Discussion:
We studied pulmonary dysfunction (prevalence, spectrum and risk factors for occurrence) and pattern of respiratory dysfunction in childhoodHodgkin lymphoma survivors from India.
The prevalence of abnormal pulmonary function test in our study was 18.33% (11 of 60)
which is comparable to two pediatric studies done in homogenous group of Hodgkin
lymphoma, 17.3% in a study by agrusa et al (9) and 13% in a study by Venkatramani et al
(8) in which only effect of radiotherapy was evaluated.
Bleomycin is known to cause pulmonary fibrosis by various mechanism and results in
restrictive lung disease (4). Radiotherapy to chest causes either acute radiation pneumonitis
or chronic pulmonary fibrosis leading to development of restrictive lung disease (5). As both
bleomycin and radiotherapy are part of treatment regimen in Hodgkin lymphoma, it is known
that they develop restrictive lung disease in long term. This was evident in our study, in
which prevalence of restrictive pattern (16.67%) of PFT was higher than obstructive (1.67%)
pattern and mostly mild (13.33%) in severity, consistent with data from St Jude life time
cohort study though it was done in a heterogenous group, majority of the study population
were survivors of Hodgkin lymphoma (49.3%) (10)
Though 11 (18.33%) patients had abnormal PFT, only 2 (3.33%) patients had clinical
symptoms i,e dyspnea on exertion and 3 (5%) patients had decreased air entry on auscultation
of lung fields at the time of evaluation. Our data is consistent with previous studies done by
Zorzi et al who reported 41% with abnormal PFT but only 8% had clinical symptoms (2).
Another study done by Aliva et al reported at least one pulmonary function abnormality in
52.5% but clinical symptoms were present only in 8.7%. This signifies higher burden of sub
clinical pulmonary dysfunction and thus need for routine pulmonary function assessment
during follow up of HL survivors.
Our study identified pulmonary dysfunction at a median time of 2 years from completion of
treatment, suggesting early development of pulmonary dysfunction and need for timely
follow up and intervention, similar to most of the studies (2,7,8,9).
Most of the studies conducted till date determined either effect of bleomycin or radiotherapy on pulmonary dysfunction in a heterogenous population (2,7,10). To best of our knowledge there are only two pediatric studies done in homogenous population of Hodgkin lymphoma survivors to determine the associated factors for development of pulmonary dysfunction
(8,10). In our study, higher age at time of treatment (chemotherapy and/or radiotherapy) i,e age ≥ 10years at the time of treatment was associated with development of abnormal PFT. Similar to study done by Venkatramani et al (8) and Azza et al (12). Supporting higher age at start of treatment associated factor for development of pulmonary dysfunction in our study we found that children of age > 10 years at evaluation had higher risk (90.91%) of abnormal pulmonary function when compared to children of age ≤ 10 years (9.09%) (p=0.043). This could be explained by reduction in lung capacity as age progresses and loss of repairing ability as age progresses.
In children bleomycin induced lung injury is reported usually at a dose above 120mg/m2 (2)
, concomitant thoracic irradiation and other chemotherapeutic agents like cyclophosphamide
can cause pulmonary dysfunction at lower doses. In our study we demonstrated a higher risk
of pulmonary dysfunction in survivors who received combined chemotherapy and radiation (54.55%) when compared to survivors who received chemotherapy alone (13.33%), comparable to previous studies (10,11). Most of the survivors i,e 57 (95%) received ABVD as chemotherapy regimen, 2 patients received BEACOPP and one patient received ABVD
alternating with COPP regimen. Median cumulative dose of bleomycin was 120mg/m2 (range 30-120mg/m2). Receiving radiotherapy was shown to have higher association with
development of pulmonary dysfunction when compared to chemotherapy alone i,e bleomycin
at a median dose of 120mg/m2.
It is interesting to note that of two patients who received BEACOPP regimen, one patient
who received cumulative bleomycin dose of 80 mg/m2 and cumulative cyclophosphamide
dose of 5200 mg/m2 with decreased ejection fraction (<60%) on echocardiography,
developed restrictive pattern on spirometry at a median follow up of 4 years. Other patient
who received cumulative bleomycin dose of 70 mg/m2 and cumulative cyclophosphamide
dose of 4550 mg/m2 with normal ejection fraction on echocardiography had normal
spirometry at a median follow up of 1 year from completion of treatment, signifying presence
of underlying cardiac dysfunction, an associated factor for development of pulmonary
dysfunction and need for evaluation of the same especially when concomitant cardiotoxic
chemotherapeutic drugs are given during therapy also longer period of follow up which may
unfold pulmonary dysfunction.
To assess functional status of HL survivors we did 3 minute step test. In our study all
survivors were able to complete 3 minute step test, had expected rise in heart rate and no desaturation post three minute test. This could be because most of the survivors had mild pulmonary dysfunction which might not cause functional limitation, other reason could be use of same 15 cm height step irrespective of patient’s age. However these children would require long term follow up as severity of pulmonary dysfunction may progress with time.
Strengths of our study are, we did a prospective study in a homogenous group of childhood Hodgkin lymphoma survivors and assessed effect of both chemotherapy and radiotherapy.
However, our study had certain limitations, we did not have baseline pulmonary function
assessment prior to start of treatment and there were no controls. DLCO could not be done in our study population which could have demonstrated higher proportion of subclinical pulmonary dysfunction as seen in previous studies (9).
Majority of Hodgkin lymphoma survivors had subclinical pulmonary dysfunction
(Clinically asymptomatic but had pulmonary dysfunction on spirometry or three minute step test) at median follow up of 2 years from treatment completion. As the survival rate of HL patients has improved, during this life time children can be exposed to environmental hazards like smoke, pollution which can accelerate the deterioration of pulmonary function. Therefore Hodgkin lymphoma survivors require thorough initial assessment of respiratory status and pulmonary function testing and long term follow up for timely detection of pulmonary dysfunction and improve quality of life.
Conflicts of interests : None to declare by any of the authors. The authors alone are responsible for the content and writing of the paper.