Discussion
Thoracic Air Leak Syndrome (TALS) is a complication of pGvHD that includes all forms of extra-alveolar air leak in the thorax, such as interstitial emphysema, spontaneous pneumomediastinum, and spontaneous pneumothorax 4, 10.
The pathophysiologic mechanism underlying TALS has been attributed to the Macklin effect, which consists in air leak into the pulmonary interstitium secondary to alveolar rupture, with retrograde dissection along the perivascular sheats toward the hilum and into the mediastinum 10, 13. In patients affected by pGvHD, alveolar wall rupture is likely to be caused by high intra-alveolar pressure, which is related to small airways stenosis and chronic coughing that occur in Bronchiolitis Obliterans, 3 associated with alveolar wall weakness caused by pulmonary fibrosis10, 14. In the subject case series, pulmonary function tests performed before the onset of TALS revealed a sharp reduction in FEF 25-75%, which has been associated with small distal airways dysfunction 15. Such observation is consistent with the proposed pathophysiologic mechanism.
The prevalence of TALS in patients with a history of allogenic HSCT is reported between 0.83% 5 and 3.08%4. Specific risk factors have been associated with increased incidence of TALS, including history of extra-pulmonary chronic GvHD, previous Bronchiolitis Obliterans (BO), previous invasive pulmonary fungal infections, male sex, age younger than 38 years and history of repeated allogenic HSCT 4, 6, 8. In the present case series, all the patients were male and younger than 38 years and three of them had at least one other risk factor for TALS, namely repeated allogenic HSCT, previous BO and extra-pulmonary chronic GvHD (see table 1).
The occurrence of TALS significantly worsens long-term prognosis of patients with a history of allogenic HSCT, with a survival rate of 44% at 1 year and 15% at 3 years 6. Early series reported a mortality rate among patients with TALS ranging between 66.7% and 100% 9 – 10; the prognosis of these patients has not significantly improved in recent years, with overall mortality ranging from 61% 6 to 100% 7.
Patients affected by TALS receive a combination of supportive therapy, increased immunosuppression and surgical treatment, including simple chest drain, chemical pleurodesis, thoracoscopic resection, open thoracic surgery 5 – 8 and even lung transplantation in extreme cases 7, with a mortality rate in patients treated with surgery reported between 64% 6 and 100%7. In these series, the rationale for therapeutic choice between medical and surgical treatment and details about surgical complications and outcome were not specified; such high mortality in patients who have undergone surgery might therefore be related to more severe forms of TALS rather than surgical complications.
In the subject case series all the patients experienced temporary relief from symptoms related to TALS after surgery, but respiratory function deteriorated and air leak relapsed in all cases. In two patients, air leak was eventually controlled but respiratory failure progressively developed, eventually leading to exitus, while two patients had tension pneumothorax as a final complicating event, that led to exitus (see table 4).
It has been proposed that the development of TALS might be interpreted as a sign of severe worsening of pulmonary GvHD, which eventually leads to respiratory failure and death, even in patients in whom resolution of air leak has been obtained 5, 6, 8; the present data are consistent with this hypothesis.
Kunou et al have described the successful use of pleural covering technique with oxidized regenerative cellulose mesh in two patients affected by recurrent TALS after HSCT16. This technique consists in covering the visceral pleura with sheets of bioabsorbable material after resection of bullae17, 18; the bioadsorbable mesh induces thickening of the visceral pleural with minimal or no pleural adhesion19 and reduces the risk of recurrence after bullectomy in patients affected by primary spontaneous pneumothorax 18. This technique might be a promising surgical option for air leak resolution in patients affected by TALS; however, it cannot address the problems related to progressive pulmonary GvHD and worsening respiratory function.
Referral for lung transplantation could be a surgical option for these patients; however, many of them might be judged as non-eligible, as happened for two of the patients in the subject series, because of history of hematologic malignancy with a disease-free interval shorter than 5 years, previous thoracic surgery, malnutrition or other comorbidities 20.
Repeated allogenic HSCT has become a therapeutic option in pediatric patients with relapsed hematologic malignancies21 – 23; as the number of children and adolescents who receive second allogenic HSCT increases, a greater number of patients affected by TALS should be anticipated.
In conclusion, surgery provides temporary relief to symptoms related to TALS but has no impact on the progression of pulmonary GvHD. When TALS develops, patients are at very high risk of respiratory failure and death.
Multidisciplinary efforts are mandatory to develop novel strategies for the prevention of TALS, the identification of high-risk patients and the treatment of TALS.