Tuberculosis (TB) is a disease with significant health implications and an economic burden on humans; approximately 50% of cases of TB in childhood are reported in children younger than 5 years of age (1). The incidence of primary pulmonary TB (PTB) is estimated to be 46% in children with tuberculosis (2). Tracheobronchial TB (TBTB) is the most common complication of PTB in children, accounting for 41.7–62.96% of PTB cases (3–5). TBTB is defined as microbiological and histopathological evidence of Mycobacterium tuberculosis in the trachea and bronchi with or without parenchymal lung lesions (6). The clinical manifestation, pathogenesis, and pathologic features of TBTB in children and adults differ owing to immunological differences (7). In adults, the active caseous necrotic form (ulcerative-necrotic type) (43.0%) is the most common type of TBTB (8). In children under 5 years of age, the neoplastic (lymph node fistula) form accounts for 73.4–96.43% (9, 10). The adjacent mediastinal or hilar lymph nodes erode the tracheobronchial wall and form bronchial lymph node fistulas in TBTB patients. Lymph node fistulas tend to compress and obstruct tracheobronchial tubes, resulting in the narrowing of the tracheobronchial lumen and inadequate secretion drainage. Ultimately, it leads to serious complications such as obstructive pneumonia, atelectasis, and lung destruction, which affect lung function and development. Due to the lack of specificity in its clinical presentation and imaging, TBTB is more likely to be misdiagnosed and underestimated in infants than in older children or adults.

The treatment of TBTB is complicated, as antituberculosis drugs have difficulty penetrating the tracheobronchial lesions. Lymph node fistula TBTB often leads to sequelae such as bronchial stenosis, although treatment with systemic antituberculosis drugs occurs without bronchoscopic intervention (8). Therefore, early bronchoscopic intervention is essential in patients with TBTB. Current interventional treatment modalities for lymph node fistula TBTB include laser therapy, cryotherapy, foreign body forceps, and local injection drugs (11). Cryotherapy has been shown to generally not damage airway cartilage, cause little to no airway perforation, have a low rate of granulation and fibrous scarring after treatment, and have fewer complications than thermal ablation (12). Consequently, cryotherapy may be more clinically helpful than interventional procedures such as thermal ablation for infants with TBTB.

There are few studies on cryotherapy for lymph node fistula TBTB in infants. This study aimed to investigate the efficacy and safety of cryotherapy for lymph node fistula TBTB in infants.

Seven patients were included in this study (Table 1). The median age of the seven infants was 8 months (ranging between 6–13 months). The most common symptoms at presentation were cough and sputum production. Moreover, five patients had lost weight and three had a fever. Two patients had wheezing and dyspnea. The most common comorbidity was pulmonary tuberculosis (five cases). Four (57.14%) patients had a Bacillus Calmette–Guerin scar and six (85.71%) had a history of household contact with PTB. Two patients were positive for pure protein derivative, and three patients had positive T-cell spot test results. The etiology diagnosis with a high positive rate was bronchoalveolar lavage fluid tuberculosis deoxyribonucleic acid. All patients were diagnosed with lymph node fistula TBTB via their endobronchial biopsy histopathological examination and macroscopic presentation results. Two cases were in the early stage of rupture and five cases were in the rupture stage; the CT findings of the patients are presented in Table 2.

Cryotherapy procedures were performed a total of 17 times; it was performed only once in two cases and three times in five patients. Bronchial involvement was seen in the right bronchus in five (71.43%) patients and the left bronchus in two (28.57%). The disease was multifocal in three cases and more commonly affected the right middle lobe. The endoscopic findings of the patients are shown in Table 3. The main type of lesion was a caseous lesion with granulation tissue. Four patients had more than one lesion type. The bronchoscopy characteristics of the patients are shown in Figure 1.

Seven patients with lymph node fistula TBTB were treated with cryotherapy combined with foreign body forceps and local injection drugs by FB. Six patients completed the full treatment course and achieved a clinical cure. One patient exhibited clinical improvement after the first intervention. However, the patient was lost to follow-up. No clinical failures occurred during the full treatment course. The mean duration from the start of therapy to the complete disappearance of the lesion was ~3 months.

