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.