|Year : 2022 | Volume
| Issue : 4 | Page : 192-200
Survival outcomes of pediatric hematopoietic stem cell transplant patients admitted to the intensive care unit: A case–control study from a tertiary care center in Saudi Arabia
Lujain Talib Aljudaibi1, Mohamed Salaheldin Bayoumy1, Hassan A Altrabolsi1, Abdullah M Alzaydi2, Nawaf Aldajani2, Nadia Hammad1, Ismail Alzahrani2, Marwa Elhadidy3, Ibraheem F Abosoudah1
1 Oncology Department, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
2 Pediatrics Department, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
3 Medical-Critical Pharmacy Services Department, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
|Date of Submission||02-Aug-2022|
|Date of Decision||30-Aug-2022|
|Date of Acceptance||12-Sep-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Ibraheem F Abosoudah
Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, Alrawdah Road, P. O. Box: 40047, Jeddah 21499
Source of Support: None, Conflict of Interest: None
BACKGROUND: Hematopoietic Stem Cell Transplantation (HSCT) increases demand on Paediatric Intensive Care Units (PICU) and survival outcomes has emerged as an area of interest in HSCT research.
AIMS AND OBJECTIVES: The aim of this retrospective case-control study is to estimate the incidence and survival outcomes, and identify variables associated with survival amongst HSCT patients:
MATERIALS AND METHODS: Patients aged ≤15 years transplanted during January 2016 to December 2019 and requiring PICU admission(s). Statistical analysis involved calculating incidence of PICU admission, 2-year overall survival using Kaplan-Meier method; univariate and multivariate logistic regression analysis performed to identify factors associated with outcomes and P-value of <0.05 considered significant.
RESULTS: Total of 130 patients underwent 150 HSCT, 31 (24%) of patients required 50 PICU admissions, discharge following PICU admission was observed in 36 (72%) admission episodes, while 14 (28%) associated with patient demise. Two- year Overall Survival (OS) amongst HSCT patients requiring PICU admission was 58% compared to 96.6% amongst patients not requiring PICU (P<0.001). subgroup analysis of cases with malignant disorders and non-malignant disorders showed similar results (P<0.001). Univariate analysis revealed reduced intensity conditioning, no engraftment at the time of PICU admission, and sepsis associated with decreased survival, however multivariate analysis revealed sepsis as the single independent prognostic factor for decreased survival. Our study reports 24% incidence of PICU admission amongst patients undergoing HSCT with a 28% mortality rate following PICU admission.
CONCLUSION: Sepsis identified as the single prognostic factor associated with decreased survival. Therefore, efforts to optimize early identification and management of sepsis in the high-acuity setting of pediatric HSCT is warranted
Keywords: Pediatric intensive care unit admissions, sepsis, stem cell transplantation
|How to cite this article:|
Aljudaibi LT, Bayoumy MS, Altrabolsi HA, Alzaydi AM, Aldajani N, Hammad N, Alzahrani I, Elhadidy M, Abosoudah IF. Survival outcomes of pediatric hematopoietic stem cell transplant patients admitted to the intensive care unit: A case–control study from a tertiary care center in Saudi Arabia. J Appl Hematol 2022;13:192-200
|How to cite this URL:|
Aljudaibi LT, Bayoumy MS, Altrabolsi HA, Alzaydi AM, Aldajani N, Hammad N, Alzahrani I, Elhadidy M, Abosoudah IF. Survival outcomes of pediatric hematopoietic stem cell transplant patients admitted to the intensive care unit: A case–control study from a tertiary care center in Saudi Arabia. J Appl Hematol [serial online] 2022 [cited 2023 Jan 27];13:192-200. Available from: https://www.jahjournal.org/text.asp?2022/13/4/192/358716
| Introduction|| |
A new area of research interest has emerged over the last decade due to an increase in patients undergoing hematopoietic stem cell transplant (HSCT), and the complicated nature of HSCT entails a range of unique complications, including hepatic veno-occlusive disease, engraftment syndrome, acute graft versus host disease (GVHD), transplant-associated thrombotic microangiopathy, and posterior reversible encephalopathy syndrome. Children receiving HSCT compose 0.7% of all PICU admissions, with a reported mortality rate of 16% in children compared to 2.4% not receiving HSCT, and this incommensurate mortality rate demands efficient and timely pediatric intensive care unit (PICU) care.
