves influenza (beware asthma) Hayden, JAMA 282:1240, 1999.

Neuraminidase inhibitors may be used together :Neuraminidase inhibitors may be used together Oseltamivir resistance is due to H274Y mutation. Zanamivir is active against such resistant isolates with this mutation. Reason is differences in binding sites Systemic effect vs respiratory tract concentrations Dual therapy would be expected to reduce selection of resistant mutants Untried but worth doing. NEJM 354;1423, 2006

Pandemic preparedness: vaccines :Pandemic preparedness: vaccines Significant component of the $3.8 billion approved by Congress used to Vaccine development Creating surge capacity of vaccines Alternative vaccine methods Development of cell based system alternative influenza cultures Working with Sanofi Pasteur & Novartis Prepandemic strain vaccine based on H5N1 virus from Vietnam in 2004. (Report in NEJM 2006) JID 194:2006;S74

Pandemic preparedness: vaccines :Pandemic preparedness: vaccines N5N1 vaccine, 451 adults given the vaccine. Instead of 7.5 or 15 mcg, two doses of 90 mcg required for great antibody response predictive of immunity. Alum adjuvant vaccine allowed 2 doses of 30 mcg each. H9N2 vaccine, another study of an avian vaccine included the new adjuvant MF59. Two doses of 3.75 mcg gave good immune responses. Can this or other methods reduce the dose needed allowing more surge capacity for vaccine preparation? Need potential is to produce 300 million doses of vaccines Time needed would be within 3-6 months The vaccine must match the pandemic or epidemic strain. JID 194:2006;S74

Avian influenza vaccine from strain 1203, a Vietnam isolate :Avian influenza vaccine from strain 1203, a Vietnam isolate H5N1 vaccine made just as for usual influenza Each dose of vaccine requires one egg. H5N1 vaccine antigenically poor (Clade 1). Only when given 90 mcg of antigen did 50% of vaccinees develop 1:40 antibody titer. If 15 mcg, 900 million doses per year potential At 90 mcg, 75 million doses Need MF59 or an alum adjuvant to use lower doses. Indonesian Clade 2 is antigenically distinct from Clade 1 used to make current vaccine. NEJM 354;1412, 2006

FDA has approved the Sanofi Pasteur H5N1 vaccine :FDA has approved the Sanofi Pasteur H5N1 vaccine A/Vietnam/1203/2004. This is a Clade 1 viral vaccine. This means it might not work for a Chinese strain of Clade 2 H5N1. This goes directly into the National Stockpile. 291 cases, 172 deaths. None in this hemisphere. 90 mcg doses gave antibody potentially protective for 45% of recipients. Requires two doses 28 days apart each with 90 mcg. No travelers can’t get it now. It all goes into the stockpile. It does contain thiomerosol.

Influenza pandemic preparations.Who would get a ventilator? :Influenza pandemic preparations.Who would get a ventilator? 1918 bird flu, 1000s died in a few weeks. Current populations are much greater. During a typical yr, ~50,000 people die of influenza. US has 105,000 ventilators functioning. 75,000 to 80,000 are in use on any given day. During an ordinary flu outbreak, >100,000 ventilators are in use. Are we ready? Pandemic needs: 425,000 ventilators needed costing $30,000 each. ($13 billion needed just to purchase new ventilators). Osterholm, NEJM 352:1839, 2005