Clinical Infectious Diseases

MAJOR ARTICLE

Mycoplasma pneumoniae Among Children Hospitalized

With Community-acquired Pneumonia
Preeta K. Kutty,1 Seema Jain,1 Thomas H. Taylor,1 Anna M. Bramley,1 Maureen H. Diaz,1 Krow Ampofo,2 Sandra R. Arnold,3,4 Derek J. Williams,5,6
Kathryn M. Edwards,5,6 Jonathan A. McCullers,3,4,7 Andrew T. Pavia,2 Jonas M. Winchell,1 Stephanie J. Schrag,1 and Lauri A. Hicks1
1
Centers for Disease Control and Prevention, Atlanta, Georgia; 2University of Utah Health Sciences Center, Salt Lake City; and 3Le Bonheur Children’s Hospital, and 4University of Tennessee Health
Science Center, Memphis, 5Vanderbilt University Medical Center, and 6Monroe Carell Jr Children’s Hospital at Vanderbilt, Nashville, and 7St Jude Children’s Research Hospital, Memphis, Tennessee

(See the Editorial Commentary by Shah on pages 13–4.)

Background.  The epidemiology of Mycoplasma pneumoniae (Mp) among US children (<18 years) hospitalized with communi-
ty-acquired pneumonia (CAP) is poorly understood.

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Methods.  In the Etiology of Pneumonia in the Community study, we prospectively enrolled 2254 children hospitalized with
radiographically confirmed pneumonia from January 2010–June 2012 and tested nasopharyngeal/oropharyngeal swabs for Mp
using real-time polymerase chain reaction (PCR). Clinical and epidemiological features of Mp PCR–positive and –negative children
were compared using logistic regression. Macrolide susceptibility was assessed by genotyping isolates.
Results.  One hundred and eighty two (8%) children were Mp PCR–positive (median age, 7 years); 12% required intensive care
and 26% had pleural effusion. No in-hospital deaths occurred. Macrolide resistance was found in 4% (6/169) isolates. Of 178 (98%)
Mp PCR–positive children tested for copathogens, 50 (28%) had ≥1 copathogen detected. Variables significantly associated with
higher odds of Mp detection included age (10–17 years: adjusted odds ratio [aOR], 10.7 [95% confidence interval {CI}, 5.4–21.1] and
5–9 years: aOR, 6.4 [95% CI, 3.4–12.1] vs 2–4 years), outpatient antibiotics ≤5 days preadmission (aOR, 2.3 [95% CI, 1.5–3.5]), and
copathogen detection (aOR, 2.1 [95% CI, 1.3–3.3]). Clinical characteristics were non-specific.
Conclusions.  Usually considered as a mild respiratory infection, Mp was the most commonly detected bacteria among children
aged ≥5 years hospitalized with CAP, one-quarter of whom had codetections. Although associated with clinically nonspecific symp-
toms, there was a need for intensive care in some cases. Mycoplasma pneumoniae should be included in the differential diagnosis for
school-aged children hospitalized with CAP.
Keywords.  community; pneumonia; mycoplasma; bacterial disease; children.

Mycoplasma pneumoniae is a common bacterial pathogen asso- US patients. In the EPIC study, Mp was the most commonly
ciated with a wide array of clinical manifestations, including detected bacterial pathogen (8%) among enrolled children
upper respiratory infections, pneumonia, and extrapulmonary (<18 years old), with an estimated annual incidence of 1.4 (95%
manifestations (eg, encephalitis, Stevens-Johnson syndrome) confidence interval [CI], 1.2–1.6) cases per 10 000 children
[1–7]. Mycoplasma pneumoniae (Mp) is also often associ- using real-time polymerase chain reaction (PCR) [15]. Using
ated with community- and facility-based outbreaks, partic- this dataset, we describe the specific epidemiological and clini-
ularly among school-aged children and young adults [8–13]. cal features of Mp CAP among hospitalized children.
However, the burden and epidemiology of hospitalized com-
munity-acquired pneumonia (CAP) due to Mp is poorly under-
METHODS
stood, largely because diagnostic testing has generally employed
serology or nonstandardized molecular approaches [14]. Study Population
The Centers for Disease Control and Prevention’s (CDC) The details of the pediatric EPIC study have been published else-
Etiology of Pneumonia in the Community (EPIC) study was a where [15]. In brief, children (<18 years of age) admitted with clin-
prospective, multicenter, active population-based surveillance ical and radiographic pneumonia were enrolled from 1 January
study of the incidence and etiology of CAP among hospitalized 2010 through 30 June 2012, at 3 children’s hospitals (Memphis,
Tennessee; Nashville, Tennessee; and Salt Lake City, Utah). Final
Received 29 November 2017; editorial decision 26 February 2018; accepted 14 May 2018; determination of inclusion in the study required independent con-
published online May 17, 2018.
Correspondence: P. K. Kutty, Centers for Disease Control and Prevention, 1600 Clifton Rd NE,
firmation by a dedicated board-certified pediatric study radiolo-
MS A-31, Atlanta, GA 30329 ([email protected]). gist [15]. Radiographic evidence of pneumonia was defined as the
Clinical Infectious Diseases®  2019;68(1):5–12 presence of consolidation, other infiltrate, or pleural effusion [16].
Published by Oxford University Press for the Infectious Diseases Society of America 2018.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
Children with recent hospitalization, previous enrollment
DOI: 10.1093/cid/ciy419 in the EPIC study, residence in an extended-care facility, an

