Revised Guidelines on the Management of Legionnaires Disease in Ireland, 2008

Chapter 1: Clinical Aspects of Legionnaires Disease

1.1 Introduction

1.2 Legionella - natural history of the organism

1.3 Recognised and potential sources of Legionella infection

1.4 Method of transmission

1.5 Risk of Infection

1.6 Treatment

1.7 Definitions

1.8 Epidemiology

1.8.1 Legionnaires disease in Ireland

1.8.2 Legionnaires disease in Europe

Clinical Aspects of Legionnaires Disease

1. 1 Introduction

Infection with Legionella bacteria can cause two distinct clinical syndromes, grouped together under the name legionellosis. The first is pontiac fever, a self-limiting influenza-like illness. The incubation period is usually 24-48 hours. Patients recover spontaneously in 2-5 days. The second and the subject of these guidelines is Legionnaires disease which is a severe and potentially fatal form of pneumonia. Symptoms include a flu-like illness, followed by a dry cough and progression to pneumonia. Diarrhoea, vomiting and mental confusion are common. The case fatality rate is about 12%, rising to about 30% in nosocomial cases.

Legionnaires disease was first recognised in 1976 following an outbreak of pneumonia among delegates at the annual convention of the American Legion held in the Bellevue Stratford hotel in Philadelphia. In that outbreak 221 persons became ill and 34 died of a previously unknown disease.2 Legionella pneumophila was the organism isolated.

1.2 Legionella - natural history of the organism

Legionella are Gram-negative bacteria that live as intracellular parasites of a variety of species of amoebae and protozoa in aquatic environments. Figure 1 shows an electron micrograph of an amoeba entrapping a L. pneumophila bacterium with an extended pseudopod.

To date, at least 50 Legionella species and 70 serotypes have been described.3 L. pneumophila serogroup 1 is the cause of 70-90% of all cases of Legionnaires disease where the aetiological agent has been isolated. L. pneumophila serogroup 1 can be further divided into many subtypes. One of these subtypes, the Pontiac subtype, is responsible for 85% of cases due to L. pneumophila serogroup 1.4 Other species identified as causing pneumonia in humans include L. micdadei, L. bozemanii, L. dumoffii, and L. longbeachae.3
Legionella bacteria are ubiquitous in nature and can be found naturally in environmental water sources such as rivers, lakes and reservoirs, usually in low numbers. Legionella bacteria have also been isolated from potting soils, particularly in Australia.5 From the natural source, the organism passes into sites that constitute an artificial reservoir (piped water in towns and cities, water networks, water systems in individual buildings, cooling towers, etc.).

Water temperatures in the range 20C to 45C favour growth of Legionella bacteria. The organisms do not appear to multiply below 20C and will not survive above 60C. They are acid-tolerant and can withstand exposure to pH 2.0 for short periods. They have been isolated from environmental sources with pH ranging from 2.7 to 8.3.7

Legionella bacteria multiply within amoebae and protozoa. However, when environmental conditions are unfavourable e.g. absence of nutrients or temperature changes, the Legionella-infected amoebae encyst, allowing the survival of the host and the parasite until more favourable conditions allow excystment. In both natural and man-made water systems, Legionella-infected amoebae are found in association with microbial biofilm containing many different microorganisms (Figure 2).4 The presence of sediment, sludge, scale and other material within water systems, together with biofilms, are thought to play an important role in the persistence of Legionella bacteria, providing favourable conditions in which the Legionella bacteria may grow. Environmental changes can disrupt the biofilm or dislodge portions of it and lead to a sudden and massive release of Legionella bacteria into the water system. If the water is then aerosolised and inhaled by humans or aspirated by humans, the bacteria can cause illness in susceptible individuals. Legionella bacteria also exist as free living organisms.

Drinking water disinfectants such as free chlorine penetrate poorly into biofilms and Legionella bacteria are further shielded within the amoebae they parasitise.9 Free chlorine levels in municipal drinking water are generally sufficient to neutralise free floating coliform bacteria but are often too low to kill Legionella bacteria living in biofilm. In addition, many drinking water disinfectants such as free chlorine do not reach distal sites in a water distribution system, can dissipate quickly in heated water, are often sequestered by biofilm, sludge and scale and are often removed during water filtering such as occurs in spa pools.

1.3 Recognised and potential sources of Legionella infection

Legionnaires disease is normally acquired through the respiratory tract, by inhalation of aerosols contaminated with Legionella bacteria. Aspiration of water contaminated with Legionella has also been described as a route of transmission. This may occur predominantly in persons with swallowing disorders or in conjunction with nasogastric feeding. Currently, there are no reports in the international literature of person-to-person transmission.

The infectious dose for Legionella bacteria in humans is unknown. Those at higher risk for Legionnaires disease include:

The incubation period is usually between 2 and 10 days although longer periods have been reported. The risk of acquiring Legionella infection is principally related to the individual susceptibility of the subject exposed and the degree of intensity of exposure, represented by the quantity of Legionella present and the length of exposure. Attack rates during outbreaks of Legionnaires disease are low- less than 5%. When a susceptible person inhales a contaminated aerosol consisting of droplets of the right size (1-5 micron), he or she can develop the disease.