| Subjects and Methods|| |
Several studies have attempted to assess various mortality risks associated with PICU patients among recent HSCT recipients, such as acute respiratory distress,, need for dialysis, sepsis,,, and a higher Oncology-Pediatric Risk of Mortality (O-PRISM-III) score,,, while several measures have been implemented to reduce or eliminate these risk factors: those include a better supportive care, reduced intensity chemotherapy, use of growth factors, improved donor selection, ex vivo stem cell manipulation, and adoptive transfer of nonalloreactive donor T-cells, but limited information about short- and long-term survival and survival subgroup analysis of this heterogeneous cohort is available. In this study, we aimed to identify factors contributing to HSCT patient mortality, incidence, and outcomes, as well as survival subgroup analysis among patients admitted to the PICU. It is worth-mentioning that our center is a Joint Accreditation Committee International Society for Cellular Therapy-Europe and the European Society For Blood and Marrow Transplantation (EBMT)-certified center located in the Western Province of Saudi Arabia and is considered a national referral center for a variety of hematology and oncology cases in the country indicated for HSCT, being the top four tertiary HSCT centers in Saudi Arabia.
This retrospective case–control study was conducted at the King Faisal Specialist Hospital and Research Center in Jeddah, Saudi Arabia, with patients aged 15 years and younger who underwent HSCT during January 2016 to December 2019 enrolled. The inpatient HSCT unit at KFSHRC-Jeddah follows EBMT international standard guidelines and is considered a high-dependency unit where nurse–patient ratio of 1:2 for patients with more stable HSCTs and a ratio of 1:1 for those with critical complications post-HSCT are maintained. The HSCT unit offers standard supportive measures and monitoring including pulse oximetry, nasal cannula, face mask, and up to 6 hourly input output charting. Patients who require transfer to the PICU are clinically comanaged by the HSCT team and the PICU team. The criteria for PICU transfer include noninvasive ventilation, invasive ventilation, inotropic treatment, or diuretics infusion.
Clinical data were collected from the departmental research data unit that included patient's demographics, pretransplant essential data, i.e., disease information, type of conditioning regimen, donor type, and dates of HSCT, and posttransplant essential data, i.e., engraftment, infectious and noninfectious toxicity, and patient survival status; in addition, data on PICU admission episodes with outcomes occurring within 1 year of HSCT were collected. Based on the eligibility criteria of the study, patients who were admitted for elective procedures (bronchoscopy) or for perioperative management were excluded, and only patients were considered index cases, if they had been admitted to PICU within 1 year of transplant with infectious or noninfectious transplant-related toxicity, while the control group constituted of patients not admitted to PICU within 1 year post-HSCT. This study seeks to examine the outcome (survival) of pediatric HSCT recipients who were admitted to the PICU and correlate survival at the time of PICU discharge with 2-year overall survival (OS) following PICU discharge and to identify individual risk factors for mortality. The study was conducted after obtaining the Institutional Review Board approval.
Categorical data were compared utilizing Chi-square test, while continuous variables were compared using Mann–Whitney U-test. Correlations between patient characteristics and prognosis were assessed utilizing univariate and multivariate logistic regression models. All reported tests were two-sided, and P < 0.05 was considered statistically significant. As HSCT patients may have multiple PICU admissions, for the purpose of analysis on this study a generalized linear mixed-effects model to account for multiple visits for one patient was utilized for survival outcomes. Kaplan–Meier method was used to calculate 2-year OS of the cohort group with date of the last contact and the date of transplant to determine survival time in months, while OS analysis of the index group was performed with date of the last contact and date of the first PICU admission to determine survival time in days; in both groups patient survival status as death was considered an event. In all survival analyses, while comparing groups, P < 0.05 was considered statistically significant.
| Results|| |
A total of 130 patients underwent 150 HSCT during the study period, with 24% (31) patients requiring 50 PICU admissions. Amongst the patients who required PICU admissions, 36 (72%) admissions episodes resulted in discharges with alive patient status, while 14 (28%) admissions resulted in patients demise. Out of the 31 patients admitted to the PICU, 17 (55%) were still alive with a median follow-up time of 797 days (range: 447–1672 days) since their last PICU admission, while among the non-survivors (14 patients), the median survival time was 41 days (range: one–632 days) and demographics shown in [Table 1].
|Table 1: Demographic and hematopoietic stem cell transplant-related data of patients admitted to pediatric intensive care unit posttransplant (n=31)|
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In terms of the PICU admission chronology observed during the 50 PICU admissions: 64.5% (20 patients) had single admissions, 22.5% (7 patients) had double admissions, 6.4% (2 patients) had triple admissions, and 3% (1 patient) needed six admissions repeatedly due to unexplained methemoglobinemia, following matched unrelated donor transplant. Indications for transplants were malignant diseases in 55%, and the remaining were non-malignant disorders including sickle cell disease and transfusion dependent thalassemia.
