Editorial: Critical complications in pediatric oncology and hematopoietic cell transplant – how far we have come and how much further we must go

COPYRIGHT © 2023 Agulnik, Mahadeo, Steiner and McArthur. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 22 February 2023 DOI 10.3389/fonc.2023.1148321

Patients transplanted in the 1980s and 1990s experienced more variable mortality and in the next 20 years, patient overall mortality improved to 40 to 60%. In the 21 st century, mortality has further improved in certain patient subsets, but remains substantial for those requiring mechanical ventilation, with severe pulmonary pathology as a cause for intubation, and with multi-organ failure (11,12). However, most recently, even extracorporeal membrane oxygenation (ECMO) support for HCT patients is being considered and successfully implemented (13)(14)(15). Clearly, collaboration between oncology, HCT, and Pediatric Intensive Care Unit (PICU) clinicians is continuing to impact patient outcomes. Considerable work, however, remains to be done, as evidenced by the variety and volume of manuscripts submitted to this Research Topic.

Current focus of pediatric onco-critical care-this research topic
Articles published in this Research Topic demonstrates how far the field of Pediatric Onco-Critical Care has moved over the past 50 years. This Research Topic received a robust response in paper submissions, resulting in 30 articles by 211 authors from 33 institutions in 9 countries worldwide ( Figure 1). As of January 2023, the Research Topic website has received over 90,000 views and over 21,000 downloads. Enthusiasm for this work continues; we have recently launched a second volume for this Research Topic, with 6 new articles published to date.

Improving patient outcomes
In this collection, Pechlaner et al. performed a retrospective study of outcomes in pediatric hematology/oncology patients admitted to their ICU between 2009-2019. They showed PICU mortality to be 11% overall, though it was higher for those that required invasive mechanical ventilation (IMV), ECMO, and IMV with continuous renal replacement therapy (CRRT) at 34.5%, 42.9% and 53.8% respectively. Additionally, researchers found a significant increase in PICU admissions over the years after the implementation of a bedside pediatric early warning system (PEWS). The authors hypothesized that the institution of PEWS enabled their teams to recognize critical illness earlier and allow for earlier and more frequent transfer to the PICU. Mortality rates described in this study are similar to outcomes recently published from the Virtual PICU Systems (VPS) database (16) and add credence to the argument that outcomes are improving in this high-risk population.

Novel therapies and interventions
Over the last decades, the field of pediatric hematology-oncology has advanced extensively to offer novel therapeutics for childhood cancer, moving childhood cancer from a universally fatal disease to a survival of greater than 80% in high-resource settings (17). These therapies, however, carry unique risks of toxicity, and optimum survival for patients can only be achieved with delivery of excellent supportive care. The topic of critical complications of novel therapies for childhood cancer care and their management is addressed extensively in this Research Topic. This includes discussion of supportive care strategies for chimeric antigen receptor therapies

Early recognition of critical illness
Early recognition of critical illness leading to prompt interventions are likely contributing to improvements in mortality seen in critically ill pediatric oncology and post-HCT patients. Agulnik et al demonstrated that patients with longer duration of higher PEWS scores on the ward prior to PICU transfer have worse outcomes including higher mortality and fewer PICU-free days, ventilator-free days, and vasopressor-free days. The same group has also shown that implementation of PEWS empowered clinicians to speak up when concerned about their patient's clinical status and improved overall (Graetz et al.) perceived quality of care during deterioration (Garza et al.).
Others in this collection similarly discuss the importance of early recognition of critical illness and prompt intervention. In a recent multi-center prospective point prevalence study, Traube et al. discovered that 45% of HCT patients experience delirium at some point in their transplant course. Delirium has been associated with worse outcomes in ICU patients (18). However, it's impact on pediatric HCT patients in unknown and warrants further study. In another study, Brown et al. found that worsening Cornell Assessment of Pediatric Delirium (CAPD) scores were seen 24 to 72 hours prior to patients developing immune effector cellassociated neurotoxicity (ICANS) after chimeric antigen receptor (CAR) T-cell therapy. They stressed the importance of prompt recognition and intervention to prevent rapid neurologic deterioration. In a multi-center retrospective study of HCT patients treated with non-invasive ventilation (NIV), Rowan et al. found that 63% of patients failed NIV, requiring invasive mechanical ventilation (IMV). The most concerning finding was that patients who failed NIV had a very high rate of cardiac arrest when transitioning to IMV with 11% suffering cardiac arrest during intubation and another 3% suffering cardiac arrest just prior to intubation. This rate is much higher than the 1.7% seen in the general pediatric population (19). The authors found that patients who continued to have a respiratory rate greater than 40 after 4 hours of NIV were likely to fail NIV and require intubation. They hypothesized that earlier recognition of NIV failure may lead to earlier intubation and mitigate the risk of cardiac arrest during the procedure. The timing of intubation in these patients continues to be an important question that requires further study.

