|

Received: 29 October 2015    Accepted: 5 February 2016

DOI: 10.1002/jgf2.15

REVIEW ARTICLE

Mycoplasma pneumoniae infection: Basics

Takeshi Saraya MD, PhD

Department of Respiratory Medicine, Kyorin

University School of Medicine, Tokyo, Japan Abstract
Mycoplasma pneumoniae (Mp) is one of the leading causes of community-­acquired
Correspondence
Takeshi Saraya, Department of Respiratory pneumonia and can cause a number of extrapulmonary manifestations in the absence
Medicine, Kyorin University School of of pneumonia. In this regard, primary care physicians should know how to suspect,
Medicine, Mitaka, Tokyo, Japan.
Email: sara@yd5.so-net.ne.jp diagnose, and manage patients with Mp infection. This review gives a general over-
view of the basic clinical aspects of Mp infection with special reference to pneumonia,
which will help further understanding of the disease.

KEYWORDS
clinical features, general overview, Mycoplasma pneumoniae pneumonia

1 | INTRODUCTION identified an agent that was the principal cause of primary atypical
pneumonia using cotton rats, hamsters, and chick embryos, which
Mycoplasma and ureaplasma species are known to occur in humans. was referred to as the “Eaton agent.” Chanock7 succeeded in cultur-
The term “mycoplasma” (Greek; “mykes”=fungus and “plasma”=formed) ing the Eaton agent in mammalian cell-­free medium and proposed the
emerged in the 1950s1 and replaced the older pleuropneumonia-­like taxonomic designation “Mycoplasma pneumoniae” in 1963. A more
organisms (PPLO) terminology. Mycoplasma pneumoniae (Mp) are detailed history is available in two different articles, “The history of
1-­2 μm long and 0.1-­0.2 μm wide, compared with a typical bacillus of Mycoplasma pneumoniae pneumonia” by Saraya8 or by Marmion.9
1-­4 μm in length and 0.5-­1.0 μm in width. The cell volume of Mp is less
than 5% of that of a typical bacillus. Typical colonies of Mp, shown in
Figure 1 like a “fried egg” on agar plates, rarely exceed 100 μm in di- 3 | EPIDEMIOLOGY
ameter. Mp lacks a cell wall, which makes it intrinsically resistant to an-
timicrobials, such as beta-­lactams that work by targeting the cell wall, Mycoplasma infections occur sporadically throughout the year,
and thus causes a wide spectrum of clinical symptoms and disease and widespread community outbreaks can occur. The Japanese
manifestations. This article focuses on the diverse clinical aspects of Respiratory Society (JRS) reports that the frequency of Mp pneumo-
Mp infection, including a review of the current literature. nia among patients with community-­acquired pneumonia (CAP) is
approximately 5.2%-­27.4%.10 Mp is one of the most common patho-
gens that cause community-­acquired pneumonia. The first and larg-
2 | HISTORY OF ISOLATION OF est prospective multicenter study involving 156 Japanese medical
MYCOPLASMA PNEUMONIAE institutions looking at atypical pneumonia in Japan was conducted
between April 2005 and September 2008.11 This study examined
In 1938, Reimann reported seven patients with an unusual form of 223 patients with Mp pneumonia who were equally distributed with
tracheobronchopneumonia and severe constitutional symptoms.2,3 regard to gender, and the mean age was 37.9±16.6 (mean±SD) years.
He believed the clinical picture of this disease differed from that of Importantly, macrolide-­resistant Mp was first isolated from
diseases caused by influenza viruses or known bacteria and “primary Japanese children in 200012 and in adults in 2007, all of whom
atypical pneumonia” was suspected. In the early 1940s, Eaton et al.4-6 possessed a 23S-­rRNA mutation. In the 2000s, the prevalence of

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2017 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.

118  |  
wileyonlinelibrary.com/journal/jgf2  J Gen Fam Med. 2017;18:118–125.
SARAYA |
      119

repeated infections can occur in the same person. In addition, per-

sons with hypogammaglobulinemia have an increased susceptibility
to Mp infections, and those with sickle cell disease may experience
more severe illness.

