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OPEN Development of a scale

for early prediction of refractory
Mycoplasma pneumoniae
pneumonia in hospitalized children
Ying Bi1,2,5, Yifan Zhu1,5, Xiao Ma1, Jiejing Xu1,3, Yun Guo1,4, Tianyu Huang1, Siqing Zhang1,
Xin Wang1, Deyu Zhao1* & Feng Liu1*
Now there is no clinical scale for early prediction of refractory Mycoplasma pneumoniae pneumonia
(RMPP). The aim of this study is to identify indicators and develop an early predictive scale for
RMPP in hospitalized children. First we conducted a retrospective cohort study of children with
M. pneumoniae pneumonia admitted to Children’s Hospital of Nanjing Medical University, China in
2016. Children were divided into two groups, according to whether their pneumonia were refractory
and the results were used to develop an early predictive scale. Second we conducted a prospective
study to validate the predictive scale for RMPP in children in 2018. 618 children were included in the
retrospective study, of which 73 with RMPP. Six prognostic indicators were identified and included
in the prognostic assessment scale. The sensitivity of the prognostic assessment scale was 74.0%
(54/73), and the specificity was 88.3% (481/545) in the retrospective study. 944 children were included
in the prospective cohort, including 92 with RMPP, the sensitivity of the prognostic assessment scale
was 78.3% (72/92) and the specificity was 86.2% (734/852). The prognostic assessment scale for RMPP
has high diagnostic accuracy and is suitable for use in standard clinical practice.

Abbreviations
ALT Alanine aminotransferase
AST Aspartate aminotransferase
CK Creatine kinase
HB Hemoglobin
LDH Lactate dehydrogenase
MPP  M. pneumoniae Pneumonia
RMPP Refractory M. pneumoniae pneumonia
WBC White blood cells

Mycoplasma pneumoniae is one of the important pathogens that cause childhood community acquired pneumo-
nia. The incidence of M. pneumoniae infection does not differ by sex, but it varies substantially by age. It is most
common in preschool and school age children. The infection rate of pneumonia in children over 5 years old can
be as high as 50%1,2. Pneumonia caused by M. pneumoniae infection is generally self-limiting, but sometimes is
refractory. After regular treatment, lung lesions can still recur or be prolonged, resulting in residual structural
and/or functional lung damage, often manifested as mosaic signs and b­ ronchiectasis3. These sequelae often cause
repeated lung infections in children, and have a significant impact on the lung function of adults, which is also
closely related to the occurrence of a­ sthma4–6. With the incidence of refractory M. pneumoniae pneumonia in
children steadily increasing and some case fatalities, early diagnosis and treatment of refractory M. pneumoniae
pneumonia is particularly i­ mportant7.

1
Department of Respiratory Medicine, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road,
Nanjing, China. 2Xuzhou Children’s Hospital, Xuzhou Medical University, Xuzhou, China. 3Department of Pediatrics,
The Second People’s Hospital of Changzhou, Affiliate Hospital of Nanjing Medical University, Changzhou, Jiangsu,
China. 4Department of Respiratory Medicine, The Affiliated Wuxi Children’s Hospital of Nanjing Medical University,
Wuxi, China. 5These authors contributed equally: Ying Bi and Yifan Zhu. *email: [email protected];
[email protected]

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For the prognosis of adult community acquired pneumonia, A variety of predictive indicators such as the
Pneumonia Severity Index and CURB-65 score have been developed to determine the prognosis of community-
acquired pneumonia in ­adults8,9. However, given the practicality of these scales and age limitations, they cannot
be directly applied to children.
There has been some research on the predictors of refractory M. pneumoniae pneumonia. Large-scale pul-
monary morphogenesis, extrapulmonary complications, and elevated CRP and LDH are clinically relevant risk
factors for refractory M. pneumoniae ­pneumonia10–12. However, the current prediction methods often use only a
single indicator to judge the prognosis, or there are few clinical data and no prospective verification. The indica-
tors included in some studies are not readily available clinically, and in some studies, the outcome was compli-
cations caused by refractory M. pneumoniae pneumonia, rather than predictors of refractory M. pneumoniae
­pneumonia13,14. Therefore, the aim of this study was to use multiple simple indicators to develop a scale for early
prediction of refractory M. pneumoniae pneumonia in hospitalized children.

