Background. Restricted Siemens Healthcare GmbH, >1 year Late latent syphilis. Restricted Siemens Healthcare GmbH, 2017

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1 Background Nonneutralizing The Evolution of Syphilis Testing: Clinical Benefits of a Reverse Screening Algorithm Katherine Soreng PhD Lafond RE, et al. Clin Microbiol Rev. 06;19(1): Disease course: Untreated ~3 4 weeks ~3 months Infection Secondary <1 year Early latent (symptoms resolved) ~2 40 years >1 year Late latent and Secondary Syphilis Rates of Reported Cases by Region, United States, Tertiary Gumma Endocarditis Aneurysm Lafond RE, et al. Clin Microbiol Rev. 06;19(1): Dementia and Secondary Syphilis Rates of Reported Cases Among Women Aged Years by Age Group, United States, Congenital Syphilis Reported Cases by Year of Birth and Rates of Reported Cases of and Secondary Syphilis Among Women, United States, * CS = Congenital ; P&S = and secondary. 1

2 Consequences of Untreated Fetal Infection Laboratory Evaluation Interstitial Keratitis Serology Molecular Microscopy Sensorineural Deafness Optic atrophy Death ~40% mortality in the developing embryo/baby without intervention Mental retardation Stillbirth Seizures IgG/IgM DNA Bacteria Lafond et al. Clin Microbiol Rev. 06;19(1): Serological laboratory testing for Laboratory Testing: Antibodies Detects antibodies against cardiolipin, lecithin, cholesterol antigens Treponemal Detects antibodies to Treponema pallidum Treponeme Lipoidal antigens (e.g., cardiolipin, lecithin, cholesterol) Human cell RPR (rapid plasma reagin test) TP PA (Venereal Disease Research VDRL Laboratory test) Typically manual Lower sensitivity FTA ABS Manual Greater specificity (T. pallidum particle agglutination) (Fluorescent treponemal antibody absorption test) Immunoassay (IA) Can be automated Sensitive Greater specificity Ratnam S. Can J Infect Dis Med Microbiol. 05;16: Singh AF, et al. Clin Microbiol Rev. 1999;12: antibody profile in Untreated : Treponemal vs. nontreponemal tests and disease stage % of infected testing positive lesion Secondary Latent (asymptomatic) Secondary lesion With treatment Tertiary Without treatment Time of Weeks 2 10 Years Time post cases (%) Secondary Weeks 10 FTA ABS (Treponemal) Late 30 Years MHA TP (Treponemal) RPR (: ~30% nonreactive in late latent phase) 40 Peeling RW, et al. Bull World Health Organ. 04;82: Larsen SA, et al.. Clin Microbiol Rev.1995 Jan;8(1):

3 Laboratory testing: Treponemal antibodies Treponemal antibody profile in Tp15 Anti Tp15 IgM IgG Tp47 Anti Tp47 IgM IgG Tp17 Anti Tp17 IgM IgG Treponeme-specific antigens % of infected testing positive lesion Secondary Latent (asymptomatic) Secondary lesion IgM (treponemal) Tertiary IgG (treponemal) Treponemal antibody is typically detectable in >85% of patients even with successful therapy Time of Weeks Years Time post Singh AF, et al. Clin Microbiol Rev. 1999;12: Peeling RW, et al. Bull World Health Organ. 04;82: CDC provided information on testing includes: Serology screening options: Traditional vs. reverse testing Includes disease background, testing, diagnosis, and treatment information Neutrally supports both traditional and reverse screening approaches Notes that in primary, nontreponemal tests are only ~75% sensitive TP PA or other treponemal test RPR or other nontreponemal test Traditional Ratman S. Can J Infec Dis Med Microbiol. 05 Jan/Feb;16:(1): Reverse 16 CDC/APHL provided Information on Traditional Testing CDC/APHL provided Information on Reverse Testing Treponemal (Immunoassay) Qualitative Non Treponemal Step 1 Step 1a Suggested Reporting Language for Syphilis Serology Testing Quantitative Non Treponemal Treponemal Step 1b Suggested Reporting Language for Syphilis Serology Testing Supplemental Treponemal* Step 2 Step 2 Step 3 Consistent with current unlikely; biological false positive likely No laboratory evidence of Consistent with current or past Consistent with past or potential early Inclusive for ; potential early or false positive No laboratory evidence of ested_syphilis_reporting_lang_1215.pdf. Accessed June, 18 ested_syphilis_reporting_lang_1215.pdf. Accessed June, 18 3

