Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many pediatric malignant and nonmalignant conditions. Gonadal insufficiency or infertility is present in almost all HSCT survivors who received a myeloablative conditioning (MAC) regimen. Reduced-intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with nonmalignant diagnoses to limit the toxicities associated with HSCT; however, the short-term and long-term gonadal toxicity of RIC regimens in pediatric and young adult survivors remains unknown. In this study, we compared the prevalence of gonadal insufficiency and infertility among pubertal and postpubertal pediatric and young adult survivors of HSCT who received a RIC regimen versus those who received a MAC regimen. Twenty-three females (RIC, n = 8; MAC, n = 15) and 35 males (RIC, n = 19; MAC, n = 16) were included in this single-center, retrospective cross-sectional study. Eligible patients were those with available laboratory results who were ≥1 year post-HSCT, age <40 years, and pubertal or postpubertal as assessed by an endocrinologist. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels were measured in females, and FSH, LH, total testosterone, and inhibin B (InhB) levels were measured in males. Twenty-one males (RIC, n = 11; MAC, n = 10) underwent semen analysis through a separate consent. Parametric and nonparametric analyses were undertaken to compare the RIC and MAC groups. Female patients who received RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P = .02) and low estradiol (P = .01) or elevated LH (P = .09). Most females in the RIC (75%) and MAC (93%) groups had low AMH levels, indicating low or absent ovarian reserve, with no significant difference between the groups (P = .53). In males, there were no significant differences between the 2 groups in the prevalence of abnormal FSH, LH, testosterone, or InhB levels. Ten of 11 RIC males (91%) and 10 of 10 MAC males (100%) had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range, 1.3 to 12.2 years). RIC may pose less risk than MAC for primary ovarian insufficiency among female survivors of HSCT; however, both female and male recipients of either RIC or MAC regimens are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling about the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.

Improving Oral Health and Modulating the Oral Microbiome to Reduce Bloodstream Infections from Oral Organisms in Pediatric and Young Adult Hematopoietic Stem Cell Transplantation Recipients: A Randomized Controlled Trial.

Bloodstream infections (BSIs) from oral organisms are a significant cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT) recipients. There are no proven strategies to decrease BSIs from oral organisms. The aim of this study was to evaluate the impact of daily xylitol wipes in improving oral health, decreasing BSI from oral organisms, and modulating the oral microbiome in pediatric HSCT recipients. This was a single-center 1:1 randomized controlled trial in pediatric HSCT recipients age >2 years. Age-matched healthy children were enrolled to compare the oral microbiome. The oral hygiene standard of care (SOC) group continued to receive the standard oral hygiene regimen. The xylitol group received daily oral xylitol wipes (with .7 g xylitol) in addition to the SOC. The intervention started from the beginning of the transplantation chemotherapy regimen and extended to 28 days following transplantation. The primary outcome was oral health at interval time points, and secondary outcomes included BSIs from oral organisms in the first 30 days following transplantation, oral microbiome abundance, and diversity and oral pathogenic organism abundance. The study was closed early due to efficacy after an interim analysis of the first 30 HSCT recipients was performed (SOC group, n = 16; xylitol group, n = 14). The xylitol group had a significantly lower rate of gingivitis at days 7, 14, and 28 following transplantation (P = .031, .0039, and .0005, respectively); oral plaque at days 7 and 14 (P = .045 and .0023, respectively); and oral ulcers >10 mm at day 14 (P = .049) compared with the SOC group. The xylitol group had no BSI from oral organisms compared with the SOC group, which had 4 (P = .04). The xylitol group had significantly lower abundance of potential BSI pathogens, such as Staphylococcus aureus (P = .036), Klebsiella pneumoniae (P = .033), and Streptococcus spp (P = .011) at the day after transplantation compared with the SOC group. Healthy children and young adults had significantly increased oral microbiome diversity compared with all HSCT recipients (P < .001). The addition of xylitol to standard oral care significantly improves oral health, decreases BSI from oral organisms, and decreases the abundance of pathogenic oral organisms in pediatric and young adult HSCT recipients.

Comparing a Neutropenic Diet to a Food Safety-Based Diet in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation.

