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

Molecular diagnostics in the future:
How will it look like and what are the
challenges!
Bert Niesters
Department of Medical Microbiology
Division of Clinical of Virology
University Medical Center Groningen
The Netherlands

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

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 identified
December 2012-April 2013
300
200
100
0
December
January
February
March
April
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
December
January
February
March
April
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
?
Neg
Infl
A
Other
virus
No
isolation
Geno-type?
H1N1
Care in cohort
H3N2
isolation
H1N1 H1N1 H1N1
H3N2 H3N2 H3N2
Care in cohort

The Challenges
• 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.

Patient Referral Network in
the Netherlands
Donker et al. Math Biol 2012
Prof Grundmann, UMCG
University Hospitals
Regional Centers
Local Hospital

Connectivity between regional centers
Labmicta, Enschede
Izore, Leeuwarden UMCG
Isala, Zwolle
LvI
Apeldoorn
UMCG
Regional Center
Satellite
Dr. Donker, Prof. Grundmann, UMCG
(does not cross borders)

Intra-Hospital travel of potentially
exposed patients
KPNEU, esbl+ outbreak, UMCG 09-2012
Day-by-day patient transfer
Start: 29.5.2012
<10
<50
>50
Mariano Ciccolini,
MMB, UMCG

How patients are moved within UMCG
Data analysed with UCINET 6
www.medicalmicrobiology.eu

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 UMCG
Nosocomial 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

The Facts on Molecular Diagnostics
• 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 ooff CClliinniiccaall VViirroollooggyy

Overview (virology)
High throughput
Sample in-result out
Commercial
Blood screening
Commercial
STD
Commercial
HPV
Medium to low throughput In-house or LDT
“Everything”
Commercial
Limited portfolio
No sample in - result
out
Point-of-Care
Point-of-Impact
Commercial
Short TAT
Influenza virus
Norovirus
Respiratory
viruses
Sample in - result
out

Alternatives for the LDT (in-house) PCR
Point-of-Care/Point-of-Impact (respiratory targets)
Cepheid GeneXpert Flu
(too insensitive). Detects not
enough clinical relevant respiratory
targets.
BioFire FilmArray Respiratory
assay.
1 Sample per instrument. Broad
panel.
GenMark NexGen Respiratory Panel
(Should be as sensitive as previous
eSensor technology)

‘QA & QC’ within the Microbiology Laboratory
Certification
Accreditation
New method Establish
Performance
Perform
Clinical tests
ISO15189:2012
Characterised
Quality
reagents
Verify method
Validate
Performance
Method
Equivalence
Quality
Improvements
Report Results
Implement
method
Assay
Verification
Assay
Validation
Assay
Implementation
Method
Maintenance
Quality
Management
System
EQA
(PT)
Internal
QC
Internal
QA

QCMD proficiency testing
Stock dilution series
Coronavirus NL63
Influenza A H1pdm09
Influenza H3
Influenza B
Parainfluenza virus 1
RSV A
RSV B
Panels
Adenovirus
Influenza virus
Parainfluenza virus
Rhinovirus
RSV
Compared eSensor technology with our LDT assays
Compare 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.

Performance of FilmArray versus LDT
FilmArray RP
Influenza A H1
Influenza A H3
Influenza A H1pdm09
Influenza B
Human Metapneumovirus
RSV
Adenovirus
Bocavirus
Coronavirus HKU1
Coronavirus NL63
Coronavirus 229 E
Coronavirus OC43
Rhinovirus/enterovirus
Parainfluenza 1
Parainfluenza 2
Parainfluenza 3
Parainfluenza 4
Routine LDT PCR
Influenza A
Influenza B
Human Metapneumovirus
RSV
Adenovirus
Bocavirus
Coronavirus NL63
Coronavirus 229 E
Coronavirus OC43
Rhinovirus/enterovirus
Parainfluenza 1
Parainfluenza 2
Parainfluenza 3
Parainfluenza 4
FilmArray RP (Ct <31-33) is more sensitive than
Influenza and RSV BinaxNOW (Ct < 21 en <24).
Influenza A H1
Influenza A H3
Influenza A H1pdm09
Influenza A N1
Influenza A N2
Negative or positive result
Turnaround 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

The Diagnostic Triangle
Time to Result
TAT
Diagnostics
Quality
LI
S

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

Norovirus II.4.Sydney

Norovirus II.4.2009

Is this affordable point-of-care?
Division ooff CClliinniiccaall VViirroollooggyy
IQuum
The lab in a tube technology
GeneXpert Infinity System Biocartis platform
FilmArray, bioMerieux GenMark 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!

Modeling infection and transmission
fHA due to delay and
background
transmission
Model based on Rhinovirus data
Model predicted impact of infection control (IC) on hospital acquired
infections (fHA); the red circle represents UMCG data (74% under
IC, 24% fHA).

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

Nursing
department
The Ideal World
Total turnaround time: ~3h
Patient with respiratory
ilness (or, Influenza like
Ilness, ILI)
Molecular
diagnostic test
application
Sampling and
sending to the
laboratory
Technician;
Medical
virologist
Interpretation
of test results
Diagnosis ;
Positioning;
Treatment plan
Nurse;
Co-assistent
Admission;
Treatment
Turnaround time : ~1 .5h
Emergency Department
Department of Medical Microbiology
Technician
Performing a
Laboratory test
(Clinical virology )
Turnaround time : ~1.5h
Physician
Increase of 288% in viral respiratoire diagnostics.

Respiratory season 2012-2013
0 20 40 60
300
200
100
0
December
January
February
March
April
Influenza A
Influenza B
hMPV
RSV
Adeno
Boca
Corona
Rhino
Parainfl
?
Neg
Infl
A
Other
virus
No
isolation
Geno-type?
H1N1
December
January
February
March
April
Care in cohort
H3N2
isolation
H1N1H1N1H1N1
H3N2H3N2H3N2
Care in cohort
H3N2
H1N1pdm09
NT

The Extended Diagnostic Triangle
Infection Control
TAT
Cost or €hr
Quality
Diagnostics
Treatment
LI
S

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) Future
Prevention
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 Effectiveness of AID-Stewardship
Cost Benefit

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

Improved 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.nl
www.MedicalMicrobiology.eu

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

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