PowerPoint Presentation€¦ · Blake W. Buchan, PhD, D(ABMM) Assistant Professor, Dept. of...
Transcript of PowerPoint Presentation€¦ · Blake W. Buchan, PhD, D(ABMM) Assistant Professor, Dept. of...
6/15/2017
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MOLECULAR DIAGNOSTICS: FISHING FOR THE RIGHT TEST
Effective Utilization to Create Value for the Patient, Clinician, and Healthcare System
Blake W. Buchan, PhD, D(ABMM)
Assistant Professor, Dept. of Pathology
Associate Director, Clinical Microbiology and Molecular Diagnostics
Medical College of Wisconsin and Wisconsin Diagnostic Laboratories [email protected]
SCACM Audioconference, June 19, 2017
PACE# 362-006-17
Objectives
1. Discuss the specific strengths and weaknesses of syndromic-based tests
2. Understand the costs to the patient and healthcare system
3. Describe potential utilization algorithms to increase the value of
syndromic testing
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◦ Scientific advisory
◦ Genmark
◦ Luminex
◦ Quidel
◦ Travel support
◦ iCubate
◦ Quidel
◦ BioFire
◦ Great Basin
◦ Research funds
◦ iCubate
◦ Quidel
◦ BioFire
◦ Great Basin
◦ Luminex
◦ Genmark
◦ Curitis
◦ Meridian
Disclosures Disclosures Disclosures
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Goals of laboratory testing
◦ Better patient care
◦ Identification of pathogen
◦ Accurate identification of potential cause of symptoms
◦ Appropriate management
◦ Antibiotic, antiviral, supportive care
◦ Speed
◦ Impact on antimicrobial stewardship
◦ Patient satisfaction
◦ Hospital admission rate
◦ Cost
◦ Patient out of pocket, private or government payor
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Approaches to testing
◦ Syndromic panels
◦ Highly multiplexed, capable of detecting a broad array of pathogens
◦ Benefits
◦ Simplify ordering for clinicians
◦ Detect potential pathogen in 30-60% of specimens
◦ Drawbacks
◦ Laboratory-based extended TAT
◦ Not flexible for risk-guided testing
◦ Higher cost/test
◦ Interpretation of results
◦ Is there value in all these fish?
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Approaches to testing
◦ Focused test
◦ Narrow, capable of detecting 2-4 pathogens
◦ Benefits
◦ High impact targets
◦ Guided by pre-test probability/risk
◦ POC or near POC rapid result
◦ Comparatively inexpensive
◦ Drawbacks
◦ Negative result…patient dissatisfaction
◦ Give antibiotics “just in case”
◦ For many patients, combination of speed, low cost, actionable result is like…
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RESPIRATORY
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Respiratory Illness
◦ Epidemiology
◦ Respiratory symptoms are leading reason for unscheduled outpatient healthcare visit
◦ Account for ~3.0% of all physician visits, 2.3M/yr in US
◦ Children: 3-8 respiratory infections/yr
◦ May lead to more severe illness
◦ Otitis, asthma exacerbation, LRTIs (pneumonia, bronchiolitis, etc.)