Before treatment, the patients had varying degrees of cough, dyspnea symptoms, complex CT abnormalities, and endoscopic lesion features. Seven patients had continuous and frequent coughing that affected their sleep and daily life to varying degrees. Two patients had dyspnea. All patients had abnormal CT findings: 85.71% (six cases) had pulmonary hilar with mediastinal lymph node enlargement; 57.14% (four cases) had bronchial stenosis; 85.71% (six cases) had patchy shadows, and 28.57% (two cases) had pulmonary emphysema. One patient developed pulmonary atelectasis and pleural effusion. In terms of bronchoscopic lesion characteristics, the fibrobronchoscopic lesion presentations were divided into five categories: 42.86% (three cases) showed localized mucosal erythema and polyps with caseous necrotic material adherence (Figure 1C). In one case, the surface of the local tracheobronchial mucosa was red, swollen, and hypertrophic, showing an external pressure bulge without ulceration (Figure 1A). One case showed localized tracheobronchial mucosal surface erythema, hypertrophy, and an external pressure bulge with caseous material attachment (Figure 1B). One case showed granulation tissue (Figure 1D), and another showed an overflow of caseous material (Figure 1E).

After the first procedure, cough symptoms improved in all patients and disappeared in two patients with dyspnea. All patients exhibited significant improvement in lumen patency on endoscopic view. One patient was lost to follow-up after the first procedure. The remaining patients had improved cough relief, mostly healed fistulas with fewer or smaller lesions, mild mucosal congestion and edema, and a slight narrowing of the lumen. Furthermore, their CT scan revealed that their lung lesion had been absorbed more than 50%. At the end of treatment, six patients attained clinical cure in terms of their cough level (no cough), endoscopic demonstrations, and CT results following the complete treatment process. CT and FB were re-performed at the end of the interventional treatment. Compared to before the intervention, all patients showed significant improvements on lung CT in terms of hilar and mediastinal enlargement, calcified lymph nodes, bronchial obstruction, emphysema, and pulmonary atelectasis (Figure 2). The FB results in the patients showed that their fistulas were closed, their bronchial lesions were significantly absorbed and improved, their lumen stenosis or obstructions were reduced, and their bronchial mucosae were relatively smooth. A comparison of the patients' endoscopic performance is shown in Figure 1. During treatment, no significant complications occurred such as respiratory distress, hypoxemia, unexpected bleeding, pneumothorax, mediastinal emphysema, airway spasms, ductal edema, or anesthesia-related complications. A few patients had minimal bleeding when the scar material and granulation tissue that obscured the lumen were removed using foreign body forceps. Hemostasis was easily achieved by administering a small amount of epinephrine (1:10 000). The CO₂ cryotherapy time was 10–20 min.

Six patients underwent bronchoscopic follow-up after 3 months. The bronchial lumen remained fully patent without stenosis, granulation, or scar formation in all patients, revealing a satisfactory lasting treatment effect.

In this study, seven infants with TBTB were treated with CO₂ cryotherapy combined with the use of foreign body forceps and local injection drugs based on systemic antituberculosis chemotherapy. There were no obvious adverse reactions or complications during or after the interventional treatment. The clinical manifestation, imaging, and endoscopic presentation results improved significantly after the cryotherapy, and there were no cases of recurrence during the follow-up process, indicating the efficacy and safety of CO₂ cryotherapy.

Liu et al. (10) studied 130 children (69 infants) with lymph node fistula TBTB who treated with bronchoscopic interventions; however, their study did not use cryotherapy techniques. Zhang et al. (13) studied eight patients with lymph node fistula TBTB who were treated with bronchoscopic cryotherapy; however, there were no infants in their study. In our study, lymph node fistula TBTB was reported in seven infants, and the outcome of cryotherapy on infants was studied in detail for the first time. Incidentally, the occurrence of TBTB with lymph node fistulas in children in studies outside China has been 33–38% (3, 15). Possible reasons for this are that the severity of primary TB varies between countries, regions, and hospitals.

When lymph node fistulas TBTB occur, they can significantly affect individuals' quality of life and even become life-threatening in infants owing to the special pathogenesis of TBTB, which is mainly due to the passage of pathogenic mycobacteria through the lymphatic system, resulting in local lymph node tuberculosis. Enlarged lymph nodes tend to compress the local tracheal and bronchial mucosa and submucosa, leading to local ischemia and necrosis, which predispose patients to tracheal and bronchial stenosis or complete occlusion, resulting in obstructive pneumonia, atelectasis, and pulmonary destruction (9). In this study, six patients had obstructive pneumonia, two had emphysema, and one had atelectasis and pleural effusion when they were admitted to our hospital.

