Molecular diagnostics in the future July 14 - Prof. Bert Niesters

Bert Niesters

Department of Medical MicrobiologyDivision of Clinical of VirologyUniversity Medical Center Groningen The Netherlands

Molecular diagnostics in the future:How will it look like and what are the

challenges!

Point of Impact: From Classical PCR to Point-of-Care Systems.

Division of Clinical Virology


Disclosures

• Executive board member of QCMD.

• Commercial developments on FlowG MiddleWare solutions.

• Assessor for the Dutch Council of Accreditation.

• Editor-in-Chief of Journal of Clinical Virology.

• Advisory board Stratec on AURORA VigiLant.


What I will present

• Introduction

• How we are interlinked, networks, cross-border

• Facts on molecular diagnostics

• The diagnostic triangle

• The €hr concept

• The Extended Diagnostic Triangle

• The AID-Stewardship Portfolio


http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=XSKsNzqJKR7jgM&tbnid=9CJumVY3YKqtJM:&ved=0CAUQjRw&url=http://www.depudding.nl/rd-hotel-umcg/&ei=Eoq9UYyCBemU0AWS6oDQCg&bvm=bv.47883778,d.d2k&psig=AFQjCNEGIpZ3VT7dnZ4PPH7zHInMNsM_0Q&ust=1371457040234052


What is the UMCG?

The UMCG is a tertiary referral hospital providing care for both adults and children and has a large Solid Organ Transplant program.

The large proportion of immune-compromised patients require isolation from patients with respiratory illness.


Introduction

• The Influenza season of 2012-2013 was characterized by co-circulation of two Influenza A types.– H1N1 2009pdm09 – H3N2

• Due to the circulation of two Influenza viruses Influenza A-positive

patients had to be admitted into single rooms.

• A large number of different respiratory viruses were circulating during a long (5 months) period of time, with RSV and influenza viruses being present simultaneously.


Number of viruses identifiedDecember 2012-April 2013

0

100

200

300

Decem

ber

Janu

ary

Febru

ary

Mar

chApril

Influenza A

Influenza B

hMPV

RSV

Adeno

Boca

Corona

Rhino

Parainfl

A total of 1259 respiratory samples were tested


Typing results of Influenza A positives

0 20 40 60

April

March

February

January

December

H3N2

H1N1pdm09

NT

166 patients had Influenza A • 59 had H1N1pdm09• 104 had H3N2• 3 NT


Isolation regiment of patients admitted with a respiratory illness

?

Other virus

Neg

InflA

Geno-type?

H3N2

H1N1

isolatio

n

No

isol

atio

n

H1N1 H1N1 H1N1

H3N2 H3N2 H3N2

Care in cohort

Care in cohort


• In our setting, the validation of BINAX Now influenza test resulted in a negative outcome. Too insensitive. Did not pass the validation process.

• Request for data on more viruses that circulated simultaneously.

• Samples from patients received at the end of the day, on Friday (after 16.00 hr) and in the weekend, had a long TAT.

• Lack of isolation rooms.


The Challenges

Patient Referral Network in the Netherlands

Donker et al. Math Biol 2012Prof Grundmann, UMCG

University Hospitals

Regional Centers

Local Hospital

Labmicta, Enschede

Isala, Zwolle

Izore, Leeuwarden UMCGLvI

Apeldoorn

Dr. Donker, Prof. Grundmann, UMCG

UMCG

Regional Center

Satellite

Connectivity between regional centers(does not cross borders)

Intra-Hospital travel of potentiallyexposed patients

KPNEU, esbl+ outbreak, UMCG 09-2012Day-by-day patient transferStart: 29.5.2012

<10

<50

>50

Mariano Ciccolini,MMB, UMCG


How patients are moved within UMCG

Data analysed with UCINET 6www.medicalmicrobiology.eu

Ems-Dollart Region

HealthCare Network EDR

-Patient transfer 2011

- 5 healthcare clusters

- Regional network building

Dr. Rocker, Dr. Pulz (NLGA) & Dr. Ciccolini (UMCG)

From TypeNed to RegioType to UMCGNosocomial Infections

Percentage of nosocomial infections in UMCG

12% for influenza A virus, 19% for influenza B virus

22-24% for rhinovirus and enterovirus 68

Around 50% for norovirus

Consequence is Infection Control

Focusing on patients

Less focusing on visitors

Sequence a select number of target viruses ASAP

Norovirus, rhinovirus



• Molecular diagnostics is an integrated, solid and important part within our diagnostic laboratory.

• Investments over the years have been high, both equipment, reagents and consumables.

• Equipment from different diagnostic companies.