5 | MP PNEUMONIA

The clinical findings of Mp pneumonia are diverse16 (Table 1) and are

characterized by the insidious onset of fever, malaise, headache, and
cough. The persistent cough is the clinical hallmark of Mp infection, of
which the severity and frequency increase over the next 1-­2 days, and
which may become debilitating. Mp infection has similar clinical find-
ings to those of respiratory viruses including but not limited to influ-
enza and adenovirus. However, Mp pneumonia is different from those
F I G U R E   1   Colonies of Mycoplasma pneumoniae on an agar plate
viral infections in that it has a more gradual onset of symptoms and
typically have a unique “fried egg” appearance
that diarrhea, nausea, and vomiting are unusual. Interestingly, com-
pared with pneumococcal pneumonia, pleuritic pain and shaking chills
macrolide-­resistant Mp having either an A2063G or an A2064G muta- are relatively rare.
tion rapidly increased in Japan13 as well as in East Asia, with a notably Goto reported that almost all patients with Mp pneumonia were
high isolation rate (92%) in China (Figure 2).14 classified as having mild (85.5%) or moderate (14.0%) infection
based on the A-­DROP severity score (A, age; D, dehydration; R, res-
piration; O, orientation; P, blood pressure) by the Committee for the
4 | CLINICAL FEATURES JRS Guidelines for the management of respiratory infections.17 The
­A-­DROP score classifies the infection as mild (score: 0), moderate
Most patients with Mp infection present with minor respiratory (score: 1-­2), severe (score 3), and very severe (score 4-­5). The mean
­illness, including pharyngitis and tracheobronchitis, and the infec- baseline body temperature of patients with Mp pneumonia was
tion is ­usually self-­limited. Only 3%-­13% of infected persons de- 37.7±1.0°C. This trend was similar to our single-­center retrospective
velop pneumonia. The illness spreads via droplets and tends to study performed between January 2006 and November 2013, gath-
spread in families with an incubation period of 2-­4 weeks. The ering 65 Mp pneumonia patients (Table 2).18 Among all 65 patients,
greatest risk of infection is in young persons aged 5-­20 years old. hypoxemia was noted in only 12.8% (n=5), and body temperature was
Lind et al.15 suggested that herd immunity lasts about 4 years 37.9±1.3°C.
(range: 2-­10 years) before people are again susceptible to Mp in-
fection. Thus, only partial immunity may follow infections, and

T A B L E   1   Frequencies of clinical findings in Mp pneumonia

Findings Frequency (%)

Country Age Year Proportion
China All ages 2012
2011
Symptom
2010
2009 Cough 93–­100
2008

Taiwan Child 2011

Malaise 74–89
2010
Headache 60–­84
Japan Child 2009-12
-15 Chilliness 58–78
16-19 2008-11
20-
Sore throat 53–­71
South Korea Child 2011
Adult Chest discomfort 42–­69
lsrael All ages 2010-11 Nasal symptoms 29–­69

Canada All ages 2007-10

Myalgias 45
Usa All ages 1997-2008
Sign
France
Germany
All ages
All ages
2011
2009-12
Fever 96–­100
Denmark All ages 2010-2011
Netherland All ages 1997-2008 Rales, wheezes 80–­84
0 20 40 60 80 100 % Pharyngeal erythema (without exudate) 12–73
Cervical adenopathy 18–­27
F I G U R E   2   Proportions of macrolide-­resistant Mycoplasma
pneumoniae in individual countries. Data are cited from Ref. 14 Table is from Ref. 15.
 |
120       SARAYA

T A B L E   2   Characteristics of 65 patients with Mp pneumonia Headache

Others
Digestive 5%
symptoms 2%
Total number of patients 65
4%
Age (mean±SD) 34.1±15.2 Fever
Chest pain 31%
Less than 40 years old 72.3% (n=47)
5%
Male 32.3% (n=21)
Cutaneous
Smoker 39.1% (n=18) symptoms
Underlying disease 43.5% (n=20) 7%

ADROP score (≥3) 0% (n=0)

Dyspnea
8%

On physical examination, more than half of the patients with Mp

pneumonia had no audible crackles and were likely to have late inspi-
Sputum
ratory crackles.19 Therefore, primary care physicians should be aware 10%
of these six factors that help discriminate Mp pneumonia from other
Dry cough
causes of CAP using the JRS “diagnostic tests”10 (Table 4). 28%