Bronchoscopy plays an important role in the diagnosis of TBTB, especially in patients with suspected negative sputum smears and endobronchial diseases (16, 17). In this study, six patients had a history of household contact with TB and five patients had a disease duration of more than 1 month. The sputum smear results were negative in all patients, and the sputum culture results were negative in five patients. All patients were misdiagnosed with pneumonia before admission. The infants were diagnosed with tracheobronchial tuberculosis (lymph node fistula type) via their bronchoscopic tissue biopsy and macroscopic endoscopic lesion results after admission. Therefore, bronchoscopy not only improved their diagnosis of TBTB but also allowed for the determination of their type of TBTB.

The typical macroscopic bronchoscopic manifestations in children with TBTB and lymph node fistulae include caseous materials breaking into their airways. In our study, the endoscopic macroscopic manifestations in the infants were predominantly caseous granulation tissue, which is consistent with the typical features of lymph node fistula in TBTB. Moreover, in our patients, the caseous materials were accompanied by congestion, granulation tissue proliferation, or were completely encased by granulation tissue. The patients' lumens were also obstructively narrowed at the lesion sites (10).

With the development of interventional bronchoscopic techniques, several new methods, including laser, cryotherapy, foreign body forceps, and local injection drugs, in combination with systemic antituberculosis drugs, have been used to treat lymph node fistula TBTB due to their effects on accelerated lesion healing and improved prognosis (11, 18). Studies have shown that as laser damage may lead to more granulation tissue formation, laser treatment can be followed by cryotherapy to prevent granulation regeneration and maintain the lumen diameter (19). Cryotherapy can promote cicatricial fibroblast differentiation into normal fibroblasts to reduce scar and granulation tissue hyperplasia, in contrast to the effects of thermal ablation (12). In their study, Liu et al. (15) used bronchoscopic foreign body forceps and local injection drug interventions alone to treat lymph node fistula TBTB in children and reported a lower efficacy rate and more frequent interventions compared to cryotherapy.

Ni et al. (12) and Zhang et al. (13) confirmed the safety and efficacy of cryotherapy for TBTB with lymph node fistula in children. However, these studies did not directly demonstrate the applicability of cryotherapy in infants. This is an important study on CO₂ cryotherapy interventions for lymph node fistula TBTB in infants. In this study, the signs and symptoms immediately improved following cryotherapy in all patients. Except for one patient who only achieved clinical improvement due to missed visits after the first cryotherapy session, six patients achieved clinical cure after cryotherapy. No serious complications occurred during or after the procedure, and no lesion recurred after 3–6 months of follow-up.

This study had several limitations. First, the small sample size may affect the power of our conclusions. Second, we did not include a control group without cryotherapy. Third, as all patients were enrolled from a single hospital, this might have led to biased conclusions. In future studies, it would be worthwhile to increase the sample size and further explore cryotherapy for lymph node fistula TBTB in infants. Moreover, a future multicenter study with a control group would increase the significance of the study.

Bronchoscopic CO₂ cryotherapy for lymph node fistula TBTB in infants can be performed safely and effectively in combination with the foreign body clamp method. This method can provide relief from symptoms, accelerate fistula closure, and avoid serious complications. Furthermore, the results of this study are important given that it provides pediatricians with more options and information when choosing the best treatment for infants with lymph node fistula TBTB.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Ethics Committee of the Tianjin Children's Hospital (No. 2021-KY-06). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

YZ and TZ contributed to the conception of the study. TZ and NY contributed significantly to the analysis and manuscript preparation. YZ performed the data analyses and wrote the manuscript. WG and YX helped perform the analysis with constructive discussions. All authors contributed to the article and approved the final manuscript.

This work was supported by Tianjin Natural Science Foundation (Grant Number 21JCYBJC00460), the General Project of Tianjin Children's Hospital (Grant Number Y2020013), and the Program of Tianjin Science and Technology Talent Cultivation (Grant Number RC20020).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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