PANDEMIC INFLUENZA:FOCUS ON LOCAL PREPAREDNESS

David J. Weber, MD, MPHProfessor of Medicine, Pediatrics, and Epidemiology

Associate Chief of StaffMedical Director, Hospital Epidemiology and Occupational Health

University of North Carolina at Chapel Hill

Structure of the Influenza Virus

Polymerase (P) Proteins

Hemagglutinin (HA)16 types in influenza A

Neuraminidase (NA)9 types in influenza A

M2M2

Nucleoprotein (NP)ssRNA–highly mutable

8 segments-allowsreassortment during

double infection

M1M1

Adapted from: Hayden FG et al. Clin Virol. 1997:911-42.

INFLUENZA: BIOLOGY & IMPACT

Single-stranded, enveloped, RNA virus (orthomyxoviridae): Causes respiratory tract disease (pneumonia) Sudden onset More severe pneumonia during pregnancy No carrier state but inapparent disease may occur

Influenza A Potentially severe illness; epidemic and pandemics Rapidly changing Hemagluttinin (HA) 16 types; neuraminidase (NA) 9 types

Influenza B Usually less severe illness; may cause epidemics More uniform

Influenza C Usually mild or asymptomatic illness

ENVIRONMENTAL SURVIVALOF INFLUENZA A

0%

20%

40%

60%

80%

100%

0 10 20 30 40 50 60

Minutes

Survival on hands Survival on surfaces

Efficacy of antisepticsAlcohol 60% gel, >99.99% reduction in 20 secEthanol 75%, >99.99% reduction in 20 sec Sattar SA, Tetro JA., 2006

Deaths25,000 - 72,000

Hospitalizations114,000 - 257,500

Infections and illnesses50 - 60 million

Physician visits~ 25 million

Thompson WW et al. JAMA. 2003;289:179-86. Couch RB. Ann Intern Med. 2000;133:992-8. Patriarca PA. JAMA. 1999;282:75-7. ACIP. MMWR. 2004;53(RR06):1-40.

Influenza Disease Burden to U.S. Societyin an Average Year

SEASONAL INFLUENZA, PEAK MONTH,1976-2009

Antigenic Drift

Antigenic Shift

Hampson AW, Mackenzie JS. MJA 2006;185:S39-43

De Clercq E. Nature Rev 2006;5:1015-25

INFLUENA PANDEMICS IN THE 20th CENTURY

Years VirusUS Mortality Greatest Risk

Spread from Asia to US

1918-1919“Spanish”

Type A H1N1

500,000 Young, healthy adults

Unknown

1957-58“Asian”

Type A H2N2

70,000 Infants, elderly

4-5 mo

1968-69“Hong Kong”

Type A H3N2

34,000 Infants, elderly

2-3 mo

HHS Pandemic Influenza Plan, October 2005

C DCC EN TE RS FOR D ISE A S E C ON TRO L

A ND P RE V EN TION

U .S. L ife Expectancy 1900-1960

30

1900 1905 1910 1915 1920 1925 1930

Year

Lif

e E

xpec

tan

cy

1935 1940 1945 1950 1955 1960

38

46

54

62

70

NY Times, 30 April 2009

INFLUENZA AND PNUEMONIA MORTALITY, US, 1911-17 VS 1918

PANDEMIC INFLUENZA PLANNING CHALLENGES

Pandemic strain unknown The ability of the virus to rapidly spread worldwide Simultaneous outbreaks throughout the US, limiting the ability of any

jurisdiction to provide assistance to other areas People may be asymptomatic while infectious Long duration (>2 years) and multiple waves Enormous demands on the healthcare system

Need for surge capacity: Medications, ventilators, beds, personnel Personnel: Exhaustion, concerns about infection

Maintaining social distancing Providing adequate antivirals including distribution/allocation Vaccine development and distribution/allocation

PANDEMIC INFLUENZA PLANNING ASSUMPTIONS

Most likely pandemic strain H5N1 (ongoing epidemic since 1999) Pandemic likely to start in Asia and then spread to US

