Culture-Independent Diagnostic Tests IMPACT ON INFECTIOUS DISEASE SURVEILLANCE

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1 Culture-Independent Diagnostic Tests IMPACT ON INFECTIOUS DISEASE SURVEILLANCE Minnesota Department of Health Joanne Bartkus Director Public Health Laboratory

2 Change Happens MDH Public Health Laboratory, 1890 s Vaccine development Diphtheria, Typhoid, TB Culture, Microscopy MDH Public Health Laboratory, 2016 Bioterrorism response Ebola, Zika PFGE, PCR, Whole Genome Sequencing

3 Rapid Diagnostic Testing Fundamental to quality care Improved medical management Improved antimicrobial stewardship

4 Culture-Independent Diagnostic Tests Diagnostic test that does not require cultivation of a microorganism to achieve a diagnostic result Many flavors of CIDTs on the market Antigen detection Molecular Single agent Multi-target Syndromic panels

5 Advantages of CIDTs Sensitive Fast Easy to use Broad range

6 Challenges of CIDTs Expensive Up to $1000! for syndromic panel No option to unbundle tests Results of syndromic panels can be difficult to interpret (TMI) No culture available for followup testing Antimicrobial susceptibility Public health testing

7 Biofire Film-array Panels Respiratory Panel 20 targets: viruses, bacteria Blood Culture Identification Panel 27 targets: G+ bacteria, G- bacteria, yeast Gastrointestinal Panel 22 targets: bacteria, E. coli/shigella, parasites, viruses Meningitis Encephalitis Panel 14 targets: bacteria, viruses, yeast

8 Gastrointestinal Panels BD Max BioFire Film Array Nanosphere Verigene Hologic Prodesse ProGastro Luminex xtag GI

9 Use of Syndromic Panels in Clinical Settings Strategies for adoption Not adopted (many are still evaluating) Unlimited use Limit frequency with which patients can be tested Restrict testing to specific groups of patients (e.g. immunocompromised) Educate clinicians to encourage ordering of less expensive tests Algorithms for use

10 Algorithm for Diarrheal Illness Testing at Institution A No testing Diarrhea <7 days No risk factors Testing (shiga-toxin, Giardia, LCMSP, O&P) Persistent diarrhea, >7 days Risk factors (Immunocompromised, pediatric, hospitalized) Travel-related Health care-associated (C. difficile) BioFire Only if multiple tests ordered by physician, otherwise not costeffective

11 Interpretation of BioFire GI Panel at Institution A 3 organisms detected or negative, and no Vibrio or V. cholera If 3 organisms and Vibrio or V. cholera If >3 organisms Report Chart review Repeat If same, report If not, record Repeat testing

12 Additional Testing and QA at Institution A Reflex cultures Quality Assurance Antimicrobial susceptibility Campylobacter Shigella/EIEC V. cholera Y. enterocolitica Positivity rate Pouch failures contamination has been reported as an issue with BioFire, need to pay attention to workflow

13 Respiratory Syndrome Testing at Institution A Start with Flu test If negative, reflex to respiratory panel

14 What about WGS in Clinical Settings? Still a ways off. Some MN facilities piloting WGS for culture-negative sterile sites (e.g. endocarditis, synovial fluid, CSF) Need to demonstrate cost/benefit

15 Impacts on Public Health Surveillance Cultivation of an Adaptive Domestic Network for Surveillance and Evaluation of Emerging Infections. Emerg Infect Dis (9):

16 Negative Impacts of CIDTs Changing methods/case definitions = disruption of trend monitoring Unnecessary case follow-up, pseudo-outbreaks = resources wasted, increased costs Loss of subtyping for outbreak detection = potential for missed outbreaks Missed outbreaks = potential for increased disease burden

17 Use of CIDTs for Campylobacter and STEC Campylobacter 2004 <3% % STEC % %

18 Foodnet Data: Culture-Confirmation of CIDT Results % not culture-confirmed % not culture-confirmed

19 CIDTs and EIP Surveillance All, or nearly all, cases of Influenza Clostridium difficile Legionella spp Bordetella pertussis reported through EIP diagnosed by CIDTs Langley et al., Emerging Infect. Dis. 21: , 2015

20 CIDTs and EIP Surveillance Culture still used for diagnosis of invasive bacterial and meningitis, however Since publication of the Langley et al. paper, BioFire Film Array Meningitis Encephalitis panel cleared by FDA Adopted by some laboratories, however some concern about false-positive S. pneumoniae results and false-negative Cryptococcus results

21 Positive Impacts of CIDTs Improved estimates of disease burden More timely identification of potential outbreaks New opportunities for public health laboratories Characterization of rare and emerging pathogens Motivation to implement advanced methods Increased visibility with clinical partners and policy makers

22 June 2015 Cyclospora (WI) Cluster of 11 cases of Cyclospora cayetanensis linked to a Mexican style restaurant First detected by a clinical lab using BioFire Clusters in WI, TX and GA ultimately linked to fresh cilantro from Puebla, Mexico. Likely would not have been detected had the clinical laboratory not been using CIDT WISCONSIN STATE LABORATORY OF HYGIENE - UNIVERSITY OF WISCONSIN