F I G U R E   3   Symptoms of 54 patients with Mycoplasma pneumoniae

pneumonia treated at Kyorin University
6 |  MACROLIDE-­R ESISTANT
MP PNEUMONIA
Figure 4, Mp infections cause various extrapulmonary complications,
Macrolide-­resistant (MR) Mp emerged and became widespread in East such as neurologic, cardiovascular, dermatological, digestive, he-
Asia after 2000. Persistent fever for more than 48 h after initiation of matological, and musculoskeletal manifestations, as well as others.
a macrolide may suggest the presence of MR-­Mp. In Japan, 87% of Neurologic complications include encephalitis, meningoencephalitis,
all pediatric Mp infections are due to MR-­Mp20 while the prevalence aseptic meningitis, myelitis, polyradiculitis, and psychosis. Central
in adult patients seems to be over 30%, mainly due to an A2063G nervous system manifestations occur in less than 1 per 1000 cases
21
mutation. Determination of MR-­Mp is difficult without application and are most often noted in hospitalized patients. Guillain-­Barré
of the test for 23S rRNA mutations. However, the duration of febrile syndrome and peripheral neuropathy have also both been reported.
illness in patients with MR-­Mp pneumonia was significantly longer The pathogenesis of CNS involvement is unknown, but direct inva-
(4.1±2.3 days) than in patients with macrolide-­susceptible (MS) Mp sion of organisms, generation of toxins, and autoimmunity (produc-
13 22
disease (1.6±0.8 days). Similarly, Suzuki et al. reported that pa- tion of autoantibodies) are possible mechanisms.26 Cardiovascular
tients with MR-­Mp pneumonia have a longer duration of febrile illness manifestations include pericarditis, endocarditis, and myocarditis.
and the number of febrile days during macrolide administration (me- The signs and symptoms are arrhythmia, congestive failure, chest
dian; 8 days, 3 days) than patients with MS-­Mp pneumonia (median; pain, and electrocardiographic abnormalities, particularly conduc-
5 days, 1 day). Another study showed that the numbers of febrile days tion defects. In patients with pericarditis, Mp is frequently isolated
or coughing days from the start of macrolide treatment were signifi- from the pericardial fluid and/or tissue.25 Regarding skin conditions,
cantly longer in patients with MR-­Mp (mean; 4 days, 11.4 days) than Stevens-­Johnson syndrome and erythema multiforme are associated
in patients with MS-­Mp (mean 1.5 days, 7 days).23 This suggests that with Mp infection. Hepatic involvement has also been reported,
if Mp-­infected patients have persistent fever for 48 h or more after characterized by liver dysfunction 7-­10 days after the onset of
initiation of macrolide therapy, we should be aware of the possibility fever. However, our preliminary data included both children (n=72)
of MR-­Mp infection. and adults (n=54) with Mp pneumonia who rarely showed derange-
Life-­threatening illness is extremely rare, and there are no appar- ment of serum alanine aminotransferase. On the other hand, the fre-
24
ent risk factors for fulminant Mp pneumonia. quency of elevation of aspartate aminotransferase was significantly
higher in children than in adults, which might reflect mild rhabdo-
myolysis as a result of musculoskeletal involvement. Among hema-
7 |  EXTRAPULMONARY MANIFESTATIONS tological manifestations, autoimmune hemolytic anemia is the most
common indirect extrapulmonary involvement. Other diseases, such
Our preliminary data showed the typical diverse symptoms of Mp as hemophagocytic syndrome, are recognized as cytokine-­storm
pneumonia (Figure 3). About 70% of patients experienced fever and disorders, and a hypercoagulable state can present as disseminated
cough (typically dry cough). Interestingly, 7% of patients had der- intravascular coagulation. Musculoskeletal diseases such as arthritis
matologic involvement. Importantly, extrapulmonary manifestations and rhabdomyolysis are rare but can be seen. Other diseases (mu-
due to Mp infection sometimes occur in the absence of Mp pneu- cositis, otitis media, and glomerulonephritis) are also sporadically
monia or even in the absence of respiratory symptoms.25 As seen in recognized.
SARAYA |
      121

F I G U R E   4   Classification of Mycoplasma
pneumoniae infection with or without
extrapulmonary involvement. DIC,
disseminated intravascular coagulation

8 | PATHOGENESIS OF MP PNEUMONIA

The severity of Mp respiratory disease appears to be related to the

degree to which the host immune response reacts to the infection.
This was confirmed by our “mice models” for Mp pneumonia sensi-
tized with various conditions.14,27-29 Mp attaches to bronchial epithe-
lial cells, mediated by a surface adhesion molecule, the P1 protein.
Several virulence mechanisms of Mp have been recognized, includ-
ing (i) lipoproteins/lipopeptides, (ii) community-­acquired respiratory
distress syndrome (CARDS) toxin, and (iii) other factors (hemolysin,
hydrogen peroxide, and superoxide radicals) (Figure 5). Mp has lipo-
proteins/lipopeptides with potent inflammatory properties, which
are recognized by host immune systems (ie, bronchial epithelial cells
and alveolar macrophages) via Toll-­like receptors TLR1, TLR2, and
TLR6.14,27,30 Recently, Shimizu et al.31 reported that TLR4 and autoph-
agy played important roles in the induction of the TLR2-­independent
pathway. Recently, CARDS toxin was recognized by Kannan et al.,32
which is involved in the pathophysiology of Mp disease. The toxin binds
to human surfactant protein A and annexin A2 on airway ­epithelial
cells and is internalized, leading to a range of pathogenetic events.33
Other factors are well known for their harmful effects via oxidative
stress.

9 |  ASSOCIATION OF MYCOPLASMA

PNEUMONIAE WITH BRONCHIAL ASTH MA

Several reports have described that Mp infection may be associated

with pediatric asthma exacerbation34 more often than in adults.35,36 F I G U R E   5   Postulated schema for generating process in human
Yano et al.37 reported that mycoplasmal respiratory infections on Mycoplasma pneumoniae pneumonia. CARDS, community-­acquired
the airway involved a complex interplay of airway inflammation via respiratory distress syndrome; TNF, tumor necrosis factor;
RANTES, regulated on activation, normal T cell expressed and
Mp-­specific IgE-­mediated hypersensitivity, resulted in the initial asth-
secreted; MCP-­1, monocyte chemotactic protein-­1. Figure cited
matic symptoms. Kraft et al.38 stated that Mp can be detected even in
from Ref. 14
the airways of chronic, stable adult asthma patients. Thus, latent Mp
infection and the asymptomatic carrier state may play a role in the infection but rather with viral infection (ie, human rhinovirus, human
pathogenesis of chronic asthma or asthma exacerbation. However, metapneumovirus, and respiratory syncytial virus) in up to approxi-
our data suggest that asthma exacerbation is not associated with Mp mately 50% of hospitalized asthmatic patients.39
 |
122       SARAYA