◦ Prevalence
◦ Seasonal distribution, spike in colder months
◦ Organisms
◦ Viral – Most common
◦ Bacterial
◦ FungalLoffelholz et al. Int. J. Microbiol. 2010
Hing et al. National Health Statistics Report. 2010 8
What Drives Resp Test Selection/Ordering?◦ Multiple factors
◦ Positivity rate
◦ Specifically flu
◦ Multitude of pathogens
◦ Flu/RSV most common but...hMPV, Parainfluenzae, Rhinovirus, Adenovirus
◦ Patient demographics/risk factors
◦ Inpatient vs. outpatient
◦ Underlying condition
◦ TAT
◦ ED/inpatient < 1h
◦ Off campus outpatient clinic <24 h
◦ Test Volume
◦ Peak respiratory season – surge volume9
What Drives Resp Test Selection/Ordering?◦ Multiple factors
◦ Positivity rate
◦ Specifically flu
◦ Multitude of pathogens/seasonality
◦ Flu/RSV most common but...hMPV, Parainfluenzae, Rhinovirus, Adenovirus
◦ Patient demographics/risk factors
◦ Inpatient vs. outpatient
◦ Underlying condition
◦ TAT
◦ ED/inpatient < 1h
◦ Off campus outpatient clinic <24 h
◦ Test Volume
◦ Peak respiratory season – surge volume10
What Drives Resp Test Selection/Ordering?◦ Multiple factors
◦ Positivity rate
◦ Specifically flu
◦ Multitude of pathogens/seasonality
◦ Flu/RSV most common but...hMPV, Parainfluenzae, Rhinovirus, Adenovirus
◦ Patient demographics/risk factors
◦ Inpatient vs. outpatient
◦ Underlying condition
◦ TAT
◦ ED/inpatient < 1h
◦ Off campus outpatient clinic <24 h
◦ Test Volume
◦ Peak respiratory season – surge volume11
Solution – Offer Multiple Tests◦ 4 orderable “viral resp tests”, multiple platforms
◦ Flu A/B
◦ Flu+RSV
◦ “Expanded Panel”
Ag
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Available tests◦ Rapid antigen tests
◦ Inexpensive, POC, Rapid
◦ Commonly used
◦ Reduce Abx by 50%, total cost by 60%
◦ Performance?
◦ Sensitivity impacted by circulating strain (2009 SOIV?)
◦ Viral load Age, Time from symptom onset
◦ ~30% are PCR (+)/RADT(-)
Journal of Clinical Virology 79 (2016) 12–17
RADT No RADT
% patients 86.9% 13.1%
% Abx 27.5% 55.0%
Mean cost $153.06 $413.70
13,037 Total patients with healthcare visit
Klepser et al. JMCP July 2015 Vol. 21, No. 7
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Key performance characteristics
◦ Pre-test probability
◦ Off-season or early season 0-5% prevalence
◦ Sensitivity or specificity?
◦ Rapid Ag tests: 95-99% specific
◦ NAATs : 97-99% specific
◦ Peak respiratory season 50-60% prevalence
◦ Sensitivity or specificity?
◦ Rapid Ag tests: 50-75% sensitive
◦ NAATs: 97-99% sensitive
Prevalence Specificity
1% 80% 90% 99%
Sensitivity PPV NPV PPV NPV PPV NPV
80% 3.8 99.7 7.4 99.7 44.6 99.8
90% 4.3 99.8 8.3 99.8 47.6 99.8
99% 4.7 99.9 90.1 99.9 50.0 99.9
Prevalence Specificity
5% 80% 90% 99%
Sensitivity PPV NPV PPV NPV PPV NPV
80% 17.3 98.7 29.6 98.8 80.8 98.9
90% 19.1 99.3 32.1 99.4 82.5 99.4
99% 20.6 99.9 34.2 99.9 83.9 99.9
Prevalence Specificity
50% 80% 90% 99%
Sensitivity PPV NPV PPV NPV PPV NPV
80% 80.0 80.0 88.8 81.8 98.7 83.1
90% 81.8 88.9 90.0 90.0 98.9 90.8
99% 83.1 98.7 90.8 98.9 99.9 99.9Prior to seasonal Flu outbreak, Rapid Ag tests have reasonable NPV
During Flu season, Rapid Ag tests should not be used to rule out Flu14
Available tests◦ Molecular
◦ High complexity
◦ Require manual setup (extraction, mastermix) and interpretation of results
◦ Laboratory-centered, often “batch” extends TAT
◦ E.g. Luminex XTAG, GenMark XT-8
◦ Moderate complexity
◦ Require volumetric transfer or complex instrumentation
◦ Automated, sample-to-result potential for POC/near-POC shortens TAT
◦ E.g. FilmArray RP, Verigene RP, Cepheid Xpert, Quidel Solana
◦ Waived
◦ Can be performed by non-skilled operator, no interpretation of results
◦ Rapid, POC, short TAT but require dedicated analyzers
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Impact of rapid on-demand Flu test
◦ Compared use of rapid Flu NAAT vs. standard Flu NAAT (Lab-based)
◦ Season 1
◦ Lab-based, batch testing daily
