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 [3–7]. However, most studies on PB and BCs consist of case reports or small case series, with few comprehensive reports of PB published in the literature. In this regard, Lu S et al. [6] reported 22 cases of BCs among 161 children with M. pneumoniae pneumonia (MPP) that underwent therapeutic FOB and BAL from November 2015 to December 2016. Moreover, PB in 63 children associated with the influenza 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. In the present study, we identified 269 children with PB from 3840 cases of pneumonia that underwent therapeutic FOB and BAL between January 2015 and December 2019. We estimated that PB accounted for 7.0% of children with pneumonia requiring FOB. The 269 cases of PB were related to respiratory tract infections. We reviewed the etiology, clinical manifestations, treatment and further explored the risk factors of multiple therapeutic FOB in children with PB.
We found that MP, bacteria, influenza virus, ADV and Candida albicans could trigger PB. In recent years, the association between PB and MP has been reported in various studies. In a study that enrolled 15 children with PB, MP infection accounted for 86.7% of the cases[4]. Moreover, in a study by Guo et al., MP infection was detected in 90.4% of children with type I PB (n=73) [16]. In the present study, MP was identified in the majority of patients (n=241, 89.6%), including single MP infection in 164 (61.0%) cases 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 significant 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 inflammatory 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 inflammation[22, 23]. Compared with bacterial and viral infections, MP infection has a greater tendency to induce an excessive inflammatory 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 (6.1 ± 2.8 years) [16]. School-aged children have a mature immune system and are prone to develop strong immune responses, leading to airway mucosal damage that increases the tendency to form BCs that block the airways. There are currently no definitive diagnostic criteria or tests for PB. The diagnosis of PB is mainly clinical and is based on the clinical presentation (expectoration of casts), bronchoscopic, and imaging findings. The clinical manifestations of PB are diverse, including fever, cough, dyspnea or respiratory distress and extrapulmonary damage. Rapid progression to hypoxemia can be regarded as a strong indicator of PB. However, when patients with mild symptoms have no or mild signs of hypoxemia, it can be difficult for clinicians to recognize it. In our study, 62 (23.0%) cases suffered from hypoxemia. Li W et al. (18)revealed that all children (n=15) in their study with PB showed no signs of hypoxemia, while Lu S et al. [6] reported that only 9 out of 22 children with MPP BCs required oxygen therapy. All the above findings suggest that hypoxemia is not a sensitive indicator to identify PB. The poor specificity of signs and symptoms emphasizes the importance of obtaining a detailed history and physical examination along with chest imaging and bronchoscopic evaluation.
ICU treatment in our study was required in 17.8% of cases (48/269), which was lower than reported by Lu et al. (58.3%, 14/24 cases) [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 significantly 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 fills 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 inflammation 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 inflammation 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 inflammatory cytokines[28]. LDH is a nonspecific inflammatory biomarker present in the cytoplasm. Xu et al.[29] identified 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 inflammation biomarkers indicated excessive inflammation, 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 fibrinolysis, representing blood hypercoagulability and the presence of thrombi [31]. Recently, D-dimer has also been recognized as an indicator for evaluating the severity of MPP. Jin X et al. reported higher D-dimer levels in children with severe MPP than in children with mild disease (0.61 vs.0.30mg/L) [32]. In Yan Z et al.’s research[33], the D-dimer level was positively correlated with inflammatory markers (N%, CRP, LDH, IL-10), suggesting that higher levels of D-dimer were associated with severe inflammation. 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 inflammation, which plays an important role in inducing mucus plugs formation in PB and is an important risk factor for patients requiring multiple therapeutic FOB.
The imaging features of PB in children are heterogeneous, including pulmonary consolidation, atelectasis, pleural effusion, emphysema and pneumothorax[16, 35]. A recent study [18] found that 13 out of 15 PB children presented with lung consolidations involving unilateral or bilateral infiltrations, and 5 cases developed pleural effusion. Our results showed the poor specificity of imaging findings associated with PB and a high incidence of lung consolidation (97.4%), consistent with previous reports (98.6%)[16]. Overall, the presence of persistent atelectasis in chest imaging is a strong indication for therapeutic FOB. The incidence of atelectasis in our research was 46.5%. In a study by Lu S et al.[6], 6 out of 22 children with BCs and lobar consolidation also presented with atelectasis. Timely therapeutic FOB is often not possible when PB patients have no signs of atelectasis. Compared with atelectasis, PB should be considered when patients with persistent fever and large chest imaging infiltration
Although PB presents with severe clinical manifestations and the critical form in children has a mortality rate as high as 7-10% due to failure to extract BCs in time[8, 9, 26], the prognosis of PB is generally favorable if the disease can be treated promptly. The lack of in-depth knowledge of the underlying pathophysiology has not prevented the gradual evolution of effective treatment options for symptomatic relief and correction of underlying causes of PB. Most reports of effective therapy are based on standard antibiotic treatment, glucocorticoids, IVIG and clearance of BCs with 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 confirmed to be effective in reducing inflammatory 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 fluid 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 efficient for the treatment of PB, including clearance of BCs to improve lung ventilation and various inflammatory 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 inflammation 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 findings 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 findings, an RCT study should be designed.