Methods
Ethics. The study was approved by the institutional ethics committee of Children’s Hospital Affiliated to
Nanjing Medical University (Approval number: 201801126-1), and was registered in the Chinese Clinical Trial
Registry (Registration number: ChiCTR1800015673). All methods were performed in accordance with the Dec-
laration of Helsinki.

Informed consent. Informed consent was obtained from all subjects or, if subjects are under 18, from a
parent and/or legal guardian.

Patients and groups. A flowchart of our research is provided in Fig. 1A. We conducted a retrospective
cohort study among children admitted to the Children’s Hospital of Nanjing Medical University with M. pneu-
moniae pneumonia from January to December 2016. This was followed by a prospective cohort from January to
December 2018. All children were first seen in Children’s Hospital. M. pneumoniae infection was confirmed by
polymerase chain reaction testing of nasopharyngeal swab specimens.
Patients with immune deficiencies, chronic diseases, heart diseases or who were using immunosuppres-
sive drugs were excluded. All those enrolled had negative tuberculosis IgM or purified protein derivative tests.
In addition, their nasopharyngeal secretions were negative for respiratory syncytial viruses, influenza viruses,
adenovirus, parainfluenza virus, and Chlamydia trachomatis. The subjects also had negative bacterial cultures of
nasopharyngeal secretions and double-negative blood cultures. Consent for participation was obtained.
Refractory M. pneumoniae pneumonia is defined as a case with prolonged fever accompanied by deteriora-
tion of radiological findings despite appropriate management and treatment with a macrolide antibiotic for ≥ 7
­days15. On the basis of this definition, we reviewed patients’ medical records and divided them into 2 groups:
RMPP group and non-RMPP group.

Data collection and study variables. We collected data on demographic and clinical characteristics
including age, sex, fever days on admission, and chest imaging findings; and laboratory test results including
complete blood count, C-reactive protein, alanine aminotransferase, aspartate aminotransferase, lactate dehy-
drogenase and creatine kinase. After preliminary screening of all indicators, statistically significant indicators
were selected for regression analysis.

Respiratory pathogens. Nasopharyngeal aspirates were tested for respiratory pathogens using a real-time,
multiplex polymerase chain reaction assay in our hospital’s clinical virology laboratory. The specific pathogens
identified included influenza A and B, respiratory syncytial viruses, adenovirus, parainfluenza virus, C. tra-
chomatis, and M. pneumoniae. A positive polymerase chain reaction result for M. pneumoniae was a copy num-
ber of > 2,500/mL(ACON Biotech Co.,Ltd, Hangzhou, China). Bacterial culture results based on nasopharyngeal
aspirates and blood were obtained from the hospital’s microbiology ­laboratory16.

Statistical analysis. Statistical analysis was performed with SPSS Version 20.0 (IBM Corp, Armonk, NY,
USA) and R Version 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria), and P < 0.05 was consid-
ered statistically significant. Categorical variables were analyzed using the chi-square test. Normally distributed
continuous data were analyzed using t tests, and non-normally distributed measurement data were analyzed
using Mann–Whitney U tests.
Multivariate analysis was performed using a stepwise logistic regression model. R software was used to trans-
form the final regression model into a nomogram. Receiver operating characteristic (ROC) curves were used to
analyze the regression model for prediction of refractory M. pneumoniae pneumonia. Calculate the sensitivity
and specificity of the predictive scale.

Results
Patient characteristics and laboratory findings. The clinical characteristics of the two cohort patients
are shown in Table 1.We enrolled 618 patients in retrospective cohort. There were 73 patients in the RMPP
group, and 545 patients in the non-RMPP group. The characteristics of the patients in the retrospective cohort
on admission are summarized in Table 2.
There was no significant difference in sex distribution between the 2 groups. The average age and fever days
were significantly greater in the RMPP group than that in the non-RMPP group. Compared with the non-RMPP

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Figure 1.  (A) Study flow. CAP, community-acquired pneumonia; RMPP, refractory M. pneumoniae
pneumonia. (B) The first line is the score corresponding to each indicator value. The following is the index
included in the scale, and finally the calculated total score and predicted probability. When using, the table
should be scaled up and printed on paper, and the score should be calculated using a tool such as a ruler. (C/D)
Scale for predicting refractory M. pneumoniae pneumonia by receiver operator characteristic curves. (C) In the
retrospective cohort; (D) In the prospective cohort.