◦ LDT
◦ Season 2
◦ Lab-based, on-demand testing
◦ Simplexa
◦ Time to result (h)
◦ Standard: 25.2 (2.7-55.9)
◦ Rapid: 1.7 (0.97-11.4)J Med Virol. 2015 December ; 87(12): 2021–26
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Impact of rapid on-demand Flu test
◦ Compared use of rapid Flu NAAT vs. standard Flu NAAT (Lab-based)
◦ Time to result (h)
◦ Standard: 25.2 (2.7-55.9)
◦ Rapid: 1.7 (0.97-11.4)
◦ Stewardship
◦ Received Abx
◦ Standard: 76%
◦ Rapid: 63%
J Med Virol. 2015 December ; 87(12): 2021–26
◦ Days on Oseltamivir
◦ Standard: 1.1 (0-4.7)
◦ Rapid: 0 (0-4.5)
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Impact of rapid on-demand Flu test
◦ Compared use of rapid Flu NAAT vs. standard Flu NAAT (Lab-based)
◦ Time to result (h)
◦ Standard: 25.2 (2.7-55.9)
◦ Rapid: 1.7 (0.97-11.4)
◦ Stewardship
◦ Received Abx
◦ Standard: 76%
◦ Rapid: 63%
◦ Cost
◦ Oseltamivir ~$15/dose
◦ 2000 tests x 40% neg = $12,000
◦ No major antiviral $ savings Easier to justify lower cost test
J Med Virol. 2015 December ; 87(12): 2021–26
◦ Days on Oseltamivir
◦ Standard: 1.1 (0-4.7)
◦ Rapid: 0 (0-4.5)
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What about broad panels?
◦ Respiratory panels detect positive target in 24-48% of specimens
◦ Sensitivity?
◦ Positivity rate?
◦ TAT?
◦ Clinical impact?
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Comparison of RV Panels◦ FilmArray
◦ ~1 h TAT, Sample to answer
◦ Reduced sensitivity (~85%)
◦ Comparable to Verigene RPFlex
◦ Throughput: 7 samples/8h
◦ eSensor
◦ 7-8 h TAT
◦ Off-board extraction
◦ Manual amplicon transfer
◦ Throughput: 21 samples/8h
◦ xTag/Fast
◦ 5-6 h TAT
◦ Off-board extraction
◦ Manual amplicon transfer
◦ Throughput: 21 samples/8h
J. Clin. Microbiol. May 2013 51(5) 1528-1533 20
Are there benefits to broad panels?
CAP Today, Jan 2016
◦ Positivity rate
◦ Respiratory panels detect positive target in 30-60% of specimens
◦ Clinical utility of all targets?
◦ Persistence of EV/hRV DNA
◦ Specific therapy?
◦ TAT
◦ Rapid (<60 min.)
◦ Can a broad, rapid result impact abx stewardship?
◦ Length of Stay? Cost of care?
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Are there benefits to broad panels?
◦ Impact on stewardship, Flu vs. Broad panel – Adult outpatients
◦ Why no impact?
◦ Not available POC…empirical Abx initiated
◦ Not exhaustive…hRV does not rule out S. pneumoniae
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Green et al., JCM, DEC 2016
Are there benefits to broad panels?
◦ Impact on stewardship, Flu vs. Broad panel – Pediatric admitted/inpatients
Rogers et al., Arch Pathol Lab Med , MAY 2015
• 12 h decrease in time to result
• 3-fold increase in result prior to admission
TAT
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Are there benefits to broad panels?
◦ Impact on stewardship, Flu vs. Broad panel – Pediatric admitted/inpatients
Rogers et al., Arch Pathol Lab Med , MAY 2015
• No significant difference in initial prescription of Abx pre/post or Pos/neg
• Duration of Abx decreased by 0.5 days in pts with positive viral result
Abx stewardship
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Are there benefits to broad panels?
◦ Impact on stewardship, Flu vs. Broad panel – Pediatric admitted/inpatients
Rogers et al., Arch Pathol Lab Med , MAY 2015
• ED stay longer post-RRP clinicians waiting for result??
• Inpatient LOS 0.2 day shorter with positive viral result clinician more comfortable if infectious agent identified??
Length of stay
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Are there benefits to broad panels?
◦ Impact on stewardship, Flu vs. Broad panel – Pediatric admitted/inpatients
Summary
◦ 0.2 day shorter inpatient LOS = $231.00
◦ 0.5 day shorter Abx = $17.00
◦ Test RRP ~$70 - $90 more than Flu/RSV
Positive results: 15% Flu, 49% RSV contained on focused test
21% enterovirus/rhinovirus rule out bacterial?
