1. Session 6: Principles of Outbreak Investigation
Facilitator notes:
Legionnaires’ disease: Risk assessment, outbreak investigation and control
Session 6: Principles of Outbreak Investigation
ECDC, 2012
Revision: 2018

2. Objectives Specific objectives of this session:
Understand principles of Legionella outbreak investigation
Understand role of Outbreak Management Team, epidemiology, microbiology and environmental science
Related to the course objectives:
A2. To know the value, steps and methods of an epidemiological LD outbreak investigation.
A5. To understand/interpret the results of an epidemiological LD outbreak investigation.
A4.To understand the principles involved in preparing a questionnaire for an epidemiological LD outbreak investigation
Facilitator notes:
A2. To know the value, steps and methods of an epidemiological LD outbreak investigation.
A5. To understand/interpret the results of an epidemiological LD outbreak investigation.
A4.To understand the principles involved in preparing a questionnaire for an epidemiological LD outbreak investigation

3. Principles of outbreak investigation Assumptions
Clinical awareness of Legionella infections
Surveillance and data quality
Communication between relevant participant groups
Understanding of the relationship between clinical and environmental testing
Skills and resources necessary for carrying out the relevant tasks

4. General definitions ECDC defines an outbreak as:
'the occurrence of more cases than expected in a particular population, in a specific geographical area and over a specified period of time’.
And a cluster as:
‘2 or more cases that are related by sharing similar characteristics in time and/or place and or personal characteristics’
Source: FemWIKI

5. Community Legionella clusters and outbreaks
Legionella Cluster Two or more cases linked by area of residence, work or places visited, with dates of onset close enough (six months) to warrant further investigation
Legionella Outbreak Two or more cases (in a six month period) with strong epidemiological evidence of a common source of infection, with or without microbiological evidence, and in response to which control measures have been applied to suspected sources of infection
Note: in this definition of an outbreak, epidemiological evidence and control measures are included. It is therefore a post-hoc definition, possible only after the ‘outbreak investigation’ has taken place.

6. Steps in community outbreak investigation
Confirm outbreak exists
Convene outbreak control team
Identify possible sources of infection
Conduct environmental sampling
Check for associated cases
Inform local GPs/hospitals/Ministry of Health
Carry out national/international alert
Please note that the first step can only be confirmed AFTER the outbreak investigation. Since the definition of a Legionella Outbreak includes having strong epidemiological evidence, and includes control measures in place, this seems contradictory.
This issue will be addressed by ECDC in a next edition of this course.

7. LD Outbreak investigation Multi-disciplinary aspects
Epidemiology - case details and case searching, descriptive or analytical studies
Microbiology - clinical and environmental laboratory investigations and findings
Environmental science - investigation into sources of infection and application of control measures
 These disciplines need to be present in the Outbreak Control Team, and shall be part of the approach to the investigation

8. Membership of outbreak control team, an example
Local public health consultant
Epidemiologist with Legionella expertise
Microbiologist with Legionella expertise
Clinical microbiologist from local hospital
Environmental health officers/Health and Safety Executive
Infection control specialist
Hospital/industrial/community link persons
Press/media spokesperson
Other relevant persons as decided by the chair
The exact composition of the outbreak control team will depend on the national public health system and its organisational structure at the local and regional level.
It will also depend on the outbreak setting. In case of an investigation related to ships, you may need an engineer on board, with expertise in maritime water systems

9. Terms of Reference Membership and composition of outbreak team
Allocation of tasks
Confidentiality and ownership of data
Preparation of reports - immediate, interim and final
Disclosure and dissemination of information
Authorship of publications
Review of outbreak procedures, management and outcomes
Documentation of lessons learnt

10. Outbreak Control Team Actions
Agree terms of reference
Review information on cases
Control
Investigate
Communicate

11. Definition of case associated with outbreak
Definition of legionellosis infection
Definition of standard case: confirmed/ probable
Definition of cluster (multiple cases in space or time) or outbreak (multiple cases in space and time)

