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KEYWORDS
Atypical pneumonia;
Legionella
pneumophila;
Chlamydophila
pneumoniae;
Mycoplasma
pneumoniae;
Antibiotic;
Laboratory;
Sensitivity;
Specicity;
Diagnosis
PALABRAS CLAVE
Neumona atpica;
Legionella
pneumophila;
Chlamydophila
pneumoniae;
Corresponding author at: Facultad de Ciencias de la Salud, Universidad Anhuac Mxico Norte, Av. Universidad Anhuac #46 Col. Lomas
Anhuac, Huixquilucan, Edo de Mxico C.P. 57286, Mexico.
E-mail address: robertobf1@gmail.com (R. Berebichez-Fridman).
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
0185-1063/ 2015 Sociedad Mdica del Hospital General de Mxico. Published by Masson Doyma Mxico S.A. All rights reserved.
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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R. Berebichez-Fridman et al.
Mycoplasma
pneumoniae;
Antibitico;
Laboratorio;
Sensibilidad;
Especicidad;
Diagnstico
Introduction
Epidemiology
Legionella pneumophila
Morphological and structural characteristics
Risk factors
Legionella pneumophila is an aerobic, Gram-negative,
nonencapsulated, non-spore-forming, agellated, intracellular bacterium, often characterized as being a coccobacillus. Its cell wall contains fatty acid with high ubiquinone
content and the capacity to form biolms. It is oxidase,
catalase and gelatinase-positive, has no nitrate-reducing
capacity, and it can be observed with fascin staining.
L. pneumophila is an insidious bacterium that requires
cysteine and iron to thrive. For this reason, it is detected
by culture on buffered charcoal yeast extract (BCYE),
polymyxin B, anisomycin and cefamandole agar. It can also
be isolated by amoebal coculture.1---3
There are over 50 species of Legionella, but evidence
has shown that only 19 of these cause infection in humans.
There are also 64 subgroups of the Legionella genus, and 15
L. pneumophila serogroups.1,3
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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Atypical pneumonias
Clinical manifestations
Serology testing has shown that infection is often asymptomatic. Symptomatic L. pneumophila infection can present
either as severe pneumonia, called Legionnaires disease, or
as a u-like condition known as Pontiac fever.9
Legionnaires disease is characterized by clinical and
radiological signs consistent with pneumonia. Initial symptoms include anorexia, vomiting, myalgia and headache.
Over 90% of patients present fever between 12 and 24 h
after onset of the rst symptoms. Fever is high grade, usually over 39.4 C, and is accompanied by shivering and cough
producing little or no sputum. Most patients complain of
dyspnoea, and in 60% the mental state is altered, with
symptoms ranging from lethargy to obtundation. Chest pain
is common in immunocompromised patients, and can be
confused with pulmonary thromboembolism. These patients
can also present fever alone, with no other symptoms
of pneumonia, despite radiological evidence of pulmonary
inltrates. Around 50% of patients present gastrointestinal
symptoms, such as diarrhoea with blood and mucous, and
intestinal colic. Other manifestations include hypotension,
bradycardia, bronchospasm, toxic encephalopathy and rash.
Radiological signs are similar to those of pneumonia caused
by other pathogens.9,10,12
In Pontiac fever, patients present u-like symptoms, with
fever, headache, shivering, myalgia and poor general condition, with no clinical or radiological signs of pneumonia. The
disease is self limiting, and resolves in 2---7 days.10
Cases of extrapulmonary infection have been documented, possibly due to haematogenous dissemination.
These include prosthetic valve endocarditis, sternotomy
wound infection, skin infections, abscess, cellulitis, sinusitis pericarditis, myocarditis, peritonitis, pancreatitis, acute
pyelonephritis with renal abscess, and osteomyelitis, all of
which are uncommon. Elevation of alkaline phosphatase and
hepatic transaminase levels are a common nding. Hyponatraemia is more common in L. pneumophila infection than
in other forms of bacterial pneumonia.12
Diagnosis
Diagnosis is conrmed in the laboratory by culture, demonstration of bacterial antigens or DNA in body uids, or
evidence of a serologic response. Polymorphonuclear leucocytosis, azotaemia, acute liver failure, hyponatraemia, and
hyperphosphataemia are all common ndings.1,10,12
Legionella can be cultivated from sputum, endotracheal
aspirate, bronchoalveolar lavage, open lung biopsy and
pleural uid. Sensitivity of expectorated sputum culture,
however, is low (50%); bronchoalveolar lavage samples are
known to have a higher sensitivity.12,13
The pathogen grows after 48 h incubation at 37 C in aerobic conditions. Colonies are characterized by their blue
colour and frosted glass appearance.13 On Gram staining,
they are shown as long, thin, Gram-negative bacilli. Samples must be incubated and regularly checked for at least
10 days before the culture is reported negative.14
Legionella can be isolated in respiratory tract and tissue specimens in 2---4 h using direct immunouorescence.
