Clinical Features and High-risk Factors Prediction of Multiple Fiberoptic Bronchoscopy Therapy of Plastic Bronchitis in 269 Children

Background. To analyze the clinical features of children with plastic bronchitis (PB) and identify the risk factors of multiple exible beroptic bronchoscopy (FOB) therapy. Methods. Retrospective analysis was performed on 269 PB children from 2016 to 2019, 144 cases were in single FOB group, 125 cases were in the multiple FOB group. The clinical manifestations, laboratory datas, imaging ndings and management were investigated. The different features were compared between the single FOB group and multiple FOB group. Results. A total of 269 PB children were collected with a mean age of 6.7 ± 2.8 years. 257 (95.5%) cases were diagnosed as Mycoplasma pneumonia (MP) infection. The mean duration of fever was 10.6 ± 3.7 days. All the patients presented with fever, and 62 (23.0%) suffered from hypoxemia, 144 (53.5%) had extrapulmonary complications. Higher levels of ESR, CRP, PCT, IL-6, LA, LDH, FER and D-dimer were observed. The proportion of pulmonary consolidation, segmental or lobar atelectasis, pleural effusion and pleural thickening were 97.4%, 46.5%, 47.9% and 63.2%, respectively. Furthermore, multivariate logistic regression analysis showed that N% >75.5%, LDH >598.5U/L, and D-dimmer>0.45mg/L were independent isk factors for multiple FOB therapy. Conclusions. MP is a signicant pathogen of PB in children. Patients with PB are more likely to suffer from persistent fever, excessive inammation and severe radiological ndings. N% >75.5%, LDH >598.5U/L and D-dimmer > 0.45mg/L may be predictors of multiple FOB treatment.


Introduction
Plastic bronchitis (PB) is an uncommon pulmonary disease characterized by formation of bronchial casts (BCs) in airways, which can partially or completely obstruct the tracheobronchial tree [1]. Previously, PB was usually reported in children with surgically palliated congenital heart disease, especially those after the Fontan procedure [2]. With the wide application of beroptic bronchoscopy (FOB) in bronchopulmonary disease, accumulating evidence indicated that PB can be triggered by common
The clinical manifestations of PB include repeated fever, shortness of breath and can rapidly progress to acute dyspnea and even life-threatening respiratory failure [8,9]. As PB is a serious disease which can endanger lives without timely management, we explored and analyzed the clinical characteristics, laboratory examinations, imaging features and management of 269 children with PB to help clinians recognize it in time and apply effective treatment promptly.To the best of our knowledge, this study is the largest research of PB in children and is the rst study to identify risk factors of multiple FOB therapy in PB patients.

Subjects And Methods
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Study population
We collected and analyzed the medical records and chest radiographic ndings of 269 children with PB, who were admitted to Respiratory Department of Tianjin Children's Hospital from January 2016 to December 2019.
All the cases received FOB and bronchoalveolar lavage (BAL) procedure. If the fever does not subside, and the chest X-ray does not improve 2-3 days after the rst FOB operation, the patient will receive multiple FOB and BAL treatments. Subjects were divided into the single FOB group and multiple group(≥2 times) according to the times of FOB treatment. The diagnosis of PB was determined according to discovery of in ammatory BCs by FOB, and further con rmed by pathology. Hypoxemia was de ned as any recorded oxygen saturation of < 92% by pulse oximetry, measured on room air [10]. MP infection is determined by serologic or MP polymerase chain reaction (PCR) tests. An MP-immunoglobulin M (IgM) titer ≥1:160 or four-fold rising titer in acute and convalescent serum specimens were considered positive [11].
Inclusion criteria : (1) All patients had an acute onset of fever and cough. (2) All patients met the criteria of type I PB con rmed by histopathology. Exclusion criteria: (1) patients who had underlying disease, such us congenital heart disease, asthma and congenital immunode ciency disease. (2) patients who had history of inhalation of foreign body and con rmed by FOB as bronchial foreign body. (3) Patients who had incomplete medical records.