Among the 50 PICU admissions, 64.5% (20 patients) were single admissions, 22.5% (Seven patients) were double admissions, 6.4% (Two patients) were triple admissions, and 3% (one patient) needed six admissions repeatedly due to unexplained methemoglobinemia, following matched unrelated donor transplant, indication for transplants were malignant diseases in 55%, and the rest were nonmalignant disorders including sickle cell disease and transfusion dependent thalassemia. A total of 77% of the admissions to the PICU were recipients of allogeneic HSCT, of which 83% were identical donor HSCT recipients that is the predominant type of transplant in the center, while patients receiving HSCT for high-risk neuroblastoma were responsible for 29% of total patients admitted to the PICU. The pretransplant treatment duration was used as a surrogate measure of cumulative therapy infectious or noninfectious toxicity. The median pretransplant duration was 20.65 months (range, 3.87–151 months) for the entire group. As shown in [Figure 1], respiratory distress and sepsis/septic shock accounted for the bulk of the 50 different PICU admissions.
|Figure 1: Reasons for PICU admission, PICU = Pediatric intensive care unit|
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Predictors of mortality associated with pediatric intensive care unit admission
The 2-year survival rate of the whole cohort was 87%. The survival rate for case versus control was 58% versus 96.6% (P < 0.001). The comparison of continuous variables and categorical variables between survivors and nonsurvivors is shown in [Table 2] and [Table 3]. We found that the recovery time from mechanical ventilation in days did not have a statistically significant contribution in predicting survival between survivors and nonsurvivors. On the O-PRISM Score scale, nonsurvivors had a higher score (27), while survivors had a lower score (21.35) with (P = 0.063). On the basis of clinical categorical data, reduced-intensity conditioning (RIC) regimen and sepsis were linked to nonsurvival among index cases with P = 0.029 and 0.001, respectively.
|Table 2: Comparison of clinical continuous variables between survivors and nonsurvivors|
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|Table 3: Comparison of clinical categorical variables between survivors and nonsurvivors|
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Results of the univariate analysis and the multivariate analysis of prognostic factors are provided in [Table 4] and [Table 5]. According to univariate analysis, nonsurvival risk factors include RIC regimen, no engraftment at the time of PICU admission, and sepsis. All variables analyzed failed to demonstrate statistical significance except sepsis in multivariate analysis. Of the 50 admission episodes, 27 events (54%) in 16 patients were associated with sepsis; of which, 48% were malignant cases subjected to allogeneic transplants, 22% malignant cohorts subjected to autologous transplants, and 30% nonmalignant cases subjected to allogeneic transplants. Subgroup analysis of patients who developed sepsis was performed and a total of 27 (54%) admission episodes were due to the sepsis with 70% (19) observed in malignant disease category and 30% (8) amongst non-malignant disease category, the type of organisms isolated are listed in [Table 6] and [Figure 2]. Of the 16 patients admitted with sepsis episodes (n = 27), 11 patients (68%) died, of whom 45% of deaths observed in malignant cases occurred following allogeneic transplants, and when the mortality was compared to patients who did not develop sepsis (n = 3), a statistical significance (P < 0.05) was observed.
A cumulative 2-year Overall survival (OS) rate of 87% was observed in the cohort as demonstrated in survival curve-1, statistically significant difference in 2-year OS when comparing patients who required PICU admission within 1 year after transplant versus those who did not require a PICU admission, as demonstrated in survival curve-2. Discharge following PICU admission was observed in 36 (72%) admission episodes. The 2-year survival rate for the post-PICU discharge population was 58% [Figure 3].
|Figure 3: Overall survival of pediatric HSCT patients admitted to ICU, retrospective study: (a) OS of the cohort;(b) Overall survival of cohort comparing PICU admissions versus without PICU admissions; (c) Overall survival of nonmalignant blood disorders patient group comparing PICU admissions versus without PICU admissions; (d) Overall survival of allogeneic transplants – malignant diseases patient group comparing PICU admissions versus without PICU admissions, (e) Autologous transplants patient group comparing PICU admissions versus without PICU admissions, PICU = Pediatric intensive care unit; HSCT = Hematopoietic stem cell transplantation; ICU = Intensive care unit; OS = Overall survival|
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When further 2-year OS of the cohort was performed based on the disease category and transplant type, a 2-year OS rate of 42.4% (survival curve-4) observed in allogeneic transplants and 28.6% (survival curve-5) for autologous transplant recipients for for malignant disorders, respectively; while non-malignant allogeneic transplant recipients demonstrated a higher 2-year survival rate of 76.9% [Figure 3].
