A t y p i c a l Pn e u m o n i a

Updates on Legionella,
Chlamydophila, and Mycoplasma
Pneumonia
Lokesh Sharma, PhDa,1, Ashley Losier, MDb,1,
Thomas Tolbert, MDc,1, Charles S. Dela Cruz, MD, PhDa,
Chad R. Marion, DO, PhDa,*

KEYWORDS
 Community-acquired pneumonia (CAP)  Walking pneumonia  Legionella  Legionnaires’ disease
 Pontiac fever  Chlamydophila  Mycoplasma

KEY POINTS
 The clinical diagnosis of atypical pneumonia remains elusive but recent advances in rapid diag-
nostic platforms show promise of earlier identification of the infectious organism.
 Macrolides and respiratory fluoroquinolones remain the antibiotics of choice for atypical pneu-
monia but there are several new antibiotics currently under development or clinical trials.
 Both Chlamydophila and Mycoplasma have been associated with chronic diseases, but Legionella
seems to occur sporadically and is not associated with chronic diseases.

INTRODUCTION controversies surrounding the diagnosis and treat-

ment of atypical CAP.
Pneumonia is a common cause of hospital admis-
sion and mortality and is categorized based on the
clinical context in which a patient develops symp- LEGIONELLA PNEUMOPHILA
toms of infection. These categories include Clinical Presentation
community-acquired pneumonia (CAP), CAP with Legionella infections are manifested mainly in 2
risk factors of resistant organisms, hospital- forms:
acquired pneumonia, and ventilator-associated
events. CAP is defined as contracting pneumonia 1. Legionnaires’ disease, which is a severe form of
with minimal or no recent contact with the health- pneumonia due to infection with Legionella. Le-
care system CAP is one of the most common in- gionnaires’ disease can manifest as a multi-
fectious diseases and is caused by various system disease most commonly involving the
infectious pathogens, including viruses, typical lungs and gastrointestinal tract and is associ-
bacteria, and atypical pathogens. This article re- ated with significant mortality.1
views the clinical considerations of atypical 2. Pontiac fever, which is a mild and self-resolving
causes of CAP that include Legionella, Myco- flu-like disease. The characteristics of Pontiac
plasma, and Chlamydophila and discusses current fever are mild fever, chills, myalgia, and
chestmed.theclinics.com

a
Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, 300 Cedar Street,
TAC S440, New Haven, CT 06510, USA; b Department of Internal Medicine, Norwalk Hospital, 34 Maple Street,
Norwalk, CT 06856, USA; c Department of Internal Medicine, Yale University School of Medicine, 330 Cedar
Street, New Haven, CT 06510, USA
1
Contributed equally to this article.
* Corresponding author.
E-mail address: chad.marion@yale.edu

Clin Chest Med 38 (2017) 45–58

http://dx.doi.org/10.1016/j.ccm.2016.11.011
0272-5231/17/Ó 2016 Elsevier Inc. All rights reserved.
46 Sharma et al

headache that lasts 2 to 5 days and often re- (FDA). Other tools, such as direct immunostaining,
solves itself without significant mortality.2 are used to detect the presence of bacterium but
frequently require invasive procedures to collect
Legionella mostly affects people above 50 years tissue for testing.11
of age but cases have been reported in infants and
neonates.3 Legionnaires’ disease is hard to distin- Prognosis
guish from pneumonia caused by other pathogens
because it presents similar clinical symptoms; Legionnaires’ disease has significant mortality
however, presence of diarrhea and elevated creat- rates if untreated or if there is delay in adminis-
inine kinase levels can be indicators of infection by trating appropriate antibiotic therapy. The risk fac-
Legionella.4 Pneumonia due to Legionella is usu- tors associated with mortality are acquiring the
ally found in clusters that are not associated with infection in nosocomial settings, diabetes, immu-
person-to-person transmissions but is related to nosuppression, and malignancies.12,13 Complete
exposure to the same source of infection. Most recovery from the infection in these susceptible
of the Legionella infections are acquired by populations might be prolonged and signs of
contaminated water or soil. Rainfall, high humidity, stress and trauma might persist for years.14
and work in gardens with compost are risk factors
Treatment
for acquiring Legionella disease.5–7 Most of the
cases of legionnaires’ disease are associated Antibiotics are the first-line therapy for Legionella
with Legionella pneumophila, but many other bac- pneumonia. Failure to administer appropriate anti-
terial species have been found to cause Legionella microbial therapies at early stage of infection is
lung infections.7,8 associated with high mortality rates.15,16 The cor-
rect choice of antibiotic depends not only on its
in vitro bactericidal or bacteriostatic activity but
Diagnostic Considerations
also on its ability to penetrate the cell membrane
Because many manifestations of Legionella are of host tissues because Legionella resides within
similar to other typical and atypical pneumonias, host tissue cells. Fluoroquinolones and macrolides
clinical symptoms or radiologic evidences are of are the 2 most commonly used and highly effective
little value for diagnostic purposes. The Centers antibiotics to treat patients with legionnaires’ dis-
for Disease Control and Prevention defines confir- ease. Including these agents in initial treatment
mation of infection if Legionella can be cultured regimen is prudent if Legionella infection is sus-
from sputum or bronchoalveolar lavage, a positive pected based on an ongoing outbreak in the area,
urine antigen test, or a 4-fold increase in anti- travel history, or extrapulmonary symptoms.17
bodies specific to Legionella.9,10 Details about It was found during the first reported outbreak of
these tests are summarized in Table 1. Polymer- legionnaires’ disease that tetracycline and erythro-
ase chain reaction (PCR)-based diagnostic tests mycin are more effective than other antibiotics,
are being tested and some of them show speci- such as b-lactam antibiotics, whereas the use of
ficity and sensitivity, although these tests are yet steroids has been associated with unfavorable
to be approved by Food and Drug Administration outcome.1 Erythromycin has been the antibiotic