Pediatric Community-acquired Mycoplasma Pneumonia  •  CID 2019:68 (1 January) • 5

alternative respiratory disorder diagnosis, or newborns who fluoroquinolones (eg, levofloxacin and moxifloxacin), and
never left the hospital were excluded, as were children with a doxycycline. Any previous outpatient antibiotic exposure was
tracheostomy, cystic fibrosis, neutropenia with cancer, recent defined as self-reported antibiotic use ≤5 calendar days before
solid organ or hematopoietic stem cell transplant, current graft- admission. Inpatient antibiotic exposure was defined as receipt
vs-host disease, or human immunodeficiency virus infection of an antibiotic at any time after admission.
with a CD4 count <200 cells/μL. After written informed con-
sent, patients and/or caregivers were interviewed, and medical Statistical Analysis
charts were abstracted for clinical and epidemiological data. We compared children hospitalized with CAP with and with-
Institutional review boards at each institution and the CDC out PCR-positive Mp using descriptive statistics, including the
approved the study protocol. Pearson χ2 or Fisher exact tests for comparison of categorical
variables and median and interquartile ranges (IQR) for contin-
Specimen Collection and Laboratory Testing uous data using nonparametric tests, as appropriate. To assess
Blood and respiratory specimens were obtained for patho- the impact of whether including children without a detected
gen testing using multiple modalities as previously described pathogen (n  =  395 [19%]) in the Mp PCR–negative group

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(Supplementary Materials) [16]. In brief, real-time PCR assays (n = 2072) would impact our findings, a sensitivity analysis was
were performed at the study sites on combined nasopharyngeal/ performed; no significant differences were identified and there-
oropharyngeal (NP/OP) swabs [16]. Further Mp confirmatory fore children without a detected pathogen were included in the
testing using a multiplex real-time PCR assay was performed Mp PCR–negative group.
at CDC; cultures were performed on Mp PCR–positive speci- We performed bivariate analyses comparing children with
mens [17]. Macrolide susceptibility testing was performed on and without PCR-positive Mp, and also stratified by age; we
all corresponding isolates of Mp PCR–positive specimens and/ assessed demographics and clinical features, including illness
or extracted nucleic acid by genotyping of the 23S ribosomal severity as assessed by intensive care unit (ICU) admission,
RNA gene using a real-time PCR assay with high-resolution invasive mechanical ventilation, acute respiratory distress
melt analysis [18–21]. The Mp research test results were not syndrome, prolonged length of hospital stay (defined as >90th
available to treating clinicians. percentile, ie, ≥6  days), hypoxia, and death. Hypoxia was
defined as oxygen saturation rate on admission <92% using
Case Definitions pulse oximetry on room air, or use of supplemental oxygen
A CAP patient with a positive Mp PCR NP/OP specimen was at presentation. For children <5  years old, white blood cell
considered to have Mp CAP (Mp PCR-positive). If Mp was not (WBC) count >15 000 cells/μL or <5500 cells/μL, and for
detected by PCR on a NP/OP specimen, the patient was con- children ≥5 years old, WBC count >11 000 cells/μL or <3000
sidered to have CAP without Mp (Mp PCR-negative). A CAP cells/μL, was considered abnormal. We also performed strati-
patient was considered to have macrolide-resistant Mp if they fied analyses assessing Mp CAP by antibiotic status and type,
had an Mp isolate and/or extracted nucleic acid with positive and codetected pathogens; and made specific comparisons
genotyping for macrolide nonsusceptibility. Codetection was between Mp CAP and CAP due to typical bacterial and respi-
defined as detection of Mp with ≥1 other bacterial or viral ratory viral pathogens.
pathogen. We used multivariable logistic regression to assess features
We also perfomed a subanalysis comparing Mp PCR–pos- independently associated with and without positive Mp PCR;
itive pneumonia to typical bacterial CAP (ie, detection of only children who had specimens tested for both bacteria and
Haemophilus influenzae or other gram-negative bacteria, viruses were included. Variables with a bivariate P value <.20 or
Staphylococcus aureus, Streptococcus anginosus, Streptococcus with known or hypothesized biological and/or epidemiological
mitis, Streptococcus pneumoniae, or Streptococcus pyogenes in plausibility were included in the models. We fitted models using
blood, endotracheal aspirate, bronchoalveolar lavage speci- all candidate variables and automated stepwise procedures, and
men, or pleural fluid using culture and/or PCR; Supplementary then fitted alternate models using only selected variables. We
Materials). If viruses such as such as adenovirus (AdV); corona- used Akaike information criterion to help select among alter-
viruses; human metapneumovirus (HMPV); human rhinovirus; nate models—this statistic simultaneously accounts for good-
influenza A/B viruses; parainfluenza virus (PIV) 1, 2, and 3; or ness of fit and complexity of the tentative models. To resolve
respiratory syncytial virus (RSV) were detected by PCR of NP/ collinearity between study site and race in the final model, we
OP swabs or if serology for AdV, HMPV, influenza A/B, PIV, or controlled for study site and not race. All statistical tests were
RSV showed a 4-fold increase in antibody titer, the patient was interpreted in a 2-tailed fashion to estimate P values and 95%
considered to have viral CAP (Supplementary Materials). confidence intervals (CIs). All statistical analyses were con-
Antibiotics considered active against Mp included macro- ducted using SAS version 9.3 software (SAS Institute, Cary,
lides (eg, erythromycin, azithromycin, and clarithromycin), North Carolina).

