Discussion
The present, retrospective study demonstrated that the LDH value and DIC
score were significant predictive factors of ARE during induction
therapy in patients with neuroblastoma. The combination of the LDH value
and DIC score was also found to be an outstanding predictive factor.
High serum LDH levels are associated with a large tumor burden and
increase the risk of TLS triggered by induction
chemotherapy.12 Moreover, a high serum LDH level in an
important biomarker for diagnosing ARDS.13 Previous
case reports described some pediatric patients with cancer, including
neuroblastoma, in whom ARE developed in the context of tumor lysis.12,14,19 The present study did not prove that any
diagnostic makers of TLS other than LDH were associated with ARE,
suggesting that ARE is an aspect of cytokine release syndrome secondary
to TLS.
Lysed tumor cells release a variety of cytokines in addition to
intracellular enzyme (e.g., LDH), which can induce severe hypoxia by
eliciting systemic inflammatory response syndrome eventually leading to
multiorgan failure.14,15 The systemic proinflammatory
cytokines stimulate the vascular endothelium16 and
prime blood phagocytes17. The activated phagocytes,
which release proteolytic enzyme and toxic oxygen species, increase
permeability in both alveolar epithelial cells and vascular
tissue18. Consequently, the cytokine release leads to
severe hypoxia. In view of this pathophysiology, a high serum LDH level
was considered to be a promising predictive factor of ARE.
The DIC score was also predictive of ARE risk. Several, previous reports
of the association of neuroblastoma with DIC20 21reported that DIC is also frequently associated with ARDS. Gando et al.
reported DIC associated with endothelial injury had prognostic value for
ARDS development.22 DIC reflects an
inflammatory disorder of the microvasculature. The derangement of
coagulation and fibrinolysis in DIC is mediated by several
proinflammatory cytokines23 which, together with
endothelial injury, can lead to severe hypoxia in the context of DIC.
In the present study, eleven of the 75 neuroblastoma patients had ARE;
three of the eleven patients experienced ARDS, and all eleven received
respiratory support in the PICU. Although ARE have not been reported to
date because of their low incidence, our data suggested that ARE might
be more common among patients with advanced neuroblastoma. If the
possibility of ARE development were able to be predicted using our
scoring system, countermeasures could be taken, such as reducing the
intensity of the first chemotherapy regimen.
Two types of ARE were identified during induction therapy in the
neuroblastoma patients, including early onset pleural effusion and late
onset ARDS or pericardial effusion. Early onset pleural effusion is
thought to be caused by infiltration of
neuroblastoma24, and late onset ARDS
and pericardial effusion are thought to be caused by SRS secondary to
TLS.25 26 A cytokine profiling study is currently
being conducted to investigate further the pathogenesis of ARDS and
pericardial effusion in the context of TLS.
Our study has some limitations. First, because it was retrospective, it
may have included various biases, such as the sampling bias. Second, the
small sample size might have led to an underestimation of the influence
of various factors on univariate analysis while also precluding the use
of multivariate analysis. Third, the DIC score was missing in 38.6% of
the patients. Fourth, ARE was chosen as the outcome. Because many of the
values required for arterial blood gas analysis were missing, oxygen
saturation alone was used to assess the respiratory disorders.