Table 1
Diagnostic tests for Legionella species

Test Sensitivity (%) Advantages Limitations

Culture 20–80 Detects all the Takes technical
Legionella species expertise, longer
duration >5 d
Urinary antigen 70–100 Quick, same-day results, Kits available are limited
not affected by mostly to Legionella
antibiotic treatment pneumophila; other
species may go
undetected
Serology 80–90 Little effect of antibiotic Paired samples are
treatment required
Direct fluorescence 25–75 Performed on Technically difficult
assay pathologic tissue
 Atypical Pneumonia 47

of choice for the treatment of legionnaires’ disease Table 2

that is highly effective but has been associated Antibiotic therapy for Legionella,
with significant side effects, especially when Chlamydophila, and Mycoplasma community-
used intravenously.16,18–20 Azithromycin, another acquired pneumonia
macrolide, has been shown highly effective in
treating patients with Legionella infection, with mi- Medication Dose
nor side effects.21 Azithromycin has been suc- Azithromycin 1.5 g over 5 d (500 mg on
cessfully used to treat Legionella infection not day 1 followed by 250 mg
responding to erythromycin and is frequently cho- for 4 d)
sen to treat patients infected with Legionella.22 Clarithromycin 500 mg PO bid for 10 d
Other antibiotics that are effective against Legion- Doxycycline 100 mg bid for 7–21 d
ella are clarithromycin, rifampin, ciprofloxacin, and
Tetracycline 250 mg qid for 7–21 d
doxycycline, and these are used either alone or
with erythromycin.18 In a prospective study, it Levofloxacin 750 mg PO/IV for 5–10 d or
500 mg PO/IV daily for
has been shown that fluoroquinolones are at least
7–14 d
as effective as erythromycin in treating patients
with legionnaires’ disease.23 Levofloxacin, either Moxifloxacin 400 mg daily for 10 d
500 mg for 10 days or 750 mg for 5 days, can Nemonoxacina 500 mg daily for 7 d or
cure most of the patients (>95%) and is becoming 750 mg daily for 7 d
the antibiotic of choice for legionnaires’ disease.24 Slorithromycina 800 mg on day 1 followed
Use of levofloxacin is increasing to treat Legionella by 400 mg daily for 4 d
infection and is associated with early clinical a
Nemonoxacin and slorithromycin remain in the trial
response and shorter hospital stay.25 A meta- phase and are not yet FDA approved. Nemonoxacin treat-
analysis by Burdet and colleagues26 revealed ment was associated with clinical in all patients with C
quinolones may be superior to macrolides in treat- pneumoniae identified as etiologic pathogen between
22 phase II clinical trials (n 5 9). Slorithromycin shows
ing the Legionella infection.
in vitro activity against C pneumoniae but has not been
The usual duration of therapy for most of the an- specifically tested in vivo.
tibiotics is 5 to 10 days and is often sufficient to Data from Refs.60,62,66
completely treat patients with Legionella infection,
but duration of therapy up to 3 weeks may be
considered in immunocompromised patients.17 as multiplex PCR assays, and may be more effica-
The route of administration used for the antibiotics cious than detection of Legionella pneumophila
depends on the severity of the infection, with serotype-1 antigen in patients’ urine.11,30
parenteral therapy preferred for severe infections. To date, there are few reported cases of Legion-
If intravenous therapy is initiated early in infection, ella species that are resistant to conventional anti-
then therapy can be transitioned to oral route to biotics resistance and there is little evidence that
complete therapy once a desirable response is combination therapy is superior to monother-
observed. Treatment options are outlined in apy.31,32 Legionella resistant to ciprofloxacin has
Table 2. been reported. It was unclear if the strain of
Acquired antibiotic resistance among Legionella Legionella was resistant at the presentation of dis-
species can be seen in vitro but is rarely reported ease or developed resistance during treatment
in vivo, although a recent report has shown the because the patient was treated with ciprofloxacin
presence of fluoroquinolone resistance in Legion- and clinically improved from severe infection.27
ella in patients who are treated with these antibi- Regardless, several new antibiotics are under
otics.27,28 These reports warrant special attention development that target intracellular organisms,
toward ineffectiveness or relapse of disease dur- such as Legionella, either by favoring a low pH
ing ongoing antibiotic therapy. enthronement or by inhibiting bacterial protein
synthesis.33–35 Currently, these therapies are not
available for clinical use.
Conflicts and Controversies
Person-to-person transfer is usually not consid-
Most cases of legionnaires’ disease reported are ered a route of transmission for Legionella; however,
due to Legionella pneumophila serotype-1 reports are emerging showing person-to-person
(80%).29 This might reflect a diagnosis bias because transfer.36,37 Despite these reports, person-to-
most of the commercial kits available detect Legion- person contact seems to be the exception. The
ella serotype-1 antigen in urine samples but not for best means of preventing disease is by thwarting
other species. Efforts are under way to develop the contamination of water supplies. Water temper-
rapid diagnostic test for Legionella species, such ature, pipe age, and pipe configuration have been
48 Sharma et al

