zachariah influenza -...

3/2/2014

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Joseph K. Zachariah D.O.

Private Practice in Infectious Disease – Hospital Based

Banner Baywood Hospital, MESA ,AZ

Founder & Director: Travelhealthadvisor.com

(Interactive Web based Medical Recommendations for Overseas Travel)

[email protected]

“Just as the day is light and night is dark ;

Winter brings us the malady, they call the flu”

Unknown

Please ladies ; this is not my good side !

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Impact of Seasonal Influenza in the US

35 – 50 million cases / year

200,000 hospital admissions / year

3000 – 40,000 deaths /year

31 million outpatient doctor visits / year

3.1 million hospital days/ year

$10.4 billion in medical costs/ year

$16.3 billion in lost earnings / years

Vaccine 2007:25; 5086-5096

JAMA 2004: 292(11) 1333-40



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Impact of Seasonal Influenza in the US

Estimate of age adjusted Mortality

Age Number Rate

<19 124/yr 0.2/100,000

19-64 2385/yr 1.5/100,000

> 65 21,098/yr 66.1/100,000

Deaths among people over 65 years of age – 89% of all influenza

associated deaths

MMWR 2010:59(33)1057-62


Influenza Virus Composition : 2013-2014

N=36,619 Respiratory Specimens

Influenza A – 97%

H1N1 - 96%

H3N2 - 3.7%

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.

Influenza A Virus : Glycoproteins – Clinical correlates

N euraminidase

inhibits viral entrapment

cleaves virions from host cell

H emagglutinin

binds to resp epithelium

H1 H2 H3……..H16 N1 N2………N9

Antigenic Drift : point mutations of H & N - local outbreaks

Antigenic Shift : RNA shift of H & N – epidemics & pandemic

Prevailing Influenza Strains Over Time

1918 : H1N1 Extreme

1957 : H2N2 Severe

1968 : H2N3 Mild

1977 : H1N1 Mod ( > 1957)

1978: H1N1 /H3N2/Inf B Mild - Mod

2009: Novel H1N1 Widespread

Reassortment of 1 human – 2 swine – 1 avian viruses

2012: H3N2 Severe

2013 – H1N1 Moderate

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Influenza Viral Characteristics -2013-14

R – Oseltamivir Zanamivir

h1n1 0.8% 0

h3n2 0 0

Infl B 0 0

cdc.gov/flu/week – 3/2/2013

Time Course of Influenza

Abrupt Onset

Peaks in 2-3 weeks

Lasts for 2-3 months

Earliest Indicators

Febrile Respiratory Illness in Children

Attack Rates : 10 -20 % of general population

50% in selected populations

Number of Febrile Respiratory Illnesses Studied from Selected Primary-Care Facilities and Number Positive for Influenza A Viruses According to Week, Houston, 1975–76.

Glezen WP et al. N Engl J Med 1978;298:587-592.

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Transmission

Large Particle Droplets - > 5 micron / 6 foot radius

Coughing

Sneezing*

Talking

Contaminated surfaces - 2 to 8 hours

Possibly Small droplets – Remain in air for extended periods

Trans ocular entry

Brankston G,Lancet Inf Dis ;2007:257

Blachere FM,CID;2009:48:438

Wong BC,CID:2010;51:1176

Noti JD,CID;2012:54:1569

Incubation:

Average : 2 days ( 1-4 days)

Secondary attack rate : 25% among household

Onset of ILI in household : 3-4 days

Killingley B, JID;2012:205:35

Cowling BJ, NEJM;2010:362:2175

Duration of Viral Shedding in Secretions

Onset : 24 hours before clinical symptoms

Peak : 48 -72 hours after clinical symptoms

Duration : 5 days

Cleared : From day 7 on ( symptoms may last 10 days)

Longer duration of shedding : children , elderly, chronic illness

F Currant, Am J Epid 2008;167:775

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Clinical Symptoms & Findings

Symptoms – Abrupt onset

Headache, myalgias, malaise, dry cough, sore-throat, nasal drainageExam

Hot & flushed, febrile, hyperemia of pharynx, mild cervical nodes

Cough 5.4 OR (3.8-7.7 ci)

Fever 3.8 OR ( 2.8-5.0 ci)

Malaise 2.6 OR ( 2.2-3.1 ci)

Chills 2.6 2.6 ( 2.0-3.3 ci)

Sneezing <<<< less likely to be influenza

Call SA, JAMA 2005;293:987

Laboratory Testing

TEST TIME COMMENTS

Rapid Antigen Tests 15 -30 min Low Sensitivity 50-65%

Immunofluorescence 2-4 hours* Mod Sensitivity 65-80%

RT-PCR 2-6 hours * High Sensitivity /High Specificity

Viral Culture 3-10 days Mod Sensitivity/High Specificity

Serology ( Antibody) ** Not useful in acute setting

Specimen: Nasopharyngeal wash > NP swab>Pharyngeal swab

Timing: 24-48 hours of illness

Concentration: Earlier in illness – higher viral load

.

