National Public Health Service for Wales
Pandemic Flu – Laboratory Diagnostics Plan
Pandemic Flu Operational Plan
Laboratory Diagnostics
Plan
Summary:

Each laboratory in Wales should produce a written plan for service delivery
during a pandemic which addresses:
o Maintaining critical local microbiology services
o Contributing to flu diagnosis, including providing appropriate samples
for referral to specialist facilities for molecular testing and typing
o Contributing to the collection and reporting to NPHS of data that will
contribute to the evidence base crucial in supporting local and national
decision-making processes and interventions aimed at minimising the
effect of the pandemic on the population of Wales

Each laboratory should create the appropriate planning and decision-making
structures to both support development and local testing of this plan prior to
emergence of a pandemic strain of influenza, and to ensure its timely and
effective implementation and operation during a pandemic.

A checklist is provided within this plan to assist laboratories in identifying some
of the key generic issues.
Version: Draft 2
Author: Edward Guy
Date: 31 August
2006
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National Public Health Service for Wales
Contents
1. Background
2
2. Developing the Laboratory Plan
4
Appendix A
Checklist for Laboratory Response Plan
6
Appendix B
Arrangements for the development, technology transfer into Wales,
and operational implementation of a new assay for the pandemic
strain
10
Appendix C
Routine laboratory methods for the diagnosis of pandemic influenza
in Wales.
12
Appendix D
Outline plan for laboratory action at various stages of the pandemic
16
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Date: 31 August
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Pandemic Flu – Laboratory Diagnostics Plan
Background
An influenza pandemic is likely to place a very heavy burden on the healthcare
system. Within pathology, microbiology services will be placed under particular strain
due, not only to the increase in diagnostic work that will need to be undertaken to
support individual patient management, but also to the contribution to local infection
control, and to national surveillance initiatives aimed at minimising the impact of the
pandemic.
Clearly, such increased demands on resources at a time where these will likely be
reduced due to the impact of the pandemic, will require a range of measures to be
introduced and arrangements put in place in order to ensure that critical functions can
be protected.
The aim of this document is to promote the establishment and development of
appropriate planning and decision-making structures within each NHS Trust in Wales,
and the introduction of appropriate procedures and arrangements, that will ensure
each laboratory is able to respond to the challenges of an influenza pandemic in
terms of delivery of local and national diagnostic and surveillance functions.
Key challenges and issues among those likely to be faced by each laboratory
include:

Increased workload associated with suspected and confirmed cases of
pandemic influenza.

Decreased workforce due to influenza affecting either staff or their
dependents, and increased fatigue or stress due to prolonged working hours.

Requirement for the introduction and maintenance of facilities, equipment and
procedures for the appropriate handling and testing of specimens from
suspected and confirmed cases of influenza.

Requirement for local policies and procedures for the collection by NHS Trust
staff of specimens from suspected and confirmed cases of influenza and
contributing to training of frontline NHS staff.

Disruption to the supply chain and access to critical inventory needs
compromised.

Disruptions affecting critical support services such as maintenance and repair
of essential facilities or items of equipment.
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Pandemic Flu – Laboratory Diagnostics Plan
Developing the Laboratory Plan
Each laboratory will require a written plan for an influenza pandemic.
In addition to addressing maintenance of critical local clinical-support services the
plan will need to ensure continuity of support for the wider NHS Trust plan (e.g.
infection control services, support of Occupational Health contingencies, etc.) and
support for regional and national initiatives. The latter will be coordinated by the
National Public Health Service for Wales and will be described in detail within the
NPHS Surveillance Plan.
In developing a pandemic influenza response plan, each laboratory should:
1) carry out a full review of the availability of Category Level 3 facilities and risk
assessments of the handling of pandemic flu both within and outwith such
facilities.
2) identify appropriate members of staff to serve as Clinical and Technical
Leads for local influenza pandemic response activities.
During the current interpandemic phase these Leads will serve as coordinators for
the development of the laboratory plan and will be a point of contact within the
laboratory for national influenza pandemic preparedness initiatives.
During a pandemic these Leads will serve as the point of contact with NPHS Wales
for the two-way exchange of health intelligence and the health information briefings
that will take place regularly. In view of the crucial nature of this role, two deputies
should be identified in case of illness.
3) carry out a review of all work undertaken and prioritise activity.
The NHS Trust plan will likely identify explicit areas of activity that will cease or be
significantly curtailed during an influenza pandemic. This will result in a decrease in
demand in some areas of the laboratory and may even permit complete cessation of
some functions. Remaining work will need to be prioritised in order to ensure that
resources can be focused upon the most critical functions. While these will include
support of national pandemic influenza initiatives, there may be differences in other
areas of work depending upon the nature of the NHS Trust in which each laboratory
is based. Work should be categorised as follows:

Critical
Failure to provide will result in either:
1) immediate risk of severe adverse outcome to patients, staff or the wider
public health.
2) compromise to the NHS Trust influenza pandemic response plan.
3) compromise to functions proscribed in the NPHS Wales Influenza
pandemic response plan.

High Priority
Failure to provide will result in either:
1) risk of severe adverse outcome to patients, staff or the wider public health if
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Pandemic Flu – Laboratory Diagnostics Plan
this work is discontinued for a prolonged period.
2) immediate low to moderate risk of severe adverse outcome to patients,
staff or the wider public health.

Lower Priority
No immediate risk of significant adverse outcome to patients, staff or the wider
public health.
4) assess impact on microbiology services during an influenza pandemic
based upon capacity to deliver the ‘critical’ and ‘high priority’ services
identified above.
Based on the assumption of infection rates of up to 25% during pandemic influenza
and current NHS rates of absence due to sickness, estimates should be based upon
peak absentee rates of approximately 15%. This is likely to persist for a period of 1-2
weeks. Any critical functions where expertise is limited should be identified,
particularly where the absence of a relatively small number of staff may cause
significant compromise to the ability to continue to provide these functions. A plan for
cross-training of staff should be developed in order to address such issues.
5) review contingency plans associated with disruptions to support services.
Based on current predictions for the duration of the initial pandemic period, significant
disruptions are likely to be experienced for 6-12 weeks and possibly longer. Each
laboratory should identify minimum critical stock levels and review and update
inventories of supplies that will be in high demand during the pandemic period.
6) ensure local infection control policies are established and arrangements in
place.
Such arrangements should include guidelines for non-laboratory staff for the
collection and transport of specimens and care of suspected or confirmed pandemic
influenza cases.
7) ensure there is an appropriate occupational health plan for laboratory staff
during the pandemic period.
This policy should include arrangements for the monitoring and management of flulike illness and provision of education and support services for staff experiencing
stress or raised concern in working with infected specimens.
Appendix A contains a summary of the above information in a format intended
to assist each laboratory in preparing for an influenza pandemic
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Appendix A
Checklist for Laboratory Response Plan
4. Microbiology Services
Key Points
Aims
4.1
Establishment
of
planning
and decisionmaking
structures
within
laboratory
To identify staff
with responsibility
for leading the
planning process
and, during a
pandemic,
to
serve as a point
of contact with
relevant national
health
information
dissemination
and
decisionmaking structures
4.2 Laboratory
diagnosis
of
influenza
To ensure early
recognition
of
introduction
of
pandemic flu into
local community,
support
clinical
management,
guide
service
planning, assist
infection control
and
inform
therapeutic
decisions.
Actions

A) To identify a
clinical lead (with
appropriate cover)
with responsibility for
the development of a
local influenza
diagnostic plan and
serve as a point of
contact during the
pandemic period

A) Establish a local
testing algorithm for
the investigation of
suspected influenza
cases, when further
guidance is provided by
the NPHS
B) Establish local
strategies for the
investigation of
suspected outbreaks
in the community and
the healthcare setting.


4.3 Provision
of surveillance
data
To guide and
inform
service
response
and
planning.
Version: Draft 2
Author: Edward Guy
A) To identify a lead
for surveillance data
collection (with
appropriate cover)
who will support the
implementation of
national surveillance
requirements as
outlined in the NPHS
Surveillance Plan
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
4.4
Service
Delivery
To
identify
diagnostic
services
that
must be delivered
throughout the flu
pandemic
and
plan
for
the
continuity of the
service

A) Categorise
diagnostic work into
priority levels

B) Develop plan for
delivery of the
essential services
taking into
consideration the
possibility that up to
15% of staff may be
unavailable due to
influenza.



