Association of lung consolidation with clinical prognosis in children with Mycoplasma pneumoniae pneumonia: a retrospective study

Caiting Chu Shanghai Jiaotong University School of Medicine Xinhua Hospital Lijun Wang Shanghai Jiaotong University School of Medicine Xinhua Hospital Huajun Li Shanghai Jiaotong University School of Medicine Xinhua Hospital Shanshan Xu Shanghai Jiaotong University School of Medicine Xinhua Hospital Liya Zhang Shanghai Jiaotong University School of Medicine Xinhua Hospital Quanhua Liu Shanghai Jiaotong University School of Medicine Xinhua Hospital Xi Zhang Shanghai Jiaotong University School of Medicine Xinhua Hospital Weixi Zhang Shanghai Jiaotong University School of Medicine Xinhua Hospital Wenhua Li Shanghai Jiaotong University School of Medicine Xinhua Hospital Lisu Huang (  huanglisu@xinhuamed.com.cn ) Shanghai Jiaotong University School of Medicine Xinhua Hospital https://orcid.org/0000-0001-81937353


Conclusion
Lobar consolidation is a stable and reliable CT feature for assessing of severity of illness and clinical prognosis for children with MPP.

Background
Mycoplasma pneumoniae pneumonia (MPP), one of the most common respiratory tract infections in children, accounts for 8-37.5% of all community-acquired pneumonia (CAP) cases [1,2]. Although M.
pneumoniae infections generally are mild and self-limiting, patients of study has shown about 12% of hospitalized children with MPP required intensive care [3]. Some patients with M. pneumoniae may develop extrapulmonary manifestations, such as encephalitis, arthritis, and pericarditis, presenting with a severe clinical course [4,5]. Hence, early and accurate assessment of the clinical course of MPP is crucial for patients and clinicians. Usually, chest radiography (CR) is the rst-line investigation for patients with suspected CAP. However, it is non-speci c for MPP [6][7][8]. CR fails to demonstrate the details and distribution of lesions, while computed tomography (CT) can clearly show interstitial abnormalities and lobular distribution, such as bronchial wall thickening and reticulonodular or centrilobular nodules, which are common features in patients with MPP [9,10]. Thus, chest CT is a favourable method for assessing radiological features in cases with MPP, and it can be applied safely in children through reasonable indication and adjustment of scan parameters, such as low-dose CT. Consolidation is more frequent in MPP than in other community-acquired pneumonia on CR, accounting for 33-79% of the cases [10,11].
However, the association between lobar consolidation and the severity and prognosis of MPP is unclear.
To our knowledge, only a few articles are presently available that describe the imaging ndings of MPP on CR or chest CT, which primarily consists of large-area or multi-lobar consolidation [12]. The quantitative correlation analysis between consolidation features and the clinical course or prognosis is under-investigated. Therefore, we aimed to verify consolidation con rmed by low-dose chest CT, as a critical feature with clinical signi cance in a large sample of patients with MPP; quantitatively evaluate the association between consolidation and the clinical course; thus, ensure that patients receive timely and reasonable treatment.

Patients
In the period between February 2016 and July 2019, 917 out of 5112 hospitalized children with CAP were diagnosed with MPP in Xinhua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine.
MPP was diagnosed based on the following conditions: (i) fever, cough, or auscultatory ndings and a pulmonary in ltrate visible on chest imaging; and (ii) M. pneumoniae DNA detected in nasopharyngeal secretions by polymerase chain reaction or ≥4-fold changes in M. pneumoniae IgM and IgG antibody titre between paired acute and convalescent sera, according to the Infectious Diseases Society of America guidelines of 2018 [13,14]. Patients with mixed infection, immunode ciency, and congenital diseases were excluded. Finally, 752 patients with MPP who underwent low-dose CT were included in the study.
The work ow is displayed in Figure 1. This retrospective study was approved by the Institutional Ethics Committee of our hospital, and informed consent was obtained.
General, clinical, and laboratory characteristics General information, clinical symptoms, and laboratory examination were re-evaluated by infectious specialists who reviewed the clinical records of patients enrolled in this study: general characteristics, including sex and age; clinical symptoms, including duration of fever prior to and after admission (days), total duration of fever (days), length of stay (days), rash, neurological symptoms, encephalitis, hypoxemia, treatment in intensive care unit, and death; and laboratory indices such as lactate dehydrogenase (LDH) and interleukin 2-receptor (IL-2R), as well as C-reactive protein (CRP) level at the time of admission.
Evaluation of CT features, including consolidation, bronchial wall thickening, nodules, ground grass attenuation, interstitial reticulation opacities, bilateral pneumonia, atelectasis, lymphadenopathy, and pleural effusion, were guided by expert consensus from a Delphi study on image assessment of patients with MPP [9,7,8,10,16] (Figure 2). Based on the related features of consolidation, all patients were further evaluated for the following features: the number of lobe consolidation, location of lobar consolidation (upper, middle, or lower right lung lobe; upper or lower left lung lobe), and the occurrence of consolidation without air bronchograms. Two chest radiologists independently assessed the CT images of each patient. Consensuses reached by both of them were as the nal appraisal reports. Disagreements were resolved by consulting a third chest radiologist with 12 years of experience.
Each patient's medical history was re-evaluated by an adjudication experts committee including paediatricians, radiologists, and infection specialists. Severe pneumonia was assessed according to the guidelines by the Paediatric Infectious Diseases Society and Infectious Diseases Society of America on the management of CAP in infants and children older than three months [17]. Refractory pneumonia was de ned as prolonged fever, worsening of clinical symptoms, emergence of extrapulmonary complications, and deteriorating radiological ndings, despite administration of appropriate macrolide therapy ≥7 days [18].