shown to play a role in the contamination of water and colleagues,43 duration of cough ranged from
supplies with Legionella.38,39 Current recommenda- 1 to 64 days with a mean of 21 days. Although
tions to prevent Legionella contamination include the classic presentation is associated with
maintaining water temperature outside the optimal nonproductive cough, approximately 70% of pa-
temperature for Legionella growth, preventing stag- tients presented with sputum production in out-
nation, superheat-and-flush or point-of-use filters, breaks of C pneumoniae infection in 2006 and
UV irradiation, and chemical disinfection.40 2013. The presentation is especially difficult to
Currently there are no clear recommendations as distinguish from pneumonia due to Mycoplasma
to optimal combination of preventative measures; pneumoniae or respiratory viruses. Despite previ-
therefore, despite the method of prevention utilized, ous suggestions that hoarseness and laryngitis
the World Health Organization recommends quar- are more common in infection from C pneumoniae
terly water testing.41 than from M pneumoniae, comparison of clinical
features of both causes have shown the oppo-
CHLAMYDOPHILA PNEUMONIAE site.44,45 Punji and colleagues45 demonstrated
Clinical Presentation that cough, rhinitis, and hoarseness were signifi-
cantly more common in M pneumoniae infection
Chlamydophila pneumoniae has been implicated
than in C Pneumoniae infection. In the same study,
in upper respiratory infections, acute bronchitis,
C-reactive protein and aspartate aminotransferase
and pneumonia.42 The common symptoms of C
elevations were significantly greater in C pneumo-
pneumoniae pneumonia and their frequencies
niae infection than in M pneumoniae infection.
are presented in Table 3. Classically, pneumonia
Other clinical symptoms and laboratory findings
due to C pneumoniae presents as a mild illness
due to the 2 pathogens were not significantly
predominated by fever and cough, often preceded
different. C-reactive protein and white blood cell
by upper respiratory symptoms of rhinitis and sore
values have been previously shown significantly
throat. In a 2013 study of an outbreak by Conklin
lower in both C pneumoniae and M pneumoniae
pneumonia than in pneumonia due to Strepto-
coccus pneumoniae.44 No single symptom, labo-
Table 3 ratory finding, or collection of findings can
Major symptoms encountered in reliably distinguish pneumonia due to C pneumo-
Chlamydophila pneumoniae community- niae from pneumonia due to other respiratory
acquired pneumonia pathogens. Additionally, C pneumoniae infection
may occur concomitantly with other pathogens,
Frequency (%) which may influence clinical presentation.44
Constitutional
Fever 68.1–97.8 Imaging
Myalgias/arthralgias 37.5–40.5
A list of roentgenographic manifestations of C
Confusion 7.5
pneumoniae is presented in Table 4. On initial
Upper respiratory/ear, nose and throat
chest radiograph, a unilateral pattern of alveolar
Headache 25–60 infiltrates or bronchopneumonia predominates.
Rhinorrhea 6.7–72.9 Findings are usually confined to a single lobe
Sinus pain 43.2 with lower lobe involvement more frequent than
Sore throat 9–72.9 middle or upper lobe involvement.46–48 A pattern
Hoarseness 15.7 of interstitial pneumonia is comparatively rare.
Up to a quarter of patients may demonstrate a
Lower respiratory
small to moderate-size pleural effusion. Hilar or
Cough 82–98
mediastinal lymphadenopathy is an uncommon
Sputum production 67.5–68.8 finding on chest radiograph. Findings may depend
Dyspnea 25–58.3 on the timing of imaging in the course of the illness,
Wheezing 58.7 the method of diagnosis, and whether concomi-
Chest pain 9–17.5 tant infection with another respiratory pathogen
Hemoptysis 7.5 is excluded. In 1 review of 17 patients classified
Gastrointestinal as having primary infection, admission chest ra-
diographs showed predominantly unilateral find-
Nausea  vomiting 5–19.1
ings with repeat chest radiographs taken an
Diarrhea 5–12.5 average of 3.8 days later showing predominantly
Data from Refs.43–45 bilateral findings.46
 Atypical Pneumonia 49

Table 4
Major imaging findings in Chlamydophila pneumoniae community-acquired pneumonia

Imaging Type Chest Radiograph (%) CT Scan (%)

