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An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant consortium entitled “Late Effects Screening and Recommendations Following Allogeneic Hematopoietic Cell Transplant for Immune Deficiency and Nonmalignant Hematologic Disease” was held in Minneapolis, Minnesota on May 10, 2016 and May 11, 2016. The purpose of the conference was to address the unmet need for greater understanding of and the screening for long-term complications in the growing population of survivors of transplantation for nonmalignant disorders. The conference focused on transplantation for hemoglobinopathy, immune deficiency, and inherited bone marrow syndromes. A multidisciplinary group of experts in the disease areas and transplantation late effects presented the current state of understanding of how the underlying disease, pretransplantation therapies, and transplantation-related factors uniquely interact to influence the development of late toxicities. Recommendations were put forth by the group for the late effects screening of survivors of transplantation for these nonmalignant disorders. The findings and recommendations that came from this conference will be presented in a series of 6 additional manuscripts in the upcoming months. In this manuscript, we explore the need for screening practices specific to the survivors of transplantation for nonmalignant diseases and the methodologic challenges associated with the study of these patients. [ABSTRACT FROM AUTHOR]

Aims and objectives To assess the consistency and safety of manual hyperinflation delivery by nurses of variable clinical experience using a resuscitator bag during physiotherapy treatment. Background Manual hyperinflation involves the delivery of larger than normal gas volumes to intubated patients and is routinely used by nurses in collaboration with physiotherapists for the management of retained sputum. The aim is to deliver slow deep breaths with an inspiratory hold without unsafe airway pressures, lung volumes or haemodynamic changes. In addition, nursing staff should be able to 'feel' differences in resistance and adjust their technique accordingly. Design Prospective observational study utilising the simulation of a mechanically ventilated patient. Methods Thirty-three nurses delivered manual hyperinflation to a SimMan3G mannequin who had three distinct lung scenarios applied (normal; asthma; Acute Respiratory Distress Syndrome) in randomised order during simulated physiotherapy treatment. Respiratory rate, tidal volume ( Vt), mean inspiratory flow rate ( Vt/Ti), and peak airway pressure data were generated. Results Over all scenarios, mean respiratory rate = 12·3 breaths/minute, mean Vt = 638·6 mls, mean inflation time = 1·3 seconds and peak airway pressure exceeded 40 cm H2O in 41% of breaths, although only in 10% of breaths during the 'normal' lung scenario. Conclusions Experienced nurses were able to manually hyperinflate 'normal' patients in a simulated setting safely. Despite their knowledge of barotrauma, unsafe airway pressures were delivered in some scenarios. Relevance to clinical practice Training with regard to safe airway pressures, breath hold and adequate volumes is recommended for all nurses undertaking the procedure. Nurses and physiotherapists must closely monitor the patient's condition during manual hyperinflation thereby recognising changes with regard to lung compliance and airway resistance, with nurses responding by altering their technique. The addition of a pressure manometer in the circuit may improve patient safety when performing manual hyperinflation. [ABSTRACT FROM AUTHOR]

We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplantation morbidity in this population. [ABSTRACT FROM AUTHOR]

Children may be at increased risk for vitamin D deficiency following HSCT because of lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, malabsorption, and the use of certain medications. We prospectively assessed the prevalence of and risk factors for 25-hydroxy (25-OH) vitamin D deficiency in 67 patients transplanted at our institution. 25-OH vitamin D levels were checked during 3 separate 4-week periods in the spring, autumn, and winter. Subjects were <2 years following transplant and/or being treated for chronic graft-versus-host disease (cGVHD). Levels less than 20 ng/mL were considered deficient, and those less than 30 ng/mL were considered insufficient. The mean 25-OH vitamin D level was 22.8 ng/mL (range: 7-46.2). A total of 80.6% (confidence interval [CI] 69.1%-89.3%) of patients had a level less than the lower limit of the institutional normal range. The deficiency rate was 37.3% (CI 25.8%-50%). The mean parathyroid hormone (PTH) level was 77.5 (SD = 80.5). There was no correlation between 25-OH vitamin D and PTH levels. We evaluated potential risk factors for 25-OH vitamin D deficiency including age, season of testing, sun exposure, sunscreen use, use of steroid or calcineurin inhibitor, race, and dairy intake. In multivariate logistic regression, only older age was found to be a risk factor for deficiency (P = .004). Patients with deficient levels were treated with 50,000 IU of ergocalciferol once weekly for 6 weeks. A postrepletion 25-OH level was available for 22 patients. The majority of repleted patients had a normal posttreatment level (63.6%). The postsupplementation level corrected into the insufficient range for 31.8% of patients and 4.6% remained deficient. Vitamin D insufficiency and deficiency are common following HSCT. Further investigation into potential risk factors and the appropriate supplementation for these patients is warranted. [Copyright &y& Elsevier]