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Retrospective cohort (n = 618) Prospective cohort (n = 944)

Age (years) 3.84 ± 2.66 4.47 ± 2.70
Sex: male 338 (54.7%) 516 (54.7%)
Fever days 4.78 ± 3.41 5.09 ± 3.76
WBC (× ­109/L) 9.45 ± 4.23 9.75 ± 4.46
Neutrophils (%) 55.08 ± 16.52 55.71 ± 17.47
Neutrophils (× ­109/L) 5.37 ± 3.32 5.52 ± 3.51
CRP (mg/L) 16.79 ± 20.22 15.93 ± 20.19
HB (g/L) 122.90 ± 10.46 125.19 ± 14.80
PLT (× ­109/L) 276.48 ± 105.23 294.10 ± 118.04
AST (U/L) 34.82 ± 20.48 30.59 ± 24.38
ALT (U/L) 22.18 ± 31.05 21.09 ± 27.82
LDH (U/L) 391.02 ± 225.65 359.15 ± 138.51
CK (U/L) 100.56 ± 119.99 98.57 ± 109.73
Pleural effusion
Small 5.34% (33/618) 5.61% (53/944)
Medium to large 8.25% (51/618) 7.84% (74/944)
Atelectasis or large area of lung consolidation 10.36% (64/618) 11.65% (110/944)

Table 1.  Admission characteristics of the children in the retrospective and prospective cohorts. Values are
presented as mean ± SD. ALT alanine aminotransferase, AST aspartate aminotransferase, CK creatine kinase,
CRP C-reactive protein, HB hemoglobin, LDH lactate dehydrogenase, PLT platelets, WBC white blood cells.

Characteristic Non-RMPP (n = 545) RMPP (n = 73) P Value

Age 3.61 ± 2.57 5.55 ± 2.71 < 0.001
Sex: male 300 (55.0%) 38 (52.1%) 0.630
Fever days 4.39 ± 3.15 7.66 ± 3.86 < 0.001
WBC (× ­109/L) 9.40 ± 4.21 9.82 ± 4.39 0.414
Neutrophil (%) 53.94 ± 16.22 63.63 ± 16.36 < 0.001
Neutrophils (× ­109/L) 5.22 ± 3.25 6.45 ± 3.70 0.008
CRP (mg/L) 15.08 ± 16.64 29.66 ± 34.93 0.001
HB (g/L) 122.78 ± 10.37 123.82 ± 11.17 0.424
PLT (× ­109/L) 275.56 ± 104.82 283.32 ± 108.80 0.555
AST (U/L) 33.76 ± 17.45 42.04 ± 34.06 0.045
ALT (U/L) 18.76 ± 14.16 45.64 ± 73.89 0.003
LDH (U/L) 379.78 ± 223.97 474.93 ± 221.89 0.001
CK (U/L) 102.96 ± 125.22 83.08 ± 66.66 0.18
Pleural effusion
Small 5.14% (28/545) 6.85% (5/73) 0.575
Medium to large 4.95% (27/545) 32.88% (24/73) < 0.001
Atelectasis or Large area lung consolidation 5.50% (30/545) 46.58% (34/73) < 0.001

Table 2.  Admission characteristics of children with Mycoplasma pneumoniae pneumonia in the retrospective
cohort according to their subsequent clinical outcome. Values are presented as mean ± SD. ALT alanine
aminotransferase, AST aspartate aminotransferase, CK creatine kinase, CRP C-reactive protein, HB
hemoglobin, LDH lactate dehydrogenase, PLT platelet, RMPP refractory M. pneumoniae pneumonia, WBC
white blood cell.

group, significantly more patients in the RMPP group had atelectasis or lobar or segmental lung consolidation,
and moderate to large pleural effusions than those in the non-RMPP group.
Compared with the non-RMPP group, the RMPP group showed significantly higher levels of C-reactive
protein, neutrophil %, neutrophils (absolute value), aspartate aminotransferase, alanine aminotransferase, and
lactate dehydrogenase. The other laboratory findings did not differ significantly between the two groups.

Chest imaging score. In order to be able to incorporate chest imaging findings into regression analysis, we
created a new indicator, the chest imaging score (Table 3).
A small amount of pleural effusion: the angle of the costal diaphragm becomes dull; a medium amount of
effusion: a large uniform dense shadow in the lower pleural cavity, the upper boundary is curved, the concave

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Chest imaging findings Yes No

Pleural effusion
Small 1 0
Medium to large 2 0
Atelectasis or Large area lung consolidation 1 0
Chest imaging score

Table 3.  Chest imaging score.