Statistical analyses
Categorical variables are expressed with n (%) and continuous variables are presented as median (interquartile range [IQR]). Differences in clinical and radiological variables in children with MPP were assessed using Chi-squared test for Categorical variables and t test or Mann-Whitney U test for continuous variables. Spearman's method was used to analyse the association between lobar consolidation and laboratory indices. Logistic regression analyses were then performed to assess the correlation between lobar consolidation and the clinical course. The association between lobar consolidation category and prognosis, including fever duration after admission and length of hospital stay, was assessed using Kaplan-Meier estimates, and using Cox proportional-hazard models to calculate hazard ratios (HRs) with 95% con dence. P < 0.05 indicated a statistically signi cant difference. Statistical analyses used R (https://www.R-project.org, R foundation for Statistical Computing, Vienna, Austria).

Results
Of the 5112 patients with a diagnosis of CAP during the study time frame, 752 patients met eligibility criteria and were included in the study cohort (Figure 1), 122 of 752 patients (16.2%) had SMPP (Table 1).
Most patients were pre-school and school-aged children. Patients with SMPP were more likely to have neurological symptoms, encephalitis, hypoxemia, refractory pneumonia and receive treatment in intensive care unit, and they had higher LDH, IL-2R, and CRP levels. Furthermore, patients with SMPP also tended to have longer median fever duration after admission, total fever duration, length of hospital stay (median 3.0 [IQR 2.0-4.0], 9.0 [IQR 7.0-12.0], and 9.0 [IQR 7.0-12.0] respectively) than those without SMPP.
Consolidation was present in 90.3% (679/752) of children with MPP, and this rate was the second only to that of bronchial wall thickening (93.2%) ( Table 2). The proportions for one, two, three, and four lobar consolidations were 65.1%, 19.3%, 4.7%, and 1.2%, respectively. Pleural effusion and atelectasis were observed in 15.8% and 9.7% of patients with MPP. Compared with zero and one lobar consolidations, two, three, and four lobes were associated with a 1-fold, 3.1-fold, and 7. The consolidation rates were 86.6%, 92.6%, 90.2%, 88.5% in patients with fever durations of ≤3 days, 3-6 days, 6-9 days and >9 days before admission. There was little change in the proportions of the lobar consolidation subclasses over the duration of fever prior to admission ( Figure 3). Levels of in ammatory markers, such as LDH, IL-2R, and CRP, consistently rose with lobar consolidation class ( Figure 4).  (Table 3). Similarly, the same trends were observed for the time to defervescence. An increasing number of lobar consolidations leads to a gradual increase in costs, including hospital charges, laboratory tests, imaging costs, and medications (Table 4).

