In recent 10 years, an increasing number of studies about PB in children associated with respiratory infections are being reported [3–7]. However, many literatures on PB and BCs are composed of case reports or small case series, and accurate epidemiological data of PB and BCs are still lacking. Lu S et al. [6]reported 22 cases of BCs among 161 MPP children with FOB and BAL treatment from November 2015 to December 2016. Wei F et al[13] analyzed a study of 63 PB children associated with influenza virus from May 2014 to April 2020. In the study, we identified 269 children with PB from 4958 cases of pneumonia with FOB and BAL treatment, and we estimated that PB accounted for 5.4% in children with pneumonia requiring FOB.
We identified that MP, bacteria, influenza virus, ADV and Candida albicans can trigger PB. In rencent years, PB associated with MP has been reported in various studies. In a investigation enrolled 15 children with PB, MP infection accounted for 86.7% of the cases[4]. Guo et al. also identified that in a study of 73 subjects with type I PB, MP infection was detected in 90.4% of the children[14]. In the present study which is the largest research to date of PB, MP was positive in 257 ( 95.5%) patients, including single MP infecton in 202 (75.1%) cases and coinfection of MP with bacteria and/ or virus in 55( 20.4%) subjects. Moreover, the seasonal distribution of PB from 2016 to 2019 indicated that the peak incidence of PB was observed in winter, especially in 2019 winter. Yan X also [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 inflammation[21, 22]. Compared with bacterial and viral infections, MP infection is more likely to induce excessive inflammatory 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 significantly 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 fills 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 extra-pulmonary complications, higher levels of inflammation indicators and D-dimer. Furthermore, multiple logistic regression identified 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 inflammation and disease severity[26] in children with MPP. LDH is a nonspecific inflammatory biomarker and exists within the cytoplasm. Xu et al.[27] identified 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 inflammation biomarkers indicate the excessive inflammation, 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 fibrinolysis, 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 significant 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 infiltration, 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 specific, 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 infiltration.
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 efficacy in treatment of PB, including direct clearance of BCs to improve lung ventilation, the clearance of various inflammatory 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 inflammation 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 inflammation indicators and large infiltration in chest imaging, FOB is of great significance 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.