Epidemiology, Transmission, Pathogenesis and Treatment of Legionellosis

Legionella is a facultative, intracellular bacterium that causes legionellosis presenting as either Legionnaires’ disease or Pontiac fever (1).

Epidemiology

Although over 50 Legionella species have been identified, the clinically relevant species include: Legionella pneumophila, Legionella micdadei and Legionella dumoffii (2). Legionella pneumophila (primarily serogroup 1) causes 95% of legionellosis in Europe, however in Australasia, Legionella longbeachae infections occur almost as frequently (3). Other Legionella species primarily cause infection in immunocompromised patients (4). The incidence of legionellosis is higher in males (5) and in the elderly. Increased susceptibility and severity of disease occurs with comorbidities such as respiratory disease, diabetes mellitus or immunosuppression (5).

Transmission

The main environmental reservoir of Legionella is within protozoa in freshwater environments. The single exception to this is L. longbeachae infections which can be isolated from potting mix (3). Transmission of Legionella to humans occurs through the inhalation of contaminated water aerosols (6) and there is no human-to-human transmission. A major source of disease outbreaks are biofilms established in warm, humid environments, such as air-conditioning systems (7) in hospitals. Biofilms aid in transmission by offering resistance against disinfectants (8) such as chlorine.

Pathogenesis

Once inhaled, Legionella reach the lung alveoli and are phagocytosed by macrophages which seal them into phagosomes. Legionella are biphasic and have a flagellated, virulent transmissive form and a unflagellated, replicative form where bacteria exist within Legionella Containing Vacuoles (LCVs) (9). Within phagosomes, Legionella assemble a Dot/Icm Type IV Secretion System which translocates effector proteins into the host cytoplasm (10). The secretion of around 300 effector proteins allow Legionella to convert the phagosome into an LCV (11) by remodelling the vacuolar membrane. Therefore, LCVs provide a replicative niche that allows evasion of phagosome maturation and bacterial degradation via phagosome-lysosome fusion. Surface structures such as lipopolysaccharide, the macrophage infectivity potentiator protein (Mip) (12), flagella and type IV pili aid in the virulence of Legionella by enhancing attachment, replication or by initiating an inflammatory cascade in the host. Eukaryotic-like genes acquired through co-evolution with freshwater protozoa (9) are thought to be critical in the persistence of Legionella in man-made environments and for the intracellular survival within human alveolar macrophages through the acquisition of virulence traits that target eukaryotic pathways. In Legionnaire’s disease, the invasion and replication of Legionella within alveolar macrophages leads to inflammation of the lung (12) and a severe form of pneumonia. Patients may also present with fever, diarrhoea and confusion. In contrast, Pontiac fever results in an acute, non-pneumonic, influenza-like disease. Legionellosis is primarily diagnosed using a culture test of sputum or through Direct Fluorescent Antibody staining (13).

Treatment

The timely administration of appropriate antimicrobials is a critical prognosis factor for Legionnaire’s Disease but not Pontiac fever which is usually self-resolving. β-lactams and other antibiotics (e.g. aminoglycosides) are ineffective against Legionella (14) as they are unable to penetrate the host cell membrane. The main classes of antimicrobials active against Legionella include the newer macrolides (e.g. azithromycin) and fluoroquinolones (e.g. levofloxacin) (15). These classes are recommended due to their greater intracellular penetration (16). In immunocompromised patients or patients with comorbidities, rifampicin is also used (15), often in combination with other antimicrobials to minimise the development of resistance.

In conclusion, Legionella poses a great risk globally and an understanding of its epidemiology, transmission and pathogenesis is vital for the effective treatment of legionellosis.

References

1. Allen JG, Myatt TA, MacIntosh DL, Ludwig JF, Minegishi T, Stewart JH, Connors BF, Grant MP, McCarthy JF.2012. Assessing risk of health care-acquired Legionnaires’ disease from environmental sampling: The limits of using a strict percent positivity approach. American Journal of Infection Control 40:917-921.

2. Percival SL, Williams DW. 2013. Microbiology of Waterborne Diseases: Microbiological Aspects and Risks, 2nd ed, Elsevier Ltd.

3. Bacigalupe R, Lindsay D, Edwards G, Fitzgerald JR.2017. Population genomics of Legionella longbeachae and hidden complexities of infection source attribution. Emerging Infectious Diseases 23:750.

4. Gobin I, Newton P, Hartland E, Newton H.2009. Infections caused by nonpneumophila species of Legionella. Rev Med Microbiol 20:1-11.

5. Phin N, Parry-Ford F, Harrison T, Stagg HR, Zhang N, Kumar K, Lortholary O, Zumla A, Abubakar I.2014. Epidemiology and clinical management of Legionnaires’ disease. The Lancet Infectious Diseases 14:1011-1021.

6. Paschke A, Schaible UE, Hein W.2019. Legionella transmission through cooling towers: towards better control and research of a neglected pathogen. The Lancet Respiratory Medicine 7:378-380.

7. Abu Khweek A, Fernández Dávila NS, Caution K, Akhter A, Abdulrahman BA, Tazi M, Hassan H, Novotny LA, Bakaletz LO, Amer AO.2013. Biofilm-derived Legionella pneumophila evades the innate immune response in macrophages. Frontiers in cellular and infection microbiology 3:18.

8. Carratalà J, Garcia-Vidal C.2010. An update on Legionella. Current Opinion in Infectious Diseases 23:152-157.

9. Albert-Weissenberger C, Cazalet C, Buchrieser C.2007. Legionella pneumophila – a human pathogen that co-evolved with fresh water protozoa. Cellular and molecular life sciences : CMLS 64:432.

10. Hilbi H. 2014. Molecular mechanisms in Legionella pathogenesis. Springer, Berlin.

11. Pike CM, Boyer-Andersen R, Kinch LN, Caplan JL, Neunuebel MR.2019. The effector RavD binds phosphatidylinositol-3-phosphate and helps suppress endolysosomal maturation of the -containing vacuole. The Journal of biological chemistry 294:6405.

12. Barer M, Irving WL, Swann A, Perera N. 2018. Medical Microbiology: A Guide to Microbial Infections: Pathogenesis, Immunity, Laboratory Investigation and Control, 19th ed, Elsevier, Edinburgh.

13. Mizrahi H, Peretz A, Lesnik R, Aizenberg-Gershtein Y, Rodríguez-Martínez S, Sharaby Y, Pastukh N, Brettar I, Höfle MG, Halpern M.2017. Comparison of sputum microbiome of legionellosis-associated patients and other pneumonia patients: indications for polybacterial infections. Scientific reports 7:40114-40114.

14. Maurin M, Raoult D.2001. Use of Aminoglycosides in Treatment of Infections Due to Intracellular Bacteria. Antimicrobial Agents and Chemotherapy 45:2977.

15. Sikora A, Gładysz I, Kozioł-Montewka M, Wójtowicz-Bobin M, Stańczak T, Matuszewska R, Krogulska B.2017. Assessment of antibiotic susceptibility of Legionella pneumophila isolated from water systems in Poland. Annals of Agricultural and Environmental Medicine 24:66-69.

16. Erdogan H, Can F, Demirbilek M, Timurkaynak F, Arslan H.2010. Erratum to: In vitro activity of antimicrobial agents against Legionella isolated from environmental water systems: first results from Turkey. An International Journal Devoted to Progress in the Use of Monitoring Data in Assessing Environmental Risks to Man and the Environment 171:689-689.