Clinical features and risk factors of plastic bronchitis caused by refractory Mycoplasma pneumoniae pneumonia in children: a practical nomogram prediction model

Mycoplasma pneumoniae (MP) is a common lower respiratory tract pathogen that causes MP pneumonia (MPP) in children. The incidence of MP infection in cases of community-acquired pediatric pneumonia can be as high as 28 − 41% and is higher in school-aged children [1, 2]. In recent years, refractory MPP (RMPP) in children has been increasingly reported and recognized. RMPP is characterized by a high fever that does not subside or progressive changes on imaging despite conventional use of macrolide antibiotics for over 7 days [3, 4]. RMPP often leads to serious complications such as pleural effusion, pulmonary necrosis, and pulmonary embolism, and the patient is prone to sequelae, such as bronchitis obliterans (BO) or bronchiectasis.

Systemic glucocorticoid treatment can effectively suppress the excessive inflammatory response in RMPP and alleviate fever and pulmonary progression [5, 6]. However, some children respond poorly to treatment with conventional doses of glucocorticoids and continue to present with high fever and progression on imaging, exhibiting large consolidation shadows and pleural effusions. Bronchoscopy in such cases reveals the presence of plastic bronchitis (PB). In PB, the decrease in productive coughing leads to airway obstruction by viscous substances that travel through the bronchi and form casts. With the increase in RMPP cases and the introduction of bronchoscopy in the management of severe pediatric pneumonia, an increasing number of cases of RMPP combined with PB have been identified [7, 8]. The development of PB increases the difficulty of RMPP treatment [8]; therefore, pediatric respiratory physicians need to remove the casts as early as possible [9].

Thus, in this study, we retrospectively analyzed children who met the diagnostic criteria for RMPP and had underwent bronchoscopic examination. The patients were screened for the presence or absence of concomitant PB, and the clinical symptoms, laboratory test results, imaging findings, and microscopic changes of patients with and without PB were compared. This study determined the risk factors for RMPP-induced PB and constructed a nomogram to facilitate the early identification of PB from the clinical features of RMPP to facilitate the early bronchoscopic removal of casts, thereby promoting recovery and reducing cases with poor RMPP prognosis.

Of the 4506 children diagnosed with MPP and hospitalized in the Department of Pediatric Respiratory Medicine of Shengjing Hospital, China Medical University, between January 2015 and December 2019, 974 were diagnosed with RMPP. Bronchoscopy was performed on the RMPP patients with large consolidation lesions or who failed drug treatment, of which 52 cases were in the PB group and 68 were in the non-PB group. Figure 1 shows the flowchart for the study.

PB has been previously reported as a rare respiratory disease in children in which a jelly-like or stiff bronchial fluid travels rapidly in a tube-shaped pattern along the bronchial tree through the airways, obstructing them and causing clinical symptoms such as shortness of breath and dyspnea that can be life-threatening in severe cases [13, 14]. However, its etiology is still poorly understood. Previous studies have reported possible associations with postoperative congenital heart disease [15‐17], asthma [18], bronchial thermoplasty [19], congestive heart failure [20], lung transplantation [21], and acute respiratory viral infections [22]. PB is also found in AIDS patients with pulmonary Kaposi sarcoma [23] and in rare cases, after lung transplantation [21]. Congenital heart disease leads to decreased cardiac function and increased pulmonary venous pressure, which increases mucus secretion and leakage of endobronchial lymph in the airways, resulting in cast formation [9, 24, 25]. Viral infections may cause a hypersecretory state in bronchial endothelial cells, leading to bronchial cast formation [22, 26, 27]. The literature reports that the incidence and mortality rates of PB are 6.8/100,000 and 7%, respectively [20]. Recently, the number of cases of PB caused by MP infection has steadily increased [8], which may be related to the epidemiological characteristics of MP in Asia [28]. The clinical manifestations of PB caused by MP infection are not specific and are often difficult to distinguish from RMPP without PB, as both present with fever, cough, and large consolidation shadows in the chest that make it difficult to distinguish them based on symptoms, signs, and imaging findings. The diagnosis and treatment of PB require fiberoptic bronchoscopy as early as possible [9]; therefore, the timely detection of PB in the context of RMPP using clinical data is particularly important. The mechanism of PB development after MP infection remains unclear and may be closely associated with MP drug resistance and excessive immune response [5]. PB caused by MP is associated with abnormally elevated levels of the cytokines IL-1β, IL-8, IL-2, and IL-10 [8], and ribosomal RNA-depleted RNA sequencing in RMPP [29]. Currently, there is no consensus on the etiology and pathology of PB, and further studies are required.

