Cost Effective Management of Influenza-like Illness in the

Neuraminidase Inhibitor Era

Wallace Greene, PhD, ABMM

Director, Diagnostic Virology Laboratory

Department of Pathology

M. S. Hershey Medical Center

Hershey, Pennsylvania

Rapid Influenza Test Kits: What You Should Know

Peter A. Shult, Ph.D.

Carol Kirk

Wisconsin State Laboratory of Hygiene

November 20, 2002

The Influenza Paradigm Shift

• 20 million cases in the U.S. each year

• Societal cost: $10 billion/year

• Appropriate treatment can improve both therapeutic and socio-economic outcomes

• Inappropriate treatment is likely to contribute to resistance

• What is the value; what is the cost?

Estimates For Next Pandemic in U.S. Alone

• 200 million will be infected

• 40 - 100 million will be clinically ill

• 18 - 45 million will require outpatient care

• 300,000 - 800,000 will be hospitalized

• 88,000 - 300,000 will die

• Economic losses of $71 - $166 billion

Interpandemic Influenza Morbidity and Mortality

• Greater than 20,000 deaths in US per epidemic

• From 20,000 to >200,000 flu-associated hospitalizations per epidemic

• Nursing home attack rate of 60%• Attack rates of 5-20% in general population• Costs in excess of $12,000,000,000 for a

severe epidemic

Influenza

• The Virus

• The Disease

• Diagnosis

• Treatment

• Management

Influenza Virus

Influenza Life Cycle

Scientific AmericanJanuary, 1999

Seasonal Variation in Respiratory Virus Infections.

Viral Reassortment

Viral Reassortment

“The Flu”

• Acute febrile illness• Usually self-limiting• Can be problematic in children and elderly• Characterized by:

– “Generic” symptoms– Fever, Chills, Myalgia, Cough, Headache,

Malaise

Symptoms

0%10%20%30%40%50%60%70%80%90%

100%

Influenza + Influenza -

Congestion Cough Sore Throat

Malaise Myalgia Chills Headache

Diagnosis of Influenza-like Illness

• Clinical Judgment

• Culture

• Rapid assays

Rapid Clinical Diagnosis

• 100 patients with an influenza illness defined as fever> 37.8 C and 2 or more these symptoms: cough, myalgia, sore throat, headache

• 72% confirmed with culture, and 79% with RT-PCR

• Cough and fever were the only symptoms significantly associated with a positive RT-PCR.

• Sensitivity = 78%, specificity = 55%, PPV 88%, NPV = 39%

Sensitivity of Clinical Judgment

Study Criteria When % PositiveEverett (1977) ILI Season 61%Glezen (1982) ILI Season 12%

Peak 35%Buffington (1993) T>100 + Season 12%Monto (1995) Fever + Season 24%

Peak 42 – 100%

(+ cough, pharyngitis, malaise)

Detection

Culture

• CLIA - Highly Complex

• 10 - 14 days to negative

• Hemadsorption and DFA confirmation recommended

• Sample transport and handling plays an important role in culture sensitivity

Cell Culture

Cell Culture

Cell Culture

Hemadsorption

Hemadsorption

Hemadsorption +DFA

RAPID TESTS

INFLUENZA A DFA

Performance - Influenza A

Product Sensitivity Specificity

Bartels 93.5% 100%

Chemicon 100% 100%

DAKO 96.2% 100%

DPC 91.2% 99.5%

Danny L. Wiedbrauk, Ph.D., Warde Medical Laboratory, Ann Arbor, Michigan

Influenza B Performance

Product Sensitivity Specificity

Bartels 94.6% 100%

Chemicon 100% 100%

DAKO 87.6% 99.5%

DPC 88.7% 99.7%

Danny L. Wiedbrauk, Ph.D., Warde Medical Laboratory, Ann Arbor, Michigan

THE FUTURE ????

RAPID ANTIGEN DETECTION TESTS

• Specificity of these tests is good DURING OUTBREAKS, but the sensitivity is poor, ESPECIALLY in adult throat swabs!

Influenza: Laboratory Diagnosis

Antigen Detection No need for viable virus…but no virus isolate

• Immunofluorescence– Rapid (20+ minutes - 2+ hours)– Subjective reading - reader expertise required– Limited to laboratories with IF capability– Variable sensitivity & specificity– Positive predictive values dependent on

prevalence & expertise

Influenza: Rapid Laboratory Diagnosis

Antigen Detection

• Enzyme Immunoassay (“rapid EIA and EIA-like”)• Rapid (10-40 minutes)• Widely available• Less expertise required • Amenable to point of care testing • Moderate or waived complexity• Can test for single agentBut…• Positive predictive values dependent on

prevalence • Variable sensitivity & specificity• No isolate for strain typing & study