Distribution
Unilateral 42–75 50
Bilateral 24–25 50
Involvement of only 1 lobe 62–86 33
Lower lobe 88 71
Middle lobe 25 46
Upper lobe 21 67
Chest radiograph patterns
Bronchopneumonia 88 —
Alveolar infiltrates 29–86 —
Interstitial infiltrates 0–4 —
Air bronchogram 57 —
CT parenchymal findings
Consolidation — 83
Bronchovascular bundle thickening — 71
Reticular or linear opacity — 62
Ground-glass opacities — 54
Pulmonary emphysema — 46
Airway dilatation — 38
Lymphadenopathy 0–17 33
Pleural effusion 14–38 25
Data from [Chest radiograph] Kauppinen MT, Lahde S, Syrjala H. Roentgenographic findings of pneumonia caused by
Chlamydia pneumoniae. A comparison with streptococcus pneumonia. Arch Intern Med 1996;156(16):1851–6; Boersma
WG, Daniels JM, Löwenberg A, et al. Reliability of radiographic findings and the relation to etiologic agents in
community-acquired pneumonia. Respir Med 2006;100(5):926–32; and [CT scan] Nambu A, Saito A, Araki T, et al. Chla-
mydia pneumoniae: comparison with findings of Mycoplasma pneumoniae and Streptococcus pneumoniae at thin-
section CT. Radiology 2006;238(1):330–8.

In a retrospective review of thin-section CT involvement, with consolidation and bronchovas-

scans of 24 patients serologically diagnosed with cular bundle thickening were the predominant
C pneumonia CAP, Nambu and colleagues49 findings. Bilateral lung involvement was seen
found a significant increase in airway dilatation in half of patients. Ultimately, the imaging findings
compared with patients with pneumonia due to S on either radiograph or CT scan are nonspecific
pneumoniae or M pneumoniae as well as an for C pneumoniae and cannot be reliably used
increased rate of pulmonary emphysema to identify the pathogen in the etiology of
compared with M pneumoniae but not S pneumo- pneumonia.46–48
niae. The study speculated that the increased rate
of airway dilatation and pulmonary emphysema
Diagnostic Considerations
may reflect obstructive lung disease as a predis-
posing risk factor for C pneumoniae pneumonia Accepted techniques for identifying Chlamydo-
and may not be caused by the infection itself. phila infection include serologic studies and cul-
Despite the statistically significant increase in ture or PCR of respiratory tract samples.
airway dilatation and/or pulmonary emphysema, Historically, diagnosis of Chlamydophila infection
neither these findings nor any other on CT was has relied on serologic studies, requiring a 4-fold
able to reliably distinguish pneumonia from C rise in IgG or IgA levels between acute and conva-
pneumoniae from pneumonia due to other patho- lescent serum samples. Serologic methods in gen-
gens. Overall, findings in C pneumoniae on CT eral are cumbersome because patients must
scan were widely variable. Involvement of more return 4 to 6 weeks after initial presentation to
than 1 lobe, usually upper and/or lower lobe retrospectively confirm the diagnosis. Moreover,
50 Sharma et al

the retrospective nature of diagnosis means sero- patients. In a recent outbreak, approximately
logic results have little effect on treatment deci- 80% of patients who were positive for Chlamydo-
sions. Alternative serologic criteria allowing phila infection by PCR of respiratory samples
diagnosis on initial presentation, such as a serum remained positive for up to 8 weeks after resolution
IgM antibody titer of 1:16 or greater, rely on the of symptoms.43 Patients may continue to harbor
timing of sample collection, because a rise in titers the pathogen in the absence of symptoms for up
may not be observed early in the course of acute to 11 months, even after appropriate antibiotic
infection or reinfection.50,51 Relying solely on initial therapy.56 Positive PCR results in patients with a
serologic samples for diagnosis (that is, forgoing history of C pneumoniae infection may, therefore,
retrospective confirmation with convalescent be challenging to attribute definitively to reinfec-
serum samples) risks missing 25% to 33% of in- tion, persistent infection or ongoing asymptomatic
fections.52 Additionally, initial serologic testing carriage with other potential pathogens causing
may take days to result, further limiting their use new symptoms.57 Furthermore, the identification
in initial management decisions. Serologic tech- of Chlamydophila in respiratory samples does not
niques are limited in specificity by potential rule out coinfection with other pathogens, which
cross-reactivity between C pneumoniae antigens has been noted to occur in multiple studies and
and antigens of other Chlamydia species. may affect clinical presentation.44,46,47,52,53
Microimmunofluorescence is considered the Alternative methods of detection include identi-
reference standard for serologic diagnosis.42,51 fication of circulating Chlamydophila lipopoly-
ELISA is also available and may be less technically saccharide in serum, C pneumoniae presence in
demanding and more objectively interpretable circulating phagocytes or atheromas, and serores-
than microimmunofluorescence.51 Complement ponse to C pneumoniae antigens. These methods
fixation is not a recommended diagnostic tech- are technically demanding, however, and currently
nique owing to a limited sensitivity and used only in research settings.51
specificity.42,52
Although considered specific due to a low rate
Prognosis
of asymptomatic carriage, the sensitivity of culture
is markedly limited by the fastidious and slow Compared with infection with typical bacterial res-
growth of Chlamydophila, which may require piratory pathogens, such as Streptococcus, Kleb-
weeks.42,50,53 Previous studies have shown a siella, and Pseudomonas species, the course and
very low frequency of growth in culture, even outcomes for pneumonia due to C pneumoniae
from specimens where infection is identified by are thought to be benign. Outcomes are typically
serology and/or PCR.52 In a 2010 study, She and reported for patients with atypical pneumonias
colleagues50 recommended against the routine as a group, however, and there are few data avail-
use of culture for diagnosis after failing to identify able on outcomes specific to C pneumoniae.
any positive culture results from 6981 specimens A 2012 study of etiologic agents in CAP and their
from patients with respiratory symptoms despite effect on outcomes by Capelastegui and col-
a rate of Chlamydophila as the cause of CAP and leagues58 identified 151 patients with pneumonia
other respiratory infections of 5% to 22%. due to atypical pathogens, 37 of whom (or 24%)
Given the limitations of serology and culture, had C pneumoniae.49 Atypical pneumonia had a
PCR of respiratory tract specimens has emerged hospitalization rate of 25.8%, an ICU admission
as the favored method of diagnosis. Specimens rate of 0.7%, and a mechanical ventilation rate of
may be assessed with multiplex PCR, allowing for 0.7%. With the exception of mechanical ventila-
the detection of multiple potential respiratory path- tion, these rates were significantly lower for atyp-
ogens without significant diminishment in sensi- ical pneumonias than for pneumonia due to
tivity compared with singleplex PCR testing.54 In typical bacteria; 30-day mortality was 1.3%
2012, the FDA approved the FilmArray Respiratory compared with 4.3% for pneumonia due to typical
Panel (BioMérieux, France), which uses multiplex bacteria, although this difference was not statisti-
PCR for the detection of C pneumoniae in addition cally significant. Outcomes more specific to C
to M pneumoniae, Bordetella pertussis, and 17 res- pneumoniae were not reported. The mortality
piratory viruses on nasopharyngeal swab (NPS) rate of C pneumoniae pneumonia is likely low,
specimens.55 PCR remains limited in specificity, with 30-day mortality rates for atypical pneumo-
however, by asymptomatic carriage, which ap- nias in general ranging from 0% to 2.2%.59 In the
proaches 5% in healthy adults.53 Specificity is 2013 outbreak studied by Conklin and col-
further limited by a pattern of persistence of Chla- leagues43 no deaths were reported among 52 pa-
mydophila identified on respiratory swabs well af- tients. However, 22 of these patients had
ter resolution of clinical symptoms in some persistently positive oropharyngeal swabs (OPSs)
 Atypical Pneumonia 51

