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
Mar 27, 2015
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????