Charlotte A. Gaydos, MS, MPH, Dr PH Professor Division of Infectious Diseases Johns Hopkins University Baltimore, Maryland, USA How epidemiology and diagnostics drive public policy-- lessons from influenza Public Health Practice Grand Rounds Johns Hopkins Bloomberg School of Public Health
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How epidemiology and diagnostics drive public … epidemiology and diagnostics drive public policy--lessons from influenza Public Health Practice Grand Rounds Johns Hopkins Bloomberg
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Charlotte A. Gaydos, MS, MPH, Dr PH Professor Division of Infectious Diseases Johns Hopkins University Baltimore, Maryland, USA
How epidemiology and diagnostics drive public policy--
lessons from influenza
Public Health Practice Grand Rounds Johns Hopkins Bloomberg School of Public Health
Objectives
1. Requirements for rapid point-of-care (POC) tests for influenza in real time
2. Limitations of some Rapid POC tests
3. Overview of some new POC tests
4. Overview of a new rapid PLEX-ID technology which can identify and genotype influenza samples for just- in- time surveillance needs
Requirements for rapid point-of-care (POC) tests for influenza in real time
1. Sensitive
2. Specific
3. Fast
4. Simple
5. Inexpensive
ASSURED: WHO recommendations:
a. Affordable b. Sensitive c. Specific d. User Friendly e. Rapid and Robust f. Equipment-Free g. Deliverable to End-Users
Current Types of Tests for Influenza and Respiratory Viruses
Rapid Tests insensitive, non-specific DFA rapid, less sensitive, specific Shell Vial culture sensitive Roller Tube culture sensitive, slow Real time qPCR/RT-PCR sensitive, slow Pyrosequencing expensive Flow through microsphere array rapid, expensive
Positivity Rates for 3 Rapid Influenza Diagnostic Tests
CDC, MMWR August 17, 2009
Performance of the QuickVue Rapid Test for Influenza
Faix D et al. N Engl J Med 2009;10.1056/NEJMc0904264
NHRC Influenza Testing: 4/20/01 – 5/30/09
3066 Total Specimens Processed
Confirmed S-OIV 273 (8.9%)
Seasonal H1N1 18 (0.61%)
Seasonal H3N2 31 (2.0%)
QuickVue Rapid Test (Quidel) results available for 767 patients
Influenza Type #Pos by QuickVue #Pos by PCR
Sensitivity 95% CI
S-OIV 20/39 52% 35% - 67%
Seasonal H1N1 12/19 63% 39% - 82%
Seasonal H2N3 6/19 31% 14% - 57%
Specificity of the test, compared to RT-PCR, was 99% in all cases
Rapid Influenza Diagnostic Test Sensitivity Specificity Binax NOW Influenza A&B 38.3% 100% BD Directigen EZ Flu A+B 46.7% 100% QuickVue Influenza A+B 53.3% 100%
Rapid Antigen Test for Diagnosis of Pandemic (Swine) Influenza A/H1N1 (N=84)
Vasoo et al. CID 2009;49:1090-1093
Influenza Diagnostic Test Sensitivity Specificity Rapid Ag Test 21.2% 99.5% (BinexNOW or 3M Rapid Detection) DFA 47.2% 99.6% R-Mix 98.49% 100%
Evaluation of Multiple test methods for Detection of Novel 2009 H1N1 in NYC
(N=1831)
Ginocchio et al. J Clin Vir 2009;45:191-195
H1N1pdm 2009 H3N2v 2011-12
Influenza: Always a challenge; always changing
•Influenza A (H3N2) variant (H3N2v) virus infection was were detected in the United States during July 2011–July 2012
H3N2 influenza A with H1N1pdm09 M (matrix) gene • In 2012, 306 cases of H3N2v infections were reported to CDC from 13 states (12 in 2011 in 5)
IN (138 cases), OH (106), WS (20), MD (12), PA (11), MI (6), IL & MN (4), WV (3), HI & UT (1) ~93% occurred in persons aged <18 years, 16 hospitalized, 1 death
New influenza H3N2v
•All reported direct or indirect exposure to swine at fairs
New variant: Minnesota Health: reports that the number of H1N2v cases has increased to 4
• H3N2v viruses can be detected by qualified U.S. public health laboratories using the CDC Flu rRT-PCR Dx Panel. Initially, if specimens tested positive for influenza A, H3, and pandemic influenza A markers and negative for H1 and pandemic H1 markers, they were reported as inconclusive.