T A B L E   3   Diagnostic methods for Mp pneumonia

10 | HUMAN PATHOLOGY AND
BRONCHOALVEOLAR LAVAGE FLUID Diagnostic method Diagnostic criteria
FINDINGS Antibody levels
PA Single ≥1:320 titer
The pathological findings of Mp pneumonia have scarcely been re-
Pair ×4
ported. However, several reports have discussed different tissue-­
CF Single ≥1:64 titer
based diagnostic techniques, such as transbronchial lung biopsy,40-42
Pair ×4
video-­assisted thoracoscopic surgery,43 open lung biopsy,44-48 and
Culture
autopsy.49-55 According to those previous reports, the characteristic
ImmunoCard®
pathological feature of Mp pneumonia is a marked plasma cell-­rich
lymphocytic infiltration in the peribronchovascular areas (PBVAs) with PCR

accumulations of macrophages, neutrophils, and lymphocytes in the LAMP

alveolar spaces. Rapid antigen test (Ribotest)

Interestingly, bronchoalveolar lavage fluid analysis of Mp pneumo-
nia has scarcely been reported until recently.56,57 Those few studies
unextracted clinical specimens.64 In this regard, the LAMP assay will
demonstrated that PMNs and lymphocytes increased more than other
enable rapid (within a few hours), low-­cost detection of Mp infection.
cell types. The elevation of CD4-­to-­CD8 ratios in the bronchoalveolar
56 57 Optimal sample site varies in terms of pathogens or age. Sputum may
lavage fluid (BALF) was noted and ranged from 2.1 to 3.5±2.1 at
be superior to nasopharyngeal swabs or oropharyngeal swabs in detec-
various sampling times.
tion of Mp by nucleic acid amplification method from adults patients.65
Ribotest Mp (Asahi Kasei Pharma Corp), a rapid antigen kit for the de-
tection of the Mp ribosomal protein L7/L12 using an immunochromato-
11 | DIAGNOSTIC METHODS
graphic assay, became available in Japan in 2013. Another study showed
the threshold of Mp for this test was 1.1×104 cfu/mL.58 However, the
Although the presence of cold agglutinins is not specific, a titer of 1:64
diagnostic sensitivity of the Ribotest compared with PCR was not high,
or more is suggestive of Mp infection. Culture is the gold standard
at approximately 60%.59 From this perspective, the diagnosis of Mp
method for diagnosis of Mp infection; however, it requires 1-­2 weeks
pneumonia should be based on the following six factors proposed by the
for definitive results and is rarely carried out. Serological methods
JRS17: (i) <60 years of age; (ii) absence of or only minor underlying dis-
such as particle agglutination (PA), complement fixation (CF), and
ease; (iii) stubborn cough; (iv) abnormal findings on chest auscultation;
rapid diagnosis such as ImmunoCard® (IC) (mycoplasma immunoglob-
(v) absence of sputum or presence of an identifiable etiological agent by
ulin M [IgM]) are commercially available. The loop-­mediated isother-
rapid diagnostic testing; and (vi) peripheral white blood cell count <10
mal amplification (LAMP) method and a rapid antigen test (Ribotest;
000/μL (Table 4). If four or more of the proposed factors are present, Mp
Asahi Kasei Pharma Corp, Japan)58,59 using throat swabs are also com-
pneumonia can be easily discriminated from the other pathogens with
mercially available.
high sensitivity (88.7%) and moderate specificity (77.5%).66
If either CF titers are higher than 1:64 or PA titers are higher than
1:320, a diagnosis of Mp infection can be made. In previous reports,
the results of the IC Mycoplasma test were not concordant with that 12 | RADIOLOGICAL FEATURES
of the PA test, especially in adults,60 which requires a fourfold rise in
titers for a diagnosis to be made in adults (Table 3). In our unpublished data, a prominent feature of chest X-­ray, both in
Although a few laboratories can use PCR-­based diagnostics, the children and adults with Mp pneumonia, was consolidation followed
sensitivity and specificity for Mp infection are 40.7%-­66.7% and by ground glass opacities, which was predominantly seen in the mid-
88.8%-­98.5%, respectively, with the serological diagnosis used as the dle to lower lung fields.
reference standard.14,61 The LAMP assay, a novel nucleic acid amplifi-
cation method for the rapid detection of Mp by throat swab, was re-
cently developed and became commercially available in 2010 in Japan T A B L E   4   Characteristics of patients with Mp pneumonia
with the same sensitivity and specificity for detecting Mp as PCR.62 Items used for diagnosis
When the results of serological tests were considered as the stan- Under 60 y of age
dard, the sensitivity, specificity, and positive and negative predictive
No or minor underlying disease
values of the LAMP assay were 94.8%, 91.9%, 91.1%, and 95.2%, re-
Stubborn cough
spectively.63 The median duration of pharyngeal carriage, as measured
Poor chest auscultatory findings
by the LAMP assay, was 9.5 days. When the LAMP assay is compared
No sputum or etiological agent identified by rapid diagnosis
to a validated real-­time PCR test, the sensitivity of the LAMP assay
A peripheral white blood cell count <10 000/μL
was 88.5% tested on extracted nucleic acid and 82.1% evaluated on
SARAYA |
      123