6 • CID 2019:68 (1 January) •  Kutty et al

RESULTS 28%; P = .2), but more likely to have pleural effusion (26% vs
Study Population
12%; P < .01) and hilar lymphadenopathy (10% vs 6%; P = .02).
Among 3803 eligible children hospitalized with CAP, 2638 Leukopenia was less common among Mp PCR–positive chil-
(69%) were enrolled; of these, 2358 (89%) met the criteria of dren than Mp PCR–negative children (1% vs 6%; P = .03).
radiographic pneumonia. Of the 2358 children with CAP, 2254 Mp PCR–positive children were less likely to require ICU
(96%) had Mp PCR tests performed and Mp was detected in admission (12% vs 21%; P < .01) or invasive mechanical ven-
182 (8%). The median age of Mp PCR–positive children was tilation (2% vs 7%; P  <  .01) than Mp PCR–negative children
7  years (IQR, 4.0–11.0  years); 60% were male and 62% were (Table  2). Among the 21 (12%) Mp PCR–positive children
white (Table 1). Mp was more prevalent among children aged admitted to the ICU, age ranged from 4  months to 17  years
5–9  years (17%) and 10–17  years (24%) compared with chil- (median, 6  years). Of the 3 children who required invasive
dren <5 years old (3%; P < .01). The highest prevalence of Mp mechanical ventilation, the 2 younger children had under-
was in Salt Lake City (11%), followed by Memphis (7%) and lying asthma, radiographic consolidation, and codetections
Nashville (6%) (Supplementary Table 1). At the Salt Lake City (8-month-old with RSV and rhinovirus and a 3-year-old with
site, Mp was detected throughout the year in 2011, with no clear rhinovirus); an older child (9 years) had congenital heart dis-

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seasonality (Figure 1). At the other sites, peaks in summer and ease, a past history of leukemia, alveolar disease on chest radi-
fall seasons were observed. ography, and no codetections.
When comparing children with Mp PCR–positive CAP with
Bivariate and Stratified Analysis CAP due to typical bacterial pathogens, children with typical
Clinical Characteristics bacterial pathogens were significantly more likely to be <5 years
The duration of symptoms before hospitalization was longer for old (58% vs 20%; P < .01) and less likely to have rales (39% vs
Mp PCR–positive children compared with Mp PCR–negative 63%; P < .01). Mp PCR–positive children were less likely to have
children (median, 6.8 [IQR, 4.6–9.5] days vs 3.6 [IQR, 2.0–5.8] consolidation (56% vs 81%; P < .01), pleural effusion (26% vs
days; P < .01). The differences in clinical manifestations between 56%; P < .01), or ICU admission (11% vs 36%; P < .01) and had a
Mp PCR–positive and Mp PCR–negative children are detailed shorter hospital length of stay (median, 2 days vs 6 days; P < .01)
in Table  2. On chest radiography, Mp PCR–positive children than children with typical bacterial pneumonia (Supplementary
were as likely as Mp PCR–negative children to have consoli- Table  3). Compared with children with viral pneumonia, Mp
dation (59% vs 59%; P = .9) and multilobar infiltrates (23% vs PCR–positive children were significantly more likely to report

