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Pavia 2010

Influenza in 2013:Continuing evolution

and challenges

Andrew Pavia MDGeorge and Esther Gross Presidential

ProfessorUniversity of Utah

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Disclosures

• Conflicts: None

• Funding:– CDC 1U181P000303

– NIH/NIAID 1 R01 AI089489-01

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Outline

• Virology

• Epidemiology

• Diagnosis

• Antivirals

• Vaccines

• H7N9 and other threats

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Influenza virus

• Orthomyxovirus; 8 gene segments

• Flu A, B and C

• Flu A has 16 HA types, 9 N types

• High error rate leads to point mutations (drift); segment reassortment leads to shift (pandemics)

• Huge reservoir in wild birds. Disease in poultry and many mammals

• Disease of the animal human interface

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A/California/7/2009 (H1N1)pdm09, the virus formerly known as swine flu

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Key Epidemiologic Factors

• Incubation 1-4 days

• People with influenza shed virus before developing symptoms

• Up to 50% of people with influenza are asymptomatic

• Serologic studies suggest up to 25% of HCWs contract flu in a season

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Influenza-Associated Hospitalizations Among Healthy and High-Risk Persons

0

20

40

60

80

100

120

140

160

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200

<6 mos 6-23 mos 2-5 yrs 5-17 yrs 18-49 50-64 65+

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er

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Healthy High risk

Glezen WP. Am Rev Respir Dis. 1987;136:550-555.

Hospitalizations for Acute Respiratory Disease in Houston 1978 – 1981 Influenza Epidemics

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Annual Hospitalization Rate for Virologically Confirmed Seasonal Influenza in Children

0

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100

150

200

250

300

<6 m 6-12 m 1 yr 2 yr 3yr 4 yr 5 yr 6 yr 7 - 15 yrs

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Age Group

Ampofo K. Pediatrics. 2006;118:2409-2417.

Salt Lake County, Utah2001-2004

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QuestionWhich of the following children are at significantly greater risk of complications from influenza, including hospitalization and death?

A. A 9 year old with repaired congenital heart disease but decreased cardiac output requiring medications

B. A healthy 18 month oldC. An 8 year old with seizure disorder and mild

developmental delayD. A 14 year old with CFE. A, C, DF. All of the above

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Groups at Risk for Complications of Influenza

Group Example/Comment

Children <5 yrs Highest hospitalization rate children <1 yr

Persons >65 yrs Highest among frail elderly

Pregnancy Highest risk in 3rd trimester

Chronic CVD Hypertension not seen as independent risk

Chronic lung Asthma and/or COPD, cystic fibrosis

Metabolic disorder Diabetes

Renal, Hematologic Includes sickle cell disease

NeurologicNeuromuscular, neurocognitive, or seizure disorder

ImmunosuppressionIncluding HIV, organ transplantation, chemotherapy

Morbid obesity Noted in several studies during H1N1

Selected underlying medical conditions in patients hospitalized with influenza, FluSurv-NET 2011–2012.

COMMITTEE ON INFECTIOUS DISEASES Pediatrics 2012;130:780-792

©2012 by American Academy of Pediatrics Pavia

QuestionA 9 year old boy with type 1 DM presents with fever to 102, cough, and malaise in January. He appears moderately ill with fever and tachycardia but remainder of exam is negative and O2 sats are normal. There is flu in the community and school absenteeism. You suspect flu and perform a rapid flu test. It is negative

What is the most appropriate approach?A. Symptomatic treatment (and glucose management)B. Begin oseltamivir or zanamivir. Consider

confirmatory PCRC. Begin amoxicillin D. Send viral PCR (24 hour turnaround) Call with

results and treat if positive

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Diagnosis

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Rapid Influenza Diagnostic Tests

• Self-contained devices; MFT, LF, OIA

• Easy to use; moderate or waived complexity

• Can do point-of-care or near-patient testing

• Assay steps are minimal

• Rapid results (15-30 min)

• Built-in internal control• Can batch or do one at

a time

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Diagnosis of influenza

• Performance of all tests depends on prevalence of virus in community and specimen quality

• Clinical diagnosis: up to 80% PPV during peak

• Rapid influenza detection tests have moderate sensitivity 50-70% (less for H1N1); reasonably specific

• Positive test in peak season high PPV; Negative test should not be used for decisions

