PowerPoint Presentation€¦ · Blake W. Buchan, PhD, D(ABMM) Assistant Professor, Dept. of Pathology Associate Director, Clinical Microbiology and Molecular Diagnostics Medical College

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


◦ Positivity rate


◦ Multitude of pathogens/seasonality





◦ TAT



◦ Test Volume



◦ Positivity rate


◦ Multitude of pathogens/seasonality





◦ TAT



◦ Test Volume


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


5% 80% 90% 99%


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


50% 80% 90% 99%


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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◦ 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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◦ 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


◦ xTag/Fast

◦ 5-6 h TAT

◦ Off-board extraction

◦ Manual amplicon transfer


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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◦ 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


◦ 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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• 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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• 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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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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■ 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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■ 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

http://burnsmcdmedia.com/careersblog/wp-content/uploads/2012/01/GirlSolvingMathProblem.jpg

http://burnsmcdmedia.com/careersblog/wp-content/uploads/2012/01/GirlSolvingMathProblem.jpg

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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.

[email protected]

Documents

PowerPoint Presentation€¦ · Blake W. Buchan, PhD, D(ABMM) Assistant Professor, Dept. of Pathology Associate Director, Clinical Microbiology and Molecular Diagnostics Medical College