Neutropenic diets were adopted as a way to decrease the infection risks in immunocompromised individuals, but these diets result in significant restrictions in the variety and types of foods an individual may consume. We used a controlled before-and-after study design in consecutive pediatric and young adult patients who underwent hematopoietic stem cell transplant at our center between January 1, 2014, and December 31, 2014. From January through June, all patients were placed on a traditional neutropenic diet; on July 1, we liberalized the bone marrow transplant (BMT) diet to a modified BMT diet. We compared the incidence of bloodstream infections in the first 100 days post-transplant, incidence of norovirus in the first 100 days, total parenteral nutrition days through day 100, incidence of grade 3 to 4 graft-versus-host disease at day 100, gastrointestinal graft-versus-host disease (any stage), and 100-day overall survival. In addition, we administered an investigator-created survey to evaluate food cravings, nausea, diet limitations, and subjective quality of life. In total, 102 patients underwent hematopoietic stem cell transplant during the study period. Forty-nine (48%) received the neutropenic diet and 53 (52%) the BMT diet. Other than more males receiving the neutropenic diet (67% versus 47%, P = 0.05), there were no statistical demographic and outcome differences between the 2 groups. Additionally, 46 subjects (45%) completed the investigator-created questionnaire. There was no difference in the perceived food cravings, nausea, diet limitations, and subjective quality of life between the 2 cohorts. These data demonstrate noninferiority of the modified BMT diet over the traditional neutropenic diet. We believe the food safety-based diet offers a greater variety of food, which may assist in the transition to a normal diet.

Sleep disruption in caregivers of pediatric stem cell recipients.

Parents/caregivers of hospitalized patients are at risk of sleep disruption. We performed a cross-sectional quantitative and qualitative evaluation of sleep in parents/caregivers of children undergoing hematopoietic stem cell transplant (HSCT; n = 17). Additionally, we explored the frequency of room entries for hospitalized patients undergoing HSCT (n = 189 nights). Twelve caregivers (71%) demonstrated significant sleep disturbance, 12 (71%) described sleep quality as poor, 15 (88%) averaged < 6 hours of sleep per night, 14 (82%) awakened at least four times per night. Patient rooms were entered a median of 12 times per night (interquartile range 10-15). Intervention studies to improve caregiver sleep during hospitalization are needed.

Oral health and hematopoietic stem cell transplantation: A longitudinal evaluation of the first 28 days.

BACKGROUND: Mucositis is well described after pediatric hematopoietic stem cell transplant (HSCT) but other aspects of oral health such as dental plaque and gingivitis are poorly understood. The aim of this study was to describe dental plaque, gingivitis, and mucositis early after HSCT. METHODS: We conducted a prospective longitudinal observational study to describe dental plaque, gingivitis, and mucositis in the peritransplant period. We conducted comprehensive oral evaluations that included the Miyazaki tongue coating, modified simplified oral hygiene, modified gingivitis of Suomi and Barbano, and mucosal ulceration indices at baseline on days 0, +7, +14, and +28. RESULTS: Data were collected from 19 patients with a median age of 8.0 years (5.1-12.8) at time of HSCT. Sixteen patients (85%) had plaque accumulation that progressively worsened, 16 (85%) developed severe gingival inflammation, 13 (68%) developed mucositis, and 11 (58%) had oral ulcerations. All oral indices worsened from baseline during the study period. Gingivitis and oral plaque persisted in most patients at day +28 while mucositis and oral ulcerations slightly improved. DISCUSSION: Gingivitis, dental plaque, mucositis, and oral ulcerations are common after HSCT. Additional studies are needed to ascertain methods that decrease plaque and gingivitis development and severity.

Improving Time to Antibiotic Administration for Bone Marrow Transplant Patients With First Fever.

