DISCUSSION
The development of TALS has been attributed to the Macklin effect, which consists in air leak into the pulmonary interstitium with retrograde dissection along the perivascular sheats9, 11. Air leak is secondary to alveolar rupture caused by high intra-alveolar pressure, related to small airways stenosis and chronic coughing2 associated with alveolar wall weakness caused by pulmonary fibrosis9, 12. The sharp reduction in FEF 25-75% described in this series, which has been associated with small distal airways dysfunction 13, is consistent with this mechanism.
Risk factors associated with increased incidence of TALS include history of extra-pulmonary chronic GvHD, previous Bronchiolitis Obliterans (BO), male sex, age younger than 38 years and history of repeated allogenic HSCT 3, 5,7.
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 5 and overall mortality rate among patients between 66.7% and 100% 8, 9despite multiple surgical strategies that include simple chest drain, pleurodesis, thoracoscopic resection, open thoracic surgery4 – 7 and even lung transplantation in extreme cases6.
In the present case series, all the patients experienced temporary relief from symptoms related to TALS after surgery, but in all cases respiratory function deteriorated, eventually leading to exitus (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 air leak has resolved 4, 5, 7; the present data are consistent with this hypothesis.
Kunou et al have described the successful use of pleural covering technique in two adults affected by recurrent TALS after HSCT14. This technique consists in covering the visceral pleura with sheets of bioabsorbable material15, 16, which induces thickening of the visceral pleural with minimal or no pleural adhesion 17 and reduces the risk of recurrence of TALS 16. This technique might be a promising surgical option for air leak resolution; however, it cannot address the problems related to 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 because of history of hematologic malignancy with a disease-free interval shorter than 5 years, previous thoracic surgery, malnutrition or other comorbidities 18.
Repeated allogenic HSCT has become a therapeutic option in pediatric patients with relapsed hematologic malignancies19 – 21; as the number of children and adolescents who receive second allogenic HSCT increases, a higher incidence of 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 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.
Conflict of Interest: 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.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and Ethical review and approval were waived for this study due to its retrospective observational structure.
Informed Consent Statement: Written informed consent was obtained from the minor(s)’ legal guardian/next of kid for the publication of any potentially identifiable images or data included in this article.
Data Availability Statement: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.