Mitigation strategies will limit epidemic: Social distancing, antivirals, vaccines

Pandemic will be characterized by distinctive waves Susceptibility to the pandemic influenza virus will be universal

Highest infection rate among school-aged children (~40%) Highest morbidity and mortality among the elderly

Asymptomatic persons may transmit infection Antivirals likely in to be in short supply Vaccine will be not be available for >6 months Number of hospitalizations and deaths will depend on virulence

Stochasic model - Germann TC, et al. PNAS 206;103:5935-5940

MODELING AN INFLUENZA PANDEMIC:CONCLUSIONS

Social distancing (travel restrictions, closing schools) Travel restrictions with >99% efficacy required to increase time

between exports to the order of weeks Delays epidemic and decreases peak Limited effect on total number ill, hospitalized, or dead

Antivirals Likely to decrease total number infected Requires early therapy or long-term prophylaxis for efficacy Adequate stockpile and distribution key

Vaccines Must be available early in epidemic Most effective if provided to children with leftover vaccine going to

middle aged adults

PANDEMIC INFLUENZA PLANNING ASSUMPTIONS

Most likely pandemic strain H5N1 (ongoing epidemic since 1999) (-) Pandemic likely to start in Asia and then spread to US (-)

Mitigation strategies will limited epidemic: Social distancing, antivirals, vaccines (-)

Pandemic will be characterized by distinctive waves (-) Susceptibility to the pandemic influenza virus will be universal

Highest infection rate among school-aged children (~40%) (-) Highest morbidity and mortality among the elderly (-)

Asymptomatic persons may transmit infection (+) Antivirals likely in to be in short supply (-) Vaccine will be not be available for >6 months (+) Pandemic influenza strain likely have increased virulence (-)

WHO INFLUENZA PANDEMIC ALERT,11 JUNE 2009 (alert raised to phase 6)

ESTIMATES OF NOVEL H1N1 IMPACT

Seasonal Influenza Novel Influenza

Attack Rate 10-20% 30-50%

Symptomatic 50-60 million 60-120 million

Hospitalizations 114,000 – 257,000 Up to 1.8 million

ICU care Up to 300,000

Deaths 25,000 – 72,000 30,000 to 90,000

President’s Council of Advisors on Science and Technology, 7 Aug 2009

NOVEL INFLUENZA H1N1, 2009CURRENT EPIDEMIOLOGY

Unique strain: Includes genetic components of human, avian, and swine origin

Worldwide outbreak Efficient human-to-human transmission documented Susceptible to antivirals (oseltamivir and zanamivir) but oseltamivir

resistance described Median age, US = 12 (highest infection incidence, 5-24 years) Older individuals may have cross-reacting antibodies (i.e., partial

protection) Risk factors:

Obesity (BMI >30) and morbid obesity (BMI >40) a newly described risk for severe illness

Pregnant women: Death rate 4-6x higher than general public

Gather D. J Clin Virol 2009;45:174-178

Emergence of Quadruple-Reassortant H1N1/09

Garten et al., Science, 2009; 325:198

IMPACT OF NOVEL H1N1

Worldwide (WHO, 8 January) 12,799 confirmed deaths; 208 countries/territories reported activity

US (CDC, April to 14 November) 47 (range, 34-67) million cases 213,000 (range, 154,000-303,000) hospitalizations 9,820 (range, 7,070-13,930) deaths

North Carolina (NC Health Dept., 13 October) 81 deaths {since April 2009}

UNC Hospitals (Hospital Epipidemiology, 4 January) 115 hospitalizations, 5 deaths

H1N1 EPIDEMIOLOGY, US

Hospitalization rate (US, 15 April to 24 July, 2009) Cases: 43,771 Hospitalizations: 5,011 (11.4%) Deaths: 302 (0.69%)

Secondary attack rate Acute respiratory illness: 18% to 19%

Definition: >2; fever, cough, sore throat, rhinorrhea Influenza-like illness: 8% to 12%

