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 million will be clinically ill million will require outpatient care 300, ,000 will be hospitalized 88, ,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 American January, 1999

Seasonal Variation in Respiratory Virus Infections.

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 CongestionCoughSore Throat MalaiseMyalgiaChillsHeadache

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 (+ cough, pharyngitis, malaise)

Detection

Culture CLIA - Highly Complex days to negative Hemadsorption and DFA confirmation recommended Sample transport and handling plays an important role in culture sensitivity

Cell Culture

Hemadsorption

Hemadsorption +DFA

RAPID TESTS

INFLUENZA A DFA

Performance - Influenza A ProductSensitivity 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 ProductSensitivity 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 agent But… 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+B Flu 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 ImmunoAssay Technology

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: 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

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) A Test 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 2-8 C/24 hr. (elute swabs) P: Nasal wash A: NP Sw NOW Flu A/B 2-8 C/24 hr. (elute swabs) P: Nasal wash A: NP Sw NOW Flu A 2-8 C/8 hr. P/A: Nasal Sw, wash, asp QuickVue Influenza 2-8 C/24 hr. P/A: Nasal asp/NP Sw /Th Sw/Sputum Flu OIA 0-40 C/24 hr. P/A: Th Sw ZstatFlu 2-8 C/No limit P: NP wash/asp; A: NP Sw/Nasal wash /Th Sw/BAL Directigen Flu A+B 2-8 C/No limit P: 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 $ $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 %

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% 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 Performance Prevalence = 1.0% 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 (H 3 N 2 ) A/New Caledonia/20/99 (H 1 N 1 ) 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 days of therapy, % of isolates from treated patients may be resistant

Neuraminidase Inhibitors

Viral Inhibitors Scientific American January, 1999

Neuraminidase Inhibitors Mode of Action Sialic AcidZanamivir (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????