Methods
The study was performed in accordance with the Declaration of Helsinki and approved by the ethics committee of the Tianjin Children's Hospital. The ethics committee waived the need for written informed consent provided by participants due to the retrospective nature of the study, because all patient data were analyzed anonymously, and no additional informed consent was required.
Clinical characteristics, laboratory ndings, imaging features, and management of the 269 patients were collected at the time of admission.
Peripheral blood samples were also obtained on admission for the determination of blood routine examination, erythrocyte sedimentation rate(ESR), C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-6, lactic acid(LA), lactic dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), ferritin (FER), D-dimer, brinogen (FG) and speci c antibody to MP. Blood routine examination was performed every 2-3 days and was compared between at admission and at discharge. Chest computed tomography (CT) was performed before admission or during hospitalization as these patients showed persistent fever or large in ltration on chest X-ray.
All the patients enrolled in our study received FOB, and the uid of BAL were collected for microbiological determination according to the Guide to pediatric bronchoscopy [12]. Virus were identi ed by direct immuno uorescence PCR, MP using PCR and bacteria were detected by culture or multiplex PCR for respiratory bacteria pathogens.
The study was performed in accordance with the Declaration of Helsinki and approved by the ethics committee of the Tianjin Children's Hospital. The ethics committee waived the need for written informed consent provided by participants due to the retrospective nature of the study, because all patient data were analyzed anonymously, and no additional informed consent was required.

Data analysis
Datas were processed using SPSS 26.0. Continuous variables were expressed as mean ± standard deviation (SD) or median values (interquartile range) and assessed by independent group t tests or Mann-Whitney U test. Categorical variables were expressed as percentage (%) and assessed by Chi-squared tests or Fisher's exact test. Receiver Operating Characteristic (ROC) curves and Logistic regression analysis were performed to identify variables associated with multiple FOB therapy in PB patients. A twosided α less than 0.05 were considered as statistically signi cant.

Clinical characteristics of PB in children.
The mean age of the subjects was 6.7 ± 2.8 years (range, 9 months-14 years), and the male-to-female ratio was 1.04. The mean duration of fever and hospitalization was 10.6 ± 3.7 and 9.3 ± 3.2 days, respectively. All the patients presented with cough and fever, and 62 ( Among these 269 patients, 144 cases underwent FOB and BAL procedure for once(the single group) and 125 underwent multiple therapy (the multiple group). There were no statistically differences between the two groups in age, sex ratio, incidence of fever. Compared with single group, children in the multiple group exhibited higher peak body temperature, longer duration of fever and hospitalization. The total incidence of extrapulmonary complications was higher in the multiple group, especially in digestive system, however differences in incidence of blood system, cardiovascular system, skin, central nervous system and lectrolyte disorder were not observed. ( Table 2 ) Data are presented as mean ± SD, or n (%). Differences between groups were determined by independent group t tests( mean) and Chi-squared tests or Fisher exact test (proportions).