| Discussion|| |
This study reports findings of pediatric HSCT patients who required PICU admission over the course of 5-year study at a tertiary care center: 50 hospitalization episodes survived to PICU discharge from 72% of the episodes, as there has been a considerable variation reported for the number of patients who survived to discharge from PICU following HSCT, with survival rate to discharge per-admission ranging from 75% to 83%,,, and survival to discharge per-patient ranging from 57% to 78%.,,,, Historically, prognosis amongst pediatric HSCT patients admitted to PICUs has been considered unsatisfactory; however, current data suggests survival rates are improving compared to previously published data i.e. rates per-patient of 22.5%–31%.,,, Nevertheless, these findings has been questioned in a meta-regression study conducted by van Gestel et al. in 2008., suggesting interpretation of such results is subject to further scrutiny pertaining to the retrospective nature of the study conduct that involves a wide range of uncontrolled variables contributing to interpretation bias,, thus warranting prospective studies to be conducted
Several factors could account for the wide variation in survival to PICU discharge as reported in the literature, including the heterogeneity of the population studied, the variety of indications for transplantation, and the variable threshold to PICU admissions, since each HSCT unit has a unique institutional protocol and resources available for implementing initial supportive measures. In our HSCT inpatient unit, the criteria for PICU transfer are the need for noninvasive ventilation, inotropic treatment, or diuretics infusion, which is in contrast to other institutions with HSCT inpatient units, who may have more stringent criteria for PICU admission.
Patients with life-threatening conditions or complication post- stem cell transplantation are reportedly admitted to the PICU and this may have its own implications and therefore, comparing mortality rate among studies may not be as homogenous resulting in a less generalized conclusion. Based on a detailed review of 31 hCT patients, who had 50 PICU admissions, we found that 72% of the patients survived to discharge from the PICU, which is comparable to the survival rate reported in the literature.,,,,
In addition, we have been able to achieve comparable survival results for our pediatric HSCT program for both transplant-related morbidity and mortality, with reported OS and EFS rates of 69.5% and 59.6%, respectively, over a median follow-up of 72 months. Based on our analysis of 2-year OS rates between HSCT patients who required PICU admission within 1 year of HSCT and those who did not, we found a significant statistical difference in 2-year survival between the two groups (58% vs. 96.6%, P = 0.001). The four patients who died not requiring PICU on the study, the primary cause of death was disease progression or relapse, which is main cause of death reported post-100 days of stem cell transplantation by the Center for International Blood and Marrow Transplant Research (CIBMTR) as 62%–88% of cases.
Subgroup analysis was performed to determine patients at an increased risk for long-term mortality after PICU admission in the following groups: allogeneic HSCT recipients with underlying non-malignant blood disorders, allogeneic HSCT recipients with underlying malignant disorders, and autologous HSCT recipients with underlying malignant disorders (71% of which were high-risk neuroblastoma cases). Following PICU admission, the 2-year OS of patients with malignancies who received either allogeneic or autologous HSCT was significantly lower (p value < 0.05) than that of patients with non-malignant disorders receiving allogeneic HSCT (42.4%, 28.6% vs. 76.9%, respectively). Among each of the aforementioned subgroups, there was significant superior OS when no PICU admission was required compared to when PICU admission was needed as depicted in the survival curves.
Autologous HSCT recipients admitted to the PICU have been reported to have dismal long-term survival compared to other subgroups; however, it was not significant when transplant type was compared in univariate analysis (P = 0.968), supporting the recommendation to choose autologous HSCT for solid tumor cases as salvage therapy given its lower treatment-related toxicity and mortality., Long-term outcomes of ICU survivors as suggested by Azoulay et al. may provide an external validation of the current PICU practices and could identify whether ICU admission acts as curative bridge or simply prolongs the process of eventual demise, that may bring ethical concerns to the surface.
The findings of multivariate analysis were significant only for sepsis, with most cases related to central line-associated blood stream infections, which is often seen in malignant patients undergoing allogeneic transplants. This finding is in agreement with results of an earlier large study involving 1278 hCT patients, 11% of whom developed central line-associated bloodstream infection (CLABSI), with a higher proportion of allogeneic HSCT patients compared to autologous HSCT patients.
