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

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

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

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 https://wiki.ecdc.europa.eu/fem/w/wiki/387.outbreak-investigations

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.

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.

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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.

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)

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

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

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

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

European outbreaks

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.