Net savings of $150-$175/Pt and a modest reduction in total Abx usage
in patients with a positive viral result (approx. 80% of patients tested)
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Selective Utilization – What can practice tell us?◦ Seasonal/Prevalence-based ordering
0%
10%
20%
30%
40%
50%
60%
70%
% Positivity of Targets
%Flu A Pos
% Flu B Pos
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Selective Utilization◦ Seasonal/Prevalence-based ordering
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Proportion of Test Orders
RESPEXP NAAT
FLURSV NAAT
RSV NAAT
FLU NAAT
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Selective Utilization◦ Location-based ordering (Oct-Apr 2016-17)
Location Total tests Flu (%) Panel (%)
Clinic 835 792 (94.8%) 43 (5.2%)
Emergency Dpt 893 875 (97.9%) 18 (2.1%)
Inpatient 3,655 1,441 (39.4%) 2,214 (60.6%)
Total 5,383 3,108 (57.7%) 2,275 (42.3%)
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Reflexive Utilization?
◦ October-February 2016-17
◦ Total Respiratory virus tests: 2,613
◦ Flu A/B: 1,152
◦ 44.1% of orders
◦ 8% positivity
◦ What about 92% with negative results?
◦ 15.2% (175/1,060) requested full Respiratory panel
◦ Offering FluA/B for primary and reflex reduced unnecessary panel usage by 37.4%
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Cost savings with multiple tests?
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Test Order Number Broad RVP Only Multiple RVPs*
Flu 3,371 $404,520 $168,550
Flu/RSV 742 $89,040 $51,940
RSV 131 $15,720 $6,550
Expanded Respiratory 1,112 $133,440 $133,440
Total 5,356 $642,720 $360,480
*Multiple platforms for Flu or RSV testing ($50), Flu/RSV testing ($65), and Broad Respiratory Viral Panel ($120)
■ Potential for laboratory cost savings though selective utilization
Laboratory 44% annual savings in reagent cost through selective utilization
Cost savings with multiple tests?■ Potential for patient cost savings though selective utilization
Common codes ($ in Nat’l limit)
Flu
87502 – Flu (up to 2 types/subtype): $115.80
87503 – Each add’l Flu type/subtype: $28.26
Multiplex
87631 – 3-5 targets: $174.58
87632 – 6-11 targets: $290.45
87633 – 12-25 targets: $567.18
Common mark-up for private payors can be 3x-5x CPT code
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Conclusions
◦ Outpatient
◦ POC/near-POC rapid Flu molecular testing reduces antibiotic utilization in ED and outpatient clinics
◦ Broad panels have no clear impact on antibiotic stewardship above Flu-only test
◦ Broad panels add cost to patient/lab reimbursement for outpatients?
◦ Inpatient/acutely ill
◦ Broad panels do result in reduction in overall antibiotic utilization
◦ Potential for better hospital IP cohorting and isolation
◦ Potential for directed therapy (PIV, RSV)
◦ Healthcare system
◦ Local real-time epidemiology weekly reports…lab added value!
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GASTEROENTERITIS
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Gastroenteritis – Scope of the problem◦ Epidemiology
Est. 50 million cases annually (US)
◦ Second leading cause of outpatient visits
◦ >$1 billion
◦ Mortality/morbidity highest in infants, elderly, immunocompromised
◦ Causes
Bacteria (toxins), Viruses, Parasites
Foodborne, environmental, person-person
◦ Clinical – similar symptoms
Geography and travel history
Season
Age
Duration of symptoms
Watery? Bloody? Mucous?
Current outbreaks/epidemics
Community or hospital/LTC
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Laboratory Diagnoses - Culture◦ Labor intensive
Screen (Non-specific) Selective/differential media
◦ BAP, MAC, XLD, HE, Campy, SMAC, MAC broth enrichment
◦ “False positives” Citro, Proteus, Pseudomonas, Serratia, VRE
Confirm
◦ API, Phoenix, Vitek2, RapID NF, MALDI-TOF (?)
• How are we doing?
TAT 48-72h
• Clinically actionable? Infection control?