for C pneumoniae up to 8 weeks after the all patients identified as having C pneumoniae,
outbreak, and many of these patients experienced although this totaled only 9 patients between the
cough symptoms for several weeks after comple- 2 trails.64,65 Slorithromycin is a novel fourth-
tion of antibiotic treatment. Patients should be generation macrolide with in vitro activity against
advised that cough could persist even after Chlamydophila that demonstrated noninferiority
completion of an appropriate antibiotic course. to moxifloxacin for the treatment of CAP in a
recent phase III clinical trial.66 No patients with
Chlamydophila were specifically identified in the
Treatment
study. AZD0914 is a bacterial DNA gyrase/topo-
Recommendations for antibiotic treatment of C isomerase inhibitor that demonstrates high activity
pneumoniae are limited by an absence of stan- against Chlamydophila and other respiratory path-
dardized diagnostic criteria and the use of ogens in vitro but is not yet under clinical investiga-
serology alone for diagnosis in most previous tion for treatment of respiratory infections.63
studies. Infectious Diseases Society of America
(IDSA) guidelines from 2007 note a lack of strong
Conflicts and Controversies
evidence to recommend specific antibiotic therapy
for the pathogen.17 Treatment recommendations C pneumoniae infection has been identified as a
continue to rely on expert opinion. Given a pattern possible contributing factor in a multitude of
of reappearance of symptoms after a standard chronic conditions. A 2013 meta-analysis by Orr-
course of therapy, longer courses of antibiotics skog and colleagues67 identified C pneumoniae
have been recommended when Chlamydophila is infection as potentially linked with 26 chronic con-
identified.42 A list of antibiotics, their doses, and ditions, most strongly with conditions of the circu-
treatment courses as recommended by expert latory system. Research interest into a causal link
opinion is given in Table 2.60 between Chlamydophila infection and atheroscle-
Because C pneumoniae is an obligate intracel- rosis has been intense since 1988, when Saikku
lular microbe, antibiotics must achieve intracellular and colleagues68 identified a higher rate of sero-
penetration to achieve efficacy. Antibiotics that logic evidence of infection in patients with a history
interfere with DNA and protein synthesis, including of coronary heart disease. Subsequently, C pneu-
macrolides, tetracyclines, and fluoroquinolones, moniae was identified by culture, PCR, and immu-
demonstrate in vitro activity against the pathogen nohistochemical methods in macrophages,
and are the recommended drug classes for clinical endothelial cells, and smooth muscle cells in
treatment. Ciprofloxacin, however, demonstrates atherosclerotic vessel walls. Each of these tech-
a higher minimum inhibitory concentration than niques has been criticized, however, given that
other fluoroquinolones and may, therefore, be isolation in culture is rare and inconsistent, PCR
less efficacious. C pneumoniae is resistant to identification is widely variable and potentially
trimethoprim, sulfonamides, aminoglycosides, prone to contamination, and immunohistochem-
and glycopeptides. Penicillin and amoxicillin have ical staining is plagued by cross-reactivity with hu-
demonstrated in vitro activity against Chlamydia man proteins.69 Furthermore, identification of C
species but are not recommended as part of pneumoniae in atherosclerotic lesions has not
routine therapy against C pneumoniae. correlated well with seropositivity. It has been sug-
Resistance to the recommended therapies is gested that the initially identified serologic
considered rare and does not seem to play a role markers, such as elevations in IgG, may be more
in either treatment failure or in the persistence of reflective of atherosclerotic processes other than
C pneumoniae identified on respiratory samples persistent C pneumoniae infection, such as smok-
after completion of therapy because isolates ob- ing and inflammation.70 In recent meta-analyses,
tained from patients after appropriate therapy elevated titers of IgG or IgA to C pneumoniae
demonstrate in vitro sensitivity. have been associated with increased stroke risk
Three novel antibiotics, nemonoxacin, slorithro- and increased inflammatory markers.71,72
mycin, and AZD0914, have all demonstrated The connection between C pneumoniae infec-
in vitro activity against Chlamydophila but are tion and atherosclerosis has been most strongly
currently in trial stages and have not yet received shaken by disappointing results in studies of anti-
FDA approval for treatment.61–63 Nemonoxacin is biotic therapy. A 2005 meta-analysis of 11 ran-
a novel fluoroquinolone with in vitro activity com- domized controlled trials, including 19,217
parable to azithromycin, doxycycline, and levo- patients with established coronary artery disease,
floxacin.62 In 2 phase II clinical trials of 256 and showed that antibiotic therapy had no effect on
192 patients with mild to moderately severe CAP, rates of myocardial infarction or all-cause mortal-
nemonoxacin led to clinical treatment success in ity.73 The CLARICOR trial, which demonstrated
52 Sharma et al

