Identification of Pediatric Bronchiolitis Obliterans Syndrome
Post Hematopoietic Stem Cell Transplantation; Surveillance Is the Key
Shivanthan Shanthikumar1,2,3, Liam
Welsh1, 2, Nicole Westrupp1,2,
Theresa Cole3,4, Katherine B
Frayman1,2,3, Colin F
Robertson1,2,3, Sarath C Ranganathan1,2,3
- Respiratory and Sleep Medicine, Royal Children’s Hospital, Melbourne,
Australia
- Respiratory Diseases, Murdoch Children’s Research Institute,
Melbourne, Australia
- Department of Paediatrics, University of Melbourne, Melbourne,
Australia
- Allergy and Immunology, Royal Children’s Hospital, Melbourne,
Australia
Corresponding Author; Dr Shivanthan Shanthikumar; Respiratory
Medicine, Royal Children’s Hospital, 50 Flemington Road, Parkville, VIC,
3052, Australia;
shivanthan.shanthikumar@rch.org.au
Acknowledgements; The authors have no conflicts of interest to
declare
Dear Editor,
We read with great interest the article by Walther et
al1 regarding long term outcomes of bronchiolitis
obliterans syndrome (BOS) in children following haematopoietic stem cell
transplantation (HSCT). The authors are to be commended on their study
as it is an important contribution to a field where there is a relative
paucity of evidence. Given the increasing numbers of HSCT being
performed and improved outcomes, timely identification and management of
pulmonary complications such as BOS is vital.
In particular, the study used multibreath washout to calculate lung
clearance index, a more sensitive test for BOS than traditional
spirometry.2 In addition, the identification of three
trajectories for children diagnosed with BOS; rapid persistent decline,
persistent obstructive disease with secondary restriction, and
resolution, is an important and novel description. This more nuanced
understanding of the natural history of BOS in this setting will be an
important consideration when designing therapeutic intervention trials.
Given there are now ample data showing that around 4.8-6.5% children
post HSCT will develop BOS, with significant associated morbidity and
mortality, well designed intervention trials should be strongly
considered.
There are however limitations of Walther et al’s study that
warrant more detailed discussion, as they limit the applicability of
this single centre retrospective chart review to wider clinical
practice. The manuscript does not adequately describe the institution’s
clinical practice regarding evaluation for BOS post-HSCT, although the
authors acknowledge a “lack of a standardised follow up protocol
for lung function. ” This is not in keeping with current international
practice. International guidelines3-5 consistently
recommend scheduled lung function surveillance. In addition, in a recent
survey of HSCT physicians and pediatric pulmonologists from North
America and Australasia, 71.4% reported that a protocol for monitoring
lung function post HSCT existed at their hospital and 53.6% reported
adhering “well” or “very well” to surveillance
protocols.6 A retrospective review of a centre with a
screening program in place showed 75.2% of patients had a lung function
test 12 months post HSCT.7 These data indicate that
the majority of HSCT centres have a screening protocol in place, and
within the limitations of self-reported and single centre data,
protocols are adhered too. A potential explanation for the lack of a
protocol in the study is that the review period started in 2000, which
predates the guidelines. However, if the results are to influence
contemporary practice, clinicians must be able to relate the reported
findings to current standards of care. In the absence of a standardised
follow up protocol, it would be useful if the authors reported the
proportion of the 526 eligible patients who underwent lung function
assessment, and what triggered a referral for testing (i.e. clinical
symptoms, graft vs. host disease (GVHD) in another organ). If a high
proportion of patients underwent testing then their findings will be
more comparable to current international practice, however if only a
small proportion underwent testing this is a significant limitation.
The prevalence of BOS in the current study is lower than that reported
in the wider literature. We suspect their prevalence is underestimated.
The overall GVHD rate (45%) is higher than might be expected for a
cohort that includes nearly 50% matched sibling
donors.8, although GVHD grading is not reported. Given
the high GVHD rate in this cohort it would be expected that the
prevalence of BOS should also be higher or at least in keeping with the
literature. The lack of a standardised protocol for screening lung
function would likely lead to an underestimation of the prevalence of
BOS. It is well established that the early phases of BOS are often
asymptomatic and diagnosed based on lung function
abnormality.9 All 14 BOS cases in this study were
symptomatic, suggesting that asymptomatic early cases of BOS cases may
have been missed due to lung function not being performed. In
particular, this would underestimate BOS cases which follow the
resolution trajectory as well as potentially the persistent obstruction
trajectory. It also would affect two of the key conclusions of the
paper; that BOS incidence is low and that BOS is associated with high
mortality.
In summary, the article by Walther et al is a useful contribution
to what is an area of growing clinical importance. Strengths of the
study include the use of the most sensitive test of small airway
function (multibreath washout with calculation of the lung clearance
index) and description of three trajectories post BOS diagnosis.
However, the lack of a formal surveillance program and likely resultant
underestimation of BOS cases is a significant limitation that should be
acknowledged before efforts are made to prevent or attenuate lung
function decline in BOS