Influenza

Objectives

INFLUENZAS old and new Jeremy Schafer, PharmD Infectious Diseases Research Fellow Experimental and Clinical Pharmacology University of Minnesota College of Pharmacy

• Be able to discuss the epidemiology and pathophysiology of influenza • Compare and contrast influenza vaccines • Discuss differences in influenza medications • Identify groups at risk for serious influenza complications • Describe avian influenza and the potential problems • Identify possible therapies for avian influenza

Influenza: still a heavy hitter

No one is safe!

• About 36,000 deaths per year in the U.S. • Influenza associated hospitalizations range from 54,000-430,000 per epidemic • 63% of these were for people > 65 years of age • Incidence of influenza associated pulmonary or circulatory death ranges from 0.498.3/100000 • Influenza associated deaths are rising

• Hospitalization rates for children < 5 yrs old are between 100-500/100,000 • Deaths among children and healthy adults are rare • Lost work days and decreased productivity substantial • And a lot of this is preventable!

Pathophysiology of influenza

Pathophysiology of influenza

• Two types: A and B • Type A is further categorized into subtypes • Different types are more than just names

• Transmitted via respiratory droplets • Incubation period is 1-4 days • Adults are infectious for about 5 days from when symptoms start • Children for >10 days • Immunosuppressed may shed virus for extended periods • Illness usually lasts 3-7 days

– – – – –

Some drugs ineffective against type B Epidemics more serious with type A Wrong strain selection for vaccine = big trouble Antigenic drift Antigenic shift

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Signs and symptoms • The usual suspects • N/V and otitis media may occur in children • Frying pan into fire…. – Can exacerbate underlying conditions – May lay groundwork for subsequent bacterial pneumonia – Has been associated with encephalopathy, myocarditis, Reye syndrome, and ARDS

Which of the following is NOT true regarding Influenza? • A. Influenza B causes more severe epidemics than influenza A • B. Influenza only kills people who are 65 years of age or older • C. Immunity to one type of influenza does not confer immunity to other types. • D. A and B • E. None of the above are true

Challenges of influenza

MMWR

• Different strains every year means a new vaccine • Vaccination rates are still too low • Changing resistance picture • Still causes considerable morbidity/mortality • Where do you go for the latest information?

• New guidelines published every year • Provided by the CDC • Latest information for up coming influenza season • Outlines criteria for at risk groups • Vaccines, drugs, prevention, and much, much more!

Treatment/Prevention options

Inactivated influenza vaccine

• Vaccine

• • • • •

– Inactivated – Live

• Neuraminidase inhibitors – Zanamivir – Oseltamivir

• Adamantanes – Amantadine – Rimantadine

Contains killed viruses Given intramuscularly by injection Inexpensive Approved for ages 6 months and up Two shots for kids 6 months-<9 years if no previous influenza vaccination • One shot for everyone else

• Infection control

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MMWR recommendations for inactivated vaccine 2006-2007 • Children aged 6-23 months • Children and adolescents on long-term aspirin therapy • Pregnant women • People with chronic CV or pulmonary conditions • People with chronic metabolic, blood, or renal diseases who required medical intervention in preceding year • Immunodeficient • People with conditions that may compromise respiratory function • Residents of nursing homes or chronic care facilities • Persons aged > 65 years

So who should get the vaccine…..

EVERYBODY!

Safety of inactivated vaccine • • • • • •

Local site irritation Systemic symptoms rare Allergic reactions GBS Thimerosal Chicken egg allergy

MMWR recommendations continued • Children aged 24-59 months • Persons aged 50-64 years • Healthy contacts or caregivers of at risk people • Health care workers • People interested in avoiding influenza

Efficacy of inactivated vaccine • Multiple studies show an advantage for 2 doses of vaccine vs. 1 for children less than 9 years old • Vaccination prevents 70-90% of influenza cases in healthy adults aged < 65 years • In persons aged > 65 years, the inactivated vaccine is 50-60% effective in preventing influenza-related hospitalization and 80% effective in preventing influenza-related death • Efficacy has been shown in preventing influenza in HIV patients

Which statement is true regarding the inactivated influenza vaccine? • A. The vaccine is most often given IV • B. Two doses should be given to children less than 9 years of age who are vaccine naïve • C. Through antigenic changes, the vaccine can cause influenza • D. The vaccine contains live, attenuated viruses • E. None of the above are true

