Pediatric Pulmonology

Effects of Prednisolone on Refractory Mycoplasma

Pneumoniae Pneumonia in Children
Zhengxiu Luo, MD, PhD,* Jian Luo, Master, Enmei Liu, MD, PhD, Xiujuan Xu, Master,
Yulin Liu, Undergraduate, Fengqiong Zeng, Undergraduate, Subi Li, Undergraduate, and Zhou Fu, MD, PhD

Summary. Objectives: To prospectively evaluate prednisolone treatment in children with re-

fractory Mycoplasma pneumonia pneumonia (MPP). Methods: Fifty-eight refractory children
with MPP were enrolled to receive either azithromycin combined with prednisolone (treatment
group, n ¼ 28) or azithromycin alone (control group, n ¼ 30). Temperature, respiratory symp-
toms and signs were examined at the time of study entry and every 8 hr after enrollment,
infiltration absorption, atelectasis resolution, pleural effusion disappearance, and serum ferritin
and LDH levels were assessed on seventh day after enrollment. Results: All patients in treat-
ment group achieved defervescence during 8–48 hr after enrollment versus no patient in the
control group. The mean duration of hypoxemia was 1.9
0.9 days in treatment group and
2.7
1.1 days in the control group (P < 0.05), and the dyspnea resolved time was 1.5
0.7
days and 2.9
0.6 days (P < 0.05), respectively. Seven days after enrollment, 80% of patients
in treatment group showed infiltration absorption versus 21.4% in control group (P < 0.05); the
figures for atelectasis resolution were 71.4% versus 12.5% (P < 0.05), and for pleural effusion
disappearance 88.9% versus 20.0% (P < 0.05). The serum ferritin and LDH level was lower in
the treatment than that in control group (P < 0.05). Conclusions: Azithromycin combined with
prednisolone is a better treatment for children with refractory MPP than azithromycin alone.
Pediatr Pulmonol. ß 2013 Wiley Periodicals, Inc.

Key words: refractory mycoplasma pneumoniae pneumonia; prednisolone;

azithromycin; children.

Funding source: none reported.

INTRODUCTION
Mycoplasma pneumoniae pneumonia (MPP) is a
common disease in children. In China, M. pneumoniae
accounts for 1.2–34.3% of pediatric community-ac-
quired pneumonia with an increasing frequency by
age.1,2 Although MPP is usually a benign self-limited
disease, it may develop into a severe life-threatening
pneumonia in rare cases.3,4,6 The refractory MPP was
defined as showing clinical, radiological deterioration
after macrolide therapy for 7 days or more.4 Cortico-
steroid has been used in adulthood refractory MPP with
satisfactory results,5 but there are only case reports on
corticosteroids in children with refractory MPP.4,6 The
dosage of corticosteroids used in children with refracto-
ry MPP has varied greatly.4,6 Azithromycin is usually
the first choice for MPP for children in our hospital. In
this paper, we evaluated the efficacy of oral predniso-
lone at a dose of 2 mg/kg/day (divided in two doses)
administered with intravenous azithromycin for 5 days
in children with refractory MPP in a prospective
fashion.
METHODS
Patients
From May 7, 2007 to May 7, 2010, 675 children
with MPP were admitted to Children‘s Hospital,
Chongqing Medical University in China. All patients
had symptoms and signs indicative of pneumonia at
Department of Respiratory, Children’s Hospital, Chong Qing Medical
University, Chongqing, China.
Conflict of interest: None.
*Correspondence to: Zhengxiu Luo, MD, PhD, Department of Respirato-
ry, Children’s Hospital, Chongqing Medical University, Chongqing
400014, China. E-mail: luozhengxiu816@163.com
Received 28 October 2011; Accepted 29 November 2012.
DOI 10.1002/ppul.22752
Published online in Wiley Online Library
(wileyonlinelibrary.com).

ß 2013 Wiley Periodicals, Inc.

