Bronchopleural fistula (BPF), an abnormal connection between the bronchial tree and pleural space, is a severe condition with high morbidity and mortality rates in patients, often seen after pulmonary resections due to lung cancer, tuberculosis, trauma, or radiation.1–3 The treatment strategy for BPF depends on the fistula size, the patient's condition, and the timing post-surgery.2 Surgical intervention is typically reserved for large fistulas and comes with high morbidity and mortality rates.1–4 In contrast, bronchoscopic techniques such as blockers, tissue adhesives, and stents are used for smaller fistulas but can still lead to recurrence and death.5–7 The complexity of treating BPF, especially small fistulas, highlights the need for further development of regenerative repair strategies.

Recent studies have highlighted the widespread application of platelet-rich plasma (PRP) in regenerative medicine. The enriched growth factors substantially promote tissue repair and regeneration across various fields such as orthopedics, dermatology, and wound healing. These studies underscore PRP's ability to expedite tissue recovery and mitigate inflammation.8,9 The use of autologous PRP significantly reduces the likelihood of immune rejection and adverse reactions, offering a notable advantage over traditional therapies. In our prior research, we successfully leveraged PRP therapy to address benign airway stenosis, effectively mitigating the risk of subsequent narrowing.10 PRP has unveiled its regenerative and reparative capabilities for airway conditions. The regenerative capabilities of PRP have sparked an increased interest in managing complex conditions, including BPF.

This pilot prospective cohort study aims to evaluate the efficacy and safety of PRP for small BPF, and endeavors to provide a novel therapeutic avenue for BPF patients, potentially improving clinical outcomes and quality of life. By rigorously analyzing PRP's utility in a clinical setting, this research intends to provide valuable insights into its potential as a novel treatment for BPF, thereby advancing regenerative medicine applications and informing future therapeutic strategies.

This pilot prospective cohort study revealed a promising potential for PRP therapy in small BPF, a condition known for its challenging management, high morbidity, and mortality, providing a theoretical basis for its subsequent clinical application. Our findings indicate an effectiveness rate of 87.6%, with 68.8% cure and 18.8% improvement and an absence of recurrence of BPF and new infection during follow-up, accompanied by significant improvement of respiratory symptoms. Furthermore, a favorable safety profile was observed in this study.

BPF, commonly following lobectomy, lacks standardized treatment. Main methods include surgical and bronchoscopic interventions. Surgical repair, primarily using pedicled intercostal muscle flaps, has a high success rate of 95.3%.13 However, Hollaus et al. reported severe complications in 7 patients (an average fistula size of 3.43mm) treated by pedicled intercostal muscle flaps, including skin flap necrosis in 1 patient, and death in 1 case caused by aspiration pneumonia 38 days post-thoracotomy.14 Alternatively, endoscopic treatment offers minimal invasiveness and flexibility, combining multiple techniques with success rates up to 80%.5 Devices like the Amplatzer occluders and Amplatzer vascular plug effectively seal BPF, achieving immediate success in 96% of cases.15 However, the application is limited by the size of the fistulas, with smaller ones being challenging to repair with occluders.16

PRP therapy under endoscopic guidance is an emerging treatment for BPF. PRP is rich in growth factors and cytokines like platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF), which are crucial for tissue repair. Its regenerative properties have been effectively applied in healing bone,17,18 cartilage,19,20 and skin injuries,21 among others. PRP has shown promise in airway regeneration, with cases reporting complete healing in bronchial anastomotic fistulas post-lung transplantation.22 Our team refined PRP formulations and focused on the active component ARF, demonstrating its effectiveness in preventing restenosis in refractory benign airway stenosis.10 Another study conducted by Wu et al. explored PRP for BPF in 3 cases. All 3 cases were cured, though the treatment duration (up to 124 days) and additional interventions clouded PRP's sole effects.23 In our structured study using endoscopic PRP application, we established a rigorous protocol, achieving an overall efficacy of 87.6%, with a cure rate of 68.8% and improvement rate of 18.8%. This approach underscores PRP's therapeutic potential in airway repair. In our study, we observed immediate swelling of the surrounding tissue after PRP infection. However, PRP offers additional benefits beyond just causing tissue swelling. The growth factors and cytokines in it can reduce inflammation and promote tissue regeneration and healing, leading to permanent close of fistula.

