InfluenzaInfluenza

• “probably the most under-rated major pathogen in the developed world…”

• John Barlett, Update in Infectious Diseases– Annals of Internal Medicine August 1999

Case 1Case 1• 38 year-old man

presented February• 2-day history of

fever, chills, cough, sore throat, nasal congestion, muscle aches, headache, fatigue

• Did not receive flu vaccine

““Influenza-like illness”Influenza-like illness”• Recent, acute onset• Fever or feverishness• Respiratory (cough, sore throat,

coryza) and systemic (malaise, headache, myalgias) components

Influenza in Healthy, Young and Influenza in Healthy, Young and Middle-aged, Unvaccinated Middle-aged, Unvaccinated

AdultsAdultsSymptomSymptom Lab-Lab-

confirmed flu confirmed flu (n=2470)(n=2470)

No lab-No lab-confirmed flu confirmed flu (n=1274)(n=1274)

Likelihood Likelihood RatioRatio

Fever(>37.8) 68% 40% 1.7

Feverishness 90% 89% 1.0

Cough 93% 80% 1.2

Nasal congestion 91% 81% 1.1

Sore throat 84% 84% 1.0

Headache 91% 89% 1.0

Myalgia 94% 94% 1.0Monto et al. Arch Intern Med 2000; 160: Monto et al. Arch Intern Med 2000; 160: 3243.3243.

Recognizing influenza in Recognizing influenza in hospitalized patients?hospitalized patients?

Influenza (n=65)

Bacteria

(n=93)

Atypical

(n=89)

fever 75 77 67

cough 78 73 83

CXR “pneum” 25 54 60

CXR “clear” 38 16 10

WBC < 12,000 78 40 55Dowell et al. JID 1996; 174:456.Dowell et al. JID 1996; 174:456.

Influenza in a Fully-Immunized Influenza in a Fully-Immunized Veteran COPD PopulationVeteran COPD Population

SymptomSymptom Lab-Lab-confirmed confirmed flu (n=107)flu (n=107)

No lab-No lab-confirmed confirmed flu (n=279)flu (n=279)

Likelihood RatioLikelihood Ratio

Fever(>100) 50 44 1.1

Chills 68 57 1.2

Cough 93 92 1.0

Nasal congestion

84 90 .93

Sore throat 62 56 1.1

Headache 72 65 1.1

Myalgia 84 64 1.3Neuzil et al. CID 2003; 36: Neuzil et al. CID 2003; 36: 169169.

Accuracy of Clinical Accuracy of Clinical DiagnosisDiagnosis

• Diagnosis from clinical signs and symptoms is of limited accuracy

• Maintain a high index of suspicion during the right time of year

• Other co-circulating respiratory pathogens: Adeno; RSV; Parainfluenza; Rhino; Strep; Chlamydia; Mycoplasma

Seasonal Occurrence of Influenza, Seasonal Occurrence of Influenza, RSV and Parainfluenza Viruses, RSV and Parainfluenza Viruses,

United States,1996-99United States,1996-99

05

10152025303540

% re

spira

tory

spe

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ens

posi

tive

Influenza RSV Para 37/997/9

77/981/987/96 1/9

91/97

Should I perform a Should I perform a diagnostic test?diagnostic test?

• Utility of test in individual patient depends on quality of sample, timing of sample, turn-around time of test

• Collecting specimens still critical because it provides information about circulating influenza types

• BMC: Antigen testing +/- reflex PCR [Antigen testing Sensitivity (40 - 90%) Specificity (90 - 99%).]

• Typing is done at state labs

How and who should be How and who should be tested?tested?

• Nasopharyngeal swabs or washes on patients

• Immunocompetent adults at high risk for complications who present within 5 days of illness.

• Immunocompromised adults with acute febrile illness regardless of time of onset

• Recently hospitalized adults with fever and respiratory symptoms regardless of time of onset.