•On August 7, CDC updated the results interpretation of the CDC Flu rRT-PCR Dx Panel for H3N2v for public health laboratories. Specimens with these findings may now be reported as “presumptive positive for influenza A (H3N2)v virus” and, for the ongoing investigations, cases with presumptive-positive test results at the state or local public health laboratory will now be classified as confirmed, as are those cases confirmed at CDC. •The CDC Flu rRT-PCR Dx Panel is available in public health laboratories but is not a point-of-care test available to clinicians
New influenza H3N2v
Evaluation of seven FDA-cleared RIDTs for the ability to detect H3N2v viral antigens — CDC, 2012
RIDT (manufacturer)
Name Approved Specimens
Analyzer interpret
BinaxNOW Influenza A&B (Alere)
BinaxNOW NP swab Nasal wash/ aspirate/swab
No
Directigen EZ Flu A+B (Becton-Dickinson
Directigen NP wash/Aspirate /swab throat swab
No
SAS FluAlert A&B (SA Scientific)
FluAlert Nasal wash/aspirate No
QuickVue Influenza A+B Test (Quidel)
QuickVue NP swab Nasal wash /aspirate/swab
No
Sofia Influenza A+B (Quidel)
Sofia NP aspirate/swab/wash Nasal wash
Required
BD Veritor System for Rapid Detection of Flu A+B (Becton) Dickinson)
Veritor NP swab/nasal swab Required
Xpect Flu A&B (Remel)
Xpect Nasal wash/swab Throat swab
No
Number of 10-fold virus dilutions (maximum = five) detected by seven FDA-cleared RIDTs, by H3N2v strain designation — CDC, 2012
Strain TCID50/ml
Binax NOW
Direct-ogen
Flu Alert
Quick View
Sofia Veritor Xpect
A/Kansas /12/2009
104.5 1 4 U U
2
4
4
A/Pennslylv 14/2012
104.5 2 4 U 2 2
4
3
A/Minnesota /11/2012
104.5 U 3 U U
3
3
2
A/Indiana /08/2011
106.0 1 3 U U
2
3
2
A/Indiana /10//2011
104.0 U 3 U U
2
4
2
A/West VA /06/2011
106.0 2 3 U 2 4
4
2
A/Iowa /07/2011
104.5 2 4 1 1 3
4
3
•The fact that a negative RIDT result should not be considered as conclusive evidence of lack of infection with influenza A (H3N2)v •Results from RIDTs, both positive and negative, always should be interpreted in the broader context of the circulating influenza strains present in the area, level of clinical suspicion, severity of illness, and risk for complications in a patient with suspected infection • Clinicians should minimize the occurrence of false RIDT results by strictly following the manufacturer’s instructions, collecting specimens within the first 72 hours of illness, and confirming RIDT results by sending a specimen to a public health laboratory, who will send to CDC
Additional CDC guidance available at http://www.cdc.gov/flu/swineflu/h3n2v-testing.htm.
