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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????