Photobiomodulation therapy (PBMT) is recommended for prevention and treatment of oral mucositis, a painful condition that occurs in cancer patients. Intraoral PBMT is limited to treating distal oral mucosa and oropharynx. Extraoral PBMT may provide a more efficient intervention. The goal of this study was to develop a clinically viable protocol for extraoral PBMT. Monte Carlo modeling was used to predict the distribution of 850 nm light for four treatment sites, using anatomical data obtained from MRI and optical properties from the literature. Simulated incident light power density was limited to 399 mW/cm2 to ensure treatment safety and to prevent tissue temperature increase. The results reveal that total tissue thickness determines fluence rate at the oral mucosa, whereas the thickness of individual tissue layers and melanin content are of minor importance. Due to anatomical differences, the fluence rate varied greatly among patients. Despite these variations, a universal protocol was established using a median treatment time methodology. The determined median treatment times required to deliver efficacious dose between 1 and 6 J/cm2 were within 15 min. The developed PBMT protocol can be further refined using the combination of pretreatment imaging and the Monte Carlo simulation approach implemented in this study. [ABSTRACT FROM AUTHOR]

Study Objective To describe the rates of use and effectiveness of gonadotropin-releasing hormone (GnRH) agonists and other forms of hormonal menstrual suppression in prevention of vaginal bleeding among young women who underwent hematopoietic stem cell transplantation (HCT). Design Retrospective descriptive study. Setting University-based pediatric HCT practice. Participants Fifty-five postmenarchal women who underwent HCT between 2004 and 2011. Interventions Administration of GnRH agonists or other forms of hormonal menstrual suppression. Main Outcome Measures Rates of use of GnRH agonists and other forms of hormonal menstrual suppression, and rates and descriptions of vaginal bleeding. Results Forty-six of the 55 patients had experienced regular or irregular vaginal bleeding before HCT and were considered to be at risk for thrombocytopenia-associated menorrhagia. Forty of the 46 (87%) received hormonal menstrual suppression. Thirty-three patients were treated with a GnRH agonist, 4 with combined hormonal contraceptive pills, 1 with a combined hormonal contraceptive patch, 1 with depot medroxyprogesterone, and 1 with oral norethindrone. Twenty-nine of the 33 patients (88%) who received a GnRH agonist had complete amenorrhea during HCT and 4 of 33 (12%) experienced some degree of vaginal bleeding. Conclusion GnRH agonists appear effective in prevention of vaginal bleeding complications in most postmenarchal women who underwent HCT. Some patients who might benefit do not receive a GnRH agonist and multiple barriers exist in identification and treatment of them. [ABSTRACT FROM AUTHOR]