• Patient diagnostics, treatment and safety is important within our work. A short TAT time has impact on the use of antibiotics.

• Limited availability of Point-of-Care (Impact) technologies.


The Facts on Molecular Diagnostics

Division of Clinical VirologyDivision of Clinical Virology

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=TEah4JqrbbQbuM&tbnid=DSVE6C3pLdBI9M:&ved=0CAUQjRw&url=http://www.ahsoman.com/GenXpert.aspx&ei=umYrUrvmJ4Wb0AXd44CQBw&psig=AFQjCNGYYfG5qQwvGuajoYrp4m8SHmsMuQ&ust=1378662377500828

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Overview (virology)

High throughputSample in-result out

CommercialBlood screening

CommercialSTD

CommercialHPV

Medium to low throughput In-house or LDT“Everything”

CommercialLimited portfolio

No sample in - result out

Point-of-CarePoint-of-Impact

CommercialShort TAT

Influenza virusNorovirusRespiratory viruses

Sample in - result out



Cepheid GeneXpert Flu(too insensitive). Detects not enough clinical relevant respiratory targets.

BioFire FilmArray Respiratory assay.1 Sample per instrument. Broad panel.

Alternatives for the LDT (in-house) PCRPoint-of-Care/Point-of-Impact (respiratory targets)

GenMark NexGen Respiratory Panel(Should be as sensitive as previous eSensor technology)

CertificationAccreditation

New method Establish Performance

PerformClinical tests

Characterised Quality

reagents

Verify method

Validate Performance

Method Equivalence

Quality Improvements

Report Results

Implement method

Method Maintenance

Assay Verification

Assay Validation

Assay Implementation

EQA(PT)

Quality Management

System

Internal

QC Internal

QA

‘QA & QC’ within the Microbiology LaboratoryISO15189:2012



QCMD proficiency testing

Stock dilution series

Coronavirus NL63Influenza A H1pdm09

Influenza H3Influenza B

Parainfluenza virus 1RSV ARSV B

Panels

AdenovirusInfluenza virus

Parainfluenza virusRhinovirus

RSV

Compared eSensor technology with our LDT assaysCompare FilmArray with our LDT assays


Conclusions FilmArray eSensor Technology

• FilmArray RP (Ct <31) is more sensitive than INF and RSV BinaxNOW (Ct < 21 en <24)

• Detects 98% of the positive patient samples with Ct values < 31. Missed a rhinovirus positive sample

• Specificity of the validated targets is 100%, with an exception for Rhinovirus 98.5%


Conclusions GenMark Technology

• GenMark eSensor Technology (Ct <35-37) is more sensitive than Influenza and RSV BinaxNOW (Ct < 21 en <24). Similar sensitivity compared to LDT.

• Initial results also indicate an improved sensitivity compared to BioFire FilmArray.

• We have not yet validated all parameters.

• A challenge for Proficiency Testing as well as for QCMD as a Proficiency Provider, is how to develop proficiency panels for multiplex system according to the ISO15189:2012 guidelines.

FilmArray RP

Influenza A H1Influenza A H3

Influenza A H1pdm09Influenza B

Human MetapneumovirusRSV

AdenovirusBocavirus

Coronavirus HKU1Coronavirus NL63Coronavirus 229 ECoronavirus OC43

Rhinovirus/enterovirusParainfluenza 1Parainfluenza 2Parainfluenza 3Parainfluenza 4

Routine LDT PCR

Influenza A Influenza B

Human MetapneumovirusRSV

AdenovirusBocavirus

Coronavirus NL63Coronavirus 229 ECoronavirus OC43

Rhinovirus/enterovirusParainfluenza 1Parainfluenza 2Parainfluenza 3Parainfluenza 4


Influenza A H1Influenza A H3Influenza A H1pdm09Influenza A N1Influenza A N2

Negative or positive resultTurnaround time 1.5 hours after

the sample arrived in the laboratory

Negative or positive result

Turnaround time 1.25 days

Influenza A with genotype

Turnaround time 2 days

Performance of FilmArray versus LDT

FilmArray RP (Ct <31-33) is more sensitive than

Influenza and RSV BinaxNOW (Ct < 21 en <24).


The Diagnostic Triangle


Time to ResultTAT

Diagnostics

Quality

LIS


Dear Dr. Riezebos, FilmArray 2 detected Influenza A, Influenza A/H1 in sample E2013100465


Norovirus II.4.Sydney


Norovirus II.4.2009

Division of Clinical VirologyDivision of Clinical Virology

IQuum The lab in a tube technology

GeneXpert Infinity System Biocartis platform

Is this affordable point-of-care?