Virology of Influenza A and B

• Orthomyxoviridae• Enveloped negative stranded RNA

viruses • Four genera are included in this

family– Influenza A and B (human pathogens)– Influenza C – Thogotovirus (sometimes called

Influenza D).

Influenza A VirusesSubtyped based on surface glycoproteins:Subtyped based on surface glycoproteins:

• 16 hemagglutinins (HA) and16 hemagglutinins (HA) and 9 neuraminidases (NA)9 neuraminidases (NA)

• current human subtypes: current human subtypes: H1N1, H3N2, H1N2H1N1, H3N2, H1N2

Segmented genomeSegmented genome

NA

HA

Antigenic Drift• H1, H2, H3 / N1 and N2• Antigenic drift:

– Both A and B– Individual point mutations

Antigenic Shift• Influenza A only • Sudden appearance of

a virus with a completely novel HA or HA and NA.

• This occurs when a strain of Influenza A that usually infects bird or other mammals crosses over to cause human infection.

• May result in emergence of pandemic strains

• Asia appears to be a fertile ground for such shifts.

HumanHuman virusvirus

ReassortantReassortantvirusvirus

Non-humanNon-humanvirusvirus

Mechanisms of Influenza Virus Antigenic Mechanisms of Influenza Virus Antigenic “Shift”“Shift”

15 HAs15 HAs9 NAs9 NAs

DIRECTDIRECT

Pandemic Influenza

• Emergence & spread of “novel” influenza A virus – HA (or HA/NA) derived from animal viruses– Sustained and efficient human-human

transmission• Near simultaneous global outbreak• Elevated rates illness & death

The Great Influenza of 1918

• First wave less pathogenic (April-May), possibly beginning in Kansas and spreading by military travel throughout the world

• Second wave (July-Nov) much more lethal; hemorrhagic pneumonia in young adults

• Between 20-100 million deaths worldwide

Barry J. The Great Influenza – Viking Press, 2004

Mortality Comparisons# DEATHS

World War II 50 million

1918 Flu Epidemic 20-100 million

World War I 15 million

Ebola 1000- 2000

SARS 774

Infectious Disease Mortality, United States - 20th Century

Armstrong, et al. JAMA 1999;281:61-66.

Pathogenesis of 1918 Influenza

• Hemagglutinin (HA) antigen the key determinant of virulence in a mouse model

• Massive inflammation in lungs with cytokine “storm” and neutrophil influx

• Might immunomodulatory therapy be a useful adjunct to appropriate antivirals?

Kobasa et al. Nature 2004:431:703-07

Timeline of Emergence of Timeline of Emergence of Influenza A Viruses in HumansInfluenza A Viruses in Humans

1918 1957 1968 1977 19971998/9

2003

H1

H1H3

H2

H7H5H5

H9

SpanishInfluenza

AsianInfluenza

RussianInfluenza

AvianInfluenza

Hong KongInfluenza

2009

H12009 pandemic

H7

2009 Pandemic Influenza A (H1N1)

H7N9 Virus• Avian influenza, first reported from

China April 1, 2013• Over 130 infections detected.

Most subjects exposure to poultry. Reported 44 deaths.

• No evidence of sustained human to human transmission

• If virus acquires ability for sustained human to human transmission, then high potential for a pandemic

Should I use antivirals?Should I use antivirals?• Amantadine and rimantadine: effective

against influenza A viruses• Neuraminidase inhibitors: oseltamivir

(oral), zanamivir (inhaled); effective against influenza A and B viruses

• Differ in terms of pharmacokinetics, side effects, routes of administration, cost

AntiviralsAntivirals

• Neuraminidase inhibitors: Inteferes with viral release from infected cell. – Ostelamivir: 75 mg BID; $55; Approved for prophylaxis.

Can use higher doses

– Zanamivir: Inhalation 10 mg BID; $45Contraindicated in people with asthma or other chronic

respiratory conditions

DURATION: Generally 5 days but can be longer in ill patients.