BACKGROUND AND OBJECTIVE: Timely antibiotic administration in immunocompromised patients is associated with improved outcomes. The aim of our study was to decrease the mean time to administration of antibiotics in hospitalized bone marrow transplant patients with fever from 75 to <60 minutes. METHODS: By using the Model of Improvement, we performed plan-do-study-act cycles to design, test, and implement high-reliability interventions to decrease time to antibiotics. Nursing, physician, and pharmacy interventions were successfully applied to improve timely antibiotic administration. RESULTS: The study period was from April 2014 through March of 2017. Through heightened awareness, dedicated roles and responsibilities, a standardized order set specifically used for first fever patients, notification to the pharmacy about newly febrile first fever patients through a dedicated order, the creation of a dedicated sticker ("STAT first dose antibiotic, give directly to nurse") to be printed when antibiotics were entered via the order set in the pharmacy, and prioritization of antibiotic delivery on arrival on the floor, we saw an increase in the percentage of patients receiving antibiotics within 60 minutes of documented fever from a mean of 40% to over 90%. Our mean time for antibiotic administration decreased from 75 to 45 minutes. CONCLUSIONS: Implementation of a standardized process for notifying providers of new fever in patients, prioritization of antibiotic preparation in the central pharmacy, and timely antibiotic order entry resulted in improved times to antibiotic administration in the febrile bone marrow transplant population.

Team-based approach to identify cardiac toxicity in critically ill hematopoietic stem cell transplant recipients.

INTRODUCTION: We observed pulmonary hypertension (PH), pericardial effusions, and left ventricular systolic dysfunction (LVSD) in multiple critically ill hematopoietic stem cell transplant (HSCT) recipients. We implemented routine structured echocardiography screening for HSCT recipients admitted to the pediatric intensive care unit (PICU) using a standardized multidisciplinary process. METHODS: HSCT recipients admitted to the PICU with respiratory distress, hypoxia, shock, and complications related to transplant-associated thrombotic microangiopathy were screened on admission and every 1-2 weeks thereafter. Echocardiography findings requiring intervention and/or further screening included elevated right ventricular pressure, LVSD, and moderate to large pericardial effusions. All echocardiograms were compared to the patient's routine pretransplant echocardiogram. RESULTS: Seventy HSCT recipients required echocardiography screening over a 3-year period. Echo abnormalities requiring intervention and/or further screening were found in 35 (50%) patients. Twenty-four (34%) patients were noted to have elevated right ventricular pressure; 14 (20%) were at risk for PH, while 10 (14%) had PH. All patients with PH were treated with pulmonary vasodilators. LVSD was noted in 22 (31%) patients; 15/22 (68%) received inotropic support. Moderate to large pericardial effusions were present in nine (13%) patients, with six needing pericardial drain placement. DISCUSSION: Echocardiographic abnormalities are common in critically ill HSCT recipients. Utilization of echocardiogram screening may allow for early detection and timely intervention for cardiac complications in this high-risk cohort.

Healthcare Burden, Risk Factors, and Outcomes of Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infections after Stem Cell Transplantation.

Mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBIs) lead to significant morbidity, mortality, and healthcare resource utilization in hematopoietic stem cell transplant (HSCT) patients. Determination of the healthcare burden of MBI-LCBIs and identification of patients at risk of MBI-LCBIs will allow researchers to identify strategies to reduce MBI-LCBI rates. The objective of our study was to describe the incidence, risk factors, timing, and outcomes of MBI-LCBIs in hematopoietic stem cell transplant patients. We performed a retrospective analysis of 374 patients who underwent HSCT at a large free-standing academic children's hospital to determine the incidence, risk factors, and outcomes of patients that developed a bloodstream infection (BSI) including MBI-LCBI, central line-associated BSI (CLABSI), or secondary BSI in the first year after HSCT. Outcome measures included nonrelapse mortality (NRM), central venous catheter removal within 7 days of positive culture, shock, admission to the pediatric intensive care unit (PICU) within 48 hours of positive culture, and death within 10 days of positive culture. One hundred seventy BSIs were diagnosed in 100 patients (27%): 80 (47%) MBI-LCBIs, 68 (40%) CLABSIs, and 22 (13%) secondary infections. MBI-LCBIs were diagnosed at a significantly higher rate in allogeneic HSCT patients (18% versus 7%, P = .007). Reduced-intensity conditioning (OR, 1.96; P = .015) and transplant-associated thrombotic microangiopathy (OR, 2.94; P = .0004) were associated with MBI-LCBI. Nearly 50% of all patients with a BSI developed septic shock, 10% died within 10 days of positive culture, and nearly 25% were transferred to the PICU. One-year NRM was significantly increased in patients with 1 (34%) and more than 1 (56%) BSIs in the first year post-HSCT compared with those who did not develop BSIs (14%) (P ≤ .0001). There was increased 1-year NRM in patients with at least 1 MBI-LCBI (OR, 1.94; P = .018) and at least 1 secondary BSI (OR, 2.87; P = .0023) but not CLABSIs (OR, 1.17; P = .68). Our data demonstrate that MBI-LCBIs lead to substantial use of healthcare resources and are associated with significant morbidity and mortality. Reduction in frequency of MBI-LCBI should be a major public health and scientific priority.