CLIA Status

Moderate Complexity

Directigen Flu A

Directigen Flu A+BFlu OIA

Waived Status

QuickVue Influenza

ZstatFlu

Antigen Tests - Disadvantages

•Expensive to perform

•Cannot perform more than 5 at a time

•Unable to assess specimen quality

•Subjective read

•Less sensitive than other methods

Influenza Diagnosis: Rapid Test Options

• Becton Dickinson Directigen® Flu A and Flu A & B– Enzyme ImmunoAssay (EIA)

• ZymeTx, Inc. ZstatFlu™– Endogenous Viral-Encoded Assay (EVEA)

• Biostar FLU OIA®– Optical ImmunoAssay (OIA)

• Quidel QuickVue Influenza®– Lateral-Flow ImmunoAssay (LFIA)

• Binax NOW® Flu A and Flu B– Immunochromatographic Membrane Assay (ICT)

• Others in development

Directigen ® Flu A+B (Becton Dickinson)

ZstatFlu

Optical ImmunoAssayTechnology

Comparison of Four Clinical Specimen Types for Detection of Influenza A and B

Viruses by Optical Immunoassay (FLU OIA ® Test) and Cell Culture Methods

• KA Covalciuc, KH Webb, CA Carlson, J Clin Micro 1999;37:3971-3974

• Overview– Performance of FLU OIA compared to 14 day cell

culture.– Sensitivity of FLU OIA and Culture compared for

each of four specimen types.

Results

Sensitivity Specificity

Nasal Aspirate 88.4% 69.4%

Nasopharyngeal Swab

83.3% 76.2%

Throat Swab 62.1% 79.5%

Sputum 81.1% 51.5%

Test Comparison: Result

A / B (not differentiated)

NOW Flu A/B

NOW Flu A

Directigen Flu A & B

QuickVue Influenza

Flu OIA

ZstatFlu

Directigen Flu A

A / B (differentiated)

ATest

Influenza Detected

Test Comparison: CLIA Status

Moderate Complexity

Directigen Flu A

Directigen Flu A+B

FLU OIA

Waived Status

QuickVue Influenza

ZstatFlu

* NOW Flu A & Flu A/B : CLIA Status Pending

Test Comparison: Specimens

2-8C/24 hr. (elute swabs)

P: Nasal washA: NP Sw

NOW Flu A/B

2-8C/24 hr.(elute swabs)

P: Nasal washA: NP Sw

NOW Flu A

2-8C/8 hr.P/A: Nasal Sw, wash, asp

QuickVue Influenza

2-8C/24 hr.P/A: Nasal asp/NP Sw /Th Sw/Sputum

Flu OIA

0-40C/24 hr.P/A: Th SwZstatFlu

2-8C/No limitP: NP wash/asp; A: NP Sw/Nasal wash /Th Sw/BAL

Directigen Flu A+B

2-8C/No limitP: NP wash/asp; A: NP Sw/Throat Sw

Directigen Flu A

Specimen Storage

Specimen Type(P/A=Preferred / Acceptable)

Test

Test Comparison: Performance Characteristics

* Per kit insert, without discrepant resolution* Performance dependent on specimen type.

Summary of Choices• Level of identification

– 2 Flu A only, 5 Flu A & B (2 differentiate A & B)• Price

– List prices range from $13.55 - $25.63 per test• CLIA status

– 3 moderate, 2 waived, 2 pending• Specimen types & time interval to test

– Varied types – Time interval allowed to test ranges from 1 hour to

undefined • Staff familiarity• Turn-around time

– Test time ranges from 15 to 35 minutes • Sensitivity/specificity

– Sensitivity ranges from 58-91%, specificity from 52-100%

Rapid Influenza Tests - Concerns

• Specimen requirements

• No viral isolates for further characterization

• Loss of surveillance data

• Rationale for antiviral therapy

• Test performance characteristics

• Results interpretation - poor positive predictive values during low prevalence

Hypothetical Influenza Test Performance

Prevalence = 20.0%

+ - + 380 64

- 20 1536

Disease

Test

Sensitivity = 380/400 = 95.0%

Specificity = 1536/1600 = 96.0%

Predictive Value Positive (PVP) = 380/444 = 85.6%

Predictive Value Negative (PVN) = 1536/1556 = 98.7%

Hypothetical Influenza Test PerformancePrevalence = 1.0%

+ - + 19 80

- 1 1900

Disease

Test

Sensitivity = 19/20 = 95.0%

Specificity = 1900/1980 = 96.0%

Predictive Value Positive (PVP) = 19/99 = 19.2%

Predictive Value Negative (PVN) = 1900/1901 = 99.9%

Suggested Algorithm for Test Interpretation

Positive rapid influenza test result:• Is there culture-confirmed influenza in your state?• Is your test PVP likely to be acceptable?