Discussion
In our large sample study, consolidation was a stable and reliable feature in assessing disease severity and prognosis in patients with MPP. Lobar consolidation was independently associated with a higher risk of SMPP, longer fever duration and length of stay, and higher costs. These results demonstrated that an increased number of lobar consolidations could predict the severity of MPP and signi cantly enhance the accuracy of clinical outcome prediction in patients with MPP at an early stage.
Radiographic manifestations of MPP vary, including bronchial wall thickening, reticulonodular, segmental and lobar consolidations, atelectasis, hilar lymphadenopathy, and pleural effusion. Of these, consolidation as a CT feature presents a homogeneous increase in lung parenchymal attenuation that obscures the margins of vessels and airway walls [12]. In this study, consolidation was the second most common imaging feature and had good stability in evaluating the MPP course. The incidence of consolidation was up to 86.6% in patients with duration of fever ≤3 days, and 88.5% for duration of fever >9 days. In other words, the rate of consolidation was quite high in the early stages of infection and did not increase signi cantly with an increase of fever duration before admission, which may be relevant to type hypersensitivity. Furthermore, we found that an increased number of lobar consolidations was associated with higher odds of SMPP. As a previous literature has reported, patients with consolidations were more likely to have hypoxia, tachypnoea, tachycardia, and extrapulmonary manifestations, which indicate severe pneumonia in children, than those without consolidation on CR [12]. However, to our knowledge, no study has investigated the association between the number of lobar consolidations and SMPP. This is the rst study to achieve a quantitative evaluation of consolidation, which is superior to the previous vague assessments of large-area and multilobe consolidations.
In ammatory cytokines were involved in the immunopathogenesis of Mycoplasma pneumoniae infection [14,19]. In our study, we found a positive correlation between lobar consolidation and LDH, IL-2R, and CRP levels in children with MPP, which is consistent with the ndings of previous studies [12,14]. Mycoplasma pneumoniae attach to the ciliated epithelial cells on the respiratory tract through the P1 protein, exerting cytotoxicity by expression of community-acquired respiratory distress syndrome and production of hydrogen peroxide, then activating host immunity, including macrophages, mast cells, neutrophils, and natural killer cells, as well as T and B lymphocytes and humoral immune responses [20].
Cell-mediated immunological responses play an important role in the development of MPP. In SMPP, the immune response is exaggerated, and interleukin levels are elevated, resulting in diffuse alveolar damage with brinous exudates within the alveolar lumens histopathologically, which was correlated with consolidation on CT [21].
The association of multilobar involvement with prognosis has been previously investigated in some studies [12,22,23]. Patients with more lobar consolidations experienced longer fever duration, length of stay and higher costs, which are consistent with the results of this study. Some previous studies suggested that prolonged fever duration was associated with MP macrolide resistance [24,25]. We investigated the presence of macrolide-resistant genes through convenience sampling and found that almost MP were shown to have an A-to-G transition mutation at position 2063 in the 23S rRNA genes. Meanwhile, one study revealed that the presence of homogeneous lobar consolidation was responsible for prolonged fever ≥7 days after the initiation of macrolides regardless of macrolide resistance. Hence, quantitative analysis of consolidation can be more accurate in predicting the clinical course of MPP and guide rational clinical medication, with major clinical signi cance.
Clinicians are cautious about using CT in children because of the problem of radiation dose. First, we used a low-dose CT assessment of MPP in this study. According to scans parameters, when patients weigh < 20 kg, the patient absorbs about 0.4-0.8 millisieverts (mSv) of radiation, equivalent to the dose of 4-8 chest radiographs, and when patients weigh 20 kg to 60 kg, the patient absorbs about 0.7-1.6 mSv, equal to the dose of 7-16 chest radiographs [26]. Therefore, low-dose CT scans ensure safe radiation doses in children. Second, in contrast to the 33-79% incidence of consolidation currently reported [10,11], our results showed that the proportion of patients with consolidation was up to 90.3%, which is attributed to the superiority of CT over X-ray for demonstrating lesion patterns and lung anatomy [7]. Consolidation of a large area or an entire lobe can be clearly observed on CR and CT, while patchy consolidation indicative of bronchopneumonia on CT may manifest as a non-consolidative feature on CR. Additionally, we performed quantitative evaluation of consolidation. It was evident that the quanti cation of consolidation by CR was not achievable. Finally, low-dose CT is recommended for assessment when patients fail to respond to treatment, had severe complications suggested by CR, or when there is a need to exclude HIV infection and tuberculosis [15]. CT examination is an important and indispensable method. Thus, using low-dose CT can not only ensure safety but also improve the validity of assessment. Low-dose CT is recommended for children with MPP with poor e cacy or requiring differential diagnoses.
Our study has some limitations. First, this study was conducted retrospectively, and therefore analysis was limited to the patient's available medical records. Second, we are unable to obtain the patients' lung pathological specimens, as a result, the correlation analysis between imaging and pathology could not be performed. Considering the repeatability and operability of the study, CT is a non-invasive examination that can best re ect the actual pathological condition. Third, as the present study was performed at a tertiary hospital, patients may present with more severe diseases than are usually admitted in primary or secondary hospitals; however, the presented associations among evaluated variables are still present and convincing.

Conclusions
Our ndings showed that consolidation is a stable and reliable CT feature for evaluating MPP. Quantitative analysis of lobar consolidation can comprehensively and accurately assess and predict the clinical course of MPP. Low-dose CT examination is recommended for complex and severe hospitalized children with MPP.

Declarations
Ethics approval and consent to participate This retrospective study was approved by the Institutional Ethics Committee of our hospital, and informed consent was obtained from the participants.

Consent for publication
All the authors consent to the publication of this manuscript.

Availability of data and materials
The data and any material can be shared.

Competing interests
The authors declare that they have no competing interests.   Male, rash, neurological symptoms, encephalitis, hypoxemia, refractory pneumonia, treatment in intensive care unit, and death are presented as n (%); the rest of the variables are indicated as median (25th-75th percentiles).       The proportions of lobar consolidation in children with Mycoplasma pneumoniae pneumonia strati ed by fever duration before admission (n = 752).