Laboratory characteristics of PB in children.
Laboratory indicators were summarized in Table 3. Higher levels of ESR, CRP, PCT, IL-6, LA, LDH, FER and D-dimer were observed in PB patients. The levels of N%, CRP, IL-6, LA, ALT, AST, LDH, FER, D-dimer in multiple group were higher than those in the single group, and the differences were statistically signi cant ( all, P < 0.05 ). ( Table 3)  Data are presented as mean ± SD and median (25th-75th percentile). Differences between groups were determined by the independent group t tests(mean ± SD) and Mann-Whitney U test (medians 3.5 Imaging characteristics of PB in children. All the 269 enrolled patients underwent chest CT scan and 262 (97.4%) showed pulmonary consolidation, 125 (46.5%) had segmental or lobar atelectasis, 127 (47.9%) with pleural effusion and170 (63.2%) with pleural thickening. The incidence of pulmonary consolidation and pleural effusion were higher in multiple group (100% vs 95.1%, 56.8% vs 38.9%, respectively, P < 0.05). However, there was no difference in the incidence of segmental or lobar atelectasis and pleural thickening between the two groups. ( Table 4)    [15]demonstrated that MPP had a higher prevalence rate in winter and peaks occurred in November 2019 in a 3-year retrospective analysis from Bei Jing. The considerable detection rate of MP in PB and epidemic consistency of PB and MPP indicated that MP is a prominent pathogen of PB. MPP is usually considered to be self-limited and benign [16], however it may proceed to severe or fulminant pneumonia, endanger the lives [17,18]. Previous studies [6,19,20] also showed that MP infection can lead to varying degrees of respiratory mucus plug, even BCs, resulting in PB. The mechanism of its role in PB maybe that MP infection not only directly cause damage to the airway, including epithelial necrosis to block the respiratory tract and cilia shedding to cause cilia removal dysfunction, but also promote airway hypersecretion by the excessive in ammation [21,22].
Compared with bacterial and viral infections, MP infection is more likely to induce excessive in ammatory response in the body [23] which can induce continuous formation of mucus plug in the airway and cause damage to the whole body.
The mean age of our patients was 6.7 ± 2.8 years (range, 9 months-14 years) which was similar to the 6.1 ± 2.8 years reported in previous study [14]. The clinical manifestations of PB are diverse, including fever, cough, dyspnea or respiratory distress and damage to extrapulmonary system, among which rapid progression to hypoxemia can be applied as a strong indicator of PB. However, when patients with mild symptoms have no or mild signs of hypoxemia, many clinicians cannot recognize it. In our study, 62 (23.0%) cases suffered from hypoxemia. Li W et al. [18] revealed that in their study all the 15 children with PB showed no signs of hypoxemia, and Lu S et al. [6] reported that only 9 out of 22 children with MPP BCs received oxygen therapy. All the above suggested that hypoxemia was not sensitive enough to discover PB. Therefore, we should comprehensively evaluate the clinical manifestations in order to recognize PB timely.
The incidence of ICU treatment in our study was 17.8% ( 48/269 cases), which was lower than that of 58.3% ( 14/24 cases) in Lu et al's study [24], and no death cases were observed in our study. The rate of critically ill and mortality was signi cantly lower than previous descriptions [8,25]. The possible explanation may be attributed to the following two aspects. On one hand, the clinical manifestation of PB depends on the location and degree of bronchial obstruction, ranging from fragmented partial BCs to a large and complete cast that lls the entire airway [6]. On the other hand, rapid FOB treatment contributed to early effective intervention and prevented the development of respiratory failure.
We found that patients in the multiple group exhibited severe clinical manifestations, including higher peak body temperature, longer duration of fever and hospitalization, higher incidence of intra and extrapulmonary complications, higher levels of in ammation indicators and D-dimer. Furthermore, multiple logistic regression identi ed that N% >75.5%, LDH > 598.5U/L and D-dimer > 0.45mg/l were the independent risk factors for multiple FOB therapy. It was reported that higher neutrophil(63.1%) was positively correlated with excessive in ammation and disease severity [26] in children with MPP. LDH is a nonspeci c in ammatory biomarker and exists within the cytoplasm. Xu et al. [27] identi ed LDH as independent risk factor for mucus plug formation in children with RMPP and our results showed that LDH > 598.5U/L is a predictor of multiple FOB therapy. Although the pathogenesis of PB was not completely clear, at present it is commonly believed that PB triggered by infection result from inappropriate immune reponse to infection and direct damage of pathogen to the airway [3,28].The higher level of in ammation biomarkers indicate the excessive in ammation, which can lead to continuous formation of mucus plug, resulting in multiple FOB to clear the subsequent BCs.