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Test and Treat or Should You Just Treat ??

Pretest Probability

If > 30 -40% : Just treat if symptoms are suggestive

If it is flu season in your state or county and symptoms are classic

Interpretation

True (+) : Positive screening test during Peak Influenza Season

False (-) : Negative screening test during Peak Influenza Season

“A Doctor can cure the flu in fourteen days

Leave it alone and it goes away in two weeks”

Unknown

Treatment - Neuraminidase Inhibitors

Oseltamivir

Decreases duration of illness by 24 hours

May decrease LRI needing antibiotics

May decrease hospitalizations

May decrease mortality

Need to treat within 24 -36 hours of symptoms

Dose : 75mg bid x 5 days ( 150 mg )

Capsule,Powder or Solution

Side effects : ? Delerium in children ( <<<)

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Treatment – Neuraminidase Inhibitor

Zanamivir

Decreases duration of illness

by 1.3 days in < 65 years

by 2 days in > 65 years

Decreases LRI needing antibiotics

Need to initiate therapy within 36 hours of symptoms

Inhalation : 10 mg bid x 5days

Intranasal : 6.4 mg qd x 5days

Side effects : Bronchospasm

Treatment – Neuraminidase Inhibitors

Pregnancy : category C

Risk of Influenza is greater than risk of medication

Treat with oseltamivir

Treat fever ( risk of neural tube defects-siezure-cp)

Treatment : Targeted groups

Residents of SNF / group homes

Age > 65

Pregnant / 2 weeks post partum

COPD

CHF / CAD

Diabetes Mellitus

Hemoglobinopathies

HIV with cd4 <200

Transplant patients

Inflammatory Bowel Disease

Immunosuppressive Medications

Neurologic Conditions that impair Respiratory function

BMI > 35

Splenectomy

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Treatment :

Any one presenting within 48 hours of illness

Those presenting after 48 hours of illness

with prior risk factors

requiring hospitalization

Vaccine Effectiveness in Healthy Adults

N = 849

Age : 18 – 64 years

Vaccine group

Upper Respiratory Illness < 25% p 0.001

Sick leave < 43% p 0.001

Doctor Visits < 44% p 0.004

NEJM 1995:333(14) 889-893

Vaccinations - How effective are influenza vaccines?

Need for Antigenic Match – Belongia EA, JID 2009;199:159

2004-05 Ag Match 5% 10% effective

2006-07 Ag Match 91% 52% effective

Endpoint Measured – Osterholm MI, Lancet ID 2012;12:36

Serology 70-90% effective

Lab confirmed Influenza 59% effective

Effectiveness of 2012-13 vaccine – ` cdc.gov/3/1/2014

Lab confirmed Influenza 62% effective

52% effective > 65 yr

,

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Vaccine effectiveness in Elderly

58% effective in >65 yrs of age

Still << hospitalization & death

cochrane data base 2010, cd004876

wong k, Arch Int Med 2012; 172:484

Effectiveness of Live vs Inactivated Vaccine in Adults – Culture (+) infection

N Inactivated virus live virus

5210 76% A 85% A

74% B 58% B

1247 74% A 74% B

80% B 40% B

1952 68% 36%

2004 8.4/1000 19.4/1000

Edmundson KM JID 1998;169:68

Ohmit SE, NEJM;2006:355:2513

Monto AS, NEJM;2009:361:1260

Wang J, JAMA,2009;301:945

Influenza Vaccines

Live virus vaccine : Flumist

Inactivated Vaccines: chicken embryo culture

Fluarix

fluvirin

Afluria

Agriflu

Flulaval

Fluzone High Dose / Intradermal

Inactivated Vaccine : non chicken embryo bases

Flucelvax – mammalian cell line

Flublok – dna recombinant

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Influenza Vaccinations – Evolving

Currently – Trivalent vaccines

2 Influenza A Antigen + 1 Influenza B antigen

Future – 2013 onward : Quadrivalent vaccines

2 Influenza A Antigen + 2 Influenza B antigen

A-california/7/2009 – h1n1

` A-victoria/361/2011 – h3n2

B-wisconsin/1/2010

B-brisbane/60/2008

Non Egg based Vaccines

Flucelvax – mammalian cell culture : 11/2012 , > 18 yrs

Flublok – recombinant DNA: 1/2013, >18-49

Vaccinations – Special circumstances

Egg Allergy: Use Flucelvax or Flublok

Safety of Flumist is not known

Pregnancy: Inactivated vaccines are safe

Multiple Sclerosis: Inactivated vaccines are safe.