• DFA better sensitivity, detects 6-7 viruses, determines sample quality

• Serology useless for clinical diagnosis

• PCR is the current gold standard

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Specimen collection matters

• For children, NP swab or aspirate generally better than nasal or throat

• Type of swab matters: Flocked swabs

• Kits have FDA approved specimen types

• PCR less dependent on sample type and quality

• In children with influenza pneumonia, NP sometimes negative when lower respiratory specimens are positive

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Influenza PCR

• Increasingly available

• Some provide typing (eg A(H1N1), A(H3N2), B

• Some part of multiplex panels with other respiratory viruses

• Turnaround time and cost vary (but improving)– Utility for outpatients varies based on TAT and ability

to influence other decisions (eg would it influence treatment of other family members)

• Cost effectiveness needs to be studied

Commercial RV PCR Assays Company IVD Products

Prodesse/GenProbe proFlu+ (Flu A & B, RSV)proParaFlu+ (PIV 1, PIV 2, PIV 3)prohMPV+ (human metapneumovirus)proFast+

Focus Diagnostics Simplexa Influenza A H1N1 (2009)Simplexa Flu A/B & RSV

Nanosphere Verigene Respiratory Virus Nucleic Acid Test.Verigene Respiratory Virus + Nucleic Acid Test (RV+)

Luminex (Abbott Molecular)

xTAG Respiratory Viral Panel

Biofire(formerly Idaho Technologies)

FilmArray. One hour multiplex PCR detection of 17 viruses, Flu A, Flu A(H1N1), A(H3N2), Flu B

*IVD, In Vitro DiagnosticPavia

QuestionA 13 year old girl develops sudden onset of fever, sore throat, malaise during January. She is prescribed amoxicillin for possible strep pharyngitis. 3 days later she becomes short of breath and dizzy. In the ED she is severely hypoxemic, hypotensive and has diffuse erythroderma. CXR shows diffuse infiltrates and pleural effusion. Labs: WBC 18K, plts 40K, Creat 1.9

Which is the most likely diagnosis?A. Stevens Johnson SyndromeB. Post influenza pneumonia with Strep pneumoniaeC. Post influenza myocarditis with CHFD. Post influenza pneumonia with Staph aureus and

toxic shock syndrome

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Complications of Influenza

• Exacerbation of underlying disease

– COPD, Asthma, CHF

• Viral pneumonia

• Hemorrhagic pneumonitis/ARDS

• Bacterial superinfection (both pulmonary and non pulmonary): – Strep pneumoniae

– GAS

– S. aureus and increasingly, MRSA

• TSS

• Encephalitis, Myositis, MyocarditisPhoto: Perez-Padilla. NEJM 2009; 361 (7): 680 Pavia

Antiviral Drugs

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Influenza antiviral sensitivity, 20132009 H1N1 Seasonal

A/H1N1 (A/Brisbane/2007)

Historical Not circulating

Seasonal A/H3N2

Influenza B

Oseltamivir Sensitive (some

treatment emergent

resistance)

Resistant Sensitive Sensitive

Zanamivir Sensitive Sensitive Sensitive Sensitive

Amantidine/Rimantidine

Resistant Sensitive Resistant Resistant

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ACIP and AAP Guidelines for Antiviral Use 2012-2013

• Antiviral treatment is recommended as soon as possible for: – Any child hospitalized with suspected influenza, or with

severe, complicated or progressive illness regardless of immunization status. Earlier treatment is better but treatment after 48 hours is likely to provide benefit

– Confirmed or suspected influenza of any severity in children at high risk of complications

• Recommended medications: oseltamivir and zanamivir

• Oseltamivir approved for treatment for infants younger than one year old, when indicated

COID Pediatrics 2012 130:780MMWR 2011 60 1-24

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Risk of Complications Among Pregnant Hospitalized for 2009 H1N1 by timing of

Oseltamivir Treatment

Relative risk < 2 days vs 3-4

Relative Risk<2 days vs > 4

days

ICU admission 2.4 (1.2-4.8)P = 0.01

6.0 (3.5-10.6)P < 0.001

Mechanical ventilation

3.8 (1.4-9.9)P =0.008

12.3 (5.4-27.7)P < 0.001

Maternal death 9.9 (1.1-87.2)P = .03

53.5 (7.3-391.7)P < 0.001

Siston, A. M. et al. JAMA 2010;303:1517-1525.