Table 1.  Epidemiologic Features Among Children Hospitalized for Community-acquired Pneumonia With and Without Mycoplasma pneumoniae (N = 2254)

Mycoplasma pneumoniae Mycoplasma pneumoniae Unadjusted OR

Characteristic PCR-Positivea (n = 182) PCR-Negativeb (n = 2072) (95% CI) P Value

Age, y
 <2 21 (12) 988 (48) Reference
 2–4 30 (16) 544 (26) 2.6 (1.5–4.6) <.01
 5–9 67 (37) 336 (16) 9.4 (5.7–15.6) <.01
 10–17 64 (35) 204 (10) 14.8 (8.8–24.7) <.01
Sex, male 109 (60) 1125 (54) 1.3 (.9–1.7) .1
Race/ethnicity
  Non-Hispanic white 113 (62) 764 (37) Reference
  Non-Hispanic black 32 (18) 744 (36) 0.3 (.2–.4) <.01
 Hispanic 29 (16) 399 (19) 0.5 (.3–.8) <.01
 Other 5 (3) 98 (5) 0.3 (.1–.7) <.01
Study sitec
  Salt Lake City, Utah 81 (45) 677 (33) Reference
  Memphis, Tennessee 60 (43) 783 (54) 0.6 (.5–.9) .01
  Nashville, Tennessee 41 (34) 612 (48) 0.6 (.4–.8) .003
Household size >5 individuals 61 (33) 668 (33) 1.1 (.8–1.4) .08
Daycare (children <6 y of age) (n = 61) (n = 1630)
  Attends daycare 12 (20) 543 (33) 0.5 (.3–.9) .03

Data are presented as No. (%) unless otherwise indicated.

Abbreviations: CI, confidence interval; OR, odds ratio; PCR, polymerase chain reaction.
a
Radiographically confirmed community-acquired pneumonia (CAP) in a patient enrolled in Etiology of Pneumonia in the Community (EPIC) study with a positive Mycoplasma pneumoniae
PCR result.
b
Radiographically confirmed CAP in a patient enrolled in EPIC with a negative Mycoplasma pneumoniae PCR result.
c
At each study site, there was one children’s hospital.

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Figure 1.  Prevalence of Mycoplasma pneumoniae among children hospitalized for community-acquired pneumonia who underwent real-time polymerase chain reaction
(PCR) testing, by time and study site, January 2010–June 2012. Prevalence = (number of M. pneumoniae PCR–positive nasopharyngeal/oropharyngeal [NP/OP] specimens/
total number of NP/OP specimens that underwent PCR testing) × 100.

