Med Clin (Barc).

2016;146(9):394396

www.elsevier.es/medicinaclinica

Editorial article

Legionellas pneumonia. When is useful the urinary antigen test?

Neumona por Legionella, cundo solicitar la antigenuria en orina?
Soraya Jodra Snchez a, , Miguel Barrueco Ferrero a,b,c
a

Servicio de Neumologa, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain

Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
c
Instituto de Investigacin Biomdica de Salamanca (IBSAL), Salamanca, Spain
b

Since Legionella pneumophila (L. pneumophila) was identied in 1976 it has been recognized as a common cause of
hospital-acquired and non-hospital-acquired pneumonia.1 The
term Legionellosis includes 2 different syndromes: Legionnaires
disease, the most common cause of pneumonia caused by Legionella
spp., and Pontiac fever, characterized by fever, headache and myalgia, but without pneumonia.2
The Legionella family consists of 50 species, L. pneumophila being
the most common,3 and within this, serotype 1 is the most frequently isolated. The incidence of community-acquired pneumonia
(CAP) caused by L. pneumophila varies from one area to another,
hovering around 1% in subjects treated as outpatients and 1528%
in hospitalized patients. Twenty ve per cent of these require
admission to an intensive care unit (ICU).4
In Spain L. pneumophila pneumonia is a notiable disease
since 1996. It is important that cases are quickly notied so
that the source can be studied as soon as possible. Outbreaks
are usually related to the contamination of cooling systems and
water tanks, although more frequently L. pneumophila pneumonia appears as sporadic cases, predominantly affecting smokers,
elderly and chronically ill patients or in routine treatment with
glococorticoids.4 Therefore, underdiagnosis of such cases is suspected.
Isolation of the bacteria by culturing respiratory specimens has
been the traditional diagnostic method. It is the only available
method to detect infections caused by any species and serotypes of
Legionella (approximately 1520% of infections are caused by different L. pneumophila species or serotypes). However, the drawback
is the time it takes to grow the microorganism, as well as the serological diagnosis, providing a late diagnosis from a clinical point of
view.5
We must note the signicant diagnostic advance the detection
of L. pneumophila antigen in urine has meant, since it allows an

Please cite this article as: Jodr Snchez S, Barrueco Ferrero M. Neumona por Legionella, cundo solicitar la antigenuria en orina? Med Clin (Barc).
2016;146:394396.
Corresponding author.
E-mail address: sorayajodra 9@hotmail.com (S. Jodra Snchez).
S.L.U. All rights reserved.
2387-0206/ 2015 Elsevier Espana,

etiologic diagnosis almost immediately.57 Since included in clinical practice, it has been shown that L. pneumophila pneumonias
are a lot more prevalent endemic disease than previously thought,
and this has also allowed to detect outbreaks that otherwise would
have gone unnoticed.
The antigen is a soluble component of the Legionellas cell wall
lipopolysaccharide. It is thermostable, and detectable from the
onset of symptomatology and in some cases for many months later.
The results do not appear clearly inuenced by the previous administration of antibiotics.
The antigen diagnostic techniques have evolved signicantly
since their inception by agglutination with latex particles, passive hemagglutination or radioimmunoassay. The latter was the
rst useful, sensitive and specic technique. It has 60% sensitivity in direct urine and 80% in concentrated urine, with a 100%
specicity in both cases. Currently these techniques have been
replaced by enzyme immunoassay and membrane immunochromatography, with a sensitivity in concentrated urine ranging
8090% and a 98100% specicity. Both systems have a similar
performance, although with 2 clear advantages for immunochromatography: a specic laboratory is not necessary and it is
faster (15 vs 90 min). These techniques detect L. pneumophila,
serogroup 1antigen, implying the possibility of false negative if
a secondary infection with L. pneumophila serogroup. However,
some enzyme immunoassay techniques are already able to detect
all serogroups of L. pneumophila and other Legionella species, but
this does not guarantee the same sensitivity for all serogroups
and species. False positives have been detected in patients with
serum sickness and in those who have had a previous infection
by Legionella, since positivity may be evident from day one and in
some cases it may last for more than a year. It should be noted
that the heat treatment of the urine does not mean the disappearance of positivity but it eliminates false positives in negative
samples.5,8,9
In the latest guidelines of the American Thoracic Society on
the CAP, L. pneumophila is the fth etiology, considering frequency, in patients requiring hospitalization and the third among
those requiring ICU admission. This regulation recommends early
identication of causative agents of pneumonia, since it requires
changes in antibiotic coverage and also due to the epidemiological