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LAIV-Live

attenuated influenza vaccine

• Contains live viruses • Administered intranasally • Approved for healthy persons aged 5-49 years • More expensive than inactivated • Dosing

MMWR recommendations for LAIV 2006-2007 • Healthy, non-pregnant persons aged 5-49 years • Caretakers of high risk individuals • Health care workers

– 5-<9 years old, no previous vaccine: 2 doses 6-10 weeks apart – 5-<9 years old, previous vaccination: one dose – 9-49 years: one dose – Do not administer until 48 hours after cessation of antivirals – Do not give antivirals until 2 weeks after LAIV

Efficacy of LAIV

Safety of LAIV

• A two season study showed efficacy of 93% for year one and 86% for year two • In adults aged 18-49 years, advantages were found in fewer lost work days, fewer health care visits, and reduced antibiotic use • A study comparing inactivated vaccine and LAIV found similar efficacy

• Adverse events include: runny nose, congestion, headache, and sore throat • LAIV should be avoided in non-indicated groups • LAIV should be avoided by caregivers of severely immunosuppressed individuals • Chicken egg allergy

Vaccine comparison

Advantages of LAIV to inactivated vaccine include….

• Similarities – – – –

Similar efficacy Well tolerated Virus types Both produced from chicken eggs

• Differences – – – –

Live vs. killed Eligible patient groups Route of administration Price

• A. Expanded indications • B. May produce a stronger immune response • C. Less invasive administration • D. Not derived from chicken eggs • E. B and C • F. B, C, and D

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Vaccine timing

Antivirals

• September: underlying risk factors and caregivers • October-November: Optimal time for vaccination • December: booster shots for patients who need two doses, other people who missed out • January-end of season: Still useful

• • • •

Adamantanes

Resistance!

• • • • •

• CDC reported 193/209 influenza A (H3N2) strains were resistant • Resistance conferred by change at amino acid 31 in M2 gene • 25% of H1N1 strains were resistant • Canada found similar results • Resistance develops rapidly during treatment • Adamantanes are no longer recommended

Includes amantadine and rimantadine Only active against type A Decrease duration of illness by 1 day Simple, 5 day regimen However, not recommended this year because…

Adamantanes Neuraminidase inhibitors Prophylaxis vs. treatment Place in therapy

Neuraminidase inhibitors

Indications for chemoprophylaxis

• Includes zanamivir and oseltamivir • Both approved for treatment and chemoprophylaxis • Resistance is infrequent • Reduce duration of illness by one day • May reduce risk of influenza related complications • Treatment course is 5 days

• In high risk individuals who receive vaccine after the influenza season has begun • Unvaccinated caregivers of high risk individuals • Persons with severe immunodeficiency • High risk persons who can not receive the vaccine

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Adverse effects/safety

Dosing

• Zanamivir is not recommended for patients with underlying airway disease • Oseltamivir may cause N/V • Drug interactions are rare • Both drugs are pregnancy category C

• Zanamivir – Treatment: 10 mg (two inhalations) twice daily x 5d – Chemoprophylaxis: 10 mg (two inhalations) once daily

• Oseltamivir – Treatment: 75 mg bid for ages 13 and up – Chemoprophylaxis: 75 mg once daily for ages 13 and up

• Hepatic dysfunction – no adjustment necessary

• Renal dysfunction – If Crcl is 10-30 ml/min reduce oseltamivir dose

Regarding antiviral therapy for influenza…

Influenza: important points

• A. Adamantanes are useful antivirals due to few side effects and low resistance • B. Neuraminidase inhibitors reduce duration of illness by more days than adamantanes • C. Oseltamivir is approved for children greater than 1 year of age • D. Resistance to adamantanes is via a mutation in the M5 gene • E. None of the above are true

• Still a significant cause of morbidity and mortality • Vaccine compliance still too low • Both vaccines effective in preventing disease • Adamantanes are no longer recommended due to resistance • Antivirals can be useful but do not take the place of vaccination

Avian influenza

Background of avian influenza • Outbreaks in humans in Hong Kong in 1997 and 2003 • First cases of current epidemic appeared in December 2003 • Cases confirmed in Azerbaijan, Cambodia, China, Djibouti, Egypt, Indonesia, Iraq, Thailand, Turkey, Vietnam, and elsewhere • Half those infected with H5N1 virus have died • Most cases occurred in children and young adults • No sustained human-human transmission, yet…..