In the United States, fungal surveillance cultures are commonly performed in pediatric hematopoietic stem cell transplant recipients. These cultures have limited clinical utility for predicting systemic fungal disease. Stool cultures show the highest yield for identifying fungal colonization.Background. Fungal surveillance cultures (FSCs) have been proposed as predictors for development of invasive fungal disease (IFD) and identifiers of the causative organism, although data supporting these are limited and predate universal initiation of antifungal prophylaxis. We aimed to define the epidemiology of fungal colonization and investigate the utility of FSCs for predicting IFD in recipients of pediatric hematopoietic stem cell transplantation (HSCT).Methods. FSCs performed from 2007 to 2011 on HSCT patients and laboratory and clinical data were reviewed, and incidence of IFD was determined. Descriptive analyses of culture results were performed to determine the yield of FSCs and their utility. A Web-based survey of national pediatric HSCT providers was undertaken to evaluate current practice and the relevance of our results.Results. Five thousand six hundred eighteen FSCs from nares, throat, and stool from 360 patients were processed. Of these, 14.8% were positive: 30.3% from stool, 13.2% from throat, and 0.9% from nares; 64.4% of patients had >1 positive FSCs. Thirty (8.3%) patients had IFD. IFD occurred in 7.9% and 10.1% of patients with positive and negative FSCs, respectively (P = .25). Antifungal coverage was changed in 69 patients (29.9%) after positive FSC; 8.6% developed IFD (n = 2 of 6 pathogen concordance with FSC) compared with 6.7% (P = .59) who had no treatment change (n = 3 of 11 concordance). The response rate to the survey was 70.8%; 40% of institutions reported performing routine FSC. Twenty-five percent of providers would not change management based on FSC results; overall rating of usefulness of FSCs was low.Conclusions. Although FSCs are commonly performed for pediatric HSCT patients, they have limited utility for predicting IFD. [ABSTRACT FROM PUBLISHER]

Background: We describe organisms found in the respiratory tracts of a multicenter cohort of pediatric hematopoietic cell transplant (HCT) recipients with respiratory failure. Methods: Twelve centers contributed up to 25 pediatric allogeneic HCT recipients requiring mechanical ventilation for respiratory failure to a retrospective database. Positive respiratory pathogens and method of obtaining sample were recorded. Outcomes were assessed using Mann‐Whitney U test or chi‐squared analysis. Results: Of the 222 patients in the database, ages 1 month through 21 years, 34.6% had a positive respiratory culture. 105 pathogens were identified in 77 patients; of those, 48.6% were viral, 34.3% bacterial, 16.2% fungal, and 1% parasitic. PICU mortality with a respiratory pathogen was 68.8% compared to 54.9% for those without a respiratory pathogen (P =.045). Those with a positive respiratory pathogen had longer PICU length of stay, 20 days (IQR 14.0, 36.8) vs 15 (IQR 6.5, 32.0), P =.002, and a longer course of mechanical ventilation, 17 days (IQR 10, 29.5) vs 8 (3, 17), P <.0001. Method of pathogen identification, type of pathogen, and the presence of multiple pathogens were not associated with changes in PICU outcomes. Conclusions: In this multicenter retrospective cohort of intubated pediatric post‐HCT patients, there was high variability in the respiratory pathogens identified. Type of pathogen and method of detection did not affect PICU mortality. The presence of any organism leads to increased PICU mortality, longer PICU stay, and increased duration of mechanical ventilation suggesting that early detection and treatment of pathogens may be beneficial in this population. [ABSTRACT FROM AUTHOR]