PRP is considered safe for airway applications. A systematic review of 21 studies on PRP treatment for osteoarthritis identified only mild adverse reactions such as pain, redness, and swelling.24 In airway applications, Wu et al. found no adverse reactions in three cases of tracheobronchial fistula treated with PRP.23 Our research also indicates that potential adverse reactions in airways, including cough, dyspnea, and chest discomfort, are typically short-lived, further confirming PRP's safety in treating conditions like BPF.10

PRP's effectiveness can vary in treating orthopedic diseases, dental issues, and chronic dermatoses,25,26 often due to factors like PRP quality, application methods, patient characteristics, and treatment timing.27 In this study, we did not observe that the type of surgery, location, or disease affected the efficacy of PRP treatment. Among the patients in our study, both cases of treatment failure were observed in patients who had undergone surgery for left lung cancer. The age, fistula size, and fistula location of these two patients were similar to those of BPF patients who were cured with PRP therapy. Upon reviewing the surgical videos, we noted that local tissue scarring around the fistula might be one of the factors affecting the action of PRP growth factors. Evidence suggests that the structural characteristics and microenvironment of the wound influence the success of regenerative therapies.26 However, this hypothesis requires further validation through larger clinical studies.

The presence of multiple BPF is another circumstance that cannot be ignored. In our study of multiple BPFs, two patients had dual fistulas, including one at the distal bronchi inaccessible by bronchoscopy. We used bronchoscopy to check the proximal fistulas’ closure, but final chest CTs showed residual cavities. Given the stability of the distal fistula and potential risks to lung function, no further interventions were pursued. This highlights the challenges in treating multiple BPFs and the need for personalized, multi-modal treatment approaches when fistulas are unreachable by standard endoscopic methods.

Recurrence of BPF after treatment is also a common concern.4,29 In our current study, we observed no recurrence of fistula, indicating initial success. However, the potential for recurrence may increase with extended observation periods and larger sample sizes. The efficacy of further PRP in patients with recurrence of fistula remains an area for future exploration to fully understand and optimize BPF management strategies.

This study has several limitations. The first one is the absence of a control group and a small sample size. Despite this, significant improvements in cure rates and respiratory symptoms were observed. These results are promising and suggest that PRP treatment might offer benefits beyond those achievable with occluders, bronchial stents, and conservative approaches, warranting further research. Second, 4 patients, of whom 2 had outcomes of ineffectiveness and 2 showed improvement, declined further PRP treatments due to concerns about the risks associated with repeated anesthesia and bronchoscopy. This refusal may have led to an underestimation of PRP's therapeutic efficacy in the study. Finally, this study does not address potential long-term safety issues like recurrence of BPF, new infections, or death. These issues are intended to be addressed through more rigorous study designs, which are multicenter randomized controlled trials and extended follow-up periods.

PRP therapy had significant potential in managing small BPF, with an effectiveness rate of around 4/5, along with notable improvements in respiratory symptoms. The absence of BPF recurrence or new infections during follow-up and few adverse events further underscored efficacy and safety of PRP. These findings laid a solid foundation for future clinical applications of PRP in small BPF treatment, suggesting a promising avenue for addressing this complex condition.

The protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No. 2021-118). The trial was registered at Clinicaltrials.gov (Clinicaltrials.gov number, NCT05304897).

This study was supported by the grant of State Key Laboratory of Respiratory Disease (SKLRD-Z-202201), Guangdong Province Key Field Research and Development Program (2023B1111050006), Innovation team of respiratory diseases and regenerative medicine (2021KCXTD028) and Clinical High-tech Project of Guangzhou (2023C-GX04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

All authors participated in manuscript writing and editing. Conception and design: Xiaobo Chen, Shiyue Li, Tingting Xu, Yongshun Ye. Recruiting subjects and acquisition of data: Xiaobo Chen, Jinxia Lin, Tingting Xu, Yongshun Ye, Yongna Cai, Zhuquan Su, Liya Lu, Yu Chen, Changgao Zhong, Chunli Tang, Weiquan Xiao. Statistical analysis: Tingting Xu, Yongshun Ye, Xiaobo Chen. Critical review and editing: Xiaobo Chen, Shiyue Li, Tingting Xu, Yongshun Ye. All authors read and approved the final manuscript.

The authors have no conflicts of interest to declare.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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