Facilitator notes: Session 2: Clinical and epidemiological aspects of Legionnaires’ disease ECDC, 2011 Major revision: 2018

Objectives Specific objectives of this session: Review knowledge of pathogenesis, pathophysiology and clinical presentation of Legionella in humans Discuss underpinning epidemiology of Legionnaire’s disease Understand epidemiological surveillance systems within Europe Discuss European Guidelines in relation to Legionnaire’s disease Understand legislative aspects Facilitator notes:

Content The pathological, physiological and clinical features of Legionnaires’ disease Epidemiological overview of Legionnaires’ disease, in particular in the context of Europe European guidelines for control and prevention of travel associated Legionnaires’ disease and their under-pinning rationale Legal context

Legionnaires’ disease Severe atypical pneumonia caused by Legionella bacterium Incubation period: usually considered 2-10 days (median 6/7 days) in outbreak situations documented up to 19 days Flu-like illness, fever, headache, dry cough, confusion, diarrhoea, multi organ failure Case fatality: ~10% for community acquired / travel associated may be up to 30% for nosocomial acquired LD Low attack rate (less than 5%)

Outcome Long term outcomes Restrictive pulmonary disease Weakness and fatigue Neurological problems Poor memory and concentration Retrograde amnesia Cerebellar dysfunction –causing problems with balance, motor control

Pontiac fever Mild illness without pneumonia Incubation period 12-48 hours Flu-like illness lasting several days 0% mortality High attack rate (> 90%) Often only identified as part of an outbreak

Cause of Legionnaires' disease >60 Legionella species At least 19 species associated with human infection L. pneumophila - 80-90% of all infections Serogroup 1 - most common cause of illness

Legionnaires’ disease: modes of infection Inhalation of aerosol particles into the lung Particles must be small enough to get down to the lung alveoli but large enough to contain at least one bacterial cell Aspiration can occur - especially for nosocomial patients Person to person transmission Not proven Suspicion once described in NEJM 2016 [1] [1] Correia AM, Ferreira JS, Borges V, Nunes A, Gomes B, Capucho R, Gonçalves J, Antunes DM, Almeida S, Mendes A, Guerreiro M. Probable person-to-person transmission of Legionnaires’ disease. New England Journal of Medicine. 2016 Feb 4;374(5):497-8.

Legionnaires’ disease: incubation periods 2-10 days for most cases - typically 6-7 days But Legionnaires' disease outbreak, Netherlands, 1999 incubation (2-19 days), median (7 days), 16% of cases >10 days Legionnaires' disease outbreak, Melbourne, 2000 incubation (1-16 days), median (6 days), 7% of cases >10 days Legionnaires' disease outbreak, Japan, 2008 incubation (2-14 days), 5% of cases > 10 days (incubation period definition inclusion criteria may have introduced bias due to most recent visit being used) Collecting information for 14 days prior onset of symptoms is reasonable compromise

Who is at risk? Smokers Heavy drinkers People aged 50 years or more Certain occupational groups Immunosuppressed by treatment or disease Underlying disease (e.g. diabetes, chronic heart disease) Hospital transplant patients Men more than women Recent travel

Where are the risks? Industrial sites with water cooling devices or large buildings with wet cooling systems used for air conditioning Hot and cold water systems used in Hospitals Hotels/holiday accommodation/office buildings Whirlpool spas Cruise ships Domestic premises Fountains/car washes Humidifiers Respiratory therapy equipment

Legionnaires’ disease: laboratory diagnosis is essential Cannot establish a diagnosis on clinical grounds Prompt diagnosis reduces mortality Accurate diagnosis improves understanding of epidemiology Diagnosis should be linked to national and international case definitions

Why case definitions are needed To set national and international standards for defining cases To verify the diagnosis To compare case details within and between countries To facilitate national and international investigations and collaborations To develop best practice within and between countries

EU Case definition: Legionnaires’ disease ICD code A48.1 Case Classification - Probable case Any person with pneumonia AND either laboratory evidence of at least one of the following: Detection of Legionella pneumophila antigen in respiratory secretions or lung tissue  Detection of Legionella spp. nucleic acid in a clinical specimen L. pneumophila non-serogroup 1 or other Legionella spp. specific antibody response L. pneumophila  serogroup 1, other serogroups or other Legionella species: single high titre in specific serum antibody OR any person with pneumonia and at least one of the following epidemiological links: Environmental exposure Exposure to the same common source  