an unexpected increase in long-term mortality af- Table 5

ter short-term treatment with clarithromycin in pa- Extrapulmonary manifestations of
tients with stable coronary heart disease, further Mycoplasma pneumoniae
contributed to doubt in the association.70 The fail-
ure of antibiotic therapies to influence cardiovas- Skin Erythema Nodosum,
cular outcomes may reflect a lack of an Cutaneous
association but could also result from the limited Leukocytoclastic
efficacy of antibiotics to penetrate atherosclerotic Vasculitis, Stevens-
plaques or eradicate infection. Alternatively, the Johnson Syndrome
initiation of atherosclerosis may depend on tran- Gastrointestinal Acute hepatitis
sient C pneumoniae infection rather than chronic Central nervous Encephalitis, aseptic
infection. Ultimately, the hypothesized association system meningitis
remains to be definitively demonstrated.74 Cardiovascular Cardiac thrombi,
Definitively implicating persistent C pneumoniae Kawasaki disease
infection in the pathogenesis of chronic diseases
will first require a method of reliably identifying
persistent infection. No standardized method yet interstitial patterns sometimes out of proportion
exists, but potential methods have been investi- to a patient’s physical findings. On CT of the chest,
gated.51 In a 2008 study by Bunk and colleagues75 the interstitial changes seen in the chest radio-
using proteomics, 12 C pneumoniae antigens were graph show up as tree-in-bud formation.82 In
identified that produce a serologic IgG antibody 2016, Gong and colleagues82 completed a pro-
response in patients shown to have persistent spective study that looked at a population of
infection by PCR of either circulating phagocytes 1280 pediatric cases with M pneumoniae pneu-
or atheromas. Two antigens, Cpaf-c and RpoA, monia between the years 2010 to 2014 and found
produced the strongest response and could that there were a high proportion of the patients
potentially be used in the future as evidence of with extensive patchy infiltrates both unilaterally
chronic infection. The possibility that C pneumo- and bilaterally indicating that the diagnosis of
niae infection, however, may play an initiating pneumonia could not be made on imaging charac-
role in the pathogenesis of chronic conditions teristics alone and should occur with clinical find-
that does not require chronic infection remains. ings. Other findings found on CT chest imaging
include bronchial wall thickening and ground-
MYCOPLASMA PNEUMONIAE glass consolidation.
Clinical Manifestations
Diagnostic Considerations
Pneumonia due to M pneumoniae can often have a
misleading clinical picture with its mild and indis- The diagnosis of pneumonia has long been
tinct symptoms, such as myalgias, cervical aden- considered a clinical diagnosis as encouraged by
opathy, nonproductive cough, and fatigue, the IDSA where a patient should have suggestive
making it difficult to distinguish from other upper symptoms and associated imaging findings corre-
respiratory infections caused by viruses and other lating with pneumonia and other associated diag-
atypical bacterium.76–78 The age group most often nostic techniques have remained controversial
affected by M pneumoniae include school-aged due to frequent low yield results.17 For an overview
children and young adults with outbreaks typically of diagnostic techniques, see Table 6.
occurring during the autumn season.76–79 Out- Confirmatory diagnostic testing plays an impor-
breaks occur among close contacts and members tant role in delineating epidemiology of infection
within the same household or confined spaces.80 and antibiotic resistance patterns. Traditionally
Apart from its atypical symptoms, M pneumoniae diagnosis of M pneumoniae has come from cul-
presentations can vary dramatically ranging from tures and serology where isolation via culture
the mild upper respiratory symptoms to pneu- was considered the gold standard. Given the
monia and other extrapulmonary manifestations fastidious nature of M pneumoniae it is not
in absence of pneumonia,6 including dermato- routinely cultured anymore because it is slow
logic, cardiovascular, and central nervous system growing and culture results are often inconsistent
findings.81 The extrapulmonary manifestations of and provide poor clinical utility given the length
M pneumoniae are outlined in Table 5. of time the organism takes to grow.77,79
Imaging characteristics of M pneumoniae infec- Alternative methods of diagnosing M pneumo-
tions also follow along with its indistinct nature. niae include serologic studies using ELISA to
The chest radiograph often shows diffuse quantify expression of antibodies to the bacteria,
 Atypical Pneumonia 53