FilmArray, bioMerieuxGenMark Dx

Luminex Aries


The € hour concept(comparable with kWhr)


• Time-to-result or turn-around-time (TAT) for critical care is important.

• Time-to-result for decision making is important.• Start or stop treatment• Isolation of patient or not• Cohorting of patients

(e.g. Influenza H1 infected patients in one room)

• Combine time-to-result with costs of assay.


The € hour concept(comparable with kWhr)


• Calculate the costs of stay in hospital and/or isolation of a patient

• Assay 30 € but TAT is 24 hr: total 720 €hr (Plus 1 extra costs of bed).

• Assay 100 € but TAT is 3 hr: total 300 €hr.• Cost –and earning- of bed (estimated between

€1700 and €3200/day)• (example critical care at Friday late afternoon).

• Calculate the costs for getting a hospital acquired infection.

• We have to work more intensively with economists and mathematicians!

fHA due to delay and background transmission

Model predicted impact of infection control (IC) on hospital acquired infections (fHA); the red circle represents UMCG data (74% under IC, 24% fHA).

Modeling infection and transmissionModel based on Rhinovirus data


Model predicted number of hospital acquired cases for five different infection control scenariosRhinovirus as model


Nursing department

Total turnaround time: ~3h

Patient with respiratory ilness (or, Influenza like

Ilness, ILI)

Molecular diagnostic test

application

Sampling and sending to the

laboratory

Interpretation of test results

Technician; Medical virologist

Diagnosis ; Positioning;

Treatment plan

Nurse; Co-assistent

Admission; Treatment

Turnaround time : ~1 .5h

Department of Medical Microbiology

Emergency Department

Performing a Laboratory test

(Clinical virology )

Technician

Turnaround time : ~1.5h

Physician

Increase of 288% in viral respiratoire diagnostics.

The Ideal World


Respiratory season 2012-2013

0

100

200

300

Decem

ber

Janu

ary

Febru

ary

Mar

chApril

Influenza A

Influenza B

hMPV

RSV

Adeno

Boca

Corona

Rhino

Parainfl

?

Other virus

Neg

InflA

Geno-type?

H3N2

H1N1

isolation

No

isol

atio

n

H1N1 H1N1 H1N1

H3N2 H3N2 H3N2

Care in cohort

Care in cohort

0 20 40 60

April

March

February

January

December

H3N2

H1N1pdm09

NT


The Extended Diagnostic Triangle


TATCost or €hr

Quality

Diagnostics

Treatment

Infection Control

LIS


The AID-Stewardship Portfolio

• The Antibiotic/Antimicrobial Stewardship• The Infection Control Stewardship• The Diagnostic Stewardship

• (Giving Antibiotics without Diagnostics should also be financially compensated to the laboratory)

(For management, the Financial Stewardship portfolio)

E-health

Current focus UMC’s

Cure (and care) Patient oriented

Based on Apple HealthKit


(Near) FuturePrevention

Society oriented

The AID-Stewardship Portfolio

• The Antibiotic/Antimicrobial Stewardship• The Infection Control Stewardship• The Diagnostic Stewardship

Determine and communicate the value of molecular diagnostics!

– Take the lead (use of POC/POI; E-health)– Cost effectiveness– Awareness (communicate)



Cost

Benefit

Cost Effectiveness of AID-Stewardship

Burden of infectious diseases

• Nosocomial infections (HAI) • and Antibiotic resistance• (MRSA, VRE, ESBL et al.)

• Pneumococci

• HIV/AIDS

• Viral Hepatitis

• Pandemic flu

• Diarrhea (v.a. Norovirus, Camplylobacter)

• Emerging infections / Zoonosen(z.B. EHEC, MERS, H5N1)

CDC-report 2005 ECDC-report 2009

The silver generation

Ageing Society

Division of Clinical VirologyImproved Infectious Diseases Diagnostics • CID 2013:57 (Suppl 3) • S139


Who detects MERS in POC?

“The only limitation is your imagination”.


Take home message

• Increase in availability of Point-of-Care/Impact technologies.

• Important is good sensitivity, however, less of a problem within the season. eSensor technology very promising.

• Not all POC/POI assays detect all relevant targets.• Costs versus benefits. The €hr concept.• Consider the AID stewardship concept.• Value of a negative result is also very important!

Network-based Infection Control

Awareness



More info: www.FlowG.nlwww.MedicalMicrobiology.eu

Molecular diagnostics in the future July 14 - Prof. Bert Niesters

Health & Medicine

Transcript of Molecular diagnostics in the future July 14 - Prof. Bert Niesters