NORD gratefully acknowledges Ariane Bergeron, MDCM Candidate, McGill University School of Medicine, and Professor David Murdoch, Dean and Head of Campus, University of Otago, Christchurch, New Zealand, for assistance in the preparation of this report.
Legionnaires’ disease, caused by the aerobic gram-negative coccobacillus Legionella, mostly L. pneumophila, is an important cause of community-acquired pneumonia (CAP), accounting for approximatively 10% of cases. The exact incidence of Legionnaires’ disease is unknown due to different awareness levels in different countries, diagnostic methods and reporting, but the US Centers for Disease control (CDC) reported nearly 10,000 cases in the USA in 2018. Infection with Legionella occurs through the inhalation of an aerosol containing bacteria generated by water droplets, usually coming from a contaminated water system. It does not spread from person-to-person. Legionnaires’ disease often affects individuals over the age of 50, people who are heavy smokers and immunocompromised individuals.
Legionnaires’ disease presents similarly to other bacterial pneumonias, such as pneumococcal pneumonia, with signs and symptoms like high fever, cough, chills, difficulty breathing (dyspnea), headache, chest pain, muscle pain (myalgia) or joint pain (arthralgia). Legionnaires’ disease can present as a more severe illness in some patients, mostly in those who are immunocompromised, and might require hospitalization and intensive care. This disease is treated with an antibiotic monotherapy, which is the use of only one antibiotic, with azithromycin or levofloxacin on an outpatient basis. Legionella pneumonia has a fatality rate of 10% in the community or 25% if healthcare-associated, which is similar to other types of bacterial pneumonia.
Legionnaires’ disease was initially recognized in early 1977, when an outbreak of a form of pneumonia affected members attending an American Legion Convention at a hotel in Philadelphia in 1976. The bacterium responsible for the disease was identified and named Legionella pneumophila by the CDC. They were later able to identify outbreaks and sporadic cases of this disease dating back to the 1940s, but the causative agent could not be identified at the time because Legionella pneumophila does not grow on traditional culture media.
Legionnaires’ disease is a respiratory disease, which means it affects the lungs. The lungs are composed of lobes, two for the left and three for the right lung. The air travels in the lungs through the bronchi, then bronchioles and then into alveoli, which are little sacs forming lung tissue. Pneumonia is an inflammation of the lungs caused by an infection, where the alveoli fill with pus and can eventually become solid (consolidation).
The incubation period for Legionnaires’ disease, which is the time between exposure to the infectious agent and the onset of symptoms, is two to 10 days. Longer incubation periods have been recorded in a minority of cases, for example in immunocompromised patients. The prodrome of symptoms, which are the early signs of illness, include headache, muscle pain (myalgia), weakness and fatigue (asthenia) and loss of appetite (anorexia).
The most common signs and symptoms are a high fever up to more than 40oC (104oF), which can be accompanied by a slow heart rate (relative bradycardia); cough, which is productive of purulent sputum in approximately 50% of patients; difficulty breathing (dyspnea); neurological abnormalities such as confusion, delirium and lethargy; muscle or joint pain (myalgia or arthralgia); diarrhea; chest pain, which is often worse on inspiration (pleuritic) and on the side affected by the pneumonia; headache; and, nausea or vomiting.
A small proportion of affected individuals can show non-respiratory manifestations such as an enlarged spleen (splenomegaly) or spleen rupture; inflammation of the pericardium, which is the bag around the heart (pericarditis); inflammation of the heart muscle (myocarditis); joint inflammation (arthritis); acute renal failure; wound infections; and, infections of the central nervous system.
Laboratory findings may include low blood sodium (hyponatremia), low blood phosphorus (hypophosphatemia), abnormal liver function tests, elevated creatine kinase, high C-reactive protein levels and blood in the urine (microscopic hematuria). These findings are common but are non-specific to Legionnaires’ disease. Radiographic finding on a chest X-Ray include pulmonary infiltrates, which are usually patchy and affecting only one lobe (unilobar) and progressing to consolidation of the surrounding lung tissue. However, there is no specific radiographic features suggestive of Legionnaires’ disease, and all the types of infiltrates have been reported in Legionnaires’ disease cases.
Legionellosis refers to disease caused by an infection with bacteria of the Legionella family, which includes 59 known species, from which 26 are known to cause disease in humans. These bacteria are gram-negative coccobacilli. The most common agent reported to cause Legionnaires’ disease is Legionella pneumophila serogroup 1.