Definition: Fever plus cough or sore throat Generation time

Acute respiratory illness: 2.0-3.1 days Influenza-like illness: 2.4-3.1 days

International EpidemiologyInternational Co-circulation of 2009 H1N1 and Seasonal

Influenza(As of 4 January 2010)

NOVEL H1N1,OUTBREAK CURVE, MEXICO,11 MARCH – 29 MAY

H1N1, NEW ZEALAND EXPERIENCE

MMWR 2009;58:918-21

ILI REPORTED BY US OUTPATIENT ILINet

INFLUENZA ACTIVITY, US, BY VIRAL TYPE

H1N1 SURVEILLANCE, CDC,30 AUGUST TO 2 JANUARY

H1N1 SURVEILLANCE, UNC

H1N1 Outcomes Count

Hospitalizations 115

Deaths 5

NOVEL INFLUENZA H1N1, 2009:SYMPTOMS

Cough 98% Subject fever 96% Fatigue 89% Headache 82% Nausea 55% Stomach ache 50% Diarrhea 48% Shortness of breath 48% Joint pain 46%

Max temperature 39.0 oC (102.2 oF)

Temperature range 37.2-40.0 39.0 oC (99.0-104.0 oF)

95% reported subjective fever PLUS cough or sore throat

MMWR. NYC. 2009;58(dispatch;1-3

H1N1 CASES RATE, US,BY AGE GROUP

15 April to 24 July, CDC

WARNING SIGNS FOR WHEN A PERSON SHOULD SEEK MEDICAL CARE

Children Fast breathing or trouble

breathing Bluish or gray skin color Not drinking enough fluids Severe or persistent vomiting Not waking up or not interacting Being so irritable that the child

does not want to be held Flu-like symptoms that improve

but then return with fever and worse cough

Adults Difficulty breathing or shortness

of breath Pain or pressure in the chest or

abdomen Sudden dizziness Confusion Severe or persistent vomiting Flu-like symptoms that improve

but then return with fever and worse cough

PERSONS AT HIGH RISK OF COMPLICATIONS FROM H1N1 INFLUENZA

Age < 2 years Age >65 years Pregnant women Immunosuppression: HIV infection, chemotherapy Persons with metabolic disorders: Diabetes, chronic renal failure, chronic

liver failure, sickle cell anemia Persons with cardiovascular disorders: Congestive heart failure (not

hypertension) Persons with compromised respiratory function: Cognitive dysfunction,

spinal cord injuries, seizure disorders, other neuromuscular disorders Persons with respiratory disorders: Asthma

Acute Febrile Respiratory Illness of <7 days Duration With Fever AND >1 Of The Following● Cough

● Sore throat

Vomiting and diarrhea do NOT exclude the diagnosis of influenza H1N1Fever defined as subjective fever or temperature >37.8 oC or 100 oF

Place surgical mask on patient immediatelyIsolate as soon as possible (private room if possible)

Use Droplet Precautions (surgical mask)For cough inducing procedures (bronchoscopy, intubation) use an N95 respirator

plus eye protection (face shield or goggles)

Obtain NP swab for influenza PCRAdditional clinical evaluation as indicated

Algorithm for Evaluation of UNC Health Care Patients With Possible Novel H1N1 Influenza

* Persons considered at high risk for complications: children less than 2 years old, persons aged 65 years or older, pregnant women, persons younger than 19 years of age who are receiving long-term aspirin therapy, and persons of any age with certain chronic medical or immunosuppressive conditions

(chronic pulmonary {including asthma}, cardiovascular {except hypertension}, renal, hepatic, hematological {including sickle cell disease}, metabolic disorders {including diabetes}; disorders that can compromise respiratory tract function or increase the risk of aspiration {e.g., cognitive dysfunction,

seizure disorders}; and immunosuppression {e.g., HIV}.

Influenza (H1N1) is susceptible to oseltamivir and zanamivir but resistant to amantadine/rimantadine

Only high risk persons should be considered for post-exposure prophylaxis and therapy. Early treatment is an alternative to chemoprophylaxis after a suspected exposure.

