Clinical Features of Plastic Bronchitis Related to Respiratory Tract Infection in 269 Children

Background. Plastic bronchitis (PB) is a pulmonary disease characterized by the formation of bronchial casts (BCs) that lead to airway blockage. The study aimed to investigate the clinical features of PB related to respiratory tract infection. Methods. A retrospective analysis was performed on data collected over a 5-year period (from January 2015 to December 2019) on children with PB (n=269). The clinical manifestations, laboratory data, imaging ndings and management, were investigated. The single beroptic bronchoscopy (FOB, n=144) and multiple-treatment groups (n=125) were compared.


Introduction
Plastic bronchitis (PB) is an uncommon pulmonary disease characterized by the formation of bronchial casts (BCs) in the airways, which can partially or completely obstruct the tracheobronchial tree [1]. PB has been reported in children with surgically palliated congenital heart disease for the past decade, especially after the Fontan procedure [2]. With the wide application of beroptic bronchoscopy (FOB) in bronchopulmonary disease, accumulating evidence indicates that PB could be triggered by common pathogens in respiratory tract infection, including in uenza virus (A and B), adenovirus (ADV) and Mycoplasma pneumoniae (MP) [3][4][5][6][7], suggesting that PB may not be a rare disease.
The main persistent symptoms of PB include recurrent fever, shortness of breath, rapid progression to acute dyspnea, and even life-threatening respiratory failure [8,9]. The heterogeneous clinical presentation of PB and its potential to progress to severe but treatable respiratory failure highlights the need to raise awareness of this condition. The prevalence and clinical characteristics of PB in children have been largely understudied. This report aimed to explore the clinical characteristics, laboratory examinations, imaging features and management of PB in children to ensure timely diagnosis and effective treatment.
Furthermore, this study provide a comprehensive analysis of risk factors for multiple therapeutic FOB.

Study population
269 children, initially diagnosed with pneumonia and con rmed as PB by bronchoscopy, were admitted to the Respiratory Department of Tianjin Children's Hospital from January 2015 to December 2019. This study was approved by the Ethics Committee of the Tianjin Children's Hospital. The patient data were collected and analyzed anonymously.

Diagnostic criteria
All patients presented with symptoms and signs suggestive of pneumonia on admission, including fever, cough, abnormal lung auscultation, and new in ltrations on chest radiography. Hypoxemia was de ned as an oxygen saturation of < 92% recorded by pulse oximetry, measured under room air conditions [10]. in such circumstances, FOB and BAL were indicated to observe the presence of tracheomalacia, stenosis, foreign body obstruction, tuberculosis or alveolar hemorrhage and BAL uid was collected for pathogenic analysis; (b) to relieve airway obstruction or pulmonary atelectasis caused by in ammatory secretions or necrotic substances which are often observed during refractory Mycoplasma pneumonia (RMPP), severe adenovirus pneumonia and in uenza virus pneumonia; (c) diagnosis of airway injury after infection.
Severe pneumonia of different etiologies can cause airway cartilage destruction, airway occlusion and other airway structural changes, which can be diagnosed and treated by FOB.
PB was diagnosed based on the following: (a) Bronchoscopy ndings [13]: respiratory mucosa congestion, edema and increased mucus discharge; the bronchial lumen was blocked by in ammatory BCs, which were removed by biopsy forceps and appeared as "branch-like" structures after immersion in normal saline; (b) Histopathology ndings: the in ammatory BCs consisted of in ammatory cells (predominantly eosinophils and neutrophils) and exfoliated epithelial cells, with positive immunohistochemistry staining for CD3, CD20, CD68, and MPO.

Inclusion criteria
Page 4/21 Children aged less than 18 years old who met the diagnostic criteria of PB.

Exclusion criteria
(1) Patients with underlying diseases, such as congenital heart disease, asthma and congenital immunode ciency disease. (2) Patients with a history of foreign body inhalation con rmed by FOB. (3) Patients with incomplete medical records.

Methods
Patient data, including the clinical characteristics, laboratory ndings, imaging features, and drug management, were collected at admission.
Peripheral blood samples were also obtained on admission to determine the Complete blood count, 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 MP-speci c antibody. Routine blood examinations were performed every 2-3 days and compared at admission and discharge. Chest computed tomography (CT) was performed before admission or during hospitalization in accordance with the criteria described above.
All the patients enrolled in our study underwent therapeutic FOB, and the BAL uid was collected for microbiological determination according to the Guide to pediatric bronchoscopy [14]. Viruses were identi ed by direct immuno uorescence PCR, including adenovirus, respiratory syncytial virus, in uenza virus, rhinovirus, human metapneumovirus. MP was detected using PCR or MP-IgM, and bacteria were detected by culture or multiplex PCR for respiratory bacteria pathogens.