EU Case definition: Legionnaires’ disease ICD code A48.1 Case Classification - Confirmed Case Any person with a diagnosis of pneumonia AND with laboratory evidence of at least one of the following: Isolation (culture) of Legionella species from respiratory secretions or any normally sterile site The presence of L. pneumophila urinary antigen determined using validated reagents/kits L. pneumophila  serogroup 1 significant antibody rise in paired serum sample COMMISSION IMPLEMENTING DECISION of 8 August 2012 amending Decision 2002/253/EC laying down case definitions for reporting communicable diseases to the Community network under Decision No 2119/98/EC of the European Parliament and of the Council

Legionnaires’ disease in Europe 2016 1.37 notification rate N/100000 7069 reported cases 30 reporting countries 8.2% case fatality % 441 reported deaths

Total European cases: country of report 2016

Total European cases: rate per 100,000 population 2016

Total European cases: Age-specific rate per 100,000 population 2016

Total European cases: Gender-specific rate per 100,000 population 2016

Age-specific rate per 100,000 population, EU/EEA, Germany, France, Spain, Italy 2016

Age-specific rate per 100,000 population, EU/EEA, UK, Portugal, Netherlands, Denmark, 2016

Added value of European surveillance Monitor trends between countries Monitor trends within countries Identify where national surveillance needs improving Target support to under-diagnosing countries training schemes laboratory expertise - EQA schemes Develop European standards for a surveillance strategy and control and prevention legislation Collaborate on research and surveillance projects

Total European cases 2007-2016

Total European cases: rate per 100,000 population 2007-2016

Cases by country of report

Cases by country of report

Cases by country of report

Case fatality (%), EU/EEA, France, Germany, Denmark, UK, Netherlands, 2007 - 2016

Percentage (%) of fatal cases by age group, EU/EEA, France, Germany, Denmark, UK, Netherlands, 2007 - 2016

In a summary… Legionnaires' disease remains an uncommon, mainly sporadic respiratory infection with low notification rates in EU/EEA countries The number of reported cases steadily increased over the last years Different trend among countries – an increasing trend in most of them Different notification rates among European countries (range from 0.00 – 4.51 cases per 100,000 population in 2016) Higher notification rate among men Higher notification rate among older people

Europe’s first recognised travel associated outbreak Benidorm, Spain 1973 and 1980 One of the first international outbreak investigations took place when this hotel in Spain had two outbreaks, the first in 1973 before legionella was discovered and the second soon after. A case control study was conducted that showed the showers to be the source of infection and the person who used them first each morning the most likely one to get infected.

The Guidelines Address differences in national responses to cluster alerts Standardise investigation procedures across Europe Increase protection of Europeans from acquiring legionnaires’ disease as a result of travel This shows the countries of infection that were visited by more than 5 cases in 2008. Italy and France often come at the top of this list because they both report a large number of cases with travel in their own country of residence.

Case definitions for travel associated Legionella infection Single cases Cases associated with one or more nights away from home in tourist or business accommodation in the two to ten days before onset of illness and where the accommodation site has not been associated with any other cases in the previous two years Clusters/outbreaks Two or more cases who stayed at the same accommodation site in the two to ten days before onset of illness and whose illness is in the same two year period [1] [1] ECDC Legionella Toolbox: https://legionnaires.ecdc.europa.eu/?pid=205

Legal Context 1 Legionella is spread by any mechanism/operation that can generate aerosols or water droplets therefore cases are usually linked to man made water/cooling systems Poorly maintained/designed water/cooling systems are usually the sources of infection and because of this there is usually someone to blame and potential for legal remedy.

Legal Context 2 Most countries have legislation governing the control of Legionella in water/cooling systems, e.g. health and safety legislation Because of this, breaches of such legislation can lead to prosecution and if cases can be linked to such breaches, then the patient has recourse to legal means to gain compensation.

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.