Background/Objective: Pediatric hematopoietic stem cell transplantation (HSCT) patients are at an increased risk for skin cancers. Sun exposure is a significant modifiable environmental risk factor. While patient education on sun protection and avoidance behaviors with regular dermatology evaluations are crucial for pediatric HSCT patients, the real‐life practice of these sun‐protection recommendations in this patient population compared to their peers is unknown. Methods: A survey‐based cross‐sectional cohort study was performed in pediatric HSCT patients seen at the Dana‐Farber Cancer Institute and Boston Children's Hospital over a 1.5‐year period compared with age/sex/Fitzpatrick skin phototype‐matched healthy controls. Study participants were surveyed using the validated Glanz survey for pediatric sun protection behavioral research. Results: Eighty‐five pediatric HSCT patients and 85 controls completed the study. Pediatric HSCT patients more frequently used sunscreen, hats, umbrellas, and sunglasses and obtained full‐body skin exams compared to controls. No difference was observed in sun exposure during hours of peak sun intensity, frequency of purposeful tanning, tanning bed use, and the number of painful sunburns received between pediatric HSCT patients and controls. Conclusions: Although pediatric HSCT patients practice more sun protection behaviors, they experienced harmful sunburns and intentional tanning behaviors at the same rate as their peers. Patient‐directed counseling and strategies to improve patient adherence to optimal sun protection behaviors could have a significant impact on the dermatology quality of life in pediatric HSCT patients. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms in hemoglobin disorders, including sickle cell disease (SCD) and thalassemia major. Managing the residual manifestations of pre-HCT disease complications and the long-term effects of HCT requires systematic monitoring, follow-up and intervention when indicated. Late complications vary with age and disease status at HCT and with transplant variables such as preparative regimen, donor source and compatibility, and immune reconstitution. An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium in May 2016 entitled “Late Effects Screening and Recommendations Following HCT for Immune Deficiency and Nonmalignant Hematologic Disorders” focused on follow-up after HCT for hemoglobinopathy. An earlier publication from experts who participated in this session described the pathophysiology and spectrum of complications that HCT recipients experience after HCT for SCD and thalassemia major. This companion publication summarizes the consensus reached by this group of experts about long-term follow-up guidelines after HCT for hemoglobinopathy. In addition, these guidelines might also be included in studies of novel curative therapies such as autologous HCT after hematopoietic progenitor stem cell gene modification. [ABSTRACT FROM AUTHOR]

Some patients with veno-occlusive disease (VOD) have multiorgan dysfunction, and multiple teams are involved in their daily care in the pediatric intensive care unit. Cardiorespiratory dysfunction is critical in these patients, requiring immediate action. The decision of whether to use a noninvasive or an invasive ventilation strategy may be difficult in the setting of mucositis or other comorbidities in patients with VOD. Similarly, monitoring of organ functions may be very challenging in these patients, who may have fulminant hepatic failure with or without hepatic encephalopathy complicated by delirium and/or infections. In this final guideline of our series on supportive care in patients with VOD, we address some of these questions and provide evidence-based recommendations on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees. [ABSTRACT FROM AUTHOR]

The number of pediatric hematopoietic cell transplant (HCT) patients who survive pediatric intensive care unit (PICU) admission is increasing, yet little is known about their functional morbidity after PICU discharge. We hypothesized that relative to control subjects, pediatric HCT patients who survive PICU admission would have greater rates of new functional morbidity at the time of PICU discharge and only some of these patients would return to their functional baseline by the end of the hospitalization. We performed a retrospective cohort study with secondary data analysis of the Trichotomous Outcomes in Pediatric Critical Care dataset. The pediatric HCT cohort was identified by querying International Classification of Diseases, 9th edition, diagnostic codes. A control group consisted of previously healthy patients matched 4:1 on age, sex, and illness severity, as estimated by the Pediatric Risk of Mortality (PRISM) score. We benchmarked our findings by comparing with a previously healthy group of children with lower respiratory tract infections. Functional impairment was measured by the Functional Status Scale, wherein new morbidity was defined as an increase of ≥3 points relative to the prehospital baseline. Relative to matched control subjects, HCT patients had similar admission PRISM scores ( P  = .516) but greater PICU mortality (12.9% [11/85] versus 6.2% [21/340], P  = .035). However, among those who survived to PICU discharge, HCT patients had similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 17.2% [55/319], P  = .622) and similar rates of resolution of new morbidity by hospital discharge (54.5% [6/11] versus 60.0% [33/55], P  = .737). Relative to the comparison group with lower respiratory tract infections, HCT patients had both greater admission PRISM scores ( P  < .001) and greater PICU mortality (12.9% [11/85] versus 1.6% [5/308], P  < .001). However, among those who survived to PICU discharge, HCT patients again displayed similar rates of new morbidity at PICU discharge (14.9% [11/74] versus 22.1% [67/303], P  = .168) as well as resolution of new morbidity by hospital discharge (54.5% [6/11] versus 71.6% [48/67], P  = .299). For pediatric HCT patients PICU survival with new functional morbidity is as prevalent an outcome as PICU mortality. Although pediatric HCT patients have greater PICU mortality than age-, sex-, and PRISM-matched control subjects, they have similar rates of new functional morbidity at PICU discharge and similar resolution of new functional morbidity at hospital discharge. Future interventions focused on improving functional status in pediatric HCT survivors of critical illness are warranted. [ABSTRACT FROM AUTHOR]