a headache (48% vs 17%; P < .01) or sore throat (48% vs 26%; a codetection (65% vs 34%; P < .01), compared with children
P < .01) but less likely to report dyspnea (61% vs 72%; P < .01) 5–9 years old (21% vs 67%; P < .01) and 10–17 years old (21% vs
or rhinorrhea (3% vs 10%; P = .02). In addition, Mp PCR–pos- 56%; P < .01), Mp PCR–positive children were less likely than
itive children were less likely to have wheezing (25% vs 46%; Mp PCR–negative children to have a codetection.
P < .01) and to have ICU admission (11% vs 21%; P < .01) than
Multivariable Analyses
children with viral pneumonia (Supplementary Table 3).
Variables independently associated with increased odds of Mp
Antibiotic Treatment detection included age 10–17 years and 5–9 years; clinical signs
A higher proportion of Mp PCR–positive children received an and symptoms of hilar lymphadenopathy, rales, headache, sore
antibiotic within 5  days before admission compared with Mp throat, or decreased breath sounds; antibiotic receipt ≤5  days
PCR–negative children (35% vs 16%; P < .01) (Table 2). When before admission; and any codetection (Table  3). Wheeze,
stratified by age, Mp PCR–positive children were more likely rhinorrhea, and chest pain, in addition to study site and ICU
to have received outpatient antibiotic treatment than Mp PCR– admission, were significantly less likely to be associated with
negative children in both the 5–9 years (39% vs 16%; P < .01) and Mp detection (Table 3).
10–17 years (44% vs 20%; P < .01) age groups, but were as likely
Macrolide Susceptibility
in those <5 years old (19% vs 16%). Among Mp PCR–positive
Of the Mp PCR–positive specimens, 176 (97%) were positive
children, there were no significant differences in outcomes (ie,
upon repeat PCR testing at the CDC; Mp isolates were recovered
ICU admission or invasive mechanical ventilation) between
from 169 (96%) specimens by culture, and 6 (4%) isolates were
children who received outpatient antibiotics with and without
macrolide resistant. All 6 (100%) children with macrolide-resis-
Mp activity. During hospitalization, among Mp PCR–positive
tant Mp isolates were non-Hispanic white; 5 (83%) were >5 years
children, length of stay was similar between children who did
old, and 4 (67%) were male. Four (67%) patients with a macro-
(median, 3 [IQR, 2–5] days) and did not (median, 2 days [IQR,
lide-resistant isolate had received a macrolide before admission;
1–3] days) receive an inpatient antibiotic with Mp activity (P = .6).
2 between 0 and 5 days before admission and 2 between 6 and
15 days before admission. Of the 6 macrolide-resistant isolates,
Codetections
3 (50%) were from Memphis, 2 (33%) were from Nashville, and
Of the 178 (98%) Mp PCR–positive children who had speci-
1 (17%) was from Salt Lake City. There were no significant dif-
mens tested for both bacteria and viruses, 50 (28%) had a
ferences in symptoms and outcomes between children with and
codetection; 46% of those with a codetection were <5 years old
without macrolide-resistant Mp.
(Supplementary Table  2). Among Mp PCR–positive children,
48 (96%) had at least 1 viral codetection, 1 (2%) had a single
DISCUSSION
bacterial codetection (S.  pneumoniae), and 1 (2%) had both
bacterial (S.  pneumoniae) and viral (rhinovirus) codetections. In this large US multicenter active surveillance study with
When stratified by age, Mp PCR–positive children <5  years prospective enrollment and systematic microbiological test-
old were more likely than Mp PCR–negative children to have ing among children hospitalized with CAP, Mp was the most

8 • CID 2019:68 (1 January) •  Kutty et al

Table 2.  Clinical Features Among Children Hospitalized for Community-acquired Pneumonia With and Without Mycoplasma pneumoniae (N = 2254)

Mycoplasma pneumoniae Mycoplasma pneumoniae Unadjusted OR

Characteristic PCR-Positivea (n = 182) PCR-Negativeb (n = 2072) (95% CI) P Value

Clinical presentationc
 Fever/feverish 174 (96) 1885 (91) 2.2 (1.01–4.5) .03
 Cough 174 (96) 1960 (95) 1.2 (.6–2.6) .6
 Fatigue 142 (78) 1425 (63) 1.6 (1.1–2.3) <.01
  Lack of appetite 141 (77) 1542 (68) 1.2 (.8–1.7) .4
 Dyspnea 121 (67) 1479 (71) 0.8 (.6–1.1) .2
 Chills 102 (56) 729 (35) 2.3 (1.7–3.2) <.01
 Headache 87 (48) 425 (21) 3.5 (2.6–4.8) <.01
  Sore throat 86 (47) 582 (28) 2.3 (1.7–3.1) <.01
 Wheezing 82 (45) 1303 (63) 0.5 (.4–.7) <.01
  Runny nose 80 (44) 1484 (72) 0.3 (.2–.4) <.01
  Abdominal pain 76 (42) 427 (21) 2.7 (2.0–3.8) <.01