Data analysis
Data 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  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).
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).WBC White blood cell, N Peripheral neutrophils, L Peripheral lymphocytes, PLT Platelets, ESR Erythrocyte sedimentation rate, CRP C-reactive protein, PCT Procalcitonin, IL-6 Interleukin (IL)-6, LA Lactic acid, AST Aspartate aminotransferase, ALT Alanine aminotransferase, LDH Lactic dehydrogenase, FER Ferritin, FG Fibrinogen. Table 4 Comparision of blood routine examination between at admission and at discharge Data are presented as mean±SD. Differences between at admission and at discharge were determined by Paired t test. WBC 2 , N 2 , L 2 , PLT 2 represented for the boood routine examination at discharge Data are presented as n (%). Differences between groups were determined by Chi-squared tests Data are presented as n (%). Differences between groups were determined by Chi-squared tests 3.3 Clinical characteristics of PB in children.
The mean age of the patients 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. Among the 269 patients, 144 cases underwent FOB and BAL once (single treatment group), and 125 underwent multiple times (multiple treatment group). There was no statistical difference between the two groups in age, sex ratio and incidence of fever. Compared with the single treatment group, children in the multiple treatment group exhibited higher peak body temperature, longer duration of fever and hospitalization. The total incidence of extrapulmonary complications was higher in the multiple treatment group, especially for the digestive system. ( Table 2 ) 3.4 Laboratory characteristics of PB in children.
Laboratory indicators of PB cases in our study are summarized in Table 3 ( Table 3) 3

.5 Comparision of blood routine examination between admission and discharge
We further compared the changes in blood routine tests at discharge and admission. Results indicated that compared with admission results, patients at discharge tended to have higher levels of white blood cell (WBC) (