95% CI For OR
Variable β SE Wald P Odds ratio Lower Upper
Age 0.157 0.057 7.731 0.005 1.170 1.048 1.307
Fever days 0.151 0.044 11.662 0.001 1.163 1.067 1.269
CRP 0.017 0.007 6.155 0.013 1.017 1.004 1.031
ALT 0.026 0.008 10.472 0.001 1.026 1.010 1.042
LDH 0.002 0.001 5.534 0.019 1.002 1.000 1.004
Chest imaging score 51.874 0.000
1 2.544 0.365 48.553 0.000 12.733 6.225 26.046
2 1.373 0.523 6.885 0.009 3.948 1.416 11.014
3 2.167 0.632 11.765 0.001 8.731 2.531 30.116

Table 4.  Logistic regression analysis predictors of M. pneumoniae pneumonia. ALT alanine aminotransferase,
CRP C-reactive protein, LDH lactate dehydrogenase.

surface is upward, and the highest point is in the armpit; Even shadow, the mediastinum is pushed to the opposite
side; Large-area lung consolidation: occupying a segment of the lung or above the range of the lung lobes (range
over 2/3 of the lung lobes), can involve single or multilobe l­ esions17–19.

Logistic regression and nomogram. All variables that were statistically significant in the comparison
between groups were considered for inclusion in the logistic regression analysis. The variables were screened
using the maximum likelihood ratio forward stepwise regression method. Finally, age, fever days, C-reactive
protein, alanine aminotransferase, lactate dehydrogenase and chest imaging score were included in the predic-
tive model. (Table 4). The final predictive model is shown as a nomogram in Fig. 1B.

Prospective cohort. From January to December 2018, 944 children admitted to our hospital with M. pneu-
moniae pneumonia were enrolled in the prospective cohort study. The characteristics of the patients in the pro-
spective cohort are shown in Table 5.

Receiver‑operating characteristic curve analysis. In the retrospective cohort, the area under the
curve for the predictive scale was 0.899 (95% CI 0.860–0.937) as determined by ROC curve analysis (Fig. 1C). In
the prospective cohort, the area under the curve was 0.871 (95% CI 0.830–0.911, Fig. 1D).
The optimal cutoff of the scale for predicting refractory M. pneumoniae pneumonia was 0.2, with a sensitiv-
ity of 74.0%, specificity of 88.3%, and consistency rate of 86.6% in the retrospective cohort. The optimal cutoff
in the prospective cohort was also 0.2, with a sensitivity of 78.3%, specificity of 86.2%, and consistency rate of
85.4% (Table 6).

Discussion
Currently, the majority viewpoint is that the main pathogenic mechanism for the lung damage that occurs in
some children with M. pneumoniae pneumonia is due to inflammatory damage mediated by human autoimmune
­function20. The symptoms of Mycoplasma pneumoniae pneumonia have a rapid onset and are changeable. After
treatment, M. pneumoniae pneumonia can also cause serious c­ omplications21–24.
In order to early predict refractory M. pneumoniae pneumonia and reduce the incidence of complications
and long-term lung damage, we identified 6 prognostic indicators, including age, fever days, CRP, ATL, LDH,
and chest imaging findings. The incidence of refractory M. pneumoniae pneumonia in the retrospective cohort
increased with age, suggesting that the pathogenic mechanism in refractory M. pneumoniae infection is related
to an excessive immune r­ esponse25. A persistent fever and CRP are common clinical indicators of infection. LDH
is also considered to replace inflammatory cytokines such as IL-18 as useful indicators for predicting refractory
M. pneumoniae ­pneumonia26.These indicators were higher in those in the RMPP group than in those in the non-
RMPP group, indicating that the children with refractory M. pneumoniae pneumonia have a more pronounced
inflammatory responses. Hepatic dysfunction is a common extrapulmonary injury after M. pneumoniae infection.

