Long-Term Survival and Late Death after Hematopoietic Cell Transplant for Patients with Sickle Cell Disease Surviving for at Least Two-Years after Transplantation

Introduction: In 2018, the National Heart Lung and Blood Institute (NHLBI) began work on BioData Catalyst, a shared cloud platform where scientists can access and analyze de-identified data from NHLBI-funded projects. Hematopoietic cell transplant for sickle cell disease is potentially curative but is associated with life threatening complications most of which occur within the first or second year after transplantation. In the current era with increasing interest in gene therapy and/or editing to cure sickle cell disease we felt it timely to report on transplant recipients who have survived beyond 2-years after their transplantation. The aim of the current analysis was: 1) estimate the conditional survival rates after hematopoietic cell transplantation stratified by time survived since transplantation, 2) identify risk factors for death beyond 2-years after transplantation and 3) to compare all-cause mortality risks to those of an age, sex, and race-matched general population in the United States. Methods: Permission to access de-identified records of 950 patients with sickle cell disease was granted and data were accessed through a BioData Catalyst PIC-SURE portal (https://picsure.biodatacatalyst.nhlbi.nih.gov). All analyses were performed in this secure cloud environment using the available statistical software package(s). Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. Cox regression models were built to identify risk factors associated with mortality beyond 2 years after transplantation. The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after transplantation and compared to age and sex-matched general population. Person-years at risk were calculated from an anchor date (i.e., 2-, 5- and 7-years) after transplantation until date of death or last date known alive. The expected number of deaths was calculated using sex and age-specific US mortality rates. The equality of SMRs was tested and two-sided 95% confidence intervals (CI) were calculated. The incidence of graft failure was calculated using the cumulative incidence estimator to accommodate competing risks. Results: Patients were transplanted at 94 transplant centers in the United States between 2000 and 2017 with 70% of transplants after 2010. The median follow-up of the cohort was 5 years (range 2 - 20 years). Three hundred patients (32%) were observed for more than 7 years. The median age at transplantation was 11 years and 8% (n=78) were older than 30 years. The predominant donor was an HLA-matched sibling (66%), the predominant graft was bone marrow (70%), and about half the cohort received myeloablative conditioning. The 10-year probability of survival in 2- and 5-year survivors was 96% (95% CI 94-98) and 98% (95% CI 96-99), respectively (Figure 1). The 12-year probability of survival in 7-year survivors was 97% (95% CI 92-99). Risk factors for late death included older age and alternative donors (Table 1). Every 10-year increment in patient age was associated with a 75% increase-risk of mortality. The risk of death is 3.5 times higher after alternative donor (mismatched relative, HLA-matched and mismatched unrelated donor) compared to HLA-matched siblings. Amongst the alternative donors, mortality risks were not different. Compared to an age-, sex- and race-matched US population, the risk for late death was higher in transplant survivors but diminished over time (Table 2). Graft failure (beyond 2-years after transplantation) remains an obstacle; 4% (95% CI 3 - 6) after HLA-matched sibling and 12% (95% CI 8 - 18), (HR 2.59, p<0.0001) after alternative donor transplantation. Mortality risk was higher in those with history of chronic graft-versus-host disease though did not reach level of significance (HR 2.18, p=0.08). Conclusion: Durable survival is likely in the majority of 2-year survivors. The expected risk for death receded over time but the risk for late death is not negligible even as late as 7-years after transplantation underscoring the need for continued surveillance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Neutrophil-to-lymphocyte count ratio in predicting prognosis of septic shock patients

Background Septic shock is one of the most common causes of admission to the intensive care unit in the world and one of the most common causes of death among intensive care patients. Since the definition of sepsis and septic shock and many studies have been designed to understand everything about sepsis regarding mechanism, pathophysiology, complications, diagnosis, management and all other aspects. Objective To find the association between neutrophil to lymphocyte count ratio and the mortality from septic shock patients. The work aims also to determine if this ratio can be used as a prognostic marker of septic shock patients and to compare this ratio with other sepsis markers as C-reactive protein (CRP) and procalcitonin. Patients and Methods This study was conducted prospectively in critical care unit in Ain Shams Hospital, a university-affiliated, tertiary referral center in Cairo, Egypt. Study subjects included 125 patients between January 2018 to January 2019. The ethics committee of our institution approved the study protocol, and written informed consent was obtained from each patient’s family. Results In our study, the neutrophils count was significantly increased in survived patients compared with early and late mortality patients in day 1 while lymphocytes count was lower in survived patient than early and late mortality patients and the NLCR in our study was higher in survived patients than early and late mortality patients. In day 4, our results revealed significant increase in neutrophils count in patients of late mortality compared with its count in survived patients, while lymphocytes didn't show any significant difference compared with its count in survived patients with significant increase in NLCR in patients of late mortality compared with those of survived patients in day 4. Both CRP and procalcitonin are increased in patients of early and late mortality groups compared with its value in survived patients in day 1 and 4. Conclusion This study demonstrates a real relationship between the NLCR and the risk of death in septic shock patients. Septic shock patients at risk of early death presented a low NLCR at admission, although late death was associated with an increased NLCR during the first 5 days. Early and late death should be distinguished because they may involve different underlying mechanisms, and the NLCR might be considered as a discriminant indicator of early or late death. In addition, our findings provide more insight into biology. The circulating neutrophil and lymphocyte trends observed in this study offer an interesting mechanistic viewpoint. We observed that circulating lymphocytes and the NLCR behave in opposite ways in early- and late death patients, supporting the hypothesis that divergent mechanisms could be involved in these two groups.