The preferred antimicrobial treatment of Legionnaires disease should be guided by the severity of the disease, degree of immunocompromise, and the availability and potential toxicity of individual drugs.4 The British Thoracic Society (BTS) guidelines recommend clarithromycin rifampicin as the treatment of choice for Legionnaires disease with a fluoroquinolone as an alternative. They also recommend that specialist advice is sought when considering what treatment to use.13;14 The Infectious Disease Society of America recommends azithromycin or a fluoroquinolone (moxifloxacin or levofloxacin) as the preferred treatment for Legionnaires disease patients who are hospitalised. Erythromycin, doxycycline, azithromycin, clarithromycin or a fluoroquinilone can be used for patients who do not require hospitalisation.

Confirmed case of Legionnaires disease
A clinical diagnosis of pneumonia with laboratory evidence of one or more of the following:

Isolation of any Legionella organism from respiratory secretions, lung tissue or blood

Demonstration of a specific antibody response (four-fold or greater rise) to L. pneumophila serogroup 1 or other serogroups or other Legionella species by the indirect immunufluorescent antibody test or by microagglutination

The detection of specific Legionella antigen* in urine using validated reagents.

A clinically compatible case, or a clinically compatible case with an epidemiological link, and one of the following:

A single high titre in specific serum antibody to L. pneumophila serogroup 1, other serogroups or other Legionella species

Detection of specific Legionella antigen in respiratory secretions or direct fluorescent antibody (DFA) staining of the organism in respiratory secretions or lung tissue using evaluated monoclonal reagents.

Studies have estimated that Legionnaires disease accounts for between 0.5% to 10% of community-acquired pneumonia requiring hospitalisation in adults.4 In a review of nine studies of community-acquired pneumonia in which admission to intensive care was required, L. pneumophila was second only to Streptococcus pneumoniae as the aetiological agent most frequently identified.18 Mortality from severe Legionnaires disease in these nine studies ranged from 0-25%. Overall, Legionella is probably the second to fourth most common cause of community-acquired pneumonia.

The proportion of hospital-acquired pneumonia due to Legionnaires disease has been reported as ranging from 0-47%.19 Numerous species and serogroups of Legionella can be present in hospital water systems. It has been shown when an active search for Legionella infection is initiated, cases are frequently confirmed.19;20 Although L. pneumophila serogroup 1 accounts for the majority of cases, other serogroups have also been associated with infection in healthcare settings.20;21 This has important clinical implications as the most widely used test for diagnosing Legionnaires disease is the urinary antigen test and this test is specific for L. pneumophila serogroup 1only

Legionnaires disease is a statutorily notifiable disease in Ireland as defined by the Infectious Disease Regulations 1981 (S.I. No. 390 of 1981). Under the Infectious Diseases (Amendment) (No.3) Regulations 2003 (S.I. No. 707 of 2003), which came into effect on 1 January 2004, laboratory and clinical notification of Legionnaires disease is mandatory. Cases should be notified to the medical officer of health (MOH) in the relevant department of public health. Table 1 summarises the number of cases of Legionnaires disease notified to the Department of Health and Children (DoHC) and the Health Protection Surveillance Centre (HPSC) from 1994 to 2007. HPSC took over responsibility for the collation of infectious diseases notifications on 1 July 2000.

There were 67 cases of Legionnaires disease reported in Ireland during the period 2000 to 2007. There were five deaths due to Legionnaires disease during this period, giving a case fatality rate (CFR) of 7.5%. Forty-five cases (67.2%) were male, and 22 (32.8%) were female. Forty-one cases (61.2%) were travel-associated, twenty-one (31.3%) were community-acquired, and five (7.5%) were nosocomial. Fifty-seven cases (85.1%) were classified as confirmed and ten (14.9%) as probable.

The median age was 48 years, with a range from 18 to 80 years. The median age for females was 45 years and 49 years for males.

Legionnaires disease is a statutorily notifiable disease in many but not all European countries. In 2006, the overall European rate of infection was 11.2 cases per million population (based on a population of 562.7 million in 35 countries).

The majority of cases were community-acquired (58.7%), 21.4% were travel-associated, 4.9% were nosocomial, 1.5% other, and 13.5% unspecified. The cases were classified as confirmed in 89.5% of cases, 9.0% were presumptive and 1.5% were unknown. The main method of diagnosis was by urinary antigen (80.2%), culture (8.6%), serology (9.6%), other (0.1%), unknown (1.6%).
Under-diagnosis and under-reporting are thought to lead to a significant under-estimation of incidence of Legionnaires disease in many countries. The causes include:

Denmark has consistently had a higher rate of infection (around 20/million population) than most other countries. The factors probably associated with this are that it is a small country which carries out high levels of testing for Legionella in patients with pneumonia and it has a centralised reference laboratory for diagnosing and reporting cases. In recent years, EWGLI has adopted the rate of 20/million population as the 'gold standard' for countries to reach in order to reflect a truer incidence of infection.

The reported incidence of Legionnaires disease in Ireland has increased from 0.3/million population in 1994 to 3.8/million in 2007. However, the rate is still low compared with many European countries and the rate falls well short of the 'gold standard' as set by EWGLI. This could suggest that a major degree of under-diagnosis and under-reporting currently exists in Ireland or that the rate in Ireland may actually be lower than in some European countries. It is critical to the control of Legionnaires disease that enhanced surveillance is maintained at a high level. Significantly, it has been reported that delay of appropriate therapy results in poor outcome.23 A rapid urine antigen test is available in Ireland. Consideration should be given for the more widespread use of this test when a patient presents with pneumonia. The importance of specimens for culture should also be considered.