12. Outbreak case definition – a template for legionella
Any person with a confirmed or presumptive diagnosis of Legionnaires’ disease and with an opportunity of exposure to xxxxxxxxxxx in the 2 weeks before onset of illness
Please be aware that there are some challenges with this case definition template
The case should have had an opportunity of exposure (in other words: has be be part of ‘the population at risk’. However, the investigators should be certain that they will NEVER include the suspected exposure as a condition in the case definition. Because if they do, any analytical study is biased, since all cases per definition were exposed to the suspected source. !
The time component is a matter of judgement. The incubation period has been described to be up to 19 days. For practical reasons (e.g. recall), this could be set to 14 days. It is generally accepted that 10 days is too restrictive as a limit

13. Example of case definition in outbreaks
Looks clear and straightforward, no?

14. Dealing with different versions of case definition
In the example of the Dutch outbreak in 1999 (De Boer et al.)
A total of 25 (!) different case definitions preceded the final published one
Version 1: drafted 13 March 1999 when outbreak was detected. Aim: case-finding
Subsequent versions: to include all different lab-methods used in the country
Version 12: first case definition used in the analytical phase
Version 25: Final case definition; took all possible (combinations of) lab tests into account, including a potentially long incubation period of 19 days
Why is this?
A case definition has different purposes in the various stages of outbreak investigation
For case finding: has to be most sensitive, may be less specific
For analytical epidemiology: has to be specific, if needed to the cost of losing sensitivity

15. Outbreak control team 1st meeting agenda
Introductions (make register of contact details)
Decide on Chair / Note taker
Review available information
epidemiology
microbiology
environmental
Discuss immediate control measures
Discuss hypotheses regarding source
Including ideas on testing those: study design required
Draw up an action plan - a “to do” list
Agree date, time and venue for next meeting

16. Legionnaires’ Disease Detecting outbreaks and sources
Community cooling towers, spa pools, fountains, water cooling devices for machinery, food humidifiers, gardening compost material Hospitals water systems, cooling towers Hotels/cruise liners water systems, cooling towers, spa pools

17. Communications Ensure you inform/liaise with the following:
National and/or regional public health institute
Local microbiology laboratory for clinical samples - (check accreditation of laboratory)
Local food and water laboratory for environmental samples
Reference laboratory for advice and assistance for diagnostic tests and results

18. A word of caution: Problems that may be encountered in outbreak investigations
Local expertise may not be available
Local laboratories may not be able to deal with large numbers of clinical samples for testing
Resources for environmental sampling may not be available
Health and Safety staff may decline to assist and in the UK do not sample
Outbreak may lead to a police investigation and a corporate manslaughter charge

19. Action plan - Epidemiological
Establish terms of reference and roles and responsibilities of members
Agree a case definition for further case finding
Inform local GPs/hospitals about the outbreak for further case finding
Prepare study protocol, including hypothesis to be tested and study design
Prepare a questionnaire for collecting data from existing and potential cases
Arrange for outbreak questionnaire results to be analysed
Prepare letter for distribution to low risk groups informing them of the outbreak
Prepare a press statement
Consider further studies e.g. case-control study

20. Epidemiological Studies
Descriptive epidemiology is most often used in small outbreaks
May suffice, provided it can be supported by robust environmental and laboratory data.
Further analytical studies may be required

21. An analytical study might be needed when:
A large number of affected persons
A high level of public or media concern
An unknown source or an unknown mode of disease transmission
Suggestions that new risk factors have been identified
An outbreak linked to an event of national or international significance
An outbreak of particular interest to national surveillance
An outbreak which may be related to standards of institutional care
Where there is uncertainty and a need for new knowledge