23 September 2009 Updates at http://intranet.unchealthcare.org/intranet_news/empnews/flu

YesNo

No influenza testing recommendedAdditional evaluation and follow-up

as clinically indicated

Do patient’s symptoms indicate need for hospitalization ORIs the patient in a high risk group for complications of influenza* or from an extended care facility

Yes

Hospitalizedbegin empiric therapy with oseltamivir

Use Droplet PrecautionsFor cough inducing procedures use an N95 respirator

plus eye protection (face shield or goggles)

DischargedConsider empiric therapy (zanamivir preferred) only if patient at “high

risk” for complications of influenzaAntivirals most effective if inititiated <48 after onset of symptoms

Patient should stay home until 24 hours afebrile off antipyreticsUse proper hand and respiratory hygiene

Call or seek emergency medical care, if warranted

No

DischargePatient should stay home until 24 afebrile off antipyretics

Use proper hand and respiratory hygieneCall or seek emergency medical care, if warranted

If zanamivir contra-indicated (by age or hx of asthma) use oseltamivir

Additional evaluation and follow-up as clinically indicated

Obtain influenza test only if clinically indicated

CDC2 Oct

SYMPTOMS OFHOSPITALIZED PATIENTS

Fever 93%Cough 83%

Shortness of breath 54%Fatigue/weakness 40%

Chills 37%Myalgias 36%

Rhinorrhea 36%Sore throat 31%Headache 31%Vomiting 29%Wheezing 24%Diarrhea 24%

H1N1 HOSPITALIZATION RATE(per 100,000), BY AGE GROUP

AGE GROUPS OF HOSPITALIZED PATIENTS: SEASONAL VERSUS NOVEL INFLUENZA

MMWR 2009;58(RR-10)

MMWR 2009:58;749

H1N1 IN HOSPITALIZED PATIENTS

High frequency of ARDS, pulmonary emboli, acute renal failure, and/or septic shock Increased LDH and CPK Infection characterized by severe hypoxemia and hypoxemic deaths

Frequent need for high-frequency oscillatory ventilation (HFOV) or extracorporeal membrane oxygenation (ECMO)

High frequency of secondary bacterial pneumonias Consider empiric antibacterial therapy Consider higher oseltamivir dosing (i.e., 150 mg PO 2x/d) and/or

longer therapy (e.g., 10 days)

H1N1 US DEATHS,BY AGE GROUPS, US

H1N1 US ILLNESS AND DEATHS,BY AGE GROUPS, MEXICO

Chowell G, et al. NEJM 2009;361:674-9

MMWR 2009;58: 941-47

SECONDARY BACTERIAL INFECTIONSIN PATIENTS WITH H1N1

Examination of 77 H1N1 cases by autopsy

22 of the 77 cases had evidence of bacterial superinfection S. pneumoniae 10 S. pyogenes 6 S. aureus 7 H. influenzae 1 Multiple pathogens 4

MMWR 2009;58:1071

ANTIVIRAL THERAPY

Consider for possible cases of novel influenza at high risk for complications

Treatment of hospitalized patients and patients at high risk for influenza complications should be prioritized

Provide therapy as soon as possible (target <48 hours) Recommended duration is 5 days Use same doses as recommended for seasonal influenza Novel influenza

Zanamivir alone, OR Oseltamivir PLUS amantadine or rimantadine (if seasonal flu possible)

TREATMENT ANDPOST-EXPOSURE PROPHYLAXIS

Treatment (oseltamivir) PEP (oseltamivir)

Adults 75-mg capsules 2x/d x 5 days 75-mg capsule 1x/d x 10 days

Child >12 mo <15 kg 15-23 23-40 >40

30-mg 2x/d x 5 days45-mg 2x/d x 5 days60-mg 2x/d x 5 days75-mg 2x/d x 5 days

30-mg 1x/d x 5 days45-mg 1x/d x 5 days60-mg 1x/d x 5 days75-mg 1x/d x 5 days

Treatment (oseltamivir) PEP (oseltamivir)

Adults 2 5-mg inhalations (10 mg) 2x/d

2 5-mg inhalations (10 mg) 1x/d

Children 2 5-mg inhalations (10 mg) 2x/d(age >7 years)