2 Luo et al.
admission, including fever (>37.58C), cough, abnormal
breath sounds on auscultation and abnormal chest X-
rays. M. pneumoniae infection was confirmed by a se-
rologic test in blood (ELISA, IgM titer 1:160) and/or
by a PCR test in nasopharyngeal secretions. Refractory
MPP was defined as showing prolonged fever
(T  38.58C) and deterioration of clinical and radiolog-
ical findings after azithromycin treatment for 7 days or
more. We prospectively enrolled 58 previously healthy
children who had refractory MPP during the 3-year
study period. All the 58 children had positive results in
both M. pneumoniae antibody and PCR tests, and all
were negative in TB-IgM and PPD tests. In addition,
direct fluorescent assays for respiratory syncytial virus,
adenovirus, influenza virus A and B, and parainfluenza
virus 1, 2, and 3 were negative in all included cases.
They also had negative results of bacterial cultures of
nasopharyngeal secretions and two blood samples.
Exclusion Criteria
The exclusion criteria were as follow: chronic cardiac
and pulmonary disease, immunodeficiency, need of me-
chanical ventilation, discharge within 8 hr after enroll-
ment, and other pathogens detected during pneumonia.
Study Design
The enrollment of patients continued exactly 3 years
with no calculation of samples size. Informed consent
was obtained from the guardians of the eligible patients
with refractory MPP. Patients were randomized to re-
ceive either azithromycin combined with prednisolone
(treatment group) or azithromycin alone (control
group). Once enrolled, the treatment group patients
were administered oral prednisolone at a dose of 2 mg/
kg/day (divided in two daily doses) combined with in-
travenous azithromycin (at a dose of 10 mg/kg/day
once daily) for 5 days. The control group patients were
administered intravenous azithromycin alone (at a dose
of 10 mg/kg/day once daily) for 5 days, respectively.
The two groups received similar supportive and
TABLE 1— Basic Clinical Information on Enrollment Day Between the Two Groups
Treatment group
Basic information (n ¼ 28)
Age (years) 7.9
4.1
Duration of fever (days) 13.2
2.5
Lobar infiltration 53.6% (15/28)
Lobar atelectasis 25% (7/28)
Pleural effusion 32.1% (9/28)
WBC (109/L) 7.85
2.67
CRP (mg/L) 45.6
13.5
Serum ferritin (ng/ml) 595.3
138.9
LDH (IU/L) 917.5
131.7
Pediatric Pulmonology
comprehensive treatments, such as sputum aspiration
and water-electrolyte balance maintenance). Tempera-
ture and respiratory symptoms and signs were examined
at study entry and every 8 hr thereafter. The chest X-
rays, and serum ferritin and LDH levels were assessed
7 days after enrollment. In this study, hypoxemia means
SaO2 <90%, dyspnea indicates labored breathing with
intercostal and tracheosternal retractions.
Ethics
The study was approved by the ethics and human
research committees of Children’s Hospital, Chongqing
Medical University. Written informed consent was
obtained from at least one guardian of each patient be-
fore enrollment.
Statistical Analyses
SPSS edition 11.5 was used to analyze all the data.
Chi-squared tests were used to compare categorical var-
iables. One-way analysis of variance (ANOVA) was
used to compare continuous variables. The mean
SD
(x
s) expresses the central tendency of the data. A P-
value <0.05 was considered statistically significant.
RESULTS
Clinical Characteristics
All the 58 children showed a persistent fever with
aggravated respiratory symptoms and signs, and their
radiographic findings had progressed to severe pneumo-
nia before enrollment. Twenty-eight patients were en-
rolled in the treatment group (16 males, 12 females),
with an average age of 7.9
4.1 years and fever dura-
tion of 13.2
2.5 days. Thirty patients were enrolled
in the control group (17 males, 13 females), with an
average age of 7.6
4.5 years and fever duration of
14.3
3.7 days. No significant differences in baseline
data were present between the two groups, as summa-
rized in Table 1.
Control group
(n ¼ 30) P-value
7.6
4.5 0.75
14.3
3.7 0.82
46.7% (14/30) 0.59
26.7% (8/30) 0.89
33.3% (10/30) 0.92
7.91
2.45 0.34
42.8
12.7 0.49
576.7
127.8 0.79
928.7
146.5 0.87