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Recommended antiviral dosagesMMWR Recomm Rep. 2011;60(1):1–24

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More influenza antiviral pearls

• Zanamivir remains active against H275Y mutant influenza and most oseltamivir resistant viruses

• Inhaled zanamivir can exacerbate asthma, not approved under 5 years

• Using commercial powder of zanamivir in ventilator circuit has caused catastrophic ventilator failure

• IV zanamivir available by eIND

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Antiviral Prophylaxis• Chemoprophylaxis should not replace vaccination

• 70-90% effective in trials

• Prophylaxis may increase selection of resistant viruses

• PEP is recommended to control influenza outbreaks in nursing homes

• PEP can be considered for high risk persons with unprotected close contact with patient with flu

• Post exposure prophylaxis should not be given after 48 hours from exposure

• Post exposure prophylaxis for otherwise healthy persons is generally discouraged; prompt empiric therapy is preferable

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Vaccines

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Vaccine pearls

• Efficacy 60-70%; decreased in elderly, children < 2, renal disease, immunosuppressive therapy and transplant pts.

• In HIV, response related to CD4 count

• Mismatch occurs at least every 10 years

• Most common mismatch is for wrong influenza B lineage (Yamagata vs Victoria)

• TIV can be given to those with egg allergy. For those with anaphylaxis consultation with allergist recommended. Anaphylaxis to flu vaccine is still a contraindication

Precautions for administering TIV to presumed egg-allergic individuals.

COMMITTEE ON INFECTIOUS DISEASES Pediatrics 2012;130:780-792

©2012 by American Academy of Pediatrics

Number of 2012–2013 seasonal influenza vaccine doses for children 6 months through 8 years of age. aThe interval between 2 doses is 4 weeks.

COMMITTEE ON INFECTIOUS DISEASES Pediatrics 2012;130:780-792

©2012 by American Academy of Pediatrics

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Laboratory-Proven Influenza in Infants WhoseMothers Received Influenza Vaccine vs Controls

Zaman et al, N Engl J Med 359:1555-64, 2008Pavia

New flu vaccines and issues• 2012

– High dose (60mcg HA) vaccine for persons > 65 years. More immunogenic but efficacy studies are pending

– Intradermal vaccine available for those 18-64

• 2013

– Quadrivalent LAIV

– Quadrivalent inactivated vaccine

– Cell culture grown virus

– Recombinant protein (baculovirus) expressed

– ? ACIP preference for LAIV

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“We made too many wrongmistakes”

— Yogi Berra

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New Approaches to Influenza-Vaccine Production.

Lambert LC, Fauci AS. N Engl J Med 2010;363:2036-2044.

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“Thou Shalt Get Flu Vaccine” –The Long Lost 11th Commandment

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QuestionHow worried should we be about the new avian influenza in China H7N9?

A. Not at all. Just more media hypeB. A little bit, but new flu strains occur all the timeC. Quite a bit. There are worrisome signsD. A lot. I am really worriedE. It’s the end of the world. I am stocking up on MRE’s

and ammo

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Influenza A(H7N9)

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Confirmed influenza A(H7N9) infection (n=126) by date of onset and province China, 19 February - 29 April, 2013

MMWR May 1, 2013 (early release)

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Geographic Distribution of 82 Confirmed and 2 Suspected Cases of H7N9 Virus Infection in China, as of April 17, 2013.

Li Q et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1304617

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Location of confirmed human influenza A(H7N9) infections, China, 19 February – 29 April, 2013

MMWR May 1, 2013 (early release) Pavia

Hypothetical Host and Lineage Origins of the Gene Segments of the Novel Reassortant Human Influenza A (H7N9) Viruses.

Gao R et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1304459

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H7 N9

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H7N9: The bad news

• Current mortality ~ 18%

• >220 cases in 8 weeks with wide dispersion

• No disease in affected birds

• Virus has features of human adaptation

– Mutation in HA conferring binding to alpha 2-6 SA receptors ( G186V, Q226L,T160K)

– Mutations in PB2 polymerase associated with efficient replication in mammal

– Encodes full length PB1-F2 protein associated with high virulence in 1918 H1N1 and H5N1

– NA stalk deletion associated with virulence in mammals

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Shinya et al Nature 2006;440:435

2-6 SA receptors abundant in the upper airway of humans, but 2-3 receptors are found in alveoli

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Summary

• Influenza causes severe disease in young kids, pregnant women and those with underlying medical conditions

• RIDT’s continue to be prone to false negatives

• Empiric treatment for those hospitalized and at high risk of complications

• Vaccines are not completely effective but are not being used optimally. Newer vaccines are needed

• Flu will continue to surprise us. H7N9 is just the latest example.