Respiratory failure and management
Pulmonary complications affect 25% of pediatric HCT patients, with nearly 10% requiring mechanical ventilation and represent a major cause of transplant-related mortality. Fitch et al. provides a thorough review of both infectious and non-infectious pulmonary complications post-transplant. The authors point out the importance of timing of complication in relation to the transplant in determining the differential diagnosis and cause. They also highlight significant knowledge gaps, particularly in non-infectious complications making them difficult to accurately diagnose and limitations in available treatments. Fan et al. additionally provide a review of one pulmonary complication, diffuse alveolar hemorrhage (DAH). Traditionally, DAH has had a very high mortality rate in HCT patients. This review discusses what is known about the pathophysiology of DAH as well as novel inhaled therapies to control bleeding.
Diagnosis of pulmonary complications in critically ill pediatric oncology and HCT patients can be complicated. While CT scans may be useful, they are often not specific, and travelling outside of the ICU when patients are unstable can be difficult. Debate continues over when and if patients should undergo invasive procedures such as bronchoscopy, bronchoalveolar lavage (BAL), and lung biopsy. Elbahlawan et al use a case report to illustrate the utility of lung biopsy in select patients. Ahmed et al show us through a retrospective chart review study that BAL is feasible and safe in these patients. In their center, BAL yielded a diagnosis in over 60% of patients and resulted in a clinical management change in over 69% of patients. To positively impact HCT outcomes, there is a need for improved understanding of the pathophysiology of pulmonary complications.
Supportive management of patients with respiratory failure is also an important topic in this field. Sallee et al. performed a secondary analysis of a retrospective multi-center study of HCT patients requiring mechanical ventilation for respiratory failure. They found that fluid overload was associated with increased risk of mortality. In patients treated with CRRT, the mortality risk was mitigated suggesting that intervention with CRRT may be helpful in improving survival rather than fluid overload simply being a marker of worse illness. These findings lay the groundwork for future studies addressing the optimal management of fluid overload in HCT patients.
Despite our limitations in understanding of pulmonary complications, there is a trend toward advocating for more aggressive management of respiratory failure in HCT and oncology patients. Ghafoor et al. describe an early mobilization program in their PICU. The authors were able to show that mobilizing intubated pediatric oncology and transplant patients was safe and feasible. While there are theoretical benefits to early mobilization of intubated patients, the true impact on outcomes needs further study.

Multinational, multidisciplinary collaboration
The most encouraging finding in this collection of publications is the interest in developing a better understanding of the pathophysiology of critical illness in this population and provide critical care resources to support these vulnerable patients. The medical community seems to fortunately be breaking away from the self-fulfilling prophecy that these children have little chance of surviving critical illness and should not be offered critical care interventions. Publications in this Research Topic demonstrate multidisciplinary collaborations using multiple research methodologies to proactively address critical complications can significantly improve care and outcomes for these high-risk patients.
In addition to increasing publications in this Research Topic, multidisciplinary, multi-center research collaboratives have been formed around the world to address these topics. The Pediatric Acute Lung Injury and Sepsis Investigator's (PALISI) Network formed a Hematopoietic Cell Transplant -Cancer Immunotherapy subgroup to advance research in the field of onco-critical care in 2006 (20). More recently, a similar group was formed in Europe, PICU Oncology Kids in Europe Research Group (POKER) (21), and the St. Jude Global Critical Care Program (22) supports critical care for children with cancer in resource-limited settings worldwide. These groups work collaboratively with oncologists, transplant physicians, multidisciplinary professionals, and other relevant pediatric subspecialists. The presence of these groups is evidence for interest in the field and the importance of collaborative research to address its most difficult challenges.