Sibley WA, JAMA:1976;236:1965

Multiple Vaccinations: Can be given with other live or inactivated vaccines

at the same sitting; give it another site. If 2 live vaccines are not given together; space it by 4 weeks

Strategies to Increase Vaccine Effectiveness

a) Higher Dose : 60 mcg of HA vs 15 mcg (Fluzone high dose)

b) Intradermal Delivery: Stimulates dendritic cells ( Ag presenting)

Increases Antibody titers

Falsey AR,JID;2009:200:172

Holland D,JID; 2008:198:650

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Vaccine Strategies for future

Target : conserved viral proteins

Matrix 2 protein

Phase 1 – M2e +salmonella flagellin adjuvant

vaccine 2011;29(32) 5145-52

Hemagglutinin stalk

Nucleoproteins

Phase 2 – cross reactive T cell booster

CID 2012;55(1) 19-25

What about Guillain – Barre Syndrome & Influenza Vaccine?

1976 : Influenza Outbreak at Fort Dix

1 fatal case had H1/N1 swine virus : similar to 1918 strain

Vaccine produced against New Jersey 1976 pH1N1 strain

President Gerald Ford took vaccine in Oval Office

GBS cases in US (10/76 - 1/77) : 1028 ( 582 had influenza vaccine)

1 extra case : 100,000 people vaccinated

Guillain Barre Syndrome & Influenza Vaccines since 1976

Influenza vaccination

Hurwitz 1978 -79 No > risk of GBS

Kaplan 1979-81 No > risk of GBS

Roscelli 1980-88 No > risk of GBS

Haber 1990 – 2003 Less risk of GBS

Stowe 1990 – 2003 No > risk of GBS

Hughes 1997-2000 No > risk of GBS

Vellozzi 1990- 2005 No > risk of GBS

Lasky 1992-1994 1 extra case / million vaccines

Nelson 2009 1 extra case / million vaccines

Lancet 2010;10:643-651

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Something New – H3N2 variant

Aug 17,2011 , Aug 24,2011, Sept 2 2011

IN: 5 yr – Resp Illness – (+) Influ A ; caretaker with swine exposure

PN: 5 yr – Resp Illness – (+) Influ A ; swine exposure at fair

PN: 2 - 10 yr – Resp Illness – (+) Influ A; swine exposure at fair

RT –PCR test at CDC: H3N2 variant, Genomic analysis confirmatory

Swine H3N2 + Matrix gene from 2009 p -H1N1 strain

mmwr; 9/2011;60(35)1213-15

Human Cases of H3N2 variant : 8/2011 to present

State 2011 2012

Indiana 2 138

Ohio 107

Wisconsin 20

Maryland 12

Pennsylvania 11

Michigan 6

Minnesota 5

Illinois 4

Wvirginia 3

Iowa 3 1

Maine 2 0

Hawaii 1

cdc.gov/flu/swineflu/h3n2 -3/2/2013

H3N2 variant

Risk Factors : Close contact with infected swine, walking thru swine barn

Limited human to human spread so far ( 2 cases)

Rare occupational exposure ( 1 case)

Younger Age group : Median age 7 years

Symptoms: Similar to seasonal influenza

Clinical Suspicion - Influenza like illness

Close contact with infected swine

In an area with outbreak of h3n2 variant influenza

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H3N2 Variant

Laboratory detection

4 rapid tests: directigen/sofia/veritor/expect

CDC flu – r RT – PCR – Dx Panel

Treatment : oseltamivir or zanamivir

Vaccine : current vaccine is not preventive

This can’t be happening again ? More blood draw?

Oh no ! It is happening again !!