Antivirals• Amantadine and rimantadine: Inteferes

with M2 protein function– Amantadine: 100 mg BID; $2 (Neuro side-

effects)– Rimantadine: 100 mg BID; $2; Approved for

prophylaxis.– Associated with CNS toxicity– Because of wide resistance, these

drugs should not be used for treatment other than special circumstances

Antiviral Resistance• Resistance to all drugs have been

described.• Generally single point mutations lead to

resistance• CDC website provides information about

% circulating variants with resistance• Durnig 2012 – 2013 season, resistance

to Tamiflu was observed in less than 1% of isolates.

Adverse Effects• Ostemlavir

– Nausea and vomiting– Mild abdominal pain– Dosing must be modified for renal

insufficiency• Zanamavir

– Broncospasm– Not recommended to be used with

ventilation tubing

Treatment in hospitalized Treatment in hospitalized with severe diseasewith severe disease

• Confirmed or Suspected disease– Therapy should be initiated prior to

diagnostic test results– With high clinical suspicion therapy

should not be stopped even if diagnostic test is negative

– For patients with severe disease therapy should be instituted even if they present after 48 hours

Oseltamivir Reduces Time to Oseltamivir Reduces Time to Alleviation of All SymptomsAlleviation of All Symptoms

00.10.20.30.40.50.60.70.80.91

0 1 2 3 4 5 6 7

Placebo

Oseltamivir

Treanor et al. JAMA 2000; 283: 1016Treanor et al. JAMA 2000; 283: 1016.

Prop

ortio

n wi

th sy

mpt

oms

Prop

ortio

n wi

th sy

mpt

oms

DaysDays

End of treatmentEnd of treatment

TreatmentTreatment• Treatment best if initiated early • Duration of illness is reduced and return

to usual activities is earlier• Treatment reduces virus shedding• None of the treatments has been shown

to prevent serious influenza-related complications (bacterial pneumonia or exacerbation of chronic disease)

Clinical Case 2Clinical Case 2• 43yo man with CML,

chronic phase, on interferon

• 2-week history of sore throat, cough, fever/chills/ myalgias/headache, dizziness, weight loss

• ?atypical pneumonia• Rx: azithromycin • (in addition to

trimeth-sulfa and PCN VK)

Clinical Case 2Clinical Case 2• Returned 12 days

later: worsening dyspnea, dry cough

• PE: cyanosis, bilateral crackles lower lung fields

• Hypoxic• BAL: Influenza A,

Staph. Aureus• Blood culture + S.

aureus

Complications of Influenza• Secondary bacterial infection

(Streptococcus or Staph. Aureus)• Myositis• CNS

– Guillan Barre, transverse myelitis, aseptic meningitis

• Cardiac– Myocarditis, pericarditis, MI

Influenza Vaccine• Each year, vaccine formulation

depends on the circulating strains.• Since 1980s vaccine have been

trivalent although quadrivalent may be standard at some point

• Current vaccines consist of a H1N1, H3N2 and influenza B

Who Should be Immunized?Who Should be Immunized?Persons at High Risk for Persons at High Risk for

ComplicationsComplications• All persons aged 6 months or older• All people including pregnant women can

receive the inactivated influenza vaccine (IIV)• Healthy, nonpregnant person age 2 – 49 without

high risk medical conditions can receive either intranasally administered live, attenuated influenza vaccine (LAIV) (FluMist) or IIV.

• Health care workers who care for severely immunocompromised persons should receive IIV.

Efficacy of Inactivated Efficacy of Inactivated Influenza VaccineInfluenza Vaccine

• Healthy children and adults: 70-90% in preventing culture-confirmed influenza

• Elderly: 30-70% in preventing hospitalization for pneumonia and influenza

• Frail elderly: 30-40% in preventing illness; 50-60% in preventing hospitalization; 80% in preventing death

MMWR 2003;52: 1-36.MMWR 2003;52: 1-36.