The future of our field
This Research Topic represents a new field in pediatric critical care-pediatric onco-critical care (POCC)-focused on improving care and outcomes for critically ill children with cancer and blood disorders. Over the past few years, multiple collaborative groups have developed POCC educational curricula (23), consensus research priorities (24), and quality and capacity indicators (25,26). This Research Topic describing 30 articles on the critical complications in pediatric oncology and HCT marks the future of this growing field. This represents the beginning of the era of POCC-a global focus on major challenges in the management of critically ill children with cancer and blood disorders. Success in this new era will require a move from epidemiology to novel intervention leveraging global, multidisciplinary collaboration and specific attention to health equity.
The future of POCC must address ongoing clinical challenges described in this Research Topic, including early identification of complications, management of respiratory failure post-HCT, endothelial dysfunction, and multisystem organ failure. Future work must move from describing the epidemiology of these challenges to developing and testing novel interventions that improve outcomes.
This work must leverage a proactive, data-driven model to identify high-risk patient populations and discover new targeted therapeutic approaches. Such research in POCC must test, among others, bedside strategies to identify organ dysfunction syndromes, ventilatory strategies to improve survival in respiratory failure, and novel therapeutics to control inflammation and improve endothelial dysfunction. As PICU mortality for POCC patients declines, the impact of such interventions must be assessed beyond mortality, focusing on resource utilization, functional outcomes, and cost of care. As emphasized by work in this Research Topic, we must also look beyond the individual patient and evaluate how our care processes impact patient families, the care team, and health systems.
Overcoming these tough challenges in POCC will require multidisciplinary approaches, both in clinical management and research. Future work must emphasize interdisciplinary (oncology, ICU, etc) and interprofessional (nurses, physician, respiratory therapists, basic scientists, etc) collaborations to develop effective interventions and implement them as part of routine care. To succeed, clinicians and researchers must break out of silos to form productive, effective partnerships across disciplines and promote cross-fertilization of ideas and strategies. It is only through such diverse future collaborations that we can address the current challenges in POCCS.
Similarly, testing interventions to improve outcomes in POCC will require collaborations between institutions and countries. Children with cancer and critical illness, particularly with specific complications, are relatively rare; adequate power for any interventional trial will require global, institutional collaboration and joint research ventures. Networks such as POKER (21), the PALISI HCT Subgroup (20), and the St. Jude Global Critical Care Program (22) must be leveraged in large-scale collaborative research trials.
Although multiple challenges remain for POCC in high-resource settings (27), most children with cancer live in low-and middle income countries (28, 29), where critical illness is more common and results in worse outcomes (30). The future of POCC must intentionally address health equity in this field through research that specifically focuses on improving care and outcomes for critically ill children with cancer and blood disorders in resourcelimited settings. This includes addressing therapeutic, resource, and implementation challenges that may be unique to POCC in these settings (26,31,32). This targeted focus is urgently needed to reduce global disparities in childhood cancer outcomes.
Finally, success in POCC must move beyond simply developing novel interventions that improve care processes and outcomes. These interventions must be usable beyond the research setting and be designed for implementation in real-world clinical environments. To accomplish this task, POCC researchers must collaborate with experts in the fields of implementation science, quality improvement, and health economics to design strategies that promote uptake and utilization of effective strategies in routine patient care. Similarly, discoveries in this field must be actively disseminated, both through open-access Research Topics such as this journal collection, as well as at academic conferences, through social media networks, and in clinician education. For lasting impact, discovery is insufficient; innovations must be actively incorporated into clinical practice on a global scale.
As curative therapies and treatment for childhood cancer and blood disorders improve over time, survival and quality of life depends on effective supportive care strategies to reduce complications of life-threating toxicities of therapy. The field of POCC addresses this need by combining multidisciplinary expertise across clinical, research, and methodologic fields to improve outcomes for critically ill children with cancer and blood disorders. This Research Topic describes the breadth and depth of this new field and lays the foundation for future work. We hope you will join us in the POCCS new frontier.

Author contributions
AA, JM, and MS contributed to writing of the manuscript; all authors critically reviewed the manuscript and approved the final submission.

Conflict of interest
KM declares investigator funding from Jazz and Atara; MS declares department of defense contract funding for cold platelet study, NIH honorarium for PumpKiN DSMB, Medtronic contract for hemostasis teaching, Octapharma honorarium for clinical trial design consultation.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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