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Influenza A H7/N9

Avian Influenza A h7/N9

N=132Deaths : 30%Age: 4 – 87

Isolated in live bird markets - chickens, ducks, pigeons ,quail

Hemagglutinin structure is associated with low virulence in bird

First time H7/N9 has infected Humans

1st case outside china - malaysia 2/2014

Avian Influenza A H7/N9

Combination of 3 different avian influenza viruses

Affinity to alpha 2-6 receptors : ability to infect humans

Prior H7 infections were associated with conjunctivitis

Testing : RT – PCR is available through CDC & WHO

Treatment: Neuraminidase Inhibitors appear to be sensitive

Index of Suspicion : Traveler’s from China

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Avian Influenza H5N1

N= 600 cases ( 2003-2014)

Mortality – 60%

1st case in North America – 1/8//2014 : Toronto

Risk – Close contact with sick or dead poultry, visiting live

Poultry markets, prolonged exposure to sick individuals

Endemic in Poultry- Bangladesh, China,Egypt,India,Indonesia, Vietnam

Index of Suspicion : Traveler’s from China

Role of Pigs

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Incidence of Influenza in HCW’s

Setting : 4 acute care hospitals - Glasgow

Year: 1993-94 ; OPD incidence 0.2 %

N = 518 HCW’s ( 90% involved in patient care)

Incidence - 120/ 518 (23%)

Asymptomatic – 59%

Sick leave – 35%

Physician Diagnosis – 18%

BMJ 1996:313;1241-42

Characteristics of Viral Shedding

Setting: US Air Force Academy

Year: 2009-2010

Samples: Nasal washings analyzed by RT-PCR

N = 167

Temp < 37.8 31/106 29%

Asymptomatic 11/58 19%

7 days post ILI 7/29 24%

Am Journ Prev Med

2010:38;121-6

Nosocomial Influenza Outbreak

Setting : Univ of Manitoba HSC, Geriatric unit

Year: Dec 1 – 20, 1989

N = 16/34 patients, 17/51 HCW’s

No shared Rooms during 1st 7 days of outbreak

9/16 HCW’s became ill first

Peak of outbreaks

Dec 1 9 HCW’s

Dec 9,10 8 patients

Dec 14 > 7 HCW’s

Vaccine Status of HCW’s 14%

Can Journal of Inf Dis

1993:4(1) 52-56

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Evidence for Nosocomial Influenza

Setting Duration #Patients

Neuro 30 days 77

NICU 7 days 3

Medical 7 days 9

Pediatric 30 days 12

NICU 7 days 8

Medical 30 days 28

Transplant 5 days 4

MICU 7 days 3

BMT 7 days 7

NICU 5 days 4

Rehab 30 days 19

Medical 30 days 10

Lancet Inf Dis 2002:2;145-55

Correlation of HCW Vaccinations & Nosocomial Influenza

Setting: Univ of Virginia Health Systems

Period: 1987-88 & 1999-2000

1987-88 1999-2000

HCW vaccination rate 4% 67%

Nosocomial Influenza 32% 0%

HCW with influenza 42% 9%

Inf Control & Hosp Epid 2004:25;923-928

HCW Vaccination Rates and Effects on Patient Mortality

Setting: 44 Long term care homes in UK

22 – vaccine intervention & 22 control group

Period : 2003-04

N = 2604 patients, 1703 HCW’s

Influenza Season

Vaccine group Control group P values

HCW vaccine rate 48% 5.9%

Death 140 203 0.002

ILI 142 300 0.004

OPD Doctor visits 125 247 0.002

Hospitalizations 4 23 0.009

BMJ Dec 1 , 2006:581354.55

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HCW Vaccination Rates and Effects on Patient Mortality

Setting: 44 Long term care homes in UK

22 – vaccine intervention & 22 control group

Period : 2003-04

N = 2604 patients, 1703 HCW’s

Non - Influenza Season

Vaccine group Control group P values

HCW vaccine rate 48% 5.9%

Death 97 94 0.93

ILI 114 114 0.93

OPD Doctor visits 87 99 0.74

Hospitalizations 3 8 0.32

BMJ Dec 1 , 2006:581354.55

Summary

Influenza was of moderate prevalence and severity this season

Potential worrying Strains - h7n9 , h3 n2 variant, h5n1

Morbidity & Mortality are higher – Age 65

During Influenza season , can treat without testing

Oseltamivir & Zanamivir are effective early on

Vaccine effectiveness is problematic – Higher Dose Vaccine

New vaccine strategies – Non variant viral regions

Mandatory Vaccination of HCW’s – Trend of the future

Risk of Guillan-Barre Syndrome :

Higher risk of it from the flu rather than the vaccine

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