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 Diarrhea 64 (35) 626 (30) 1.3 (.9–1.7) .2
 Myalgia 63 (35) 366 (18) 2.5 (1.8–3.4) <.01
  Chest pain 50 (27) 436 (21) 1.4 (1.01–2.0) .04
  Chest retraction 46 (25) 953 (46) 0.4 (.3–.6) <.01
Underlying condition
  Any condition (≥1 condition) 83 (46) 1066 (51) 0.8 (.6–1.1) .1
  Asthma/reactive airway disease 55 (30) 700 (34) 0.9 (.6–1.2) .3
  Preterm birthd 6/21 (29) 201/988 (20) 1.6 (.6–4.1) .4e
  Congenital heart disease 14 (8) 147 (7) 1.1 (.6–1.9) .8
  Neurological disorder 11 (6) 180 (9) 0.7 (.4–1.3) .2
  Chromosomal disorder 16 (9) 112 (5) 1.7 (1.0–2.9) .06
Examination findings at presentation
  Decreased breath sounds 114 (63) 842 (41) 2.4 (1.8–3.3) <.01
 Rales 110 (60) 814 (39) 2.4 (1.7–3.2) <.01
 Tachypneaf 78 (43) 740 (36) 1.4 (1.0–1.8) .05
  Documented feverg 67 (36) 1003 (48) 0.6 (.5–.8) <.01
 Hypoxiah 77 (42) 768 (37) 1.3 (.9–1.7) .2
  Chest indrawing 55 (30) 1172 (57) 0.3 (.2–.5) <.01
 Rhonchi 49 (27) 855 (41) 0.5 (.4–.7) <.01
 Wheezing 48 (26) 875 (42) 0.5 (.3–.7) <.01
Radiographic findingsi
 Consolidation 108 (59)j 1219 (59) 1.0 (.8–1.4) .9
  Single lobar infiltrate 59 (32) 534 (26) 1.4 (1.0–2.0) .05
  Multilobar infiltrates 42 (23) 573 (28) 0.8 (.5–1.1) .2
  Multilobar infiltrates (unilateral) 20 (11) 155 (7) 1.5 (.9–2.5) .09
  Multilobar infiltrates (bilateral) 22 (12) 420 (20) 0.5 (.3–.9) <.01
  Pleural effusion 48 (26) 244 (12) 2.7 (1.9–3.8) <.01
  Complicated bronchiolitis 21 (12) 610 (29) 0.3 (.2–.5) <.01
  Hilar lymphadenopathy 18 (10) 114 (6) 1.9 (1.1–3.2) .02
Laboratory findings
  Abnormal WBC countk
  Leukopenia 2/160 (1) 98/1074 (6) 0.2 (.05–.8) .03
  Leukocytosis 40/160 (25) 463/1074 (27) 0.9 (.6–1.3) .6
  Abnormal platelet countl
  Thrombocytopenia 6/159 (4) 73/1681 (4) 0.9 (.4–2.0) .7
  Thrombocytosis 15/159 (9) 182/1681 (11) 0.9 (.5–1.5) .6
 Hyponatremiam 12/110 (11) 125/1352 (9) 1.2 (.6–2.3) .6
Severity of illness
  ICU admission 21 (12) 431 (21) 0.5 (.3–.8) <.01
  Invasive mechanical ventilation 3 (2) 143 (7) 0.2 (.07–.7) <.01
  Length of stay, d, median (IQR) 2 (2–4) 3 (2–4) .1n
Antibiotics
  Receipt of an outpatient antibiotic 90 (50) 482 (23) 3.2 (2.4–4.4) <.01
  Receipt of antibiotics prior to admission within 5 d 64 (35) 338 (16) 2.8 (2.0–3.9) <.01

Pediatric Community-acquired Mycoplasma Pneumonia  •  CID 2019:68 (1 January) • 9

Table 2. Continued

Mycoplasma pneumoniae Mycoplasma pneumoniae Unadjusted OR

Characteristic PCR-Positivea (n = 182) PCR-Negativeb (n = 2072) (95% CI) P Value
  Penicillins 44/64 (69) 173/338 (51) Reference
  Cephalosporins 13/64 (20) 101/338 (30) 0.5 (.3–1.0) .05
  Macrolides 7/64 (11) 56/338 (17) 0.5 (.2–1.2) .1
  Inpatient antibiotics 175 (96) 1794 (87) 3.9 (1.8–8.3) <.01
  Macrolideso 75/175 (43) 351/1794 (20) 2.3 (1.6–3.3) <.01
  Penicillins 72/175 (41) 776/1794 (43) Reference
  Cephalosporin 27/175 (15) 639/1794 (36) 0.5 (.3–.7) <.01

Data are presented as No. (%) unless otherwise indicated.

Abbreviations: CI, confidence interval; ICU, intensive care unit; IQR, interquartile range; OR, odds ratio; PCR, polymerase chain reaction; WBC, white blood cell.
a
Radiographically confirmed community-acquired pneumonia (CAP) in a patient enrolled in the Etiology of Pneumonia in the Community (EPIC) study with a positive Mycoplasma pneumo-
niae PCR result.
b
Radiographically confirmed CAP in a patient enrolled in the EPIC study with a negative Mycoplasma pneumoniae PCR result.
c
Clinical presentation is based on patient history.