The increase of D-dimer is an important indicator of high brinolysis, representing blood hypercoagulability and the presence of thrombi [29]. It was reported [30]that the D-dimer level in the severe MPP group was higher than that in the mild group in children(0.61 vs.0.30mg/L), and the level of D-dimer was positively correlated with the severity of MPP. In the study, we found an elevated D-dimer level in PB children and D-dimer > 0.45mg/l was a risk factor for multiple FOB and BAL treatments, which was consistent with the view of Zhang et al [31]. Their study showed that children receiving multiple FOB treatments for RMPP had higher D-dimmer levels (1.808 mg/L) compared with the monotherapy group (0.567mg/L). However, the median level of D-dimer in our study was lower than that of Zhang et al and we speculated that there are two possible explanations. On one hand, the enrolled subjects in the two study were different. RMPP children may exhibit higher D-dimmer level duo to intensive body reponse to MP infection. On the other hand, in the present study, D-dimer level of a signi cant number of children may not be measured at the peak of disease process. In summary, we speculated that hypercoagulability play an important role in inducing subsequent mucus plugs formation of PB and higher D-dimer level is an important risk factor for patients requiring multiple FOB treatments.
The imaging features of children with PB were diverse, including pulmonary consolidation, atelectasis, pleural effusion, emphysema and pneumothorax [14,32]. Recent literature [18] found that 13 out of 15 PB children had lung consolidation involved unilateral or bilateral in ltration, and 5 cases developed pleural effusion. Lu S et al. [6] also observed that all 22 children with BCs had lobar consolidation and 6 cases developed atelectasis. Our results showed that the imaging manifestations of PB were not speci c, and PB patients were more likely to be associated with lung consolidation (97.4%), which was consistent with the 98.6% of PB children with lung consolidation or atelectasis reported previously [14]. Therefore, we concluded that PB should be considered when patients with persistent fever and large chest imaging in ltration.
Although PB presented with severe clinical manifestations and the critical form in children has a mortality rate as high as 7-10% due to failing to extract BCs in time [8,9,25], the prognosis of PB is generally favorable if the disease can be treated promptly. Most reports [4,6] of effective therapy were based on standard antibiotic treatment, glucocorticoids, IVIG and clearance of BCs with FOB. In agreement with this notion, all patients in the present study received appropriate antibiotic treatment, up to 95.5% subjects received glucocorticoid therapy, and 20.4% received IVIG to modulate immunity. FOB procedure is of prominent e cacy in treatment of PB, including direct clearance of BCs to improve lung ventilation, the clearance of various in ammatory factors and easy access to the lower airway for the pathogenic detection. Recent studies [33,34] found that compared with late FOB therapy, FOB therapy during the early disease process in RMPP patients with large pulmonary lesions resulted in faster recovery of clinical and in ammation characters and shorter hospital stay. Furthermore, there are a considerable number of children with PB requiring multiple FOB therapy. In our study, the proportion of patients in mutiple group was 46.5% (125/269) which was consistent with the result of Cai L [35]. Their study showed that more than 50% children with PB received multiple FOB treatment and all achieved favorable prognosis. In summary, we believed that in patients with persistent fever, higher level of in ammation indicators and large in ltration in chest imaging, FOB is of great signi cance in timely diagnosis and effective treatment.
There were several limitations to this study. Firstly, it was a retrospective study and there may have been some selection bias. Secondly the patients were enrolled from a single center and the results may not easily extrapolate to patients admitted to other regions. Thirdly, to timely identify PB and avoid improper application of FOB, a RCT study should be designed between PB and such diseases.

Conclusion
In conclusion, our study showes that MP is a signi cant pathogen of PB. The clinical manifestations of PB are not speci c, children with PB might be easier to suffer from persistent fever, excessive in ammation and severe radiological ndings. N% >75.5%, LDH >598.5U/L and D-dimer >0.45mg/L are important risk factors for multiple FOB procedures. Favorable prognosis can be expected with timely diagnosis and appropriate FOB treatment.

Declarations
Ethics approval and consent to participate All procedures performed in studies involving human participants were performed in accordance with the Declaration of Helsinki and approved by the ethics committee of the Tianjin Children's Hospital. The ethics committee waived the need for written informed consent provided by participants due to the retrospective nature of the study, because all patient data were analyzed anonymously, and no additional informed consent was required.
The ethics committee waived the need for written informed consent provided by participants due to the retrospective nature of the study, because all patient data were analyzed anonymously, and no additional informed consent was required.
Consent for publication.
Not applicable.
Availability of data and materials.
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.