4 Interpretation of treponemal values example: ADVIA Centaur assay results Traditional Testing Algorithm Qualitative Index Unit (ADVIA Centaur assay) cutoff based on clinical data <0.90 Report negative Equivocal Retest in 0.90 to <1.10 duplicate 1.10 Report positive 2 of 3 results <0.90 Report negative 2 of 3 results 0.90 to < of 3 results 1.10 Equivocal Supplemental testing recommended Report positive; proceed with testing algorithm Syphilis Confirm with treponemal assay RPR False positive Autoimmune disease Acute viral s Drug addiction Age Pregnancy Temperature Interpretation False negative Prozone reaction Interpretation Temperature ADVIA Centaur SYPH IFU _EN Rev. F, Janier M, et al.. J Eur Acad Dermatol Venereol. 14;28: Workowski KA, et al. MMWR Recomm Rep. 15;64: Algorithm from Reverse Sequence Syphilis Screening Algorithm Advantages /Treponemal Discordants in a Reverse Sequence Testing Algorithm Confirm with (repeat if required) Automated assay significantly reduced workload Data suggested increased detection of Confirm with (repeat if required) False positives? Early? Latent? (~30% untreated s) CDC and IUSTI recommendations: Use a second treponemal to resolve discordance. Active, treat Active, treat Trep+/nontrep discordance? Janier M, et al.. J Eur Acad Dermatol Venereol. 14;28: Workowski KA, et al. MMWR Recomm Rep. 15;64: Janier M, et al.. J Eur Acad Dermatol Venereol. 14;28: Workowski KA, et al. MMWR Recomm Rep. 15;64: CDC/APHL Suggests Confirming Discordants using a Second Automated treponemal assay advantages Syphilis unlikely Alternate treponemal test Quantitative RPR Syphilis (past or present Active, treat (repeat if required) If the nontreponemal test is negative, the laboratory should perform a different treponemal test (preferably based on different antigens than the original test) to confirm the results of the initial test. Clinical Can identify cases missed by nontreponemal tests, e.g., early primary, latent, tertiary Workflow Can reduce labor time and costs Automation allows increased test volume with faster TAT Decreased opportunity for human error/subjective interpretation Workowski KA, et al. MMWR Recomm Rep. 15;64: Ratman S. Can J Infec Dis Med Microbiol. 05 Jan/Feb;16:(1): Larsen SA. Clin Microbiol Rev.1995 Jan;8(1):