Discussion
It has long been thought that the majority of pediatric cases of PB were associated with surgical correction of congenital heart disease. In the past ten years, an increasing number of studies have reported that PB in children is related to respiratory infections [3][4][5][6][7] Moreover, PB in 63 children associated with the in uenza virus was analyzed in a study by Wei F et al. [15]. The incidence of PB remains largely unclear. However, it should be borne in mind that PB may be underdiagnosed due to its rarity, limited pediatrician awareness, and milder presentation in some children. and mixed infections of MP with bacteria and/ or virus in the remaining (n=77, 28.6%) subjects. Moreover, the seasonal distribution of PB from 2015 to 2019 indicated that the peak incidence of PB was in winter.
Yan X et al. also demonstrated that MPP had a higher prevalence rate in winter in a 3-year retrospective analysis [17]. The signi cant detection rate of MP in PB cases and epidemic consistency between PB and MPP indicated that MP is a prominent pathogen associated with PB.
Whether the cause of PB is actually related to respiratory infections remains largely unknown. The possible mechanisms may be attributed to pathogens that directly damage the airway and are secondary to the in ammatory process. MPP is usually considered self-limited and benign(18); however, it may progress to severe or fulminant pneumonia and become life-threatening [18,19]. Previous studies [6, 20,21] also showed that MP infection could lead to varying degrees of respiratory mucus plugs, even BCs, resulting in PB. The mechanism underlying the role of MP infection in PB could be that MP infection directly causes damage to the airway, including epithelial necrosis to block the respiratory tract and cilia shedding to cause cilia removal dysfunction and promotes airway hypersecretion induced by excessive in ammation [22,23]. Compared with bacterial and viral infections, MP infection has a greater tendency to induce an excessive in ammatory response in the body [24], thus inducing the continuous formation of mucus plug in the airway and causing damage to the whole body.
In the present study, the mean age of patients was 6.7 ± 2.8 years (range, 9 months-14 years), similar to the results reported in a previous study (6.  [25]. Moreover, three children died of acute respiratory distress syndrome (ARDS) and multiple organ failure due to failure to remove the casts in time. The incidence of critically ill patients and mortality was signi cantly lower than in the literature [8,26]. Indeed, the clinical manifestations of PB depend 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]. However, it should be borne in mind that rapid therapeutic FOB is highly effective and can prevent the development of respiratory failure.
We found that patients in the multiple FOB group exhibited severe clinical manifestations, including higher peak body temperature, longer duration of fever and hospitalization, higher incidence of intra and extrapulmonary complications, and higher levels of in ammation indicators and D-dimer. Furthermore, multiple logistic regression found that N% >75.5%, LDH >598.5U/L, and D-dimer>1.2mg/l were independent risk factors for multiple therapeutic FOB. Previous studies have found that a high neutrophil count was positively correlated with excessive in ammation and disease severity in children with MPP [27], which was attributed to the fact that increased neutrophils can injure the airways during the acute stage through the release of proteases, reactive oxygen and in ammatory cytokines [28]. LDH is a nonspeci c in ammatory biomarker present in the cytoplasm. Xu et al. [29] identi ed LDH as an independent risk factor for mucus plug formation in children with RMPP. In our study, LDH >598.5U/L was a predictor for multiple therapeutic FOB. Although the pathogenesis of PB is still widely unknown, it is commonly believed that PB triggered by infection results from an inappropriate immune response to infection and direct damage of pathogen to the airway [3,30]. The higher levels of in ammation biomarkers indicated excessive in ammation, leading to continuous formation of mucus plugs, requiring multiple therapeutic FOBs to clear the BCs.
It is widely acknowledged that an increase in D-dimer is an important indicator of high brinolysis, representing blood hypercoagulability and the presence of thrombi [31]. suggesting that higher levels of D-dimer were associated with severe in ammation. In the present study, we found an elevated D-dimer level in PB children, and D-dimer >1.2mg/l was a risk factor for multiple therapeutic FOB and BAL, consistent with the study by Zhang et al. [34]. This study showed that children receiving multiple therapeutic FOB for RMPP had higher D-dimer levels (1.808 mg/L) than the monotherapy group (0.567mg/L). In summary, we speculate that a high D-dimer level is an indicator of excessive in ammation, which plays an important role in inducing mucus plugs formation in PB and is an important risk factor for patients requiring multiple therapeutic FOB.  [4,6]. In agreement with this notion, all patients in the present study received appropriate antibiotic treatment; up to 95.5% of subjects received glucocorticoid therapy, and 20.4% received IVIG to modulate immunity. Glucorticosteroid and IVIG have been con rmed to be effective in reducing in ammatory cast formation and alleviating PB symptoms. It is worth noting that the essence of BCs is the accumulation of thick mucus plugs. A majority of the PB patients present with a high fever. Indeed, the loss of water from the respiratory tract cannot be underestimated, resulting in the thickening of the mucus secretions. Accordingly, ensuring an adequate uid intake is essential. During the early stage of the disease, techniques that improve expectoration, including moisturizing the airway, mechanical vibration expectoration, local application of phlegm-reducing drugs and glucocorticoids, can prevent the formation and improve the discharge of BCs.
It has been established that FOB is highly e cient for the treatment of PB, including clearance of BCs to improve lung ventilation and various in ammatory factors and easy access to the lower airway for pathogenic detection. Recent studies [36,37] found that compared with late therapeutic FOB, FOB therapy during the early disease process in RMPP patients with large pulmonary lesions resulted in faster recovery of clinical and in ammation biomarkers and shorter hospital stay. Furthermore, a considerable number of children with PB require multiple therapeutic FOBs. In our study, the proportion of patients in the multiple FOB group was 46.5% (125/269), consistent with the results of Cai L et al. [38], who showed that more than 50% of children with PB required multiple therapeutic FOB and all patient had favorable outcomes.
There were several limitations to this study. First of all, the retrospective nature of our study suggests that our ndings may be subject to selection bias. Moreover, the patients were enrolled from a single center, and the results cannot be extrapolated to patients from other regions. Indeed, to enhance the robustness of our ndings, an RCT study should be designed.

Conclusion
In conclusion, our study showed that MP is a signi cant pathogen associated with PB. The clinical manifestations of PB are not speci c. Children with PB experience persistent fevers, excessive in ammation and severe radiological ndings. FOB is an effective treatment for patients with PB, and in some cases, multiple therapeutic FOBs are required for cast removal. N% >75.5%, LDH >598.5U/L and Ddimer >1.2mg/L are important risk factors for multiple FOB procedures. A favorable prognosis can be expected with timely diagnosis and therapeutic FOB, when appropriate. "See image above for gure legend"