Increasing Activities of Daily Living Is as Easy as 1-2-3.

BACKGROUND: Human flora are the most common cause of bacteremia in immunocompromised patients. Activities of daily living (ADL), including oral care and daily chlorhexidine gluconate bathing, can lower the risk of infection. METHODS: To address ADL compliance in our pediatric oncology and bone marrow transplant patients, we adopted the ADL 1-2-3 initiative: daily chlorhexidine gluconate bath and linen change, at least 2 activities per day, and oral care 3 times per day. Using the Model for Improvement we created a standardized ADL process that involved all providers. Interventions included addressing ADL 1-2-3 compliance during rounds, establishing accountability in care delivery, an oral care order set and algorithm, daily text message reminders, and physician intervention with noncompliant and high-risk patients. RESULTS: With our interventions, we increased our median compliance with the all-or-none ADL 1-2-3 initiative from 25% to 66% in 90 days. We have sustained our median compliance to 75% sixteen months after implementation. The greatest impact on compliance was seen with text message reminders to staff to complete and document the ADL 1-2-3 components, designated roles and responsibilities, and physician discussion with noncompliant and high-risk patients. DISCUSSION: Oral care algorithm and order set, daily text message reminders, and physician intervention with noncompliant and high-risk patients has improved our compliance. Units where compliance with ADL participation is low can benefit from incorporating elements from this ADL 1-2-3 initiative.

Clinical Utility of Computed Tomography and Magnetic Resonance Imaging for Diagnosis of Posterior Reversible Encephalopathy Syndrome after Stem Cell Transplantation in Children and Adolescents.

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by vision changes, altered mental status, and seizures, typically caused by an acute rise in blood pressure. PRES has been reported after hematopoietic stem cell transplantation (HSCT) in association with hypertension from calcineurin inhibitors and corticosteroids. The imaging evaluation of PRES after HSCT in children and young adults has not been well described. We performed a retrospective review of all HSCT recipients presenting to the intensive care unit with new neurologic symptoms. A neuroradiologist reviewed all radiologic images and compared computed tomography (CT) versus magnetic resonance imaging (MRI) findings indicative of diagnosis of PRES. Alternative imaging diagnoses explaining the patients' symptoms were also recorded. Fifty-four transplant recipients were admitted to the intensive care unit with new neurologic symptoms. Thirty-nine percent (21 of 54) of subjects had imaging findings consistent with PRES, 24% (13 of 54) had imaging findings consistent with an alternative diagnosis, 9% (5 of 54) had a nonspecific finding, and 28% (15 of 54) had no acute imaging findings. PRES was diagnosed at a median of 49 days (interquartile range, 29 to 94) after HSCT. The presenting symptom for the majority of patients with PRES was seizures (86%), whereas 14% presented with acute encephalopathy. Ninety-five percent of subjects diagnosed with PRES (20 of 21) underwent a head CT as their initial imaging evaluation. CT scan was diagnostic of PRES in 40% (8 of 20). Subsequently, 16 patients underwent brain MRI with 12 additional patients being diagnosed with PRES on MRI. The median time elapsed between negative CT and a positive MRI examination was 20 hours (range, 3.6 hours to 9 days). CT serves as an excellent screening test for acute pathology, such as intracranial hemorrhage; however, it lacks sensitivity for the diagnosis of PRES. Patients with clinical symptoms suggestive of PRES who have a negative CT should be treated appropriately for PRES and should undergo MRI of the brain as soon as clinically stable to confirm the diagnosis.