S. Jodra Snchez, M. Barrueco Ferrero / Med Clin (Barc). 2016;146(9):394396

implications involving some etiologies, as in the case of L.

pneumophila. Nevertheless, it does not establish the use of L. pneumophila antigen in urine as routine use, restricting it only to CAP
hospitalized cases requiring ICU admission, treatment failure in
patients with CAP treated on an outpatient basis, a history of alcohol abuse, recent trip and in case of pleural effusions. However, it
would be optional in outpatients.10 In the paper by Engel et al.11
recently published, the authors analyze the cost-effectiveness ratio
of their routine determination for the detection and early treatment
of CAP caused by Legionella spp. They recommend restricting the
use of urinary antigen to CAP patients with severe disease and/or
risk factors. The paper by Molinos on antigen detection in urine
also states that only in case of an outbreak of Legionnaires disease
(regardless of treatment) or if CAP is serious, its presence should be
investigated.8
Therefore, even though the various publications do not establish
routine use, from our point of view there are 2 different aspects in
terms of cost-effectiveness to be considered: (1) the importance of
early detection and the inuence it may have on treatment, and
(2) the potential importance as sentinel for the early detection of
outbreaks.
Regarding the rst point, in the opinion of several authors,
early detection would help obtain a proper treatment early, leading to a better prognosis of the disease.1217 However, it should be
noted that no randomized clinical trials are available to assess the
effectiveness of a targeted therapy as an option, based on the positivity of urinary antigen test, compared to using standard empirical
antibiotic treatment, in order to improve clinical outcomes. An
example of this point is reected in the clinical practice guidelines
of the National Institute for Health and Care Excellence published
in 2014, which raises the question whether in cases of moderate
and severe CAP the routine use of urinary antigen would improve
treatment outcomes. It states that routine use to conrm or rule
out pneumonia due to L. pneumophila would improve the administration of antibiotics and compliance, and would reduce costs,
but it stresses that there are no randomized studies to conrm this
theory.18
The second aspect concerning the sentinel character of antigenuria to detect outbreaks has not yet been reected in the
literature. It is clear that in an epidemic of Legionnaires disease
(regardless of treatment) we would have to request the proper
antigen,8,10 but since an important part of CAP patients visit the
emergency departments, would it be advisable to request L. pneumophila antigenuria in urine in all pneumonias treated in those
departments? Would this attitude allow to discover endemic outbreaks and, therefore, prevent them? The cost of antigenuria
determination in urine in a hospital is around 5.80 D . Therefore, its
implementation, protocolised at the emergency services, in both
Primary Care and Specialized Care, would certainly be efcient
from the sentinel perspective of early detection of cases. Neither in this case there is evidence to recommend for or against
its use.
In short, Legionella pneumonia is an endemic and underdiagnosed disease that can occur as epidemics or by sporadic outbreaks.
The prevalence of endemic cases is unknown and might be precisely related to the routine non-determination of antigenuria in
urine, given the CAPs not requiring hospitalization and treated
as outpatients after having been diagnosed mainly in Primary
Care and Emergency services. Up to date this is just a theory,
but it makes us consider the possibility of requesting routine
antigenuria in urine to any CAP, regardless of diagnosis and
severity.
Therefore, the application of sensitive and specic tests, along
with better outbreak investigation, will help us achieve a more
accurate understanding of its epidemiology. As noted by Torres et Cayl,14 it is clear that when the legionellosis occurs in