A B

C D

F I G U R E   6   Thoracic computed
tomography demonstrates massive
consolidation in the left lower lung lobe
with air bronchograms (A), GGO in the
peribronchovascular area (B, C) with
thickening of bronchovascular bundles
(C). (D) shows centrilobular nodules with
bronchial thickening. GGO, ground glass
opacity

T A B L E   5   Recommended treatment for Mp pneumonia based on bid for 7-­10 days or azithromycin [AZM] 2 g once only or AZM 500 mg/d
different individual guidelines
for three days or erythromycin [EM] 800 mg-­1200 mg/d for 7-­10 days)
JRS IDSA/ATS BTS and second-­line oral therapy (minomycin [MINO] 200 mg/d or fluo-
roquinolones for 7-­10 days) as an outpatient. In the inpatient setting,
First line No description Macrolides Clarithromycin
Tetracycline the Society recommends intravenous treatment with MINO 200 mg/d
Alternative No description Fluoroquinolone Doxycycline or EM 600 mg-­1500 mg/d for 7-­10 days or AZM 500 mg once only
Fluoroquinolone as first-­line therapy, and intravenous fluoroquinolones as second-­line

JRS, Japanese Respiratory Society; IDSA, Infectious Diseases Society of therapy. Systemic steroid treatment as additive therapy may improve
America; ATS, American Thoracic Society; BTS, British Thoracic Society. the outcome of severe Mp pneumonia, but the effects are controversial.
If the fever persists for 48-­72 h after the initiation of macrolides,
oral or intravenous MINO 200 mg/d is recommended as MR-­Mp ther-
Regarding thoracic computed tomography of Mp pneumonia, only
apy, both in outpatient and inpatient settings. The recommended treat-
several small case series have been reported so far. The radiologi-
ment for Mp pneumonia by Infectious Diseases Society of America/
cal findings are diverse; however, consolidation (Figure 6A), ground
American Thoracic Society70 or British Thoracic Society guidelines71 is
glass opacities (Figure 6B), and bronchovascular bundle thickening
shown in Table 5. These treatments are intended for broad-­spectrum
(Figure 6C) with peribronchovascular (Figure 6B,C) or centrilobular
initial coverage and do not intend to differentiate the atypical patho-
nodules (Figure 6D) are prominent features of Mp pneumonia.18,67,68
gens from other CAP pathogens at the time of initial treatment.
In differentiating from Streptococcus pneumoniae pneumonia, the pres-
Mp pneumonia can manifest diverse clinical effects, and the diagnosis
ence of centrilobular nodules indicates Mp pneumonia.18
can sometimes be challenging for primary care physicians. However, an un-
derstanding and recognition of the wide variety of clinical manifestations of
Mp infection can lead to more accurate diagnosis and effective treatment.
13 | TREATMENT

Macrolides have direct effects on neutrophil function and produc- AC KNOW L ED G EM ENT
tion of cytokines involved in inflammation cascades. They have an
oral bioavailability of 50% and tissue concentrations of up to 300-­fold I am very grateful to Satoshi Kurata (Kyorin University School of

the serum concentration in the epithelial lining fluid, alveolar mac- Medicine, Department of Infectious diseases) who kindly provided a

rophages, and neutrophils. 69

For Mp infections, 14-­ or 15-­membered picture of Mp colonies.

ring macrolides are usually considered the first-­line agents, which are
well known for anti-­inflammatory, immunomodulative effects.
CO NFL I C T O F I NT ER ES T
Although JRS guidelines do not refer to the treatment regimen for
Mp pneumonia10 (Table 5), the Japanese Society of Mycoplasmology70 The authors have stated explicitly that there are no conflicts of inter-
recommends the first-­line therapy (oral clarithromycin [CAM] 200 mg est in connection with this article.
 |
124       SARAYA

