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INFLUENZAS old and new

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

Influenza: still a heavy hitter

• 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 0.4-


• Influenza associated deaths are rising

Pathophysiology of influenza

• Two types: A and B

• Type A is further categorized into subtypes

• Different types are more than just names

– Some drugs ineffective against type B

– Epidemics more serious with type A

– Wrong strain selection for vaccine = big trouble

– Antigenic drift

– Antigenic shift


• 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

No one is safe!

• 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

• 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

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

for subsequent bacterial pneumonia – Has been associated with encephalopathy, myocarditis, Reye syndrome, and ARDS

Challenges of influenza

• 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?

Treatment/Prevention options • Vaccine – Inactivated – Live • Neuraminidase inhibitors – Zanamivir –
Treatment/Prevention options
• Vaccine
– Inactivated
– Live
• Neuraminidase inhibitors
– Zanamivir
– Oseltamivir
• Adamantanes
– Amantadine
– Rimantadine
• Infection control

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.

• E. None of the above are true

A and B


• 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!

up coming influenza season • Outlines criteria for at risk groups • Vaccines, drugs, prevention, and

Inactivated influenza vaccine

• 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

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…


So who should get the vaccine… EVERYBODY!

Safety of inactivated vaccine

• Local site irritation

• Systemic symptoms rare

• Allergic reactions


• 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

LAIV-Live attenuated influenza vaccine

• Contains live viruses

• Administered intranasally

• Approved for healthy persons aged 5-49 years

• More expensive than inactivated

• Dosing

– 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

• 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

Vaccine comparison • Similarities – Similar efficacy – Well tolerated – Virus types – Both
Vaccine comparison
• Similarities
– Similar efficacy
– Well tolerated
– Virus types
– Both produced from chicken eggs
• Differences
– Live vs. killed
– Eligible patient groups
– Route of administration
– Price

MMWR recommendations for LAIV


• Healthy, non-pregnant persons aged 5-49 years

• Caretakers of high risk individuals

• Health care workers

Safety of LAIV

• 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

Advantages of LAIV to inactivated vaccine include….

• 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

Vaccine timing

• 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


• 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…

Neuraminidase inhibitors

• 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


• Adamantanes

• Neuraminidase inhibitors

• Prophylaxis vs. treatment

• Place in therapy


• 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

Indications for chemoprophylaxis

• 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

Adverse effects/safety

• 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

Regarding antiviral therapy for influenza…

• 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

Avian influenza


• Zanamivir

– Treatment: 10 mg (two inhalations) twice daily x


– 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

Influenza: important points

• 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

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…

Nations with confirmed cases of avian influenza H5N1

Nations with confirmed cases of avian influenza H5N1
Nations with confirmed cases of avian influenza H5N1 Which is true regarding avian influenza? • A.

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

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

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

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

Current state of affairs

• 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

Drug therapy options

• 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

– Non urban setting

– Early intervention

– Virus of low to moderate transmissibility

– Prophylaxis of 80-90% of population

– High compliance

– Movement restrictions, social distancing

The Hong Kong experience - 1997

• 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

Vaccine status

• Vaccine development is underway

• Multiple types, multiple routes

• Pandemic vaccine should:

– 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

NEJM 353;25 December 2005

• 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/mm 3 , platelet count 183,000 cells/mm 3

• X-ray reveals small focal infiltrate in right middle lobe

NEJM 353;25 December 2005

• 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

Pharyngeal viral loads during Oseltamivir treatment for


Pharyngeal viral loads during Oseltamivir treatment for H5N1

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

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


• 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

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.

• E. all of the above

A and B