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d
Only for those children <2 years of age.
e
Fisher exact test.
f
Tachypnea: For children <2 months: >60 breaths/minute; 2 months to <12 months: >50 breaths/minute; 12 months to 5 years: >40 breaths/minute; >5 years: >25 breaths/minute were
considered as abnormal.
g
Temperature ≥38.0°C or ≥100.4°F.
h
Hypoxia: Oxygen saturation rate <92% on admission using pulse oximetry on room air or requirement of supplemental oxygen at the time of presentation.
i
The radiographic findings are not mutually exclusive and could overlap.
j
Thirty-two (30%) of the Mycoplasma pneumoniae CAP children with a consolidation had a codetection.
k
For children <5 years old, WBC count >15 000/μL or <5500/μL and for children ≥5 years old, WBC count >11 000/μL or <3000/μL was considered abnormal.
l
Platelet count of <150 000 cells/μL or >500 000 cells/μL was considered abnormal.
m
For children <1 year of age, serum sodium <130 U/L and for those >1 year of age, serum levels of <135 U/L were considered abnormal.
n
Wilcoxon 2-sample test.
o
Macrolides received as inpatient treatment: azithromycin 74 (99%); clarithromycin: 1 (1%).

commonly detected bacteria and most prevalent in school-aged (21.2% in the Netherlands) [30], Mp was infrequently detected
children ≥5 years old. Although there were no deaths and few among our convenience sample of asymptomatic controls
patients required mechanical ventilation, 1 in 10 hospitalized (0.6%), suggesting that Mp is the likely cause of illness when
children with Mp PCR–positive CAP were admitted to the ICU. detected by PCR (Supplementary Materials). The differences in
Clinically, Mp CAP children had nonspecific symptoms that the study results may be a result of differences in control defi-
were not sufficiently distinctive to differentiate CAP due to Mp nitions, temporal or geographical variation in Mp activity, or
from other etiologies. The clinical symptoms associated with the length of the study (24 months vs 16 months, respectively).
Mp CAP on multivariable analysis are similar to those observed Our results indicate that Mp was the most commonly
with respiratory viral illnesses, including influenza infection detected bacteria among children hospitalized with pneumonia
[22, 23]. In addition, the clinical features independently asso- and those symptoms, signs, and radiographic findings would
ciated with Mp detection, such as rales, have historically been not help to distinguish Mp from viral pneumonia; therefore,
associated with typical bacterial infections [22]. clinicians may not have a reliable way to suspect Mp infection
Respiratory viral PCR panels are increasingly being used without diagnostic testing. In our study, results of assays done
for clinical purposes with US Food and Drug Administration– only for research purposes, including Mp tests, were not availa-
approved and validated assays for Mp. However, their use is not ble to guide clinical decisions. We did not identify differences in
yet widespread [14, 24, 25]. PCR is the current gold standard length of stay between Mp patients who did and did not receive
for diagnosis of Mp, due to its superior specificity compared to an antibiotic with activity against Mp. This finding is also con-
serology [17–19, 26–28]. A 2004 US pediatric population-based sistent with another study that compared the effectiveness of
study reported a Mp prevalence of 14% among 154 children hos- empirical β-lactam monotherapy vs β-lactam plus macrolide
pitalized with CAP using serology (positive if enzyme-linked combination therapy using data from the EPIC study; there were
immunosorbent assay immunoglobulin M was ≥1:10, or ≥4- no differences in length of stay, rehospitalizations, or recovery at
fold rise in immunoglobulin G titer) [29]. However, among the follow-up, including among the subgroup of children with Mp
21 children who were seropositive and who had a correspond- [31]. The EPIC study, however, was observational and limited
ing NP/OP swab collected within 24 hours of admission, only 12 to hospitalized children. Thus, there is a need for high-quality
(57%) had Mp detected by PCR [26]. While Mycoplasma detec- randomized trials to definitively address the impact of antibi-
tion in asymptomatic children has been previously reported otic therapy with Mp activity on CAP patient outcomes [32].

10 • CID 2019:68 (1 January) •  Kutty et al

Table  3. Characteristicsa Associated With Mycoplasma pneumoniae significant role of Mp among older children. Although Mp ill-
Among US Children (<18 Years) Hospitalized for Community-acquired ness is often mild and self-limited [6], in this study 12% of hos-
Pneumonia in Multivariate Analysis
pitalized children with Mp were admitted to the ICU. Increasing
Adjusted OR access to Mp PCR could facilitate prompt diagnosis resulting in
Characteristic (95% CI) P Value more targeted and appropriate treatment. In addition, there is
Age, y a need to understand and define the burden of disease of Mp in
 2–4 Reference group the community that is not only causing pneumonia. This can be
 5–9 6.4 (3.4–12.1) <.01 addressed by systematic surveillance for Mp infection as a cause
 10–17 10.7 (5.4–21.1) <.01
of CAP and other clinical syndromes, which could further facil-
Hilar lymphadenopathy 3.1 (1.6–5.8) <.01
Receipt of antibiotics prior 2.3 (1.5–3.5) <.01
itate case and outbreak identification, better characterize the
to admission within 5 d prevalence of macrolide resistance, and inform treatment and
Rales 2.2 (1.5–3.2) <0.01 infection prevention guidance.
Codetected pathogens 2.1 (1.4–3.3) <.01
Headache 1.6 (1.04–2.5) .03
Supplementary Data
Sore throat 1.6 (1.1–2.3) .03