Legionella bacteria are found in aquatic environments, both natural and artificial. They can be found in water with temperatures ranging from below 0oC to up to 60oC, but are mostly found in hot water services, such as evaporative cooling water systems that serve air conditioning plants or hot tubs. Bacterial growth occurs most in stagnant water with temperatures between 20-45oC, with the optimal temperature for multiplication being between 32-42oC. Some species, such as L. longbeachae, are associated with soil exposure. Legionella species are intracellular organisms, which means they cannot grow by themselves; they need the support of other organisms (usually protozoa) to multiply. Due to the bacteria growing inside protozoa and being a part of a biofilm, which is slime made by microorganisms, Legionella bacteria are protected from normal water treatment processes. Thus, Legionella bacteria can spread through towns in the drinking water system. The source of an outbreak can often be linked to either air conditioning or water systems, since Legionnaires’ disease is caused by the inhalation of contaminated water droplets.
The incidence of Legionnaires’ disease in the USA was estimated to be 10,000 cases in 2018. There is seasonal variation as most patients are diagnosed in the summer and early autumn. Studies show that most cases were community-acquired pneumonia (CAP) while about a quarter of the cases were travelled-related and less than 10% were health-care-related. However, it is hard to get an accurate estimate of the incidence of this disease since it is underdiagnosed, underreported and it has been shown that some people will develop only mild illness or show no symptoms at all.
This disease mostly affects people over the age of 50, children rarely getting sick with it. Studies also show that men are more at risk than women to develop Legionnaires’ disease, with a ratio of 3:1. Some risk factors increase the incidence of this disease in specific populations, including: cigarette smoking, heavy alcohol consumption, diabetes, chronic respiratory disease, chronic kidney disease and immunosuppression due to cancer or organ transplantation. Hospitalized patients can be at an increased risk of contracting Legionnaires’ disease in certain situations such as after an organ transplant, after receiving general anesthesia because of the increased risk of aspiration or use of immunosuppressant drugs.
As mentioned above, a failure to respond to beta-lactam antibiotics or the appearance of gastrointestinal and neurological symptoms in pneumonia patients should raise suspicions about an infection with Legionella. Legionnaires’ disease can be diagnosed with different laboratory tests such as PCR, cultures and a urinary antigen test. Legionella bacteria are very hard to detect on gram-stain so this is not the diagnostic method of choice in the case of Legionella pneumophila pneumonia. Blood tests can also be done to detect the presence of specific antibodies in the serum, but they are not a reliable diagnostic method as it takes several weeks for antibodies to appear in the blood and a positive result could be from a previous Legionella subclinical infection.
The best method for diagnosis is a polymerase chain reaction (PCR) test. In a PCR test, the genetic material (DNA) can be amplified and identified more easily. The advantage of the PCR is that it can detect all the species and serogroups from the Legionella family and is a rapid test, but its availability can be limited. PCR testing is the test with the highest sensitivity and specificity for the diagnosis of Legionnaires’ disease.
Other diagnostic tests for Legionnaires’ disease are a combination of respiratory sample culture and urinary antigen test.
Legionella can be isolated by culture from a lower respiratory tract sample, lung tissue or pleural fluid. It usually takes three to five days to get the results from a culture. Cultures can detect Legionella species and serogroups that cannot be detected by the urinary antigen test, which only detects Legionella pneumophila serogroup 1. It is important to note that while a positive culture is diagnostic of Legionnaires’ disease, a negative culture does not rule out the disease due to the poor sensitivity of the test. Cultures from blood yield poor results and should not be performed.
The urinary antigen test consists of looking for “pieces” (antigens) of Legionella in the urine. The antigens can be detected, and a positive test can be reported within 48 to 72 hours from the onset of the symptoms and remain positive for approximately two months. As mentioned, the limitation of the urinary antigen test is that it only detects Legionella pneumophila serovar 1. Since this serogroup represents at least 80% of the cases of Legionnaires’ disease in the USA, this is still the most widely used test. If Legionnaires’ disease is suspected after a negative urinary antigen test, a respiratory sample should be sent for PCR or culture to confirm the diagnosis.
Studies show that early therapy can reduce mortality. Legionnaires’ disease is treated effectively by many classes of antibiotics: macrolides, tetracyclines, ketolides and quinolones. The first line of treatment is a course of azithromycin, doxycycline or levofloxacin on an outpatient basis. Erythromycin is no longer used as first-line treatment as the newer macrolides and quinolones have a better activity against Legionella bacteria. In individuals with more severe disease who require hospitalization, the use of intravenous fluoroquinolones is recommended. In transplant patients, quinolones, doxycycline and azithromycin should be favored to avoid interactions with other drugs. Drug resistance has not been linked to treatment failure in cases of Legionella infections. There is no evidence supporting combined therapy, thus monotherapy is the mainstay of treatment.
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