This method, however, can give false positives due to
3
cross-reactivity, and the sensitivity of the test ranges from
25% to 66%.13,14
Immunochromatography, which can detect antigens in
urine in around 15 min, is considered to be a good L. pneumophila detection method. The test has 56---97% sensitivity,
and 97% specicity, although it will only detect L. pneumophila serogroup 1.14,15
Serology using indirect immunouorescence can take
between 3 and 4 weeks to detect antibodies. A fourfold
or higher rise in titre is considered diagnostic. In a single
sample, a titre of 1:256 with documented pneumonia is considered diagnostic. These tests should be interpreted with
caution due to the large number of patients with asymptomatic infection.2,15,20
Nucleic acid amplication tests for detecting Legionella
in respiratory tract, urine, serum and leukocyte samples
have a sensitivity of between 30% and 86%.13 Table 1 shows
the different characteristics of the methods used to diagnose L. pneumophila infection.
Chlamydophila pneumoniae
Morphological and structural characteristics
Chlamydophila pneumoniae is an obligate intracellular
Gram-negative bacterium that can exist as either an elementary or reticulate body. Elementary bodies, which are
biologically inactive and can survive in hostile environments,
are the infective form of the bacteria. In this form, the
bacterium enters the host cell, usually via the respiratory
tract, where it transforms into a reticulate body. In this
metabolically active, intracellular, non-infectious form, the
bacterium undergoes binary ssion and returns to its elementary body form. The elementary bodies are released
from the host cell after cell lysis.23
Sometimes, due to external factors such as lack of nutrients, reticulate bodies remain in an aberrant form, which
is a relatively larger reticulate body that is still viable
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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Table 1
Diagnostic test
Pros
Cons
Specicity (%)
Sensitivity (%)
Reference
Culture
Sputum, respiratory
tract samples, open
lung biopsy
specimens and
pleural uid.
Considered the gold
standard for
diagnosis.
Useful in epidemics.
Sample collection
can be invasive.
Sensitivity is low.
Requires special
culture media.
Culture takes 2---4
days.
100
80---90
95
30---50
<60
25---66
Serology
Detects antigens
in urine
Fast results
(15 min). Results
remain positive for
weeks/months.
Only detects L.
Pneumophila
serogroup 1.
99---100
75---99
PCR
Fewer false
negatives than
immunouorescence. Test is fast
and comprehensive
(all Legionella
species).
Not commercially
available.
94---99
33---92
Epidemiology
In the United States, C. pneumoniae is estimated to cause
over 300,000 cases of pneumonia each year. Anti-C. pneumoniae antibodies are detected in around half (50%) of
individuals of 20 years of age. The rate increases with age,
and antibodies are detected in 70---80% of elderly individuals.
It is thought to cause 20% of all lower airway infections, and
that 70% of these are either asymptomatic or not serious
enough to compel the patient to seek medical attention. It
has been suggested that between 3% and 10% of all community acquired pneumonias are caused by C. pneumoniae,
and in Latin America it is thought to cause around 6% of all
such diseases. The pathogen is also responsible for 20% of
all upper respiratory tract infections.24,25
Risk factors
Risk factors for C. pneumoniae infection are thought to
involve immune system functions and the genetic predisposition of the host. In studies carried out in Asia, researchers
have observed that infection is extremely seasonal, and
peaks in the summer months.26
Although many studies have associated C. pneumoniae
infection with an increased risk for heart disease due to the
inammatory response elicited by the pathogen, the results
remain inconclusive.26---30 The presence of this pathogen has
also been associated, albeit insignicantly, with a number of diseases, including asthma exacerbations, multiple
sclerosis, chronic fatigue syndrome, Alzheimers disease,
age-related macular degeneration, chronic skin lesions,
cerebrovascular disease.26,27
Clinical manifestations
C. pneumoniae causes sinusitis, pharyngitis and pneumonia, although in most cases infection is asymptomatic. The
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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Atypical pneumonias
Table 2
Diagnostic test
Pros
Cons
Specicity (%)
Sensitivity (%)
Reference
Culture
Gold standard
method for
identifying the
pathogen.
100
50---70
Burillo &
Bouza31
Microimmunouorescence
(MIF) and
immunouorescence
Serotype-specic
detection of IgM,
IgG and IgA (IgM
greater than 1:16
or a four-fold rise
in IgG by MIF).
Not effective after
start of antibiotic
treatment.
Being an obligate
intracellular
pathogen, specimens
drawn must include
host cells, and must
be preserved for
between 2 and 6
days. Special cell
lines and in vitro
culture methods must
be used.
Cost, availability,
trained technicians.
86
79
Burillo &
Bouza31 ,
Oba25
93
68
Burillo &
Bouza31
PCR
Absence of a true
gold standard
prevents accurate
evaluation of this
method.
elevated, and serum antibodies may be detected. On histology, tissue samples of infected patients show slight
intra-alveolar inammation and cytoplasmic inclusion. It is
important to note that absence of antibodies does not rule
out C. pneumoniae.29 Table 2 shows the characteristics of
different C. pneumoniae diagnostic procedures.