95% of specimens “negative for x, y, z”
• Why so poor?
Culture only 50-75% sensitive
• High LoD (106-107 CFU/mL), fastidious bugs, Preanalytic phase (preservation/transport)
Culture is narrow spectrum
• Focused on only 4 pathogens (Campylobacter, EHEC, Salmonella, Shigella) 36
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Enteric pathogen “panels”◦ Potential benefits
◦ Higher sensitivity for detection/identification of enteric pathogens
◦ More rapid TAT
◦ Considerations
◦ Cost of molecular methods
◦ Technical expertise
◦ Test complexity
◦ Level of automation
◦ Sample to result? Off-line extraction or PCR?
◦ Breadth of targets
◦ All inclusive (viral, protozoan, bacterial, toxin)
◦ Targeted (most common causes of CA-enteritis)
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Comparing platformsProGastro
SSCS
BD MAX EBP Portrait SBPP Verigene EP xTAG GPP FilmArray GI
Targets 4 4 5 9 11 22
Automation Off-line
Extraction,
Manual PCR
setup
Sample to Result Sample to Result Sample to Result Off-line
Extraction,
Manual PCR
setup
Sample to result
Technology RT-PCR RT-PCR RT-PCR PCR+Array PCR+xTAG Nested PCR
Throughput Batch, limited by
SmartCycler
capacity
Batch, up to 24 1 sample/run 1 sample/run Batch, limited by
Extractor
capacity
1 sample/run
TAT 3 h 1.5 h 2 h 2 h 4 h 1 h
Cost/test $$ $ $ $$$ $$$ $$$$
Cost
Value?
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Causes of community acquired illness
Prevalence: Salmonella, Shigella, Campylobacter, EHEC
Campylobacter34%
Salmonella40%
Shigella13%
STEC O1573%
STEC non-O1572%
Vibrio1%
Yersinia1%
Cryptosporidium6%
Cyclospora0%
CDC FoodNet 2004-2015
92%
0
50
100
150
200
250
300
350
400
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
WSLH 2012 – Bacterial Enteric Pathogens Reported
Aeromonas Campylobacter Edwardsiella
Escherichia Plesiomonas Salmonella
Shigella Vibrio Yersinia 98%
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But what about viruses?Leading cause of food-borne illness with identifiable etiology
http://www.cdc.gov/features/dsnorovirus/figure3.html40
Broad Panel Benefits Simplified ordering
• Missed diagnosis (n=709 stools)
◦ 18.1% positive by SOC, 54.2% positive by FilmArray
◦ 65% of positive results did not have appropriate test order
■ Most commonly “missed”
• Pathogenic E. coli (45%)
• C. difficile (11%)
• Yersinia (9%)
• Protozoa (5%)
Class. et al. J. Micro. Biotechnol. 2013
Spina et al., CMI 2015
56%
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Large Panel-Additional Benefits FilmArray GI
Higher positivity rate
◦ 33% total positivity
◦ 3% by bacterial culture
◦ Noro + Sapo
◦ Equal prevalence
◦ Combined 36% of positive results!
◦ Inclusive of Pathogenic E.coli
◦ Undetectable by culture
◦ 12% of positive results!
◦ Cdiff
◦ Most common positive trarget
◦ 42% of positive results
Khare. et al. JCM 2014
~54%
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Large Panel- PitfallsThe (anti-) C. difficile argument
◦ Prevalence – Pretest probability
◦ Up to 21 % asymptomatic carriage (2/3 toxigenic)
◦ Carriage NOT associated with abx/healthcare exposure
◦ Testing community patients w/o risk factors will likely result in clinical FP results
Alasmari CID 2014
Surawicz, CM Am J Gasteroenterol 2013Testing needs to be reserved for population with high pre-test probability!
■ Consequence of Clinical False Positive?
– Therapy not effective at eliminating carriage – non-vegetative spores!
– Treatment of carriers may increase shedding of spores
– NHSN reporting based on lab value, not clinical diagnosis
■ Cdiff rate increase infection control and hospital brass not happy….
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Broad Panel- PitfallsPathogenic E. coli??