Even though hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic cell transplantation (HCT), there is paucity of research on the management of associated multiorgan dysfunction. To help provide standardized care for the management of these patients, the HCT Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium, collaborated to develop evidence-based consensus guidelines. After conducting an extensive literature search, in part 2 of this series we discuss the management of fluids and electrolytes, renal dysfunction; ascites, pleural effusion, and transfusion and coagulopathy issues in patients with VOD. We consider the available evidence using the GRADE criteria. [ABSTRACT FROM AUTHOR]

Veno-occlusive disease (VOD) is a common and potentially fatal complication in children undergoing hematopoietic cell transplantation (HCT). It occurs in about one-third of all patients undergoing transplantation and is fatal in 50% of patients with severe disease. Early intervention and specific treatment with defibrotide are associated with improved outcomes. However, there is a lack of supportive care guidelines for management of the multiorgan dysfunction seen in most cases. There is high variability in the management of VOD, which may contribute to the increased morbidity and mortality. Although there is ample research in the specific treatment of VOD, there is paucity of literature regarding the management of ascites, transfusions requirements, fluids and electrolyte dysfunction, delirium, and investigations in children with VOD. The joint working committees of the Pediatric Acute Lung Injury and Sepsis Investigators and the Pediatric Blood and Marrow Transplantation Consortium collaborated to develop a series of evidence-based supportive care guidelines for management of VOD. The quality of evidence was rated and recommendations were made using Grading of Recommendations, Assessment, Development and Evaluation criteria. This manuscript is part 1 of the series and focuses on the need to develop these guidelines; methodology used to establish the guidelines; and investigations needed for diagnosis, prophylaxis, and treatment of VOD in children. [ABSTRACT FROM AUTHOR]

Patients with inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita (DC), or Diamond Blackfan anemia (DBA), can have hematologic manifestations cured through hematopoietic cell transplantation (HCT). Subsequent late effects seen in these patients arise from a combination of the underlying disease, the pre-HCT therapy, and the HCT process. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium on late effects screening and recommendations following allogeneic hematopoietic cell transplantation for immune deficiency and nonmalignant hematologic diseases held in Minneapolis, Minnesota in May 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. This multidisciplinary group of experts in rare diseases and transplantation late effects has already published on the state of the science in this area, along with discussion of an agenda for future research. This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS. [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled “Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease” held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group. [ABSTRACT FROM AUTHOR]

A number of studies have shown that autologous and allogeneic hematopoietic cell transplantation (HCT) contribute to an increased incidence of cardiovascular disease (CVD) and worsening of cardiovascular risk factors that could contribute to further CVD over time. These observations, combined with a notable increase in the number of survivors after HCT in recent years, highlight the need for studies aimed at modifying risk or preventing these outcomes by changing specific approaches and/or post-HCT interventions. To address these issues, the National Heart, Lung and Blood Institute and National Cancer Institute co-sponsored an international initiative on late effects after HCT. This report summarizes the major gaps in knowledge along with detailed recommendations regarding study priorities from the Cardiovascular Disease and Associated Risk Factors Committee, a multidisciplinary panel of international experts. The committee calls for specific studies aimed at understanding and preventing arterial disease and cardiac dysfunction (heart failure, valvular disease, and arrhythmias), as well as decreasing cardiovascular risk factors (hypertension, hyperglycemia, dyslipidemia, and sarcopenic obesity) after HCT. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all-cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with an estimated prevalence of MetS of 31% to 49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. [ABSTRACT FROM AUTHOR]

Allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) provide the potential to cure otherwise fatal diseases but they are resource-intense therapies. There is scant literature describing the burden of hospital readmission in the critical 6-month period of immunosuppression after HCT. We report the incidence, causes, and outcomes of readmission in the 6 months after day 0 of HCT and in the 30 days after hospital discharge. This study is an institutional review board–approved retrospective medical record review of children who underwent HCT at a single institution. Between January 1, 2008 and December 31, 2011, 291 children underwent HCT at our institute. Of these, 140 patients were excluded because they were not followed primarily at our institute for the first 6 months after transplantation, 14 patients were excluded because they died during their initial hospitalization, and 1 patient was excluded because the initial hospitalization was longer than 6 months. Of the remaining 136 patients, 63% had at least 1 readmission. Of the patients who underwent allo-HCT, 78% were readmitted, in contrast to 38% of auto-HCT patients ( P < .001). For the 206 readmissions, the mean length of hospital stay was 10.7 days (range, 1 to 129). Seventy-two percent of auto-HCT patients were initially readmitted for fever, and 46% ultimately had a source identified. No risk factors for readmission were found in the auto-HCT group. Fifty-two percent of allo-HCT patients were readmitted for fever and 28% of these patients ultimately had an identified source. Gastrointestinal-related problems accounted for 30% of primary readmissions among allo-HCT patients. Patients with an unrelated donor had a trend towards increased rates of 30-day readmission ( P = .06) and were more likely to have a second readmission ( P = .002). Patients who were cytomegalovirus (CMV) positive before transplantation were more likely to be readmitted ( P = .02). The majority of children who undergo HCT are readmitted during the critical 180 days after transplantation. Readmission is much more common among allo-HCT patients, in particular those with unrelated donors and CMV-positive serologies before transplantation. Fever is the most common cause of readmission in these patients, and serious infections are identified in a significant portion of patients. These findings and future research in this area will help improve both patient education and resource utilization. [ABSTRACT FROM AUTHOR]

We present a case of a three-yr-old child with a history of multisystem Langerhans cell histiocytosis treated with systemic chemotherapy, who developed progressive liver failure and received an orthotopic split liver transplant while continuing on chemotherapy. One month following transplant, he developed acute graft-vs.-host disease of the skin and gastrointestinal tract. Peripheral blood chimerism studies post-transplant demonstrated an increasing predominance of donor lymphocytes and granulocytes. Shortly after, the patient developed vitiligo, and two yr after transplantation, the patient developed skin manifestations of psoriasis. We discuss and review the current literature, which demonstrates that chimerism following liver transplantation is rare and in our patient may be related to his profound immunosuppression around the time of liver transplant as well the development of acute graft-versus-host disease. While autoimmune disease can occur after solid organ and stem cell transplant, our patient developed skin manifestations of autoimmunity after liver transplantation, which is also rarely described. [ABSTRACT FROM AUTHOR]

Objective The objective of this study is to systematically review the literature onworldwide numbers of leukodystrophy patients undergoing hematopoietic stem cell transplantation (HSCT) as well as the safety and efficacy of the procedure in this patient population. Materials andMethods A PubMed and EMBASE search up to June 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. The effect estimates of HSCT upon survival in early-stage disease versus late-stage disease were compared. Results One hundred and fifty-two studies qualified for inclusion and reported on a total of 689 patients. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Meta-analysis in a subset of larger studies indicates that transplantation in earlier stages of disease fairs better than in the late stages. Beyond survival, little longitudinal data on functional outcome is reported and neurological outcome is sparse. Conclusion Further studies are needed to determine the neurological outcome following HSCT in the leukodystrophies. HSCT in the early stages of cerebral disease is still recommended for select leukodystrophies. [ABSTRACT FROM AUTHOR]

