Results
In the examined period, four patients, all male, aged 16 to 25 years, underwent surgical procedures for TALS.
All the patients had history of hematological malignancies; two patients had acute lymphoblastic leukemia (ALL), one had acute myeloid leukemia (AML) and one had ALK-positive Non-Hodgkin lymphoma (NHL).
All the patients received allogenic HSCT; the two patients affected by ALL received a second allogenic HSCT for relapsed disease. Two patients had Bronchiolitis Obliterans (BO) in the early phase (i.e. earlier than 100 days after HSCT).
All the patients developed pulmonary graft-versus-host disease (pGvHD) as a late complication of allogenic HSCT, i.e. after a mean of 340 days (range 202 – 582) and presented with clinical symptoms (i.e. exertional dyspnea and dry cough in the absence of pulmonary infection), evidence of air trapping, bilateral ground glass lesions and bronchiectasis on high-resolution chest CT scan (Fig 1) and evidence of restrictive or mixed restrictive/obstructive pattern at pulmonary function tests.
In three of the four patients, pulmonary function tests were performed in the 30 days before the diagnosis of TALS; in all these patients forced vital capacity (FVC), forced expiratory volume (FEV1) and forced expiratory flow (FEF 25-75%) were markedly reduced compared to previous tests (see table 2). The remaining patient did not repeat pulmonary function tests due to poor compliance.
All these patients had associated comorbidities; three of these patients had evidence of extra-pulmonary GvHD, three had malnutrition, defined as age- and sex-adjusted body mass index below 17.012, and two had cardiac dysfunction.
Clinical characteristics and pulmonary function tests of these patients are summarized in table 1 and table 2, respectively.
All the patients developed TALS with a mean time lapse of 615 days from last HSCT (range 327 – 1094) and a mean of 276 days from the diagnosis of pGvHD (range 42 – 513); these patients experienced on average 4.5 air leak episodes (range 3 – 6). All the patients experienced at least two episodes before surgery.
Surgery was indicated as an emergency in case of acute deterioration of respiratory symptoms (i.e., sudden onset of chest pain, tachypnea and oxygen desaturation) associated with radiological evidence of tension pneumothorax (Fig 2), or as an elective procedure in case of failure to improve after initial observation or emergency treatment (Fig 3).
At the first episode of TALS, all patient presented with mild, progressive worsening of typical symptoms of pGvHD, namely exertional dyspnea and dry cough; no patient had chest pain or desaturation. Therefore, the first episode of TALS was treated conservatively in all the patients.
Patient one had two episodes of TALS that were managed conservatively and underwent emergency right tube thoracostomy at the third episode for acute respiratory distress and evidence of tension pneumothorax; this patient rapidly worsened towards respiratory failure, was admitted to Intensive Care Unit and passed away 25 days after emergency tube thoracostomy.
Patient two underwent emergency left tube thoracostomy for respiratory distress and tension pneumothorax at the second episode of TALS. This patient had persistent pneumothorax after 24 days of negative pressure chest drain and underwent left thoracotomy and wedge resection; pathology demonstrated pleuroparenchymal fibroelastosis. Based on pathological diagnosis and worsening respiratory function, oral nintedanib and chronic oxygen supplementation were started. This patient had ipsilateral relapse three months after surgery, that was managed conservatively, and contralateral pneumothorax that required emergency chest drain insertion and, 30 days later, thoracoscopy and pleural scarification. Pulmonary function progressively worsened with the development of chronic respiratory failure and hypercapnia. This patient was referred for pulmonary transplant but was judged non-eligible due to history of acute myeloid leukemia with a disease-free interval shorter than 5 years, previous thoracic surgery, ventricular systolic dysfunction and malnutrition (body mass index 12). Five months after thoracoscopy, this patient had right tension hydropneumothorax that required emergency chest drain; the episode of TALS resolved but general conditions progressively deteriorated and the patient eventually passed away for respiratory failure five months after the last episode of TALS.
Patient three underwent elective right thoracoscopy and chemical pleurodesis at the second episode of TALS after failure of conservative management. This patient underwent contralateral thoracoscopic bullectomy and chemical pleurodesis one and half months after initial surgery, followed by thoracotomy and wedge resection for persistent left pneumothorax after 10 days; pathology demonstrated pleuroparenchymal fibroelastosis. This patient had left tension pneumothorax 40 days after thoracotomy that required emergency chest drain; respiratory function rapidly deteriorated and the patient died 12 days after the last episode of TALS.
Patient four underwent elective right thoracoscopy and chemical pleurodesis at the third episode of TALS after failure of conservative management. This patient had contralateral pneumothorax 14 months after surgery and two more episodes of TALS, all managed conservatively. Pulmonary function slowly progressed and the patient started chronic oxygen therapy 18 months after surgery. This patient was referred for pulmonary transplant but was judged non-eligible due to history of acute lymphoblastic leukemia with a disease-free interval shorter than 5 years, previous thoracic surgery, ventricular systolic dysfunction and malnutrition (body mass index 14.2). The patient ultimately died for respiratory failure two years after surgery.
Surgical procedures and outcomes are summarized in table3 and table 4, respectively.