Prevalence
• Present in 5-30% of symptomatic patients
◦ 12-30% of positive results
■ Significance/Impact
• Leading cause of infantile diarrhea
• Present in 7-10% of asymptomatic children
• Common in “mixed” infections
• Not able to recover in routine culture No AST
24.9% 14.4%21.6%28.3%37.3%46.4%33.1%
Potential for over-prescription/broad therapy?
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Broad Panel- PitfallsMixed infections - Mixed interpretations
Prevalence
• 5-50% of positive stools are multiple detections
Class. et al. J. Micro. Biotechnol. 2013
Spina et al., CMI 2015
68% of Pathogenic E. coli in “mixed” infections
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Broad Panel- PitfallsPathogenic E. coli??
■ Log CFU statistical significance between groups
• Symptomatic patients 299 vs 29 CFU/mg (p=0.16) No Significance!!!!!
• Age < 12 months 178 vs 5 CFU/mg (p=0.006)
• Single pathogen present 463 vs 24 CFU/mg (p=0.006)
N=53 N=90 N=26 N=31 N=27 N=59 N=9 N=13 N=44 N=77
Q-PCR for EPEC (eaeA)
Clin. Infect. Dis. 2011;53(12):1223–9
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Broad Panel- PitfallsPathogenic E. coli??
■ Study of renal transplant patients (n=30 in each group)
A. Patients with history of severe diarrhea 6 months ago
B. Matched renal transplant patients with no history of diarrhea
C. Matched non-transplant patients with no history of diarrhea
EPEC account for 58-100% of “pathogens” detected in all 3 groups
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Cost/benefit – Can the lab/patients afford this?
Some simple math – Lab cost
Culture
• Stool culture $15 + EIA $18 = $33
• Multiply by 4% positivity = $825/positive stool
Focused panel
• $35 x 7% positivity = $500/positive stool
Broad panel
• $140 x 35% positivity = $400/positive stool
40% clearly “actionable” $1000/positive stool
We are “buying” positive results cheaper with molecular Dx! Is this a Value?
For 5K stools/yr lab cost is additional $10,000 for focused panel, additional $535,000 for broad panel 48
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Algorithms?Can we optimize the benefits of Molecular Dx?
Hybrid
• Selective use of broad panels where they provide the most value!
• ACG guideline for acute diarrheal infections in adults (2016)
CA-diarrhea
No sign of severe/systemic illness
Immuno-competent
No Microbiology
CA-diarrhea
Persistent (>7 days)
Travel Hx
Signs of severe/systemic illness
immunocompromised
Broad NAAT Panel
HA-diarrhea
>3 days admit
Hx of Abx
Cdiff NAAT
CAP Today, Jan 2016
But still missing important pathogens in “mild” CA-enteritis due to low culture sensitivity
Epidemiology, infection control? 49
Conclusion
• Broad panels identify potential pathogens in up to 50% of specimens from symptomatic patients
Improve the ability to identify uncommon pathogens or pathogens not in differential
Rapid identification of pathogens in patients with systemic symptoms or risk factors for severe disease
Enable the recognition of outbreaks of uncommon pathogens Isospora
The good:
The bad:
• Broad panels not guided by pre-test probability
Clinical or analytic false positives
Interpretation of colonizers (EPEC, Cdiff) and detection of persistent asymptomatic shedding
High per-test cost
For outpatients must demonstrate “clinical necessity” for reimbursement
High out of pocket expense the $1,500 stool
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Conclusion
• Most efficient utilization requires…
Multiple approaches Culture, focused/narrow, and broad panels depending on patient
Thoughtful ordering that considers the patient hx, risk, and cost/benefit
i.e. what will you do with the result?
Diagnosis of gastroenteritis probably not a “one size fits all” solution
• High sensitivity, rapid rule-out for the most common causes of CA-gasteroenteritis
Enable clinical decisions (EHEC/Salmonella no treat)
Still enable identification of common food-borne outbreaks (EHEC, Shigella, Salmonella)
Cost-neutral for laboratory to implement
Reimbursable (currently…)
Focused GI panels:
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Final thoughts on Syndromic panels
“It is not appropriate for a lab to simply report everything in
a specimen, rather, to provide clinically impactful results”
While easier to offer a single, broad panel, it may not be in the best interest of the
patient and healthcare $$$s. Through selective utilization the lab can provide both
better care and real value to the patient, provider, and healthcare system.