2 5-mg inhalations (10 mg) 1x/d(age >5 years)

INFLUENZA: PROPHYLAXIS AND THERAPIES

Oseltamivir (Tamiflu)*: Influenza A & B Treatment: 75 mg PO 2x/day x 5d** Post-exposure prophylaxis: 75 mg PO 1x/day x 10 days Seasonal prophylaxis: 75 mg PO 1x/day x 4-8 weeks

Zanamivir (Relenza)*: Influenza A & B Treatment: 10 mg (2 nasal inhalations 2x/d x 5d) Post-exposure prophylaxis: 10 mg (2 nasal inhalations 1x/d x 10d) Seasonal prophylaxis: 10 gm (2 nasal inhalations 1x/day x 4-8 weeks)

Ramantidine*: Influenza A*** Treatment: 100 mg PO 2x/d (adult); 100 mg PO 1x/d (>65, elderly in ECF) Prophylaxis: 100 mg PO 2x/d (adult); 100 mg PO 1x/d (elderly in ECF)

*Should begin therapy within 2 days of onset of illness Reduce dose if creatinine clearance <30mL/min**, or <10mL/min***

ANTIVIRAL RESISTENCE

CDC data (Since 1 October 2008) Resistance in seasonal H1N1 (N=1,148)

Oseltamivir 99.6%, zanamivir 0%, adamantanes 0.5% Resistance in seasonal H3N2 (N=261)

Oseltamivir 0%, zanamivir 0%, adamantanes 100% Novel H1N1 (N=1,678)

Oseltamivir 0.6%, zanamivir 0%, adamantanes 100%

Reports of resistance 2 immunocompromised patients, Seattle (MMWR 2009;58:893) 2 linked cases (normal hosts) in NC

COMBINATION THERAPY WITH OSELTAMIVIR, AMANTADINE, AND RIBAVIRIN ON H5N1

Smee DF, et al. AAC 2009;53:2120-2128

surveillance

select strains

prepare reassortants

standardize antigen

assign potency

review/license

formulate/test/package

vaccinate

WHO/CDC)

WHO/CDC/FDA

CDC/FDA

FDA

FDA

FDA

manufacturers

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

clinic

Vaccine Development

Effective of VaccineUsing Different DeliveryStrategies

Medlock J, Galvani AP.Science 2009;325:1705

H1N1 VACCINE

Made in a similar fashion to seasonal influenza vaccine Egg based production Single dose syringes and inhaled vaccine are thimerosal free Multi-dose vials have miniscule amount of thimerosal (no human harm

demonstrated from thimerosal per IOM report) No adjuvant Risk of Guillain-Barre = 1 additional case per 1,000,000 vaccinated

Both inactivated and live-attenuated vaccines will be available Licensed by FDA 15 September 2009: CSL Limited, MedImmune LLC,

Novartis Vaccines and Diagnostic Limited, and Sanofi Pasteur Inc. Available for clinical use in early to mid-October

Requires one dose in adults, 2 doses in children: Robust immune response produced in healthy adults in 8-10 days (15ug dose 96.7%):

Vaccine provided free by Federal Government

H1N1 VACCINE: TITER >1:40

Zhu F-C, et al. NEJM 2009;361

EFFICACY OF INACTIVATED VS ATTENTUATED SEASONAL INFLUENZA VACCINE

Monto AS, et al. NEJM 2009;361:1260-7

EFFICACY OF INFLUENZA VACCINE PRODUCED MAMMALIAN CELL CULTURE

J Infect Dis 2009;200:841-8

TARGET GROUPS FOR H1N1 VACCINE

Initial Pregnant women People who live with or care for infants younger than 6 months of age Healthcare and emergency medical personnel Anyone from 6 months through 24 years of age Anyone from 25 through 64 years of age with certain chronic medical

conditions or a weakened immune system As more vaccine become available, these groups should also be

vaccinated Healthy 25 through 64 year olds Adults 65 years and older

Children through 9 years of age should get 2 doses of vaccine about a month apart

