Introduction
In the year 2015, it was reported that there
were
5.9 million deaths of children under 5 years of age
globally, of which 1.2 million (20%) occurred in
India alone [Lancet Report, 2015]. Currently,
India bas an under 5 morraliiy rate of 18 per I 000
live births [Wodd Bank, 2015]. Community
acquired pneumonia (CA.P) contributes to
about one sixth of this mortaliry [United
Nations
Children's Emergency Fund (UNICEF) and
World Heahh Organization (WHO), 2006].
CAP is an infective intlammarion of Jung paren
chyma due to bacterial or viral pathogens. The
key symptom of CAP is fast breaming. WHO
(1994] bas defined fasr breathing as respiratory
~erapeutic Advances in Infectious Disease 313-4)
rate of >60 per minure for infants less than
2 months, >50 per minute for infants of 2-
12 months, and >40 per minute forchildren
more than 12-59 months. Previously, CAP was
catego- rized into three groups by WHO namely
pneumo nia, severe pneumonia, and very
severe disease. Fast brealb.iog alone was
csregonsedas pneu.mo nia, fast breathni g with
chest indrawing as severe pneumonia, end fasr
breathing with chest in- drawing along with
any of the danger signs> namely inability to
feed, drowsiness or altered consciousness,
convulsion, cyanosis, as very severe disease.
Recently,however, WHO (2014] carcgonzed
CAP in children under 5 years of age inro two:
pneumonia and severe pneumonia, Fast
breathing with orwithout chest indrawing is now
 categorizedas pneumonia and fast breathing with Literature search
any of the dangersigns as severe pneumonia. T,1,·o primary databases, PubMed
-··L- ... J ····-' .. -.1 r .... -1.. t• .. L

etiology using whole blood or NPA samples [Picot 8.8% [Capoor ti aL 2006] and Su,phylOC1Jcc1,s
el al. 2014; Levine el aL 2012). Also, scrotyping of aureus 723% [Capoor et al: 2006; Tiewsoh et al.
certain bacteria has been atrempted by PCR 2009; Pandey et al. 2000). In Indian children,dif
method [Picor e1 al 2014). ferent serorypes of S. pneumoniae were isolated
with serotypes I and 5 being most prevalent fol
lowed by 4, 6A and 6B, 7, 12, 141 15, J9F, 23,
Etiology and 45 (Nisarga et al. 2015; Balaji et al 2015;
From cases of WHO defined CAI' in children John et al. 1996; Kuricn et al. 1999; Kanungo and
bacteria, viruses, and atypical bacteria have Rajalakshmi, 20011,
been isolated in different studies (fables 35).
The rate of isotauoo of organism was different in Other organisms had also been isolated like
vari ous studies and age groups. Unlike the Aci,u1obaaer in 20% [Capoor a al. 2006] and
developed countries where viruses were l(leb<iellapneumomae in 3.320.5% [Capoor ti al
responsible for most cases of pneumonia in 2006; Tiewsoh et al 2009; Mat:bew et al
children between 2months and 5 years, 2015]. In the Severe Pneumonia Evaluation
bacterial infections contributed max- imum Antimicrobial Research (SPEAR) study [Rai et al.
number of cases in developing countries 2008( and the CAPES study (Nisarga etal. 20151,
[Berman, 1991). S. a,,nu.s was the commonesr organism isolated
from severe cases of pneumonia in children
Several studies showed thar 5;. pneumonio» under
was 5 years of age.
most common organism (3050%) [Capoor ct al
2006; Farooqui el al. 2015; Rudan el al. 2013; There is a relative dearth of studies on viral
Mathew ei al. 2015; Tiewsoh el al. 2009; Awastbi etiol- ogy of CAP. "Ibis may be because viral
and Pando, 1997; Pandey et al. 2000; Bahl isolation is difficult as compared with
et lll.1995] followed by H. influem:ac l)'PC b in bacterial isolation,
DIAGNOSIS
Current case definitions for pneumonia vary considerably and arc highlyseufog dependent (18). In WHO-
defined pneumonia, cough or breathing difflculues, and ageadjusted tachypnea are sufficient fordiagnosing
mildtomoderate pneumonia, but these criteria we redesigned for health wcekers with relativelylittle train ing.