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Supplementary materials are available at Clinical Infectious Diseases online.
Decreased breath sounds 1.5 (1.01–2.2) .04
Consisting of data provided by the authors to benefit the reader, the posted
Wheezing (symptom) 0.6 (.4–.9) <.01
materials are not copyedited and are the sole responsibility of the authors,
Runny nose 0.6 (.4–.8) <.01 so questions or comments should be addressed to the corresponding
Study site (Salt Lake City) 0.5 (.4–.8) <.01 author.
Chest pain 0.4 (.3–.7) <.01

Abbreviations: CI, confidence interval; OR, odds ratio. Notes

a
For this analysis, only children who had specimens tested for both bacteria and viruses
Author contributions.  Supervised the study: S. J. Designed the analytic
were included. Variables that were tested in the model but did not reach significance: sex;
clinical presentation of fever/feverish, fatigue, chills, abdominal pain, myalgia, dyspnea; plan: P. K. K. Contributed to study design: S. J., A. M. B., K. A., S. R. A., D. J.
examination findings on presentation: hypoxia, rhonchi, wheezing, chest indrawing, tachy- W., K. M. E., J. A. M., A. T. P., S. J. S., L. A. H. Obtained funding: S. J., K. A.,
pnea, chest retraction; radiographic findings: single and multiple lobar infiltrate, pleural K.  M. E., J.  A. M.  Enrolled patients and collected data at the study sites:
effusion; comorbid condition: chromosomal disorder; household size; interaction between
K. A., S. R. A., D. J. W., K. M. E., J. A. M., A. T. P. Created and managed the
age and codetection.
database: A. M. B. Analyzed and/or interpreted the data: P. K. K., S. J., T. H.
T., A. M. B., M. H. D., K. A., S. R. A., D. J. W., K. M. E., J. A. M., A. T. P.,
J. M. W. Acted as supervisor for data analysis and/or interpretation: S. J. S.,
Macrolide-resistant Mp isolates have been described in the L. A. H. Drafted the initial manuscript: P. K. K. Reviewed and/or revised the
United States (3%–10%) and several other countries, partic- manuscript: P. K. K., S. J., T. H. T., A. M. B., M. H. D., K. A., S. R. A., D. J.
W., K. M. E., J. A. M., A. T. P., J. M. W., S. J. S., L. A. H. Approved the final
ularly in Europe and Asia [33–35]. We identified very few (6 manuscript: P. K. K., S. J., A. M. B., K. A., S. R. A., D. J. W., K. M. E., J. A. M.,
[4%]) macrolide-resistant Mp isolates and thus were not able A. T. P., S. J. S., L. A. H.
to adequately assess factors or outcomes associated with resis- Acknowledgments.  We thank the children and families who gra-
ciously consented to participate in the Etiology of Pneumonia in the
tance. However, continued vigilance is needed to better under- Community study.
stand the extent and clinical implications of macrolide-resistant Disclaimer.  The findings and conclusions in this report are those of the
Mp infections. authors and do not necessarily represent the official position of the Centers
for Disease Control and Prevention’s (CDC).
Our study has several limitations. By including Mp with
Financial support.  This work was supported by the Influenza Division
codetections, some of the symptoms, especially among those of the National Center for Immunizations and Respiratory Diseases at the
<5 years old, could be attributable to other pathogens. In addi- CDC through cooperative agreements with each study site and was based
tion, test sensitivity may be variable between detection assays on a competitive research funding opportunity. 
Potential conflicts of interest.  K.  A. received grant support through
for some pathogens, especially for bacteria. Another possible his institution from CDC, GlaxoSmithKline, Cubist Pharmaceuticals,
limitation is that some patients received antibiotics with Mp and National Institutes of Health for enrollment of patients in other stud-
activity before NP/OP collection, which may have affected the ies.  A.  T.  P. received grant support through his institution from CDC,
National Institute of Allergy and Infectious Diseases, and Biofire; received
detection of Mp. However, Mp was detected by PCR in 11% of royalties from Antimicrobial Therapy. All other authors report no poten-
the children hospitalized with CAP who received an antibiotic tial conflicts. All authors have submitted the ICMJE Form for Disclosure of
with Mp activity before admission [36]. Finally, our findings Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
may not be representative of Mp CAP in the United States,
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