Comparison and analyses of the PB and non-PB group data indicated that the duration of fever was less in the PB group than in the non-PB group; however, more cases of fever were observed before bronchoscopic treatment in the PB group than in the non-PB group. Additionally, the timing of bronchoscopy treatment was earlier in the PB group than in the non-PB group, and the fever in the PB group was significantly relieved after bronchoscopy. Most cases of cast removal are associated with immediate relief of respiratory obstruction and inflammatory response [30, 31]. Cough duration was less in the PB group than in the non-PB group, and our clinical observations indicated that children with PB had a less pronounced cough. It is unclear whether this was owing to a weakened cough reflex that was not conducive to sputum elimination or to a severe inflammatory response that promoted sputum coagulation and PB, leading to a weakened cough. The frequencies of extrapulmonary complications, pleural effusion, LDH, and the immune indicator CD4⁺ were higher in the PB group than in the non-PB group, suggesting that the local immune response and systemic immune-inflammatory response were stronger in the MP-induced PB cases than in the non-PB cases. The incidence of lesions involving more than 2/3 of the lungs was lower in the PB group than in the non-PB group, suggesting that pneumonia in the PB group was smaller and more localized. Additionally, plastic casts were mostly confined to one lung segment, with uniform and consistent solid lung lesions rather than exudate involvement along the bronchial routes of multiple lobe segments. Pleural effusion resulted from severe local inflammation, luminal occlusion, and increased local hydrostatic pressure.

Additionally, the present study found that most cases of PB due to MP were relatively mild with no life-threatening manifestations, in contrast to previous reports of PB caused by viral infections [22, 26, 31]. However, untimely removal of casts may lead to an increased incidence of poor prognosis in RMPP. We found a correlation between PB and BO [12], and some children had sputum casts even at the second or third bronchoscopy.

Unlike previous single-factor analyses of risk factors for PB [8], this study employed a multifactor analysis of the risk factors for developing PB in RMPP. Additionally, a nomogram was constructed, in which each risk factor was assigned a score, thus allowing them to be quantified. The scores corresponding to the risk factors can be added, and the total can be used to predict the risk of PB in children with RMPP. In this study, blood LDH level, which is currently receiving increasing attention in diagnosing and predicting RMPP [4, 32, 33], was significantly higher in the PB group than in the non-PB group. It is significantly elevated in children with RMPP who develop PB and is also a risk factor for developing PB [8], consistent with the results of the present study. LDH level was a factor in the nomogram developed in this study. Each high-risk factor in the nomogram is assigned a score. Whether this indicator gradually increases or decreases in the nomogram is governed by many factors, and it is necessary to differentiate it from the correlation of the quantitative tendency of the development of PB. The scores assigned to each indicator are added to determine the total score, which can be used to predict the probability of the development of PB in RMPP.

Regardless of the etiology, the most important treatment for PB is the removal of casts via fiberoptic bronchoscopy [9, 34]. Treatments with 3% hypertonic saline and bronchodilators have also been reported [35]. Furthermore, reports describe physical therapy with high-frequency chest wall oscillation, nebulized urokinase, local irrigation with tissue plasminogen activator (t-PA) [21, 36], and recombinant human deoxyribonuclease [35]. A combination of local t-PA and cryotherapy has also been used [37]. The use of nebulized heparin inhalation [9, 34], acetylcysteine, and diuretics [38] has been reported. Because different primary diseases have varying mechanisms of cast formation and differences in disease severity and incidence, PB is mostly mentioned in the literature in case reports. PB is also treated with a combination of intravenous drugs; therefore, it is difficult to determine which drug approach is the most effective. However, fiberoptic bronchoscopy is now accepted as the most effective technique for removing casts from the airways.

In the present study, sputum casts were cleared using fiberoptic bronchoscopy combined with repeated saline flushing or diluted acetylcysteine solution (1:1 dilution) for lavage aspiration or using biopsy forceps or foreign body retrieval baskets. In all cases, the pathogen detected was MP, and the patients were treated with intravenous macrolide antibiotics and administered intravenous methylprednisolone [6, 39]. These treatments have been correlated with MP resistance and an excessive inflammatory response [5, 6, 28, 39]. The primary sequela of MP-induced plastic bronchitis is BO [12]. Early diagnosis and treatment and repeated bronchoscopic flushing to completely clear the airway in some cases may result in an improved prognosis. This study was a retrospective data analysis. A prospective study is proposed to investigate the patterns of this disease.

In summary, our research has developed a nomogram with five factors, including fever or not before bronchoscopy, extrapulmonary complications, effusion, cough, and LDH with the purpose to predict the risk of PB in children due to RMPP. The nomogram has performed well and may help the clinical identification and decision-making of PB patients caused by RMPP.