5 TPHA, RPR, and ADVIA Centaur in the detection of early Automated assays in the detection of primary Overall agreement: TPHA and RPR consensus 99.8% Positive Negative ADVIA Positive Centaur Syphilis Negative Sample 1: MSM patient with genital ulceration Positive according to the VDRL treponemal specific IgM assay Confirmed very recent (true positive) Sample 2: Woman without a genital ulceration TPHA and RPR negative Considered ADVIA Centaur false positive The resolved clinical specificity was 99.89% (913/914) Poster: Evaluation of four fully automated immunoassays for diagnosis of Laboratoire Biomnis, Ivry sur Seine, France VDRL TPHA ARCHITECT IMMULITE LIAISON BioPlex IgM BioPlex IgG Immunoblot IgM Tp 15,17, 47 Tp17 Tp17 Tp17 Tp47 Tp17 TmpA Tp17 Tp15 Tp47 Tp47 Tp15 1 N N P P P N P N N N P P P P 2 N N P P P N P N N N P N N P 3 N N P P P N P N P P P P N P 4 P N P P P P P N P N P P P P 5 N N P P P P P N P P P P N P 6 N N P P P N P N P N P P N P 7 P N P P P P P P P P P P P P Sednaoui L, et al. Poster # RICAI, Paris, France Ly TD, et al. Poster P618. th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Vienna, April 10 13, 10. Timeline of reported Zika cases Polynesia, Brazil, Caribbean, US Yap Island Zika: Clinical Background and Testing Katherine Soreng, PhD 1952 First human case reported 07 African lineage Adapted from Wilder Smith, A. J. Travel Med. 18, July 1, 25(1) Asian lineage % of infants born to mothers with Zika had birth defects Piorkowski, G. New Microbe and New Infect. 16; 11:52 53 Global areas with Zika Zika transmission Mother to child (Zika has been transmitted from breast milk but no consequent pathology documented) Sex (semen appears to harbor virus for an extended period of time) Blood transfusion (no documented US cases but multiple reports from Brazil) Lab transmission (rare but at least one report confirmed in the US) CDC has resources and guidance to reduce risk of occupational exposure map areas with zika accessed Jan. 23, 18 5

6 ZIKA Symptoms ZIKV can result in severe complications Only about % of s are symptomatic Symptoms may include: cutaneous maculopapular rash; conjunctivitis; retro orbital pain; arthralgia, notably of small joints of hands and feet; myalgia; headache; and mild fever (37.8C 38.5C). Significant increase of the birth defect microcephaly and other severe fetal brain damage if mother passes the virus to developing fetusthe Guillain Barré syndrome being reported in regions with Zika outbreak First trimester maternal may have greater risk of fetal microcephaly vs. 2 nd or 3 rd. Microcephaly image courtesy of cdc.gov Source: WHO and Pregnancy Image purchased from Shutterstock Zika is a reportable disease (17 case counts in the US) Current CDC guidance for Zika testing US States 407 symptomatic Zika virus disease cases reported: 398 cases in travelers returning from affected areas 4 cases acquired through presumed local mosquito borne transmission in Florida (N=2) and Texas (N=2) 5 cases acquired through sexual transmission US Territories 631 Zika virus disease cases reported 1 case in a traveler returning from affected areas 630 cases acquired through presumed local mosquito borne transmission case counts.html Accessed Jan. 23, 18 Serology profile for acute Zika CDC: Zika testing recommendations for symptomatic nonpregnant individuals with exposure to Zika virus Start w/ NAT (if symptoms <14 days) (for NAT use patient matched serum and urine) If NAT negative: Test for Zika IgM If IgM non negative: perform PRINT analysis *New data now shows some individuals may remain NAT detectable for months Note: Non negative can include Positive Presumptive positive Equivocal Possible positive Source: MMWR, July 28, 17 / 66(29); July 17 Update: guidance.html 6

7 Example: ADVIA Centaur ZikaAb US data: Most initial Zika test results will be non reactive 4.4% of tested samples were IgM positive 85.9% of samples were negative CDC: Zika testing recommendations for symptomatic and pregnant individuals with exposure to Zika virus CDC recommendations for Zika testing for pregnant, asymptomatic but possible Zika exposure Test as soon as possible (through 12 weeks since symptom onset) Test BOTH with NAT and IgM serology (serum and urine for NAT/serum for IgM) Non negative IgM: PRINT analysis On going exposure: Test 3 times during pregnancy (NAT serum and urine) Recent possible exposure but not on going: Testing not routinely recommended but should be considered Test following the algorithm for symptomatic pregnant women MMWR, July 28, 17 / 66(29); MMWR, July 28, 17 / 66(29); July 17 Update: guidance.html July 17 Update: guidance.html Thanks for attending! Q&A katherine.soreng@siemens healthineers.com 7