CDC. 2 October 2009

H1N1 VACCINES FOR USE IN THE US, 6 OCTOBER, 2009

FDA APPROVED 2009 H1N1 VACCINES: CONTRA-INDICATIONS & WARNINGS

Inactivated vaccines (contra-indications) Anaphylaxis to a previous dose of influenza vaccine Hypersensitivity to eggs or chicken proteins Hypersensitivity to gelatin (Sanofi), formaldehyge (Sanofi), polymyxin

(Novartis, CSL), neomycin (Novartis, CSL), nonylphenol ethoxylate (Novartis)

Inactivated vaccines (warnings) Guillain-Barre syndrome within 6 weeks of a previous dose of

influenza vaccine Immunocompromised persons may have a diminished immune

response

FDA APPROVED 2009 H1N1 VACCINES: CONTRA-INDICATIONS & WARNINGS

Live attenuated vaccine (contra-indications) Anaphylaxis to a previous dose of influenza vaccine Hypersensitivity to eggs, chicken protein, gelatin, gentamicin, or

arginine Live attenuated vaccine (warnings and precautions)

Do not administer to persons with asthma or children <5 years of age with recurrent wheezing

Guillain-Barre syndrome within 6 weeks of a previous dose of influenza vaccine

Pregnant women Immunocompromised persons Persons at high risk of complications from influenza

NOVEL INFLUENZA H1N1, 2009INFORMATION NOT AVAILABLE

Will seasonal H3N2 influenza virus disapper Number of persons who will develop disease in Fall/Winter Duration of viral shedding Modes of transmission: Droplet (presumed), airborne?, contact? Ability to develop an accurate rapid diagnostic test Efficacy of H1N1 vaccine Likelihood of antiviral resistance developing Efficacy of IV neuraminidase inhibitors Morbidity* (Hospitalization rate) Mortality*

* Current data subject to ascertainment bias

CDC GUIDELINES: CONTROVERSIES

Duration of furlough for ill healthcare workers Initially 7 days from onset of illness or afebrile x 24 hours Afebrile x 24 hours off antipyretics

Respiratory protection N95 respirator Surgical mask

Vaccine Live attenuated Inactivated

SURGICAL MASK VS N95 FOR PREVENTING INFLUENZA AMONG HCWs

Randomized clinical trials, 2008-2009 influenza season Location = Ontario tertiary care hospitals 446 nurses enrolled

Outcome = Laboratory confirmed influenza (PCR, serology)Loeb M, et al. JAMA 2009;302:E1

UNC HOSPITAL PREPAREDNESS:ISSUES

Critical issues Surge capacity Maintaining adequate

staffing Provision of essential

services/supplies

Additional issues Surveillance Diagnosis Protecting personnel Occupational health Stockpiling antiviral agents Triage of limited

supplies/beds Security

UNC HOSPITAL PREPAREDNESS:PROVIDING ESSENTIAL SERVICES

Explicit statement by University/Hospital that all employees are expected to provide service Requirement that illness be documented if unable to work

Food supplies: Ability to use UNC University supplies (>6 weeks) Water: Infrastructure to support supply via trucks Electrical: University generator

UNC Hospitals highest priority Additional capacity planned

Medical gases: 1 week supply; additional supply to be added Beds

Outpatient: Plans to use medical student training area Inpatient: Plans to use unlicensed beds (e.g., PACU, 24 hour hold

area)

UNC HOSPITAL PREPAREDNESS:SURGE CAPACITY - STAFFING

Supplementation of staff Use of allied faculty (e.g., Schools of Nursing, Public Health,

Pharmacy)(e.g., Nursing = ~20 faculty, ~200 students) Use of medical/nursing students Use of retired medical personnel and volunteers Use of UNC University staff (e.g., security, housekeeping, etc.) Assumption of malpractice costs & provision of worker’s

compensation (in case of acquisition of illness) Day care under consideration

Plan for flexible shifting of personnel to meet demand

Many many thanks to all persons who aided in development of our highly communicablerespiratory plan and have contributed to ourresponse to swine influenza