Vaccine Efficacy 2012 - 2013• Overall effectiveness 56%• Against H3N2 – 47%

– Only 9% for individuals 65 or older• Against Flu B 67%

Influenza Vaccine Effectiveness:Influenza Vaccine Effectiveness: Hospitalizations per 1000 65+ Hospitalizations per 1000 65+

0

10

20

30

40

P&I Acute resp CHF

Vax Unvax

Nichol et al. N Engl J Med 1994; 331: 778Nichol et al. N Engl J Med 1994; 331: 778

Special Target PopulationsSpecial Target Populations• Healthcare workers• Household members (including children) of

persons in high-risk groups• Employees of chronic-care facilities, assisted

living facilities or persons who provide home care to persons in high-risk groups

• Household and close contacts of young children (< 2 years)

MMWR 2003;52: 1-36.MMWR 2003;52: 1-36.

Who Should Not be Immunized?Who Should Not be Immunized?

• LAIV and TIV are grown in embroyonated hens’ eggs. Therefore vaccine should not be given to those with anaphylactic hypersensitivity to eggs or other components of the influenza vaccine. (Newer vaccine formulations are now available that are egg free. Flucelvax and FluBlok)

• Persons with acute febrile illness should not be vaccinated until their symptoms have abated

MMWR 2003;52: 1-36.MMWR 2003;52: 1-36.

Which vaccine should I Which vaccine should I recommend/administer?recommend/administer?

LAIV TIV

Route Nasal spray Injection

Virus Live, attenuated Killed

Antigens A/H3N2, A/H1N1, B A/H3N2, A/H1N1, B

FDA use Healthy 2-49yrs All > 6 mos

Schedule Annual Annual

Side effects

Nasal congestion,

sore throat

Sore arm

Potential advantages of Potential advantages of live vaccine?live vaccine?

• Broad mucosal and systemic immune response

• Ease of administration• Intranasal route of administration

Potential disadvantages?Potential disadvantages?

• Expense• Limited viral replication and

potential for transmission (rare)• After vaccination, antigen and PCR

tests can be positive• Less experience• Storage requirements

Live versus DeadLive versus Dead• Multiple head to head randomized

controlled trials.– RCT in ~5000 subjects no difference – RCT 2004/05 season in ~1300 subjects,

both vaccine similar efficacy against A but IIV better than LAIV against B

– RCT 2007/08 season in ~2000 subjects, IIV was more effective (72%) versus LAIV (29%)

– Surveillance study 2004 – 07 IIV associated with lower healthcare associated visits compared to LAIV.

Efficacy differences likely depend on year (circulating strains) and patient characteristics

•

Clinical Case 3Clinical Case 3• 56 yo man 14

days s/p autologous pbsct for multiple myeloma

• Fever, hypoxia, respiratory failure

Case 3Case 3• Prescribed imipenem, tobramycin,

levofloxacin, metronidazole• “This will cover his pulmonary

pathogen for sure”• BAL: FA and culture positive for

influenza A virus

Nosocomial InfluenzaNosocomial Influenza• Outbreaks in long-term care facilities,

acute care hospitals and specialized units well-documented in medical literature

• Testing is important • Focus on:

– Reducing reservoirs of infection (vaccinations, keeping ill staff and visitors out of the hospital)

– Infection control principles– Antivirals when needed

Effectiveness of Flu Vaccine in Effectiveness of Flu Vaccine in Health Care WorkersHealth Care Workers

• Randomized, double-blind, controlled trial over 3 consecutive years from 1992-1995

• 264 healthy health care professionals (75% resident physicians)

• Main outcome measure: Serologically defined influenza infection, days of febrile respiratory illness, days absent from work

Wilde et al. JAMA. 1999; 281: 908.