REFERENCES 22. Suzuki S, Yamazaki T, Narita M, et al. Clinical evaluation of macrolide-­

resistant Mycoplasma pneumoniae. Antimicrob Agents Chemother.
1. Edward DG, Freundt EA. The classification and nomenclature 2006;50:709–12.
of organisms of the pleuropneumonia group. J Gen Microbiol. 23. Matsubara K, Morozumi M, Okada T, et  al. A comparative clinical
1956;14:197–207. study of macrolide-­sensitive and macrolide-­resistant Mycoplasma
2. Reinmann H. An acute infection of the respiratory tract with atypi- pneumoniae infections in pediatric patients. J Infect Chemother.
cal pneumonia: a disease entity probably by a filtrable virus. JAMA. 2009;15:380–3.
1938;111:2377–84. 24. Izumikawa K, Izumikawa K, Takazono T, et  al. Clinical features, risk
3. Reimann HA. Landmark article Dec 24 1938: an acute infection factors and treatment of fulminant Mycoplasma pneumoniae pneu-
of the respiratory tract with atypical pneumonia. A disease entity monia: a review of the Japanese literature. J Infect Chemother.
probably caused by a filtrable virus. By Hobart A. Reimann. JAMA. 2014;20:181–5.
1984;251:936–44. 25. Narita M. Pathogenesis of extrapulmonary manifestations of
4. Eaton MD, Meiklejohn G, van Herick W. Studies on the etiology of Mycoplasma pneumoniae infection with special reference to pneumo-
primary atypical pneumonia : a filterable agent transmissible to cotton nia. J Infect Chemother. 2010;16:162–9.
rats, hamsters, and chick embryos. J Exp Med. 1944;79:649–68. 26. Fernald GW. Immunologic mechanisms suggested in the association
5. Eaton MD, Meiklejohn G, van Herick W, Corey M. Studies on the eti- of M. pneumoniae infection and extrapulmonary disease: a review.
ology of primary atypical pneumonia : II. Properties of the virus iso- Yale J Biol Med. 1983;56:475–9.
lated and propagated in chick embryos. J Exp Med. 1945;82:317–28. 27. Saraya T, Nakata K, Nakagaki K, et al. Identification of a mechanism
6. Eaton MD, van Herick W, Meiklejohn G. Studies on the etiology of for lung inflammation caused by Mycoplasma pneumoniae using a
primary atypical pneumonia: III. Specific neutralization of the virus by novel mouse model. Results Immunol. 2011;1:76–87.
human serum. J Exp Med. 1945;82:329–42. 28. Hirao S, Wada H, Nakagaki K, et  al. Inflammation provoked by
7. Chanock RM. Mycoplasma pneumoniae: proposed nomenclature for Mycoplasma pneumoniae extract: implications for combination treat-
atypical pneumonia organism (Eaton agent). Science. 1963;140:662. ment with clarithromycin and dexamethasone. FEMS Immunol Med
8. Saraya T. The history of Mycoplasma pneumoniae pneumonia. Front Microbiol. 2011;62:182–9.
Microbiol. 2016;7:364. 29. Kurai D, Nakagaki K, Wada H, et  al. Mycoplasma pneumoniae ex-
9. Marmion BP. Eaton agent–science and scientific acceptance: a histor- tract induces an IL-­17-­associated inflammatory reaction in mu-
ical commentary. Rev Infect Dis. 1990;12:338–53. rine lung: implication for mycoplasmal pneumonia. Inflammation.
10. The JRS guidelines for the management of community acquired pneu- 2013;36:285–93.
monia in adults. Nihon Kokyuki Gakkai Zasshi. 2007;(suppl):2–85. 30. Shimizu T, Kida Y, Kuwano K. A dipalmitoylated lipoprotein from
11. Goto H. Multicenter surveillance of adult atypical pneumonia in Mycoplasma pneumoniae activates NF-­kappa B through TLR1, TLR2,
Japan: its clinical features, and efficacy and safety of clarithromycin. J and TLR6. J Immunol. 2005;175:4641–6.
Infect Chemother. 2011;17:97–104. 31. Shimizu T, Kimura Y, Kida Y, et al. Cytadherence of Mycoplasma pneu-
12. Okazaki N, Narita M, Yamada S, et  al. Characteristics of macrolide-­ moniae induces inflammatory responses through autophagy and toll-­