Table 6
Diagnosis of Mycoplasma pneumoniae

Diagnostic Test Sample Type Advantages/Disadvantages of Test

Culture Sputum Advantages
 If positive, 100% specific and considered the gold standard
Disadvantages
 Long growth period that provides limited clinical utility
Serology Serum Advantages
 Test has ability to quantify expression amount
Disadvantages
 Poor sensitivity and specificity
 Requires paired sera (acute and convalescent phases) leading
to retrospective results
High false-positive rate likely due to carrier state
Molecular Sputum, NPA, Advantages
NPS, OPS  Readily available with fast results; high specificity
Disadvantages
 Expensive commercial kits
 Improved standardization among kits required to determine
optimal sample specimen

microparticle agglutination studies and comple- multiplex PCR, which often allow for the detection
ment fixation assays. For a definitive diagnosis in of several atypical pathogens, including C pneu-
the serologic studies paired sera were needed to moniae, C psittaci, and Legionella species, among
demonstrate a significant 4-fold elevation of IgG other respiratory viruses.54,79 There still remains
or a subsequent seroconversion of IgG in the some debate over which sample type has the
sera collected 3 to 4 weeks later.83–86 Due to the best sensitivity and specificity while performing
delay in antibody production during initial infection these assays, with current studies showing that
and the time needed to allow for seroconversion, sputum samples yield more positive results than
the serologic tests also have poor utility in diag- both nasopharyngeal aspirates (NPAs) and NPSs
nosing acute M pneumoniae infections in clinical as well as OPSs.85,87
practice and functioned more as a retrospective
confirmation for epidemiologic studies.79,83–85 Prognosis
With the many disadvantages of culture and
The clinical course of M pneumoniae infections is
serology in diagnosing M pneumoniae infections,
usually mild and self-limiting in nature and resolves
diagnostics are evolving toward more rapid mo-
within 2 to 4 weeks regardless of treat-
lecular techniques including nucleic acid amplifi-
ment.77,78,83,84 There have been cases of severe
cation techniques.
infections, however, resulting in acute respiratory
Molecular diagnostic techniques allow for a
distress syndrome and severe neurologic compli-
timely diagnosis of M pneumoniae infections and
cations that are associated with increased
are quickly becoming the mainstay for diagnosis
morbidity and mortality.88
in clinical practice with the development of a vast
repertoire of laboratory techniques including
Treatment
nucleic acid amplification techniques, multilocus
variable number tandem-repeat analysis, multilo- Infection from M pneumoniae is often underdiag-
cus sequence typing, among many others.79 nosed, where patients tend to not seek treatment
These tests have quickly become preferential given the subacute nature of their symptoms.76–79
with their ability to produce fast results with high The bacterium has a long incubation of approxi-
specificity and sensitivity.79,83 Many of the new mately 3 weeks with prolonged bacterial shedding
tests undergo real-time PCR to look at specific where symptoms can last up to 4 months; howev-
gene regions of M pneumoniae as the regions er, most cases resolve naturally within 2 to 4 weeks
encoding 16S ribosomal RNA, P1 gene, ATPase without treatment.77,79,83
operon, and the community-acquired respiratory When patients present for clinical care, treatment
distress syndrome (CARDS) toxin.79,83–86 This is often guided by the IDSA guidelines for CAP
technology allowed for the development of based on a patient’s symptoms and imaging
54 Sharma et al

results.17 M pneumoniae, as a small, self-replicating novel molecular diagnostic techniques, it is