395

outbreaks they hardly go unnoticed but, what might happen when a

few cases occur or when it is isolated cases? It is what the authors
call Guadiana, a disease that comes and goes periodically, reaching signicance only when it comes to outbreaks acquiring public
signicance.
Conict of interests
The authors report no conicts of interest related to the content
of this manuscript.
References
1. McDade JE, Shepard CC, Fraser DW, Tsai TR, Redus MA, Dowdle
WR. Legionnaires disease: isolation of a bacterium and demonstration of its role in other respiratory disease. N Engl J Med.
1977;297:1197203.
2. Glick TH, Gregg MB, Berman B, Mallison G, Rhodes WW
Jr, Kassanoff I. Pontiac fever: an epidemic of unknown etiology in a health department. Am J Epidemiol. 1978;107:
14960.
3. Benson RF, Fields BS. Classication of the genus Legionella. Semin
Respir Infect. 1998;13:909.
4. Rodrguez de Castro F, Zalacan Jorge R. Neumologa adquirida
en la comunidad. In: lvarez-Sala Walther JL, Casan Clar P,
Rodriguez de Castro F, Rodrguez Hermosa JL, Villena Garrido V, editors. Neumologa Clnica. Barcelona: Elsevier; 2010.
p. 27080.
5. Cercenado E, Cantn R, editors. Procedimientos en Microbi
de
ologa Clnica. Recomendaciones de la Sociedad Espanola
Enfermedades Infecciosas y Microbiologa Clnica. Diagnstico
microbiolgico y control de la legionelosis. 2005. Available
from: https://www.seimc.org/contenidos/documentoscienticos/
procedimientosmicrobiologia/seimc-procedimientomicrobiologia
20.pdf [accessed 14.10.15].
6. Berdal BP, Farshy CE, Feeley JC. Detection of Legionella pneumophila
antigen in urine by enzyme-linked immunospecic assay. J Clin
Microbiol. 1979;9:5758.
7. Domnguez J, Gal N, Matas L, Pedroso P, Hernndez A, Padilla E,
et al. Evaluation of a rapid immunochromatographic assay for the
detection of Legionella antigen in urine samples. Eur J Clin Microbiol
Infect Dis. 1999;18:8968.
8. Molinos L. Deteccin de antgenos en la orina. Arch Bronconeumol.
2006;42:1013.
9. Pontoizeau C, Dangers L, Jarlier V, Luyt CE, Guiller E, Fievet MH, et al.
Ruling out false-positive urinary Legionella pneumophila serogroup 1
and Streptococcus pneumoniae antigen test results by heating urine.
J Clin Microbiol. 2014;52:43479.
10. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD,
Dean NC, et al. Infectious Diseases Society of America/American
Thoracic Society consensus guidelines on the management of
community-acquired pneumonia in adults. Clin Infect Dis. 2007;44
Suppl. 2:S2772.
11. Engel MF, van Manen L, Hoepelman AI, Thijsen S, Oosterheert JJ.
Diagnostic, therapeutic and economic consequences of a positive
urinary antigen test for Legionella spp. in patients admitted with
community-acquired pneumonia: a 7-year retrospective evaluation.
J Clin Pathol. 2013;66:797802.
12. Jeric Alba C, Nogus Soln X, Santos Martnez MJ, Flez Flor M, Gar
Marr M, et al. Brote epidmico de neumona
cs Jarque JM, Marinosa
comunitaria por Legionella pneumophila en Barcelona: el brote de la
Barceloneta. Efecto del diagnstico y tratamiento precoz. Rev Clin
Esp. 2004;204:704.
13. Yu VL, Stout JE. Community-acquired legionnaires disease: implications for underdiagnosis and laboratory testing. Clin Infect Dis.
2008;46:1365.
14. Torres A, Cayl JA. Las legionelosis: un Guadiana no slo neumolgico. Arch Bronconeumol. 2002;38:13.
15. Maldonado R, Jans JM, lvarez J, Valls FX. Legionelosis y retraso
diagnstico. Enf Emerg. 2000;2:1212.

396

S. Jodra Snchez, M. Barrueco Ferrero / Med Clin (Barc). 2016;146(9):394396

16. Nelson KE. Emerging and new infectious diseases. In: Nelson KE,
Williams CM, Graham NMH, editors. Infectious disease epidemiology. Theory and practice. Gaithersburg: Aspen Publishers, Inc.; 2001.
p. 3334.
17. Falc V, Molina I, Juste C, Crespo M, Almirante B, Pigrau C, et al. Treatment for Legionnairess disease. Macrolides or quinolones? Enferm
Infecc Microbiol Clin. 2006;24:3604.

18. National Institute por Health and Care Excellence. NICE clinical
guideline 191. Pneumonia: diagnosis and management of community and hospital-acquired pneumonia in adults; 2014. p. 178.
Available from: guidance.nice.org.uk/cg19.