Outcomes of Therapeutic Effects
The clinical and radiological findings improved better
in treatment group than that in control group. All
patients in treatment group achieved defervescence dur-
ing 8–48 hr after enrollment, compared with none in
the control group within 48 hr. The mean duration of
hypoxemia was 1.9
0.9 days in treatment and
2.7
1.1 days in the control group (P < 0.05). The
dyspnea resolved time was 1.5
0.7 days and
2.9
0.6 days (P < 0.05), respectively. Seven days af-
ter enrollment, 80% of patients in treatment group
showed infiltration absorption versus 21.4% in control
group (P < 0.05); the figures for atelectasis resolution
were 71.4% versus 12.5% (P < 0.05), and for pleural
effusion disappearance 88.9% versus 20.0% (P < 0.05).
The serum ferritin and LDH level was lower in the
treatment than that in control group (P < 0.05), as sum-
marized in Table 2.
Adverse Events
No patient in treatment group had worsening in the
clinical and radiographic findings after discontinuation
of prednisolone, and no patient had further complica-
tions of infection.
DISCUSSION
Pneumonia caused by M. pneumoniae is usually a
self-limited benign infection. However, MPP may rarely
develop into a life-threatening disease despite appropri-
ate antibiotic therapy. Corticosteroid has been used in
adults with refractory MPP, but the use of corticoste-
roids for children with refractory MPP is not estab-
lished. In a case report, Lee et al.4 demonstrated that
oral prednisolone of 1 mg/kg/day tapering within a
week for severe MPP in children may be helpful;
Tamura et al.6 reported that intravenously administered
methylprednisolone at a dose of 30 mg/kg once daily
for three consecutive days is effective for refractory
MPP in children. In this study, we prospectively demon-
strated that oral prednisolone at a dose of 2 mg/kg/day
(divided in two daily doses) combined with intrave-
nously azithromycin for 5 days is a better treatment for
children with refractory MPP than azithromycin alone.
TABLE 2— Clinical Information on 7th Day After Enrollment Between the Two Groups
Information Treatment group
Infiltration absorption rate 80% (12/15)
Atelectasis resolution rate 71.4% (5/7)
Pleural effusion disappearance rate 88.9% (8/9)
Serum ferritin (ng/ml) 237.5
87.6
LDH (IU/L) 415.6
103.5
Effects of Prednisolone on Refractory Mycoplasma 3
Prednisolone combined with azithromycin improved
clinical symptoms faster, and relieved radiographic and
laboratory findings earlier than azithromycin therapy
alone. All patients in treatment group achieved defer-
vescence within 48 hr after star of the therapy versus
no patient in the control group, hypoxemia and dyspnea
alleviated faster in treatment group than that in the con-
trol group, more children obtained infiltration absorp-
tion, atelectasis resolution, pleural effusion
disappearance in treatment group than that in control
group; serum level of ferritin and LDH reduce more in
treatment group than that in control group.
Pulmonary injury associated with severe MPP may
be due to host immune response rather than to direct
microbial damage.7,8 If refractory MPP is an immune-
mediated disease, immune suppressive therapy is a ra-
tional approach. The use of systemic steroids, in addi-
tion to antimicrobial therapy, to diminish host immune
response in refractory MPP has been demonstrated in
both children and adults with satisfactory effects.3,4,6,9
Corticosteroids can significantly reduce quantitative
mycoplasma cultures in lung tissue compared to place-
bo in animal.10,11 IL-12 p40, RANTES, MCP-1 have
been found to be elevated and to correlate with
disease severity in mycoplasma infection.12–14 In this
article, we observed that oral prednisolone combined
with intravenously azithromycin therapy reduced serum
ferritin and LDH levels (which are non-specific
markers of inflammation) more, relieved infiltration, at-
electasis, and pleural effusion earlier than azithromycin
therapy alone.
There were some important limitations in this study.
First, we did not study other macrolides than azithro-
mycin, but there are no reasons to expect that the
results would have been different. Moreover, we did not
test macrolide resistance, and in fact, some mycoplas-
mal strains may have been resistant the antibiotic used.
Second, we did not do serology in paired sera, but since
all cases were positive in both serology and PCR, the
diagnoses were reliable. Third, prednisolone was not
given without antibiotics, but this approach would not
have been ethically justified. Fourth, serum ferritin and
LDH levels were not compared with those in children
with non-refractory MPP children. Therefore, further
research is needed to demonstrate whether serum
Control group P-value
21.4% (3/14) 0.002
12.5% (1/8) 0.041
20% (2/10) 0.005
466.7
97.5 0.023
795.3
132.7 0.012
Pediatric Pulmonology
4 Luo et al.
ferritin and LDH values can be used as parameters to
determine which patients are candidates for corticoster-
oid therapy.
In conclusion, azithromycin combined with predniso-
lone is a better treatment for children with refractory
MPP than azithromycin alone, as prospectively docu-
mented by clinical, radiological, and laboratory means.
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