bacteria that lacks a cell wall, is inherently resistant becoming faster and easier for clinicians to make
to the family of b-lactam type of antimicrobials but is a formal diagnosis; however, with the many new
routinely covered in the empiric treatment of CAP techniques, there is still no standardized test rec-
treatment with macrolide therapy, usually without ommended by IDSA guidelines. Several barriers
a formal laboratory diagnosis. Treatment with that may arise in the primary care settings are
such antimicrobials can shorten the course of the that many of these molecular tests are expensive
illness by using a 5-day to 2-week course of anti- and many of these techniques require specialized
biotic therapy dependent on the choice of antibiotic laboratory equipment. There have been several as-
in infected individuals.89,90 Because M pneumoniae says developed that allow for the convenience of
often affects children and young adults, macrolides testing for multiple pathogens, with current tests
have become the treatment of choice because both approved for clinical use, including the Bioscience
tetracyclines and fluoroquinolones have unfavor- USA illumigene assay (Meridian Bioscience, USA)
able side-effect profiles that can occur in the approved by the FDA in the United States and
younger patient population, such as discoloration the FilmArray Respiratory Panel (BioMérieux,
of dentition with tetracyclines and tendinitis with France) approved in parts of Europe.83,87 These
fluoroquinolones.90 multiplex assays can often detect a positive result,
The treatment of extrapulmonary symptoms or which may not always correlate with the presence
complicated M pneumoniae pneumonia remains of disease because many patients may be a car-
unclear apart from the administration of antibi- rier, have a coinfection, or have overcome the clin-
otics. In patients with extrapulmonary conditions ical infection but still are undergoing a prolonged
associated with M pneumoniae, it is important to period of bacterial shedding.87,94 It remains un-
understand the inflammatory nature of the bacteria clear whether the asymptomatic carriage of M
where, through pathways associated with Toll-like pneumoniae or colonization can be differentiated
receptor 2, the bacteria are able to induce proin- from active infection with the new diagnostic tech-
flammatory cytokines and inflammasome activ- niques. Such results can cause confusion, make
ity.91 This partially helps explain why the interpretation of results difficult, and may lead to
symptoms are present more often in young adults unnecessary treatment with antibiotics and
who express a more robust immune response increased health care resources based on initiation
rather than infants or geriatric patients who are un- of respiratory precautions in hospitalized patients.
able to mount the same level of response.92 In pa- Macrolide resistance in M pneumoniae has been
tients with central nervous system syndromes a rapidly emerging phenomenon with reports of
from M pneumoniae, such as encephalitis and increasing resistance in Asia, Europe, and the
stroke, case reports have suggested the use of United States.79,95–97 Countries in Asia have shown
steroids and immunoglobulin therapy may be of a large amount of macrolide resistance; in Beijing it
benefit, although this has not been validated in has been reported that as many as 98% of certain
clinical trials.5,93 Similar reports have been made populations infected with M pneumoniae between
for patients with severe M pneumoniae pneumonia 2008 and 2012 are resistant to macrolide therapy.95
resulting in acute respiratory distress syndrome, The emerging resistance patterns have also been
suggesting possible benefit from extracorporeal found in the United States, where up to 13% to
membrane oxygenation and steroids.5,84,88 Anti- 27% of M pneumoniae infections have been resis-
microbial options are summarized in Table 2. tant to macrolide therapy.96,98 Resistance to mac-
rolides can come by various mechanisms,
including the most common, a single-nucleotide
Conflicts and Controversies
polymorphism at one of the residues around the
Infections with M pneumoniae are usually mild, binding site of the peptidyl transferase loop of the
which can make it a difficult diagnosis; however, 23s ribosomal RNA subunit preventing binding,
complications can occur with severe infections which ultimately can inhibit protein synthesis.99 It
that sometimes correlate with macrolide-resistant remains unclear as to how the emerging resistance
strains and reiterate the importance of therapy patterns are going to affect clinical prescribing
guidelines. patterns in the near future in the United States;
With its mild clinical presentation, M pneumo- however, at this time, there are no formal recom-
niae can be a challenging clinical diagnosis as mendations for macrolide prophylaxis in close con-
one that often mimics mild respiratory viruses; or, tacts of infected individuals. The mainstay of
patients fail to present for evaluation due to their preventing infection spread remains handwashing
low-grade symptoms, making it an underdiag- and respiratory droplet isolation to limit transmis-
nosed infection. With the development of many sion of the bacteria.
 Atypical Pneumonia 55

There have also been studies linking M pneumo- 4. Sopena N, Sabrià-Leal M, Pedro-Botet ML, et al.
niae to asthma, supporting that the presence of Comparative study of the clinical presentation of Le-
the bacteria can precede the onset of asthma gionella pneumonia and other community-acquired
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acute asthma exacerbations were positive for M gionellosis risk in the greater Philadelphia metro-
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SUMMARY
testing for detection of legionella spp.: a system-
CAP due to Legionella, Chlamydophyla, or Myco- atic review. J Clin Microbiol 2016;54(2):401–11.
plasma continues to be a diagnostic challenge 12. Marston BJ, Lipman HB, Breiman RF. Surveillance for
due to the nonspecific clinical and radiographic Legionnaires’ disease. Risk factors for morbidity and
presentations. The vague clinical presentations of mortality. Arch Intern Med 1994;154(21):2417–22.
atypical CAP contribute to its underdiagnosis and 13. Farnham A, Alleyne L, Cimini D, et al. Legionnaires’
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fluoroquinolones are currently the antibiotics of 14. Lettinga KD, Verbon A, Nieuwkerk PT, et al. Health-
choice, but this may change in the near future as related quality of life and posttraumatic stress
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atypical CAP. Several controversies still exist in naires disease. Clin Infect Dis 2002;35(1):11–7.
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investigation of preventing atypical CAP and deter- pneumonia due to Legionella pneumophila: prog-
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