However,the diagnostic threshokls for respiratory rate differ between the WflO, OS. and United Kingdom
(UK) guidelines (30,
31). Purtherruore, even within affluent countries such as the US,
the diagnostic criteria, and testing for pneumonia wltbln hospital f.rnergencyDcpartruents vanes widely (32).
Communi1y healthcare workers often diagnose pneumonia on history and exaruination (respiratory rate.
dyspnea, auscultatory
findings). However, in young children with a cough, chest aus cuhatQry findings. even by doctors (general
practitioners], are unreliable with kappa values (0.39, 95% Cl 0.260.53) (33) below the acceptable. clinical
range.
While many studies use CXRs as the gold standard (18), there is disagreement over whether a CXR should
be an index test, Cur rent USA.(31) and UK (34) guidelineson childhood pneumonia do net advocate(:XRs
outside of hospitalsettings. Furthermore, their
interpretation is subjective often rcsuhj1.1g in additional diagnos
tic variability. Also, CXRs arc insensitive when compared to chest computed tomography (CT) scans (35).
While chest Gr scans will
not be: used 10 diagnose pneumonia in the usual clinicaJ setting. the poor Stn$ilivity of (:X.R$1rt~11\$ they 100
cannot be used as a diagnostic gold standard.
Laboratory tests (e.g., C~reactive protein, peripheral blood
white cell count,erythrocyte sediruenrariontale) are ancillary and nondiagnostic lCSIS. In aduhs with
communityacquired pneu monia, employing procalc.itonin levels to initiate and cease anti bi· oticsmightbe
useful, however,procalcitonindiagnostic thresholds
in childhood pneumonia are less defined and their usefulness and safety in guiding management has not been
established ( LS).

THE KNOWLEDGE GAPS

World HealthOrganization has published a standardized method to define radiographic pneumonia (based on
CXRs) for epidemi ological studies and vaccine trials (36). Tbe WHO definition foe primary i:ndpoinl
consclidauon \.\flafOMEPC (36) was framed 10 he more specific for likely bacterialpneumonia than thoscused
for clinical purposes. However.some authors have applied the WHO~ EPC definitlon t·n the clinical context
(24), an approach that we do no1 recommend (37). In a blinded study, a pediatric pulrno nologist's
assessment of radiographic pneumonia in a cohort of children hospitalized with clinical pneumonia, had
significantly higher positive predicted value for the presence of auscultatory crackles and elevated pcripbeml
blood white o::11 counts when compared to WHOllPC read by a panel standardized to inter pret WHOEP(:
(37). Others have raised similar concerns, with left IO\V¢r and rit;hl middle lobe consolldeticn and non-
alveolar pneumonia causing the greatest levels of disagreement (37, 38).
A systematicreview cont pared t 1 different ..gold standards"for
identifying bacterial pneumonia and found that diagnostic tests used (or pediatric pneumonia have not been
validated rigorously ( 18). Some advocate chest ultrasounds for diagnosing pneumonia (24), but tbis npproacb
has not been validated. While chest ultra
sounds 1n.ay provide adequate images or sorne lobes. they will not forothers, particularly the righl middle lobe.
Thus, using another suboptimal diagnostic tool will only complicate the field further.
Tbe lack of a universally agreed diagnosuc gold standard foe
childhood pneumonia. especially one that can also difftren1.ia1c between bacterial and nonbacterial
pneumonia ls a major limi tation in clinical research in this area. Vaccine.probes have proven
useful at a population level. but they underestimate the bur· deu of disease as no vaccine is l 00%
efficacious or, i11 the case of PCVs. protects against all disease causing serotypes, Instead. valid standards.
useful for various scenarios should be devel oped. These include standards for clinical, epidemiological, and
treatment purposes, such as defining when antibiotics sbou1d be used (as opposed to conceptually a purely
bacterial or viralbased etiology).