› If answers to both questions are YES: report result.› If > 1 answer is NO: qualify result & submit specimen

for culture confirmation.

Negative rapid influenza test result:• Are you at peak influenza season?• Is your PVN likely to be less than acceptable?

› If answers to the above questions are YES: qualify result & submit specimen for culture confirmation.

› If answers to the above questions are NO: report result.

Summary

• Increase PVP by testing during periods of high prevalence.

• Utilize laboratory and/or surveillance data to estimate prevalence & predictive values and optimize testing.

• Recognize value of PVN & negative result.• Confirm out-of-season & early-season

positives. • Confirm peak-season negatives as needed. • Provide clinicians with understanding of

limitations of test results and predictive values.

Vaccine for the 2002 Influenza Season

– The trivalent influenza vaccine prepared for the 2002 season includes

A/Moscow/10/99 (H3N2)

A/New Caledonia/20/99 (H1N1)

B/Hong Kong/330/01

Preventing Influenza Complications

• Complications in children

• Complications in the elderly

• Rapid Diagnosis

• Antiviral Treatments

Complications in Children

• Review of ICD9 data from a large insurance plan • Over 10,000 children (0-14 years) diagnosed with

influenza• Tonsillitis, nasopharyngitis, laryngitis, sinusitis,

tracheitis, and otitis media • 24% developed complications, mostly otitis media• These lead to at least 1 additional office visit, and

antibiotic prescriptions in 62% of cases (only 25% in uncomplicated cases)

Vaccination and Otitis Media

• 133 children with previous history of OM

• During the next 4-6 weeks, 1/3 of vaccinated children developed OM, compared with >50% of the unvaccinated children

Otitis Media and Oseltamivir

• Children 1-12 years old with influenza, randomized oseltamivir(183) vs placebo(200) 5 days

• 12% of treated children developed OM, 21% of untreated.

• Duration and severity were longer and more severe in the untreated group

• Effect was seen for the 28 days the study was conducted.

Complications in the Elderly

• 500 elderly subjects (mean age 81)• Oseltamivir vs. placebo• 90% reduction in the incidence of influenza,

in addition to that provided by vaccination• Of those treated and developed influenza,

only 1of 23 developed complications, compared with 7 of 23 who did not receive treatment

Transmission – Family Ties

• 415 subjects lived with someone having the flu, and 540 lived in households not having flu.

• 21% living in homes with flu became infected, where as only 6% of those not living with flu were infected.

• Household contacts are 3 times more likely to transmit influenza than contacts outside the home.

• Chemoprophylaxis

Treatment

• Supportive

• Antiviral Therapy

– Amatidine/Rimantadine

– Neuraminidase Inhibitors

Anti-Viral Therapy

• Anti-viral compounds have been available for 30 years

• Until recently, most anti-viral therapeutics focus on diseases outside the general population.

• The effectiveness of antiviral therapy has become limited by viruses ability to mutate and become resistant.

• Introduction of first generation neuraminidase inhibitors allows for treatment of a disease affecting the general population.

Amatadine/Rimantadine

• Mode of action - inhibition of replication by interference with ion channel activity

• Effective against Influenza A only

• Can reduce severity and duration of illness

• CNS/GI side effects

• Resistance– By 5 - 7 days of therapy, 16 - 45% of isolates from

treated patients may be resistant

Neuraminidase Inhibitors

Viral Inhibitors

Scientific AmericanJanuary, 1999

Neuraminidase InhibitorsMode of Action

Sialic Acid Zanamivir(Relenza)

Oseltamivir(Tamiflu)

Neuraminidase Inhibitors

• Relenza ® (Zanamivir)– Glaxo Wellcome– Inhaled

• Tamiflu™ (Oseltamivir phosphate)– Roche– Oral

• Mode of action - inhibition of replication by interference with neuraminidase activity

Neuraminidase Inhibitors

• Effective against Influenza A and B• Can reduce severity and duration of illness• Prophylactic use• Slight GI side effects (Tamiflu)• Resistance

– Laboratory only - reduces viral infectivity– Potential for clinical resistance

Treatment: Time is IMPORTANT!

• Neuraminidase inhibitors are effective ONLY if given within 48 hours of onset

• 1,426 subjects randomized to receive oseltamivir or placebo

• 67% had CONFIRMED influenza infections• Measured the time from onset of fever to the

end of ALL symptoms• Earlier the time to treatment, the shorter the

duration of symptoms

Nursing Homes – Rimantadine vs. Zanamivir

• Vaccination may only be 60% effective• 375 elderly residents of a nursing home were

randomized to receive either rimantadine or inhaled zanamivir

• Lab confirmed influenza in 7% rimantadine treated, and 3 % in zanamivir treated

• 8/25 developed resistance to rimantadine, but no resistance developed to the NI

THE FUTURE????