CDC Recommendations
Two new amplified flu POC tests
GeneXpert® Flu, Cepheid
FilmArray, Idaho Technology
GeneXpert® Flu No Requirement for dedicated PCR area
CLIA Moderate Complexity
3
• Results in ~ 1 hr • POC, random access
Flocked swab or Nasal Asp/wash
3. Binding reagent into port 1
Xpert® Flu Assay Result Interpretation
• Xpert Flu provides display of: – Flu A Positive – Flu A Positive with
2009 H1N1 Detected or
– Flu B Positive • Reporting of 2009
H1N1 requires presence of both Flu A and 2009 H1N1 targets
Xpert® Flu Assay Published Data
Denver Children’s Hospital: Xpert® Flu is a highly
accurate. No prior molecular training
required. Clinically actionable
Prodesse ProFlu+
Sensitivity Specificity
Xpert Flu (Flu A)
99.1% 100% Xpert Flu
(Flu B) 100% 100%
Xpert Flu (2009 H1N1)
97.9% 99.5%
University of Virginia:
Xpert® Flu is a rapid, robust, sensitive, highly specific and user-friendly test
Reduced complexity allows for 24hr test availability
Comparison of the FilmArray System to Real-Time PCR for Detection of Respiratory Pathogens in Children •215 frozen archived pediatric respiratory specimens previously characterized as either negative or positive for one or more pathogens by real-time PCR were examined using the FilmArray RP •Agreement between FilmArray RP and real-time PCR assays for shared analytes was 98.6% (kappa0.92 ) The combined positive percent agreement was 89.4%; the negative percent agreement was 99.6% Positive % agreement Negative % Agreement •Influenza A virus H1 100 100 Influenza A virus H3 88.2 100 Influenza A virus 2009 H1 94.1 100 Influenza B virus 88.2 100
Pierce et al. JCM 50:364-371, 2012
Recent Reviews
Chartrand et al. Annals Inter Med 156:500-511, 2012
Vijayan et al. Emerg Infect Dis 18:1414-1421, 2012
Kumar at al. Clin Microbiol Rev 25:344-361, 2012
Evaluation of Sofia fluorescent immunoassay for
Influenza A/B virus
Lee et al. J Clin Vir 2012 (in press)
Sofia FIA displayed sensitivities of 82.2% and 77.8% for strains A and B respectively, compared to the RT-PCR
Sensitivities of BinaxNOW A/B antigen kit, and Directigen Flu A and B were 54.8%, and 68.5% for influenza A
Sensitivities of BinaxNOW A/B antigen kit, and Directigen Flu A and B were 62.5%, and 52.8% for influenza B
How Do We Do Surveillance?
Challenges for Influenza Typing and Surveillance for Respiratory Viruses
•*Challenge to have a surveillance tool that gives a rapid diagnosis, as well as a genotype, that can provide public health guidance for “just-in-time” diagnostics
•Epidemics happen quickly: 4wk H1N1pdm
•Called Type A influenza: “not H3” and “not H1”, thus “un-subtypeable”
*Metzgar, D. et al. J Clin Microbiol. 48:4228-4234., 2010
PLEX-ID as a New Surveillance Tool
• PLEX-ID Technology combines broad amplification with PCR, and electrospray ionization mass spectrometry
• Designed to provide broad identification, detailed genotyping and characterization, and recognition of known and emerging strains
• Designed to track a potential pandemic in real time
•Comprehensive sample tracking •Analysis of 300+ samples in 24 hours
•Simplified, easy to interpret results
Respiratory Virus Surveillance I Assay
• Influenza virus validation at Ibis • >650 blinded samples
–Correctly identified all Influenza A types • 149 H3N2 • 34 H1N1
–67 Influenza B InfluenzaSensitivity 96.8%Specificity 97.5%
PPV 96.0%NPV 98.0%
Sampath. R., K.L. Russell, C. Massire, M.W. Eshoo, V. Harpin, L.B. Blyn, et al. Rapid Surveillance of the Global Spread of Emerging Influenza Virus Genotypes by Mass Spectrometry. PLoS ONE. May 2007, issue 5, e489.
Novel Influenza Virus: 2009 H1N1
Human Avian Swine
Before the H1N1 pandemic strain was added to the PLEX database, it appeared as a hybrid of several strains from different hosts – human, avian, and swine
CDC ID T5000 Inferred Subtype PB1 NP M1 PA NS1 NS2 Comparison to CDC ID
Pandemic Influenza Samples Johns Hopkins University October-December 2009
• Know your Rapid POC test, its strengths and limitations
• Some POC tests may not work well with new strains of influenza
• Promising new POC tests are becoming available
• The PLEX-ID Influenza Surveillance Typing Assay can detect newly assorted and shifted or drifted strains (including avian strains such as H5 and other H and N types)
• Be aware of the potential of new influenza strains
Conclusions
Questions?
[email protected] 855 N Wolfe St 530 Rangos Bldg. Baltimore, MD 21205 PH 410-614-0932 FAX 410-614-9775