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.