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Nations with confirmed cases of avian influenza H5N1

Avian influenza pathophysiology • • • •

Caused by influenza A virus H5N1 subtype is most concerning Normally carried in bird intestines One of the few strains to cross species barrier • Most human cases result from poultry contact

Avian influenza clinical features • Incubation is 2-8 days • Initial symptoms include: high fever, influenza-like symptoms • Other early symptoms: diarrhea, vomiting, abdominal and chest pain, bleeding from nose and gums • Nearly all patients will develop pneumonia • Clinical deterioration is rapid • Multi-organ dysfunction

Which is true regarding avian influenza? • A. Pandemic potential is limited by lack of human to human spread • B. Cases have been limited to the Asian continent only • C. Human cases mortality is 30% • D. Pneumonia is rarely seen in human cases • E. H5N1 is an influenza B virus

The Hong Kong experience-1997 • In 1997 there were 200 active chicken farms in Hong Kong • 120,000 live poultry sold each day in markets • Local farms supplied about 22% of live chickens to market • Outbreak began in March and spread to two more farms in vicinity • First virus isolated in April

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The Hong Kong experience - 1997

The Hong Kong experience - 1997

• 100% mortality on first farm, 75% on other two • First human case occurs in May • Atypical influenza virus isolated from 3 year old boy • Patient expired • Source of infection not established

• Additional human cases occur in November • By end of December a total of 17 human cases have occurred • Infection in main wholesale market occurs shortly after • Additional outbreaks occur in markets and farms in late December • Decision made to depopulate all Hong Kong poultry markets and farms

Current state of affairs

Vaccine status

• Vietnam hardest hit • Human cases detected from Turkey to Indonesia • Virus in poultry detected in Sudan, Pakistan, Russia, and Romania • Virus detected in wild animals in Germany, UK, Denmark, and Sweden • Still limited evidence of human to human transmission

• Vaccine development is underway • Multiple types, multiple routes • Pandemic vaccine should:

Drug therapy options

NEJM 353;25 December 2005

• Neuraminidase inhibitors are frontline choice • Oseltamivir is most studied • Administration within 48 h of symptom onset is necessary • WHO reserve is at 3 million courses • Conditions for successful prophylaxis

• Previously healthy 13 year old Vietnamese girl • Presents with one day history of fever and cough • Mother recently deceased from H5N1 infection • H5N1 suspected in young girl, oseltamivir given, patient referred • On admission: temp 40.3 C, pulse 106 bpm, RR 36 breaths per minute, WBC 4800 cells/mm3 , platelet count 183,000 cells/mm3 • X-ray reveals small focal infiltrate in right middle lobe

– – – – – –

Non urban setting Early intervention Virus of low to moderate transmissibility Prophylaxis of 80-90% of population High compliance Movement restrictions, social distancing

– Stimulate immunity quickly – Preferably active after only one dose – Able to produce in massive quantities – Effective despite differences to pandemic strain

• Current vaccine candidates may require 2 doses

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NEJM 353;25 December 2005

NEJM 353;25 December 2005

• • • •

• On fourth day, condition worsens • O2 given by nasal cannula, then continuous positive pressure • Pneumonia now involves most of right middle lobe • Condition continues to worsen by day 5 • Placed on ventilator on day 6 • Radiograph on day 7 showed pneumonia of entire right lung with extension to the left lung • Patient expires on day 7 • Resistant virus isolated post therapy

Patient receives second dose 6h after first Third dose 24 hours after admission Treatment continued for 4 more days Patient stable 3 days post admission

NEJM 353;25 December 2005

NEJM 353;25 December 2005 • Six of 8 patients given oseltamivir within 48 hours survived • Drug-resistant variants isolated from two patients • Extended use or higher doses may be beneficial • Data on chemoprophylaxis is absent

Pharyngeal viral loads during Oseltamivir treatment for H5N1

Conclusions • H5N1 is unable to cause a pandemic in current form • Disease is characterized by rapid deterioration, multi-organ failure, and death • Over 50% of known human cases have expired • Vaccine is still a ways off • Oseltamivir may be effective if given within 48 hours

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H5N1 has become transmittable from human to human. Outbreaks have occurred in major cities around the world. The vaccine developed is a poor match and is ineffective. What do you do now?

• A. Begin fast-track development of a new vaccine • B. Mass produce oseltamivir and distribute to as many people as you can • C. PANIC! The apocalypse is upon you! • D. A and B • E. all of the above

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