Mycoplasma pneumoniae
Diagnosis
Morphological and structural characteristics
Diagnosis should be based on clinical suspicion. Certain
radiological features are suggestive of C. pneumoniae
infection, such as subsegmental, generally single patchy
inltrate, lobar or sublobar consolidation, or interstitial
inltrate with hilar adenopathy. In 20---25% of all cases, pleural effusion, generally bilateral, is also seen.28,31
Laboratory studies will usually nd no changes in
leukocyte levels, inammatory parameters can be slightly
This is the most important species in the Mycoplasmataceae family of bacteria. M. pneumoniae is an extracellular,
free-living obligate aerobe that only infects humans. In its
coccus morphology it measures between 0.2 and 0.3 nm;
in its bacillus morphology it is 1---2 nm long and 0.2 nm
wide. It does not have a cell wall, which makes it resistant to penicillins, cephalosporins, vancomycin and other
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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Epidemiology
M. pneumoniae infection is more common in toddlers in
day care centres and in children aged 5---15 years. It causes
between 10% and 20% of all cases of community-acquired
pneumonia, of which 60% occur in children. Extrapulmonary
complications occur in 25% of all cases. It has recently
started to be considered the main cause of bacterial pneumonia on military bases. It colonizes the nose, throat,
and trachea, and is transmitted via respiratory aerosols.
Respiratory disease caused by M. pneumoniae infection
is marginally more common in the summer and autumn
months.34
Each year, 2 million new cases of M. pneumoniae pneumonia are reported in the United States, with 100,000
hospitalizations. It reaches epidemic proportions every 4---8
years.35
M. pneumoniae is the leading cause of atypical pneumonia among children and adolescents, causing between
10% and 30% of all cases. Although it is usually associated
with mild acute respiratory infections, such as sore throat,
pharyngitis, rhinitis, and tracheobronchitis, it can also cause
more serious infections, such as pneumonia or lung abscess.
It is associated with acute asthma exacerbations, chronic
obstructive pulmonary disease, and can even cause community outbreaks on a scale similar to u epidemics.35,36
Clinical picture
Infection is usually asymptomatic. In the case of recurrent
infection, or infection in children, the following symptoms
may present:
It mainly presents as tracheobronchitis, followed 2 or
3 weeks later by fever, general malaise, headache and
unproductive cough, which can be accompanied by acute
pharyngitis. Symptoms can worsen and persist for up to 2
more weeks, and can even lead to pneumonia.36,37
Uncommon manifestations include myalgia and digestive symptoms. Secondary extrapulmonary complications
can include meningoencephalitis, paralysis, myelitis, pericarditis, haemolytic anaemia, arthritis, and mucocutaneous
lesions.34
Diagnosis
Early, accurate diagnosis of M. pneumoniae infection is
essential in order to start the right antibiotic therapy. As
it is impossible to reach a diagnosis based solely on the nonspecic clinical signs and symptoms, laboratory tests must
be performed.
Chest X-ray ndings include unilateral or bilateral alveolar inltrates, centrilobular peribronchovascular nodules,
areas of ground glass attenuation, intrathoracic lymphadenopathy, and even pleural effusion.
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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Atypical pneumonias
Table 3
Diagnostic test
Pros
Cons
Culture
Serology
PCR
Conclusion
Atypical pneumonias are an important, worldwide health
problem, and all physicians should be skilled in recognizing, diagnosing and treating the main forms of atypical
pneumonia. There is scant reference in the literature to
epidemiological studies on the prevalence of atypical pneumonias in Mexico, and what little information is available is
out-dated. We believe, therefore, that this review should
pave the way for future studies on this topic. It is also
important to analyse the short- and long-term impact of
atypical pneumonias in Mexico, and the systemic implications of infection by each pathogen.
Conict of interest
The authors declare they have no conict of interest.
Funding
No funding was received for this study.
References
1. Cosentini R, Tarsia P, Blasi F, et al. Community-acquired pneumonia: role of atypical organisms. Monaldi Arch Chest Dis.
2001;56:527---34.
2. Fernndez R, Surez I, Rubinos G, et al. Neumona adquirida en
la comunidad por grmenes atpicos: tratamiento y evolucin.
Arch Bronconeumol. 2006;42:430---3.
3. Arnold FW, Summersgill JT, LaJoie AS, et al. A worldwide
perspective of atypical pathogens in community-acquired pneumonia. Am J Respir Crit Care Med. 2007;175:1086---93.
Specicity (%)
Sensitivity (%)
Reference
100
80---90
92
30---80
64---99
69---92
Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005
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Please cite this article in press as: Berebichez-Fridman R, et al. Atypical pneumonias caused by Legionella
pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia. Rev Med Hosp Gen Mx. 2015.
http://dx.doi.org/10.1016/j.hgmx.2015.06.005