23 The Minnesota CIDT Experience # Results Reported # Specimens Received

24 # of specimens Clinical Specimens Received BioFire Verigene

25 # of specimens CIDT Result Confirmation Pending Negative Positive

26 Percent Confirmed STEC Confirmation by Day Received from Collection Days Post-Collection

27 CIDT Result Confirmation Pending Negative Positive

28 Enteropathogenic E. coli (EPEC) First associated with infantile diarrhea in the 1940s Important pathogen for children and cause of persistent diarrhea worldwide Symptoms diarrhea, fever, vomiting Originally defined by serotype Now classified based on virulence factors Most common E. coli identified by CIDTs

29 Croxen et al., Clin Microbiol Rev Oct; 26(4):

30 EPEC Identification eae stx Sorbitol bfp STEC + + N/F - EPEC (typical) + - F + EPEC (atypical) + - F -

31 Things that CIDTs called EPEC Typical EPEC Atypical EPEC E. coli 0157 (stx-) E. albertii S. boydii Citrobacter sp. Others??

32 EPEC 166 EPEC clinical specimens submitted 91 monomicrobial (60% confirmed) 75 polymicrobial detections (50.7% confirmed) EPEC + virus = 11 (7 confirmed) EPEC + EAEC + ETEC = 8 (2 confirmed) EPEC + EAEC + ETEC + EIEC = 3 (3 confirmed) 2 typical EPEC

33 Discordant Findings 1 EPEC/ETEC 1 STEC eae + stx2f 2 possible STECs that lost their shiga-toxin phage O145, hly+ 5 E. albertii 3% of all EPECs 1 positive for stx2f

34 E. albertii a newly emerging enteric pathogen First identified in 2003 in Bangladeshi children with diarrhea Associated with an outbreak in Japan Found in wild and domestic birds Forms attaching and effacing lesions and may produce shiga-toxin Misidentified as EPEC because they are eaea +

35 Positive Impacts of CIDTs Improved estimates of disease burden More timely identification of potential outbreaks New opportunities for public health laboratories Characterization of rare and emerging pathogens Motivation to implement advanced methods Increased visibility with clinical partners and policy makers We can use CIDTs too!

36 Recent MN Outbreak Restaurant-associated outbreak with catering (22 cases) Diarrhea: 22/22 (100%) Cramps: 17/21 (81%) Fever: 4/18 (22%) Vomiting: 2/22 (9%) Bloody Stools: 1/21 (5%)

37 MDH Laboraory Testing Norovirus PCR negative Friday afternoon testing Ran 1 on the BioFire EPEC positive Subsequent testing 11/12 EPEC positive (stx-, bfp-, eae+) 3/4 C. perfringens toxin positive, unable to culture

38 MDH Laboratory Testing Colonies isolated Serotype O167 Same or similar PFGE patterns EPEC not suspected, so BioFire data critical in solving this outbreak

39 2014 Raw Milk Outbreak-WI High school football team gathering; sharing of food and beverages Chocolate milk served by parents store-bought choc milk raw milk (supplied by parents of one team player) with choc syrup added 38 attendees were sickened in total One early case seen at a local clinic was diagnosed with Campylobacter by RCA WISCONSIN STATE LABORATORY OF HYGIENE - UNIVERSITY OF WISCONSIN

40 2014 Raw Milk Outbreak- Continued Campylobacter suspected but raw milk potentially contains >1 pathogen WDPH epidemiologists requested Luminex xtag GPP testing on 9 more stool specimens collected by the county health department: 8 Campylobacter positives 3 Stx1 (Non-O157 STEC) positives 1 Giardia positive WISCONSIN STATE LABORATORY OF HYGIENE - UNIVERSITY OF WISCONSIN

41 2014 Raw Milk Outbreak- Continued All pathogens confirmed by a second method Subsequent samples also yielded STEC and Giardia STEC and Giardia likely would not have been detected if investigation focused solely on Campylobacter RCA result and the multi-target assay not been utilized WISCONSIN STATE LABORATORY OF HYGIENE - UNIVERSITY OF WISCONSIN

42 Responding to the Threat Short-term Maintain or increase culture capacity in PHLs (reflex culture in clinical laboratories unlikely) Encourage clinical laboratories to submit cultureready specimens in a timely fashion Capture information on type and brand of CIDTs Review and modify surveillance case definitions

43 Information about CIDTs What clinical labs/phls/cdc should be doing to respond

44 Clinical labs should contact PH before changing to CIDT Culture for isolation for reportable pathogens Send specimens/isolates to PHLs within 24 hours

45 Responding to the Threat Long-term If you can t lick em, jine em Senator James E. Watson, The Atlantic Monthly, February, 1932 Develop culture-independent methods for characterization Genotyping Serotype Antimicrobial susceptibility

46 CITMs (Culture Independent Typing Methods) Amplicon sequencing Pathogen-specific PCR targets, flank variable regions, extended MLST Challenges; target identification, linkage Timeframe: 2 years? Shotgun Metagenomics Sequence directly from specimen, analysis pipeline to identify and type enteric pathogens Challenges include high cost, volume of data, improving signal to noise Timeframe: 3-5 years? Single-cell sorting and sequencing Needs technological development

47 WHERE are we GOING? Edward Monkton

48 Acknowledgements MDH-PHL Dave Boxrud Sara Vetter Enterics Unit MDH-IDEPC Carlota Medus Institution A Rachael Liesman Wisconsin Department of Health and Human Hygiene Mike Rauch CDC John Besser Heather Carlton Raj Mody APHL