It may be that these results reflect carryover effects of repeated cytotoxic treatments in malignant patients undergoing allo-HSCTs, as most of them were relapse cases in their second or higher remission status. According to one study, preventing CLABSI can improve 1-year survival post-HSCT supporting the need for appropriate infection control measures. On one study of pediatric HSCT recipients, infection was associated with a 22.2% mortality rate and an odds ratio (OR) of 2.30 (P = 0.001), and on a retrospective analysis of 1002 cancer patients, 14% of whom had undergone HSCT; only the history of HSCT and initial lactate level were significantly associated with unfavorable outcome (OR: 7.7, 95% CI: 1.2–52.2, and OR: 1.6, 95% CI: 1.2–2.2, respectively).
As a result of prolonged pancytopenia following myeloablative therapy, disruption of the physiologic mucosal barrier, and prolonged central line placement, combined with end-organ toxicities from pretransplant chemotherapy/disease complications (iron overload), HSCT patients in particular are at a higher risk of mortality with sepsis. It is, therefore, vital to evaluate this factor among different subgroups of HSCT patients to initiate risk-adapted prophylaxis and provide more innovative supportive care considering the rise of multidrug-resistant CLABSI., Respiratory distress is a leading cause of PICU admissions in these group of patients and accounts for 28% of all admission episodes on this study, this finding may not reach the threshold of prognostic significance as reported in other studies.,, The risk of post-HSCT mortality is known to be influenced by the rate of cytomegalovirus (CMV) reactivation following HSCT, however no significant difference in percentages of reactivation of CMV between survivors and non-survivors (P = 0.651) were observed, this may be attributed to a smaller sample size. Failure to engraftment (absolute neutrophil count recovery) at the time of PICU admission had a statistically significant effect on mortality with P = 0.030; however, upon multivariate analysis the same did not hold its prognostic significance that is comparable to a large comprehensive prognostication study conducted among critically ill pediatric HSCT patient as reported from CIBMTR data and other pediatric registries. This is suggestive of the fact that more sensitive measures of immunity other than absolute neutrophil count engraftment are needed to capture an accurate profile of immunologic risk.
Clinical research, aimed at estimating mortality risk factors in PICU patients, has led the researchers and clinicians to create a variety of risk scores. PRISM is a risk assessment tool that has been developed since 1988 and depends on 14 routinely measured physiologic variables directly influencing mortality risk. In multiple logistic regression, the predictive strength of PRISM score was enhanced when GVHD grading, macroscopic bleeding, and C-reactive protein levels were considered in HSCT settings. We found a higher O-PRISM score amongst non-survivors, in contrast to a lower O-PRISM score among survivors,with an inclination toward a statistically significance (P = 0.063), which may be compared to other larger studies., It was observed that myeloablative conditioning regimen marginally outperformed RIC regimen in terms of survival (P = 0.059), which may have been confounded by the selection bias of using this kind of therapy on patients with comorbidities including primary immunodeficiency, hemophagocytic lymphohistiocytosis, inherited bone marrow failure syndrome, and heavily pretreated malignant cases, which might account for the greatest mortality in this subgroup. The lack of significance of this finding when several variables were evaluated may also be attributed to selection bias.
Limitations of our study lie in the retrospective single-center study design with a small sample size that lacks enough power to replicate other prognostic parameters related to HSCT, such as veno-occlusive disease or posterior reversible encephalopathy syndrome. In addition, the retrospective design of the study made it difficult to distinguish deaths due to treatment-related toxicity from deaths that occurred due to disease-related progression or relapse or both. However, the study provides unique long-term survival data in a case–control setting for HSCT patients following PICU discharge and survival subgroup analysis comparing HSCT cohorts, which has been rarely reported in the literature.
Another retrospective study spanning the period from 2005 to 2011 reported a differential survival rate for HSCT patients admitted to the PICU with a survival rate of 15% for those with PICU admission and a survival rate of 56% for those not admitted to the PICU within the study period. A challenge remains in comparing survival outcomes due to differences in patient characteristics, as 39% of those in the previous study were malignant cases in their second or subsequent remission, which was not the case in the present study. Similarly, another study found a poor long-term survival rate of 20% only among patients who survived in PICUs.
| Conclusion|| |
The short- and long-term outcomes from this study cohort may provide significant information for supporting appropriate counseling and for future studies implementing triage measures of these patients into different PICU utilizing models such as intensive care unit (ICU) trial, palliative ICU, and prophylactic ICU. It is evident that pediatric HSCT mortality following PICU admission is significantly higher than PICU all-cause mortality, and therefore, mitigation measures are required to be implemented, including measures to reduce CLABSI rates, to reduce PICU admissions, and to identify and treat sepsis as early as possible. However, existing literature and findings from this study warrant a discussion among the scientific community for a dedicated and subspecialized HSCT-PICU, as it seems to be the appropriate approach based on the highest acuity care requirements of patients post-HSCT.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]