Influenza Infection During Influenza Infection During Annual Epidemics 1992-1995Annual Epidemics 1992-1995

25/179(13.9%)

3/180(1.7%)

Total 1992-1995

7/77 (9.1%)1/77 (1.3%)1994-1995

4/52 (7.1%)0/51 (0%)1993-1994

14/50 (28%)2/52 (3.9%)1992-1993

ControlFlu VaccineYear of Study

Influenza Vaccination of HCW in Influenza Vaccination of HCW in Long-Term-Care HospitalsLong-Term-Care Hospitals

• 1059 residents in 12 geriatric long-term-care hospitals in Glasgow

• Hospitals randomized for their HCWs to be routinely offered either flu vax or no vax

• Primary outcome: patient mortalityPotter et al. JID 1997; 175: 4.Potter et al. JID 1997; 175: 4.

Total Patient Mortality in Total Patient Mortality in Long-Term Care HospitalsLong-Term Care Hospitals

0

0.05

0.1

0.15

0.2

0 20 40 60 80 100 120 140

Potter et al. JID 1997; 175: 4.Potter et al. JID 1997; 175: 4.

Patients Vaccinated

Patients Not Vaccinated

Total Patient Mortality in Total Patient Mortality in Long-Term Care HospitalsLong-Term Care Hospitals

0

0.05

0.1

0.15

0.2

0 20 40 60 80 100 120 140

Potter et al. JID 1997; 175: 4.Potter et al. JID 1997; 175: 4.

Staff Not Vaccinated

Staff Vaccinated

SummarySummaryInfluenza is a major cause of morbidity, mortality and lost productivity worldwide.Influenza vaccine can reduce influenza and its complications in individuals, and may affect the spread of influenza in populations.Health care workers need to get the influenza vaccine!

Avian Influenza• Several recent outbreaks,

including:– 1997 (H5N1) in Hong Kong; 18 human

cases and 6 deaths; 20 million chickens culled

– 2003 (H7N7) in Holland; 83 cases and 1 death; 30 million chickens killed (JID 2004;190:2088-95)

– 2004 (H7N3) in Canada (18 farms in BC); 2 humans to date; 19 million chickens killed

– 2003/2005 (H5N1) in > 8 Asian countries

H5N1 Cases & MortalityThrough April 05, 2005*

(*more since)

Country H5N1 Cases

Deaths Case Fatality

Thailand 17 12 71%

Vietnam 60 35 58%

Cambodia 1 1 100%

Total 79 49 62%

Avian Influenza Poultry Outbreaks, Asia, 2003-04

2005 H5N1 Avian Influenza

• Continued evolution, with host range expansion to mammals (pigs, cats, tigers)

• Potentiated by large, densely populated poultry farms; minimal human to human spread so far

• Viral pneumonia and lymphopenia in children and young adults

• Over 100 million poultry killed in Asia

Transmission of Avian Influenza

• Direct contact with infected birds or their secretions

• Possible contacts with fomites (eg, contaminated equipment, clothing, etc.)

• Human-human rare to date; rare healthcare worker transmission (HK), unlike SARS

How quickly will the next Influenza pandemic spread?

• Larger, denser population

• Increase in international travelers since 1918

• Experience with SARS: Between Feb 21 – June 10, 31 countries involved

Comparisons of 1918 and 2005

•Similarities– Likely new virus strain emerging– ARDS in previously healthy young

adults– High mortality

•Differences– Better surveillance mechanisms– Antibiotics for secondary infections– Anti-influenza drugs and vaccines

(??)

H5N1 Vaccine Strategies• Currently, manufacturers would

need 6-10 months minimum to produce vaccine

• Major hurdles are political and economic, not scientific

• Some companies/governments are testing small batches in 2005

• NIH, Japanese, and French are beginning programs to test and stockpile vaccines

• Avian vaccines also under study

InfluenzaInfluenza

Type A BGene 8 7SegmentsHosts wide humansStructure NA,HA NA,HA

M2Epi shift & drift drift

pandemics epidemics

M2M2

NANAHAHA