Extended Stent Coverage Decreases Distal Aortic Segmental Enlargement After the Endovascular Repair of Acute Complicated Type B Aortic Dissection: A Multi-Center Retrospective Study of 814 Patients

Purpose: This study aimed to investigate the effect of distal aortic segmental enlargement (DASE) after thoracic endovascular aortic repair for complicated type B aortic dissection (cTBAD). Materials and Methods: From March 2003 to October 2018, 814 patients with acute cTBAD from 5 medical centers were retrospectively identified. DASE is indicated as the enlargement of distal aortic segmental volume ≥1.6 fold of the preoperative volume compared with the most recent postoperative computed tomography angiography (CTA) scan. Of these patients, 635 (78%) were identified as non-DASE, and 179 (22%) were identified as DASE. Competing risk analysis was performed to compare late death and distal aortic reintervention between the groups. The morphological variables and false lumen thrombosis at 7 aortic levels were measured based on the preoperative CTA and the most recent CTA. Univariate and multivariate Cox regression analyses were used to assess the independent predictors of DASE. Results: The mean follow-up time of the entire cohort was 5.6 years (interquartile range: 2.4–8.3 years). There were total of 208 late deaths, including 94 (14.8%) deaths in non-DASE group versus 114 (63.7%) deaths in the DASE group. Distal aortic reintervention was observed in 89 patients, with 43(6.7%) in the non-DASE group versus 46 (25.7%) in the DASE group. The cumulative incidence of late death and distal aortic reintervention were significantly higher in the DASE than in the non-DASE group (p<0.001). In morphological analysis, significant incomplete false lumen thrombosis was observed in all distal aortic segments above the aortic level of celiac artery (p<0.01). According to multivariate analysis, the Marfan syndrome, stent coverage to the level of diaphragm and the level of celiac artery were independent predictors of the DASE (p<0.001). Patients with extended stent coverage to the level of celiac artery have shown a lower incidence of DASE (p<0.010). Conclusion: Compared with the non-DASE group, patients with DASE demonstrated a higher rate of late death and distal aortic reintervention. For the cTBAD population, extended stent-graft coverage to the aortic section between diaphragm and celiac artery might serve as a “cost-efficient” cutoff point aiming to reduce the risk of DASE.

Clinical Phenotypes from Fatal Cases of Acute Respiratory Distress Syndrome Caused by Pneumonia

Background: The COVID-19 pandemic has renewed interest and discussion about clinical phenotypes of acute respiratory distress syndrome (ARDS). Since the Berlin definition, various clinical disease courses with fatal outcome have been described but early objective indicators predicting distinct clinical courses have remained elusive. Objectives: Identify clinically available predictors that distinguish between two phenotypes of fatal ARDS due to pneumonia.Methods: 104 Japanese patients with pneumonia induced ARDS were extracted from our prospectively collected database. Fatal cases were divided into early (< 7 days after diagnosis) and late death (≥ 7 days) groups and their clinical variables and prognostic factors were statistically evaluated.Results: Of 50 cases, fatal within 180 days, 18 (36%) comprised the early death group (median 2 days, IQR [1, 5]) and 32 (64%), the late death group (median 16 days, IQR [13, 29]). Multivariate regression analyses showed APACHE II score (HR 1.14, 95%CI 1.01-1.28, p 0.047) was the only independent prognostic factor for early death. Late deaths were associated with disseminated intravascular coagulation score (HR 1.30, 95%CI 1.07-1.58, p 0.007), culture sensitivity to initial antimicrobials (HR 3.42, 95%CI 1.86-6.29, p <0.0001), and high-resolution computed tomography (HRCT) score indicating early fibroproliferation. ROC analyses estimated a late death propensity score for HRCT score ≥ 211, of 5.42 (95%CI 1.54–19.12; p 0.008).Conclusions: The extent of fibroproliferation on HRCT, along with coagulation abnormalities and APACHE II scores, should be considered for use in predictive trial enrichment and personalized medicine for patients with ARDS due to pneumonia.

Trends in conditional survival and predictors of late death in neuroblastoma.

10533 Background: Significant advances in the treatment of neuroblastoma have been made in the past several decades. There are scant data examining how these improvements have changed over time and differentially affected conditional survival among high- and non-high-risk patient groups. Methods: We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results Database. We analyzed clinical characteristics and survival outcomes for 4717 neuroblastoma patients. Kaplan-Meier methods were used to estimate overall survival (OS) and conditional overall survival (COS) conditioned on having survived 1, 2, or 5 years from diagnosis, with estimates compared between groups using log-rank tests. Results: Five-year OS was 41.46% (95% CI 38.77-44.13) for the high-risk group and 91.13% (95% CI 89.49-92.53) for the non-high-risk group. Both groups saw significant improvements in OS by decade (p<0.001). Five-year COS among 1-year survivors was 52.69% (95% CI 38.77-44.13) for the high-risk group and 96.75% (95% CI 95.57-97.62) for the non-high-risk group. One-year survivors in the high-risk group showed a statistically significant improvement in COS over time. No difference in COS was observed among 5-year high-risk survivors. There were no statistically significant changes in COS over time for 1- and 5-year survivors in the non-high-risk group. In the high-risk and non-high-risk groups, 82% and 32% of late deaths (>5 years from diagnosis) were attributable to cancer, respectively. Statistically significant adverse prognostic factors for late death were age >1 year at diagnosis, metastatic disease, and non-thoracic primary site (p=0.001). Conclusions: Improvements in COS over time have largely benefited high-risk patients, though they are still at higher risk for late death due to cancer when compared to non-high-risk patients. Age, stage, and primary site, but not treatment decade, influence outcomes among 5-year survivors. [Table: see text]