22. Cohort study
Epidemiological study, studying exposure and outcome in a population
Study population includes all (or representative sample of) people with an opportunity of exposure (=at risk)
Exposure may include different degrees, to potential source(s)
Cohort members should be free of the outcome at the start of the cohort
Cohort members are divided in exposure groups
Exposed / Not exposed (or even different levels of exposure)
Occurrence of outcome (disease incidence) is compared between groups
Risk of disease (exposed) / Risk of disease (unexposed) = Risk Ratio
A cohort can be studied retrospectively
This is usual in outbreaks

23. Case Control study
Epidemiological study, comparing exposure between cases and controls
Cases: people who comply to the ‘case definition’
Usually a diagnosis (disease)
Sometimes serological evidence of infection
Controls: people representative of the population where the cases came from
May have the disease (case-cohort study) or may exclude the disease (case-non case study)
Occurrence (odds) of exposure are compared
Odds of exposure (cases) / Odds of exposure (controls) = Odds Ratio

24. Advantages
Disadvantages
Cohort
Can be performed retrospectively or prospectively;
Can be used to obtain a true (absolute) measure of risk (relative risk);
Can study many disease outcomes;
Are good for studying rare risk factors.
May be time-consuming and costly (especially prospective studies);
Can study only those risk factors measured at the beginning of the study;
Can be used only for common diseases
May have losses to follow up
Case-control
May be done quickly and inexpensively;
Possible when disease being studied is rare (prevalence <1%) such as Legionnaires’ Disease.
Many risk factors can be considered and this makes case-control studies useful for testing different hypotheses concerning the sources of exposure
Can obtain only a relative measure of risk (odds ratio)
(however odds ratios are similar to risk ratios for rare diseases);
Are subject to recall bias;
Selection of controls may be difficult;
Temporal relationships may be unclear;
Can study only one disease outcome at a time.

25. Travel associated outbreak investigations
European Guidelines
Introduced 1 July 2002
Endorsed by the EC June 2003
Revised in 2017:
Technical Guidelines for the Investigation, Control and Prevention of Travel Associated Legionnaires' Disease (2017)
Related to ELDSnet Operating Procedures (2012)

26. Country of infection response
Good/poor public health response
Ministry of Health has other priorities
Ministry of Tourism wants no adverse publicity
Hotel denies any liability
Well/poorly developed tourist economy
High/low level of public health investigation expertise
Tour operator denies any liability X
No standard approach

27. The role of epidemiological investigations in hotel associated outbreaks
Most cases have a positive urinary antigen test to confirm the diagnosis
This test is mainly specific to L pneumophila sg1
Test is unsuitable for linking to source of infection even if Lpsg1 is found in the water system
More than one case at the same hotel increases likelihood that hotel may be the source of infection
Epidemiological evidence usually not sufficient on its own for most legal actions unless a large outbreak occurs

28. ELDSNet: Single case action
Case is reported to collaborator in country of infection
Collaborator ensures that hotel receives 14 point checklist of good practice for minimising risk of Legionella infection
No further action necessary at international level

29. Procedures for clusters
Collaborator in country of infection must arrange for local health authorities to carry out investigations at cluster site:
a technical site inspection and risk assessment (Form A)
environmental investigations, sampling and implementation of emergency control measures (Form B)
Information about the investigation must be passed back to ECDC in 2 weeks and 6 weeks
Sanctions are imposed in the country of infection if these procedures fail
Cluster details and hotel published on ECDC website.
Immediate withdrawal by relevant tour operators

30. European outbreaks

31. Facilitator notes:
Acknowledgements The creation of this training material was commissioned in 2010 by ECDC to Health Protection Agency (UK) and the University of Chester (UK) with the direct involvement of Louise Brown, Janice Gidman, Emma Gilgunn-Jones, Ian Hall (on behalf of the ECDC Legionnaires Disease Outbreak Toolbox Development Group), Tim Harrison, Rob Johnston, Carol Joseph, Sandra Lai, John Lee, Falguni Naik, Nick Phin, Michelle Rivett, and Susanne Surman-Lee. The revision and update of this training material was commissioned in 2017 by ECDC to Transmissible (NL) with the direct involvement of Arnold Bosman and Kassiani Mellou.