4.5
Contingency
Planning
To
identify
circumstances
and factors that
present
a
significant threat
to
service
provision during
the
pandemic
period
Version: Draft 2
Author: Edward Guy
B) Surveillance plan
in place that covers
electronic reporting
of:
influenza A
diagnoses
(CoSurv)
bacterial isolates
and antimicrobial
susceptibilities
from blood
cultures and post
mortems (CoSurv
to migrate to
DataStore)
C) Identify and
undertake any
additional training to
ensure continuity of
essential diagnostics
and key laboratory
functions (eg IT
support)
D) Ensure
appropriate laboratory
facilities for likely
increase in respiratory
work to be carried out
with appropriate
biosafety level
A) Identify stock
levels of critical
consumables and
implement a review
process to ensure
that minimum levels
required for the
pandemic period can
be achieved within
the anticipated time
between emergence
of the pandemic strain
and its arrival in the
UK
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



4.6
Infection
control
To ensure safety
of local NHS staff
in the collection
and
transportation of
specimens
4.7 Training
Introduce specific
training aimed at
increasing
capacity
within
the laboratory to
respond to the
influenza
pandemic
Version: Draft 2
Author: Edward Guy
and
to
C) Consider options
for acquiring
additional staff, e.g.
by maintaining a
register of staff
recently retired.
D) Define ‘essential’
and ‘non-essential’
visitors to the
laboratory and
introduce an
appropriate policy
during the pandemic
period
A) Produce
guidelines for
collection of
specimens from
suspected and
confirmed cases of
influenza and ensure
clinical staff are fully
aware of
arrangements for safe
transportation to the
laboratory
A) Introduce training
of specific staff to
supplement expertise
where this is
presently limited to a
relatively small
number of individuals

B) Maximise general
cross-training of staff
in key areas of
laboratory function
C) Consider areas
where adjusting the
skill-mix may be
possible during the
pandemic emergency
and ensure relevant
staff have sufficient
training to contribute
as required
A) Identify staff
member(s) with
responsibility for
internal audit of plan
and introduce audit

Introduce
measures
processes
assess
B) Identify critical
items of equipment
and facilities where
failure would
compromise service
provision and ensure
appropriate
safeguards are in
place.