resistant Mycoplasma pneumoniae strains isolated from patients like receptor 4. Infect Immun. 2014;82:3076–86.
and induced with erythromycin in vitro. Microbiol Immunol. 32. Kannan TR, Provenzano D, Wright JR, Baseman JB. Identification and
2001;45:617–20. characterization of human surfactant protein A binding protein of
13. Morozumi M, Takahashi T, Ubukata K. Macrolide-­resistant Mycoplasma Mycoplasma pneumoniae. Infect Immun. 2005;73:2828–34.
pneumoniae: characteristics of isolates and clinical aspects of 33. Becker A, Kannan TR, Taylor AB, et  al. Structure of CARDS toxin, a
community-­acquired pneumonia. J Infect Chemother. 2010;16:78–86. unique ADP-­ribosylating and vacuolating cytotoxin from Mycoplasma
14. Saraya T, Kurai D, Nakagaki K, et al. Novel aspects on the pathogen- pneumoniae. Proc Natl Acad Sci USA. 2015;112:5165–70.
esis of Mycoplasma pneumoniae pneumonia and therapeutic implica- 34. Biscardi S, Lorrot M, Marc E, et  al. Mycoplasma pneumoniae and
tions. Front Microbiol. 2014;5:410. asthma in children. Clin Infect Dis. 2004;38:1341–6.
15. Lind K, Benzon MW, Jensen JS, Clyde WA Jr. A seroepidemiological 35. Nisar N, Guleria R, Kumar S, Chand Chawla T, Ranjan Biswas N.
study of Mycoplasma pneumoniae infections in Denmark over the 50-­ Mycoplasma pneumoniae and its role in asthma. Postgrad Med J.
year period 1946-­1995. Eur J Epidemiol. 1997;13:581–6. 2007;83:100–4.
16. Clyde WA Jr. Clinical overview of typical Mycoplasma pneumoniae in- 36. Kurai D, Saraya T, Ishii H, Takizawa H. Virus-­induced exacerbations in
fections. Clin Infect Dis. 1993;17(suppl 1):S32–6. asthma and COPD. Front Microbiol. 2013;4:293.
17. Committee for the Japanese Respiratory Society Guidelines for the 37. Yano T, Ichikawa Y, Komatu S, Arai S, Oizumi K. Association of
Management of Respiratory Infections. Guidelines for the manage- Mycoplasma pneumoniae antigen with initial onset of bronchial
ment of community acquired pneumonia in adults, revised edition. asthma. Am J Respir Crit Care Med. 1994;149:1348–53.
Respirology. 2006;11(suppl 3):S79–133. 38. Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneu-
18. Saraya T, Ohkuma K, Tsukahara Y, et  al. Relationships among clini- moniae in the airways of adults with chronic asthma. Am J Respir Crit
cal features, HRCT findings, and a visual scoring system in patients Care Med. 1998;158:998–1001.
with Mycoplasma Pneumoniae pneumonia. Am J Respir Crit Care Med. 39. Saraya T, Kurai D, Ishii H, et al. Epidemiology of virus-­induced asthma
2015;191:A1781. exacerbations: with special reference to the role of human rhinovirus.
19. Norisue Y, Tokuda Y, Koizumi M, Kishaba T, Miyagi S. Phasic charac- Front Microbiol. 2014;5:226.
teristics of inspiratory crackles of bacterial and atypical pneumonia. 40. Ganick DJ, Wolfson J, Gilbert EF, Joo P. Mycoplasma infection in
Postgrad Med J. 2008;84:432–6. the immunosuppressed leukemic patient. Arch Pathol Lab Med.
20. Okada T, Morozumi M, Tajima T, et al. Rapid effectiveness of mino- 1980;104:535–6.
cycline or doxycycline against macrolide-­resistant Mycoplasma pneu- 41. Nakajima M, Kubota Y, Miyashita N, et  al. An adult case of pneu-
moniae infection in a 2011 outbreak among Japanese children. Clin monia due to Mycoplasma pneumoniae and Chlamydia psittaci.
Infect Dis. 2012;55:1642–9. Kansenshogaku Zasshi. 1996;70:87–92.
21. Miyashita N, Kawai Y, Akaike H, et al. Macrolide-­resistant Mycoplasma 42. Ohmichi M, Miyazaki M, Ohchi T, et al. Fulminant Mycoplasma pneu-
pneumoniae in adolescents with community-­acquired pneumonia. moniae pneumonia resulting in respiratory failure and a prolonged
BMC Infect Dis. 2012;12:126. pulmonary lesion. Nihon Kokyuki Gakkai Zasshi. 1998;36:374–80.
SARAYA |
      125