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Variable Non-RMPP (n = 852) RMPP (n = 92) P value

Age 4.35 ± 2.68 5.63 ± 2.66 < 0.001
Sex: male 468 (384) 48 (44) 0.614
Fever days 4.88 ± 3.72 7.00 ± 3.65 < 0.001
WBC (× ­109/L) 9.70 ± 4.46 10.16 ± 4.51 0.352
Neutrophil (%) 55.05 ± 17.45 61.92 ± 16.54 < 0.001
Neutrophils (× ­109/L) 5.43 ± 3.45 6.30 ± 4.02 0.048
CRP (mg/L) 14.68 ± 18.44 27.55 ± 29.85 < 0.001
HB (g/L) 125.11 ± 13.37 126.02 ± 24.52 0.575
PLT (× ­109/L) 294.23 ± 117.93 292.85 ± 119.66 0.915
AST (U/L) 30.05 ± 21.74 35.64 ± 41.39 0.205
ALT (U/L) 20.03 ± 21.74 30.91 ± 59.10 0.083
LDH (U/L) 355.25 ± 137.18 395.33 ± 146.20 0.013
CK (U/L) 100.81 ± 113.39 77.65 ± 63.16 0.056
Pleural effusion
Small 4.11% (35/852) 19.57% (18/92) < 0.001
Medium to large 6.22% (53/852) 22.83% (21/92) < 0.001
Atelectasis or Large area lung consolidation 6.46% (55/852) 59.78% (55/92) < 0.001

Table 5.  Admission characteristics of children with Mycoplasma pneumoniae pneumonia in the prospective
cohort according to their subsequent clinical outcome. Values are presented as mean ± SD. ALT alanine
aminotransferase, AST aspartate aminotransferase, CK creatine kinase, CRP C-reactive protein, HB
hemoglobin, LDH lactate dehydrogenase, PLT platelets, RMPP refractory M. pneumoniae pneumonia, WBC
white blood cells.

Area under the Consistency rate

Cohort curve Cutoff Sensitivity (%) Specificity (%) Positive LR Negative LR (%)
Retrospective 0.899 0.2 74.0 88.3 6.3 0.3 86.6
Prospective 0.871 0.2 78.3 86.2 5.7 0.3 85.4

Table 6.  Predictive value of the predictive scale. Receiver operating characteristic curve analysis was
performed with suitable parameters to create cutoffs to determine the predicted probability with regard to
refractory M. pneumoniae pneumonia. LR, likelihood ratio.

Both AST and ALT can reflect hepatocyte function, but ALT is often considered to be a specific indicator of liver
injury in patients with M. pneumoniae ­pneumonia27.
There are many factors affecting the prognosis of children with pneumonia, but because there is no support
for big data, there are no established criteria for predicting which children are at risk of a poor outcome. Some
existing prediction scales often lack the universality of clinical application because of a bias of the original
data, or are derived from the improved adult scale and has a narrower scope of ­application28–30. Some previous
reports have also shown that increasing age, severe chest imaging findings, and elevated inflammatory markers
can effectively predict the occurrence of refractory M. pneumoniae pneumonia and its complications. Clinical
features combined with laboratory results can improve the diagnosis of refractory M. pneumoniae ­pneumonia31.
The predictive power of the scale obtained in this study on refractory M. pneumoniae pneumonia has good
performance in both retrospective and prospective cohorts. The area under the ROC curve in the retrospective
and prospective cohort was 0.899 and 0.875, respectively, indicating that the predictive scale can correctly distin-
guish between children with refractory M. pneumoniae pneumonia and those with simple disease. The scale has
high sensitivity and specificity in the two cohorts. Compared with other studies, the clinical indicators included
in this study are relatively simple and easy to obtain, which is more conducive to application in clinical work.

Conclusions
In summary, we finally included six readily available clinical indicators to predict refractory M. pneumoniae
pneumonia. This predictive scale helps to determine whether a child will develop refractory M. pneumoniae
pneumonia early in the disease. In the retrospective and prospective cohort, the scale has good discrimination,
high sensitivity and specificity.

Received: 24 August 2020; Accepted: 9 March 2021

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Author contributions
Y.B. performed experiments, statistical analysis, made the figures and tables and drafted manuscripts; Y.Z. par-
ticipated in the study design, collected and interpreted the clinical information, determined the clinical status
for each children involved in the study; X.M. participated in the revision of the article and the supplement of
the data. J.X., Y.G., T.H., S.Z., and X.W. participated in the collection of clinical data; D.Z. participated in study
design and contributed to the interpretation of data; F.L. designed the study, analyzed the data and revised the
manuscript. All authors read and approved the manuscript.

Funding
This work was supported, in part, by Grants from Jiangsu Province Special Funds for Key Program (Social
Development) (BE2019607), Key Projects of Nanjing Health and Planning Commission (ZKX18041), Jiangsu
Province Young Medical Talents (QNRC2016087).

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Competing interests
The authors declare no competing interests.

Additional information
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