molecular diagnostics in the future july 14 - prof. bert niesters
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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
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.
Division of Clinical Virology
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
Division of Clinical Virology
Division of Clinical Virology
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.
Division of Clinical Virology
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.
Division of Clinical Virology
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
Division of Clinical Virology
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
Division of Clinical Virology
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
Division of Clinical Virology
• 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.
Division of Clinical Virology
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
Division of Clinical Virology
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
Division of Clinical Virology
Division of Clinical Virology
Division of Clinical Virology
• 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.
Division of Clinical Virology
The Facts on Molecular Diagnostics
Division of Clinical VirologyDivision of Clinical Virology
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
Division of Clinical Virology
Division of Clinical Virology
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
Division of Clinical Virology
Division of Clinical Virology
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
Division of Clinical Virology
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%
Division of Clinical Virology
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
Division of Clinical Virology
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).
Division of Clinical Virology
The Diagnostic Triangle
Division of Clinical Virology
Time to ResultTAT
Diagnostics
Quality
LIS
Division of Clinical Virology
Dear Dr. Riezebos, FilmArray 2 detected Influenza A, Influenza A/H1 in sample E2013100465
Division of Clinical Virology
Division of Clinical Virology
Norovirus II.4.Sydney
Division of Clinical Virology
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
Division of Clinical Virology
The € hour concept(comparable with kWhr)
Division of Clinical Virology
• 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.
Division of Clinical Virology
The € hour concept(comparable with kWhr)
Division of Clinical Virology
• 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
Division of Clinical Virology
Model predicted number of hospital acquired cases for five different infection control scenariosRhinovirus as model
Division of Clinical Virology
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
Division of Clinical Virology
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
Division of Clinical Virology
The Extended Diagnostic Triangle
Division of Clinical Virology
TATCost or €hr
Quality
Diagnostics
Treatment
Infection Control
LIS
Division of Clinical Virology
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
Division of Clinical Virology
(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)
Division of Clinical Virology
Division of Clinical Virology
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
Division of Clinical Virology
Who detects MERS in POC?
Division of Clinical Virology
Division of Clinical Virology
Division of Clinical Virology
“The only limitation is your imagination”.
Division of Clinical Virology
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
Division of Clinical Virology
Division of Clinical Virology
More info: www.FlowG.nlwww.MedicalMicrobiology.eu
Division of Clinical Virology
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