43. Chan ED, Kalayanamit T, Lynch DA, et  al. Mycoplasma pneumoniae-­ 59. Miyashita N, Kawai Y, Tanaka T, et al. Diagnostic sensitivity of a rapid
associated bronchiolitis causing severe restrictive lung disease antigen test for the detection of Mycoplasma pneumoniae: comparison
in adults: report of three cases and literature review. Chest. with real-­time PCR. J Infect Chemother. 2015;21:473–5.
1999;115:1188–94. 60. Fuse ET, Genma H, Sato M, et  al. Evaluation of ImmnoCard myco-
44. Coultas DB, Samet JM, Butler C. Bronchiolitis obliterans due to plasma for diagnosis of Mycoplasma pneumoniae infection. Nihon
Mycoplasma pneumoniae. West J Med. 1986;144:471–4. Kokyuki Gakkai Zasshi. 2007;45:936–42.
45. Rollins S, Colby T, Clayton F. Open lung biopsy in Mycoplasma pneu- 61. Martinez MA, Ruiz M, Zunino E, Luchsinger V, Avendano LF. Detection
moniae pneumonia. Arch Pathol Lab Med. 1986;110:34–41. of Mycoplasma pneumoniae in adult community-­acquired pneumonia
46. Llibre JM, Urban A, Garcia E, Carrasco MA, Murcia C. Bronchiolitis by PCR and serology. J Med Microbiol. 2008;57(Pt 12):1491–5.
obliterans organizing pneumonia associated with acute Mycoplasma 62. Yoshino M, Annaka T, Kojima T, Ikedo M. Sensitive and rapid detec-
pneumoniae infection. Clin Infect Dis. 1997;25:1340–2. tion of Mycoplasma pneumoniae by loop-­mediated isothermal amplifi-
47. Ebnother M, Schoenenberger RA, Perruchoud AP, Soler M, Gudat F, cation. Kansenshogaku Zasshi. 2008;82:168–76.
Dalquen P. Severe bronchiolitis in acute Mycoplasma pneumoniae in- 63. Gotoh K, Nishimura N, Takeuchi S, et  al. Assessment of the loop-­
fection. Virchows Arch. 2001;439:818–22. mediated isothermal amplification assay for rapid diagnosis of
48. Wachowski O, Demirakca S, Muller KM, Scheurlen W. Mycoplasma Mycoplasma pneumoniae in pediatric community-­acquired pneumo-
pneumoniae associated organising pneumonia in a 10  year old boy. nia. Jpn J Infect Dis. 2013;66:539–42.
Arch Dis Child. 2003;88:270–2. 64. Petrone BL, Wolff BJ, DeLaney AA, Diaz MH, Winchell JM. Isothermal
49. Parker F Jr, Jolliffe LS, Finland M. Primary atypical pneumonia; detection of Mycoplasma pneumoniae directly from respiratory clinical
report of eight cases with autopsies. Arch Pathol (Chic). 1947;44: specimens. J Clin Microbiol. 2015;53:2970–6.
581–608. 65. Loens K, Van Heirstraeten L, Malhotra-Kumar S, Goossens H, Ieven
50. Maisel JC, Babbitt LH, John TJ. Fatal Mycoplasma pneumoniae in- M. Optimal sampling sites and methods for detection of pathogens
fection with isolation of organisms from lung. JAMA. 1967;202: possibly causing community-­acquired lower respiratory tract infec-
287–90. tions. J Clin Microbiol. 2009;47:21–31.
51. Benisch BM, Fayemi A, Gerber MA, Axelrod J. Mycoplasmal pneu- 66. Yin YD, Zhao F, Ren LL, et al. Evaluation of the Japanese Respiratory
monia in a patient with rheumatic heart disease. Am J Clin Pathol. Society guidelines for the identification of Mycoplasma pneumoniae
1972;58:343–8. pneumonia. Respirology. 2012;17:1131–6.
52. Meyers BR, Hirschman SZ. Fatal infections associated with 67. Nambu A, Saito A, Araki T, et al. Chlamydia pneumoniae: comparison
Mycoplasma pneumoniae: discussion of three cases with necropsy with findings of Mycoplasma pneumoniae and Streptococcus pneumo-
findings. Mt Sinai J Med. 1972;39:258–64. niae at thin-­section CT. Radiology. 2006;238:330–8.
53. Halal F, Brochu P, Delage G, Lamarre A, Rivard G. Severe disseminated 68. Miyashita N, Sugiu T, Kawai Y, et  al. Radiographic features of
lung disease and bronchiectasis probably due to Mycoplasma pneumo- Mycoplasma pneumoniae pneumonia: differential diagnosis and per-
niae. Can Med Assoc J. 1977;117:1055–6. formance timing. BMC Med Imaging. 2009;9:7.
54. Kaufman JM, Cuvelier CA, Van der Straeten M. Mycoplasma pneumo- 69. Emmet OM, Restrepo MI, Martin-Loeches I. Update on the combina-
nia with fulminant evolution into diffuse interstitial fibrosis. Thorax. tion effect of macrolide antibiotics in community-­acquired pneumo-
1980;35:140–4. nia. Respir Investig. 2015;53:201–9.
55. Koletsky R, Weinstein A. Fulminant Mycoplasma pneumoniae infec- 70. Mandell LA, Wunderink RG, Anzueto A, et  al. Infectious Diseases
tion. Report of a fatal case, and a review of the literature. Am Rev Society of America/American Thoracic Society consensus guidelines
Respir Dis. 1980;122:491–6. on the management of community-­acquired pneumonia in adults.
56. Hayashi S, Ichikawa Y, Fujino K, et al. Analysis of lymphocyte subsets Clin Infect Dis. 2007;44(suppl 2):S27–72.
in peripheral blood and bronchoalveolar lavage fluid in patients with 71. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the man-
pneumonia due to Mycoplasma pneumoniae. Nihon Kyobu Shikkan agement of community acquired pneumonia in adults: update 2009.
Gakkai Zasshi. 1986;24:162–7. Thorax. 2009;64(suppl 3):iii1–55.
57. Hayashi Y, Asano T, Ito G, et  al. Study of cell populations of bron-
choalveolar lavage fluid in patients with pneumonia due to Chlamydia
psittaci and Mycoplasma pneumoniae. Nihon Kyobu Shikkan Gakkai How to cite this article: Saraya T. Mycoplasma pneumoniae
Zasshi. 1993;31:569–74.
infection: Basics. J Gen Fam Med. 2017;18:118–125.
58. Itoh H. An immunochromatographic device for rapid detection of ri-
bosomal protein L7/L12 as a diagnostic test for Mycoplasma pneumo-
https://doi.org/10.1002/jgf2.15
nia. Rinsho Biseibutshu Jinsoku Shindan Kenkyukai Shi. 2014;25:17.