4.8
Review
and audit of
pandemic
influenza
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effectiveness and
functionality
of
the plan
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Pandemic Flu – Laboratory Diagnostics Plan
Appendix B
Arrangements for the development, technology transfer
into Wales, and operational implementation of a new assay
for the pandemic strain
There is currently no pandemic strain of influenza. For a pandemic to occur a
new variety of influenza must appear.
Current UK arrangements for the acquisition and co-ordinated delivery of any new
assay for the detection and confirmation of the pandemic flu strain will be via
dissemination of an international assay to key centres throughout the UK from the
HPA Centre for Infection (WHO National Laboratory for Influenza - Head, Dr Maria
Zambon). The designated centre within Wales is the NPHS Virology (Molecular Unit)
Cardiff which will liaise directly with CfI (MZ) to agree technology transfer and
implementation.
During a pandemic the following process is anticipated:
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Multiple cases of influenza with rapid person
to person spread identified outside of the UK
New “pandemic” strain identified
WHO Alert Phase 6
UK Alert Level 1
WHO-led International effort to establish
sequence of new virus
New assay established and rolled out to
UK’s WHO Influenza Laboratory (HPA
Centre for Infection - CfI)
New assay rolled out from CfI to UK
regional centres (NPHS Cardiff in Wales)
Specialist service offered to laboratories
throughout Wales (co-ordinated with by CfI)
In practice once the assay is established at the Centre for Infection it is
anticipated that technology transfer should be possible within a few
days/weeks and subsequent laboratory diagnosis of pandemic influenza will
rely upon molecular testing.
Other Respiratory Virus Molecular Diagnostic assays available in Wales
Current molecular diagnostic assays available to laboratories in Wales via the NPHS
Molecular Unit Cardiff include:
a)
b)
c)
Assays for seasonal influenza including H3N2 H1N1
Assays for other respiratory viruses (RSV)
Assays for Avian Influenza (H5N1)
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Appendix C
Routine laboratory methods for the diagnosis of pandemic
influenza in Wales.
1. OVERVIEW
Viral Culture
Non-molecular assays are more widely available in Wales. Virus culture will need to
be maintained in order to produce virus strains for referral to CfI and part of the WHO
pandemic plan. However, culture of virus outside of specialist facilities is not
recommended. Such work would be undertaken on behalf of Wales by NPHS.
Immunofluorescence Assays
The role of direct immunofluorescence microscopy for influenza is difficult to predict
since there is no way of knowing whether or not current assays will work and the
availability of skilled technicians and fluorescent microscopes is variable across
Wales.
Serological Assays
Serology for detection of influenza specific antibody will have little or no role during a
pandemic. Samples sent to the laboratory can be stored for retrospective analysis.
Point of care testing (POCT)
There are developments in point of care testing for influenza (mostly based on EIA
technology), such assays may be very useful during the flu season or a pandemic to
enable rapid local diagnosis. Generally such assays are specific but not very
sensitive. There is as yet no POCT for pandemic flu as this would be a new virus
whose properties are not known, experience of POCT for respiratory infections is
very limited in Wales.
2. TECHNICAL FRAMEWORK FOR LABORATORY DIAGNOSIS
Laboratory diagnosis of viral respiratory infection is undergoing rapid development.
The availability of solid phase EIA formats for detection of respiratory virus antigens,
suitable for use in the clinic or non specialised laboratory, and the successful
development of real time molecular assays for respiratory targets have greatly
improved the potential availability and sensitivity of laboratory diagnosis of respiratory
illness whether seasonal or in the event of a pandemic.
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In the immediate future it is likely that specialised assays (molecular and flu typing
assays) will be performed in Wales at central specialist facilities on behalf of patients
in hospital and the community.
If near patient testing devices perform well, these are likely to be an important
addition to direct IF as a rapid diagnostic test and could be offered directly by NHS
Trusts throughout Wales.
1. Quality assurance and control
In order to ensure reliability of health information provided during the influenza
pandemic, all assays MUST be validated and operated according to the
following principles:
i. CPA accreditation of the testing laboratory
ii. Standard operating procedures should be established across
Wales for all influenza assays used, with any local variations
both explicit and agreed by the NPHS National Coordinating
Centre.
iii. Evidence of validated sensitivity and specificity at a satisfactory
level
iv. Internal quality control and quality assurance procedures in place
2. Virus isolation in cell culture
It is currently envisaged that Virus Culture will be undertaken by NPHS during
an influenza pandemic
a. Use of specific cell lines/strains able to support the growth of pandemic
flu will follow advice from WHO.
b. Stringent Biosafety measures will be required.
c. Virus growth in culture will be essential for
i. Strain typing during a pandemic
ii. Assays to determine susceptibility/resistance to antivirals
3. Direct immunofluorescence assays
a. Commercially available assays target different components of the
influenza virus.
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b. The nature of any pandemic strain will determine whether current
assays will be of any use.
c. Rapid development of appropriate assays will likely follow the
appearance of a pandemic strain, but there will be delay in large-scale
production.
d. Reading IF is subjective and difficult to control.
e. Satisfactory performance in NEQAS as well as arrangements for IQC
will be essential.
f. Staff training for IF work is essential and will need to be incorporated
into training plans to create a sufficient base of expertise if this method
is to be used.
g. High throughput is difficult
4. Near patient EIA assays
a. These are largely untested in Wales
b. Commercially available assays target different components of the
influenza virus
c. The nature of any pandemic strain will determine whether current
assays will be of any use.
d. Rapid development of appropriate assays will undoubtedly follow the
appearance of a pandemic strain, but there will be delay in large-scale
production.
e. Satisfactory performance in NEQAS as well as arrangements for IQC
are desirable, but schemes not currently available.
f. No need for specific equipment for many assays.
g. High throughput difficult.
h. Ongoing review should be considered for the use of these assays for
the whole of Wales as any significant new developments arise.
5. Serology
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a. The production of anti-influenza antibody follows infection or
immunisation and serology can be used to diagnose recent/past
infection and/or the level of immunity in an individual or community.
b. The usefulness of serology to diagnose acute infections during a
pandemic is likely to be small.
c. Retrospective detection of specific antibody mat be of use in some
clinical situations.
d. Serology is likely to be of more value in determining levels of population
immunity following immunisation campaigns than in acute diagnostics.
e. All serological methods must be subject to the same quality standards
specified above.
6. Molecular testing for Pandemic Influenza
a. This will probably be the mainstay of diagnosis of pandemic influenza.
b. Development of an appropriate assay will depend on the nature of the
pandemic strain.
c. An identified international network of centres will develop assays
d. Wales will probably be guided by the WHO’s UK Influenza Reference
Laboratory based within the Health Protection Agency.
e. The number of laboratories in Wales able to offer molecular assays will
depend on:
i.
The availability of molecular diagnostic facilities and equipment
ii. The availability of skilled staff able to undertake molecular work
iii. Biosafety considerations, especially if molecular suites employed
during the pandemic have been designed primarily for noninfectious disease work.
iv. The satisfactory performance of molecular laboratories in
available internal and external quality schemes for infectious
disease targets.
v. The ability of labs to report molecular data to CDSC.
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Pandemic Flu – Laboratory Diagnostics Plan
Appendix D
Outline plan for laboratory action at various stages of the
pandemic
WHO Phases 1, 2 and 3 (UK Alert level 0 – a pandemic strain does not
exist)
PRE PANDEMIC
1.
This is the current situation, there is no pandemic influenza but there is concern over
avian influenza and its severity and also evidence of circulation in the population of
“normal” seasonal influenza, albeit at a low level at present.
Laboratory Action:



Maintain current practice – Utilise NPHS specialist molecular diagnostic
facilities for seasonal influenza assays. Avian influenza investigated only if
specifically indicated according to NPHS/HPA algorithms.
Non-molecular assays provided by laboratories in Wales according to local
protocols
Each diagnostic laboratory in Wales should draw up a flu pandemic plan to
rationalise work and maintain essential services.
WHO Phases 4 and 5 (UK Alert level 1 – a pandemic strain does not exist)
PRE PANDEMIC but human to human spread of a potentially emerging virus
is being reported by WHO
2.
At this stage, a new potential “pandemic” flu strain will have been recognised outside
the United Kingdom. Person to person spread will have been established and
simultaneous outbreaks not confined to one geographical area will have occurred. (a
single large outbreak may be enough to trigger WHO upgrading its alert phase from 4
to 5) It is possible that “seasonal” flu may exist in the UK whilst a pandemic develops
in the Far East for example. The pandemic strain is expected rapidly to replace
seasonal circulating virus as the pandemic develops.
Laboratory Action:

Enhanced investigation of flu-like illness utilising the increased molecular
diagnostic resources that will be provided by NPHS. The latter will include
efforts to establish, s quickly as possible, a robust assay for pandemic
influenza in collaboration with colleagues in the UK and elsewhere. Continued
delivery of H5N1 assay will depend on whether this is related to the new
pandemic strain.
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
3.
Pandemic Flu – Laboratory Diagnostics Plan
Enhanced data collection will be introduced according to the NPHS Pandemic
influenza Surveillance Plan.
WHO Phase 6 (a pandemic strain has been confirmed) UK alert level 1 – a
pandemic virus exists outside the UK. UK alert level 2 – a small number
of cases of the strain have been recognised in the UK but with no
evidence to confirm an outbreak
EARLY PANDEMIC
This is the situation when the pandemic strain has arrived in the UK and one or a few
cases have occurred. However, any such cases are isolated with no convincing
evidence that the virus has yet spread.
NPHS will initiate daily investigation of suspected cases and will be directed by the
Welsh Assembly Government to make daily reports on influenza investigation and
diagnosis
Laboratory Action:

4.
All laboratories in Wales will be requested to support this effort by providing
appropriate specimens and clinical information.
WHO Phase 6 – UK Alert level 4 –outbreak swidesoread throughout UK
NB UK Alert level 3(several outbreaks in UK) is expected to be very
transient
PANDEMIC PHASE:
Multiple cases occurring throughout the United Kingdom, hospital and laboratory
personnel affected. Attempts to control the spread of infection failed. Maintenance of
infrastructure and critical services are now a priority.
Laboratory Action:



5.
prioritise all laboratory work
full activation of contingency plans
The extent to which influenza diagnosis continues will depend on local
factors and requirements indicated by WAG and communicated through
the NPHS National Coordinating Centre.
UK Post Pandemic phase
Fewer cases, people return to work, school and hospital services start to return to
normal. A second wave of the pandemic is likely to follow, but forecasts regarding its
scale and timing will depend upon the dynamics of the first wave.
Laboratory Action:
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

6.
Pandemic Flu – Laboratory Diagnostics Plan
Surveillance and testing for influenza will continue for several weeks or longer
and will include provision of daily reports in the first instance. The point at
which these processes will be downgraded will be directed by WAG via the
NPHS National Coordinating Centre.
Ongoing targeted surveillance may be introduced in anticipation of a second
wave.
PANDEMIC OVER:
(No new cases)
Laboratory Action:

Resume normal service
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