SURVEILLANCE OF M. pneumoniae
PNEUMONIA IN JAPAN
In Japan, the National Epidemiological Surveillance of lnfectious Diseases (NESffi) program is conducted
under the Infectious Diseases Control La'A' (Law Concerning the Prevention of Infecttous Diseases and
Medical Cere for Patients of Infections), which includes nationwide surveillence of pneumonia cases
caused by Mywplas,na pne.umoniae. M. pneumoniae pneumonia
is classified as a category V infectious disease in the NESID. and the numbers of affected patients
(total of outpatients and in1>aticn1s) are reported weekly from sentinel hospiu·,ls. Approximately 500
hospitals across Japan that have departments of pediatrics and internal medicine and more than 300 beds
ate currently selected as the sentinels for surveillance of M. prreumoniae pneumonia in Japan. For
notification of eech new M. pneumoniae pneumonia patient. confirmation is required using one of the tests
listed in 'fable 1 in addition to clinical S)'1np10m5 observed by a clinician, Previously, culture isol.ation of M.
pne.umoniac and detection of serum antibodies against M. pne.umoniae were employed as the tests for
notification. However, detection of M. pneumoniae genomic DNA by polymerose chain reaction (PCR)
or looprnedtated isothermal ampliJication (LAMP) and detection of M. p11eumo11iac antigens by
immuno·chromatographic methods have been recently included in the tests for nonficericn 1• The data
from sentinels are Integrated at the lnfecliovs Disease Surveillance Ceurer (TDSC). National Institute of
tnfectlous Disease. (NTID) and published weekly'. Since the NESID program was initiated in July 1981, the
surveillance of primary atypical pneumonia (PAP) was continuously performed until March 1999. The crtterta
of PAP include pneumonia other than M. pneumoniae pneumonia•
.i.'Uch as that caused by Cl1lar11ydopf1Uapnew-noniae, Legionella pneumopniia. or several viruses. I Iowever, as
the maj,)r cause of t>AP is M~ pneumoniae. this surveillance largely represented
INTRODUCTION
Tbe clinical entity of "atypical" pneumonia was recogntzed in the .1930s 1n3oy years before the
etiological ngent was esteblished (McCoy. 1946). The term separated this entity of pneumonia
from classical pneumococcal pneumonia due to its lack of response to available antibiotics and
the distinct clinical presentation without typiLal lobar pneumonia and a Jess severe disease course.
Tbat is why the term ..walking pneumonia .. has been Introduced 10 de110Le this mild fonn of
pneumonia,
It was in a patient with "atypical.., pneumonia in l914, where ..\fycoplasn1a pneumoniac was
6rst isolated from sputum in tissue culture by Eaton et al. (1944). At that time, it was believed to
be a virus because il was resistam to penicillin and sulfonamides and passed through bactenaretainlng filters.
Experiments with Marine recruits and adult prisoners demonstrated that the so called Eaton agent caused
lower respiratory tract Infections in humans (Cbanoclt et nl.. 1961>,b). In 1963, it was first cultured on cell-
free medium and classified as M. pnLu,noniae (Ol.anod:c ct al., 1962; Chanock, 1963). Todoy we know that
mycoplasmas
are prokaryotes that lack a cell wall and represent the smallest selfreplicatjng organisms (Figure 1). Wilh a
size of 816..394 base pairs. the genome of M. pneumoniae is at least Hve times smaller than that of
Escherichia coli (Himmclreich cl al; 1996). The absence, of a cell wall and the specialized attadunent
organelle facilitate close con tad with the host respirator)' epithelium, which suppliesthe bacterium with tbe
necessary nutrients (or its growth and proliferation.
Afycoplas,na pneumaniae causes both upper and lower respiratory tract jnfecrions, with
comrnunltyacquired pneumonia (CAP) as the major burden of disease. Although M. pneumoniae
infections are generally m.ild and selflimiting. palients of every age can develop severe and fulrninant
disease (Ko.nnan ct. al, 2012). M. pneumoniae can also cause
extrapulmonary manlfestauons that affect almost every organ
(Narita, 2010).
In children, Ai pncun,oniac infections. were first reported in
1960 when 16% of 110 children with lower respiratory tract disease were tested positive by a fourfold
rise .in antibody titers
against the Ea100 agent (O,anock el al., 1960). To date, it is known that the locidence of M.
pntnn,oniae Iofecnoos is generally higher in children thon in adults (Poy ct al., 19?9). This review
focuses on the. characteristics of M. pneumoniae infections in children, and discusses simple clinical
decision rules that n1ay further aid clinicians in identifying patients at high risk for M. pner,moniae CAJ>.