An in vivo validation study was performed to confirm the accuracy of extraoral photobiomodulation therapy (PBMT) dosimetry determined by modelling. The Monte Carlo technique was utilized to calculate the fluence rate and absorbed power of light delivered through multi-layered tissue. Optical properties used during Monte Carlo simulations were taken from the literature. Morphological data of four study volunteers were acquired using magnetic resonance imaging (MRI) scans. Light emitting diode (LED) coupled to a power meter were utilized to measure transmitted power through each volunteer's cheek, in vivo. The transmitted power determined by Monte Carlo modelling was compared to the in vivo measurements to determine the accuracy of the simulations. Experimental and simulation results were in good agreement for all four subjects. The difference between the mean values of the measured transmission was within 12% from the respective transmission obtained using Monte Carlo simulations. The results of the study indicate that Monte Carlo modelling is a robust and reliable method for light dosimetry. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell (HSC) transplantation (allo-HSCT) is a treatment option for several monogenic diseases; however, its use is limited by the need for a matched donor and risk of HSCT-related complications. Autologous HSC gene addition does not have some of these limitations and may have similar efficacy with an improved safety profile. Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion-dependent β-thalassemia (TDT) using betibeglogene autotemcel (beti-cel, LentiGlobin for TDT) in the HGB-204, -205, -207, and -212 studies, sickle cell disease (SCD) using LentiGlobin for SCD in HGB-205 and -206, and cerebral adrenoleukodystrophy (CALD) using Lenti-D in ALD-102. The safety outcomes following autologous gene modified HSCT in these ongoing studies are summarized. HSCs are collected using disease-appropriate procedures, then CD34+ cells are transduced with LVV encoding disease-specific therapeutic transgenes. After myeloablation with busulfan (SCD, TDT) or busulfan/cyclophosphamide (CALD), patients are infused with LVV-transduced CD34+ HSCs. Patients are followed for two years and offered participation in long term follow-up studies (LTF-303 [NCT02633943] or LTF-304 [NCT02698579]). Across all 6 studies, 110 patients have been treated as of most recent analyses (Table 1). Patients have been followed for <1 to 60.6 months and 47 patients have >2 years follow-up. No patient experienced primary or secondary graft failure. One patient with CALD experienced disease progression and died 22 months after drug product (DP) infusion of disease complications. Two additional patients with CALD withdrew from the study after DP infusion and were referred for allo-HSCT. All other patients with CALD, TDT, and SCD remain alive. Most (107/110) patients had ≥ one grade 3 or 4 adverse event (AE) attributed to conditioning; most common AEs were cytopenia, febrile neutropenia, and stomatitis. Myelodysplastic syndrome was reported in one patient with SCD. After investigation for LVV insertion in malignant cells, the AE was assessed as not related to LentiGlobin insertion or transgene expression. AEs reported as related to the DP are shown in Table 1. There was no GVHD and no clinically relevant clonal dominance or LVV-mediated replication competent lentivirus. Data from 110 patients followed for up to 5 years supports that the safety profile of gene-modified autologous HSCT does not carry the risks of GVHD, graft rejection, and long-term immunosuppression attendant to allo-HSCT. While the safety profile beyond 5-years is still being established, these data suggest that HSC gene therapy may be an acceptable therapy for patients with TDT, SCD, and CALD, particularly in patients at increased risk of complications from allo-HSCT, such as those who lack a suitable donor or are more advanced in age. [ABSTRACT FROM AUTHOR]

Bivalirudin, a direct thrombin inhibitor, has recently emerged as a promising option for anti-coagulation during cardiopulmonary bypass in patients who cannot receive heparin. There is limited experience with the use of bivalirudin in children. We present the case of a child with heparin-induced thrombocytopenia with thrombosis (HIT Type II) who underwent successful orthotopic cardiac transplantation using bivalirudin as the primary anti-coagulant for cardiopulmonary bypass. [Copyright &y& Elsevier]

Resident physicians from a pediatric academic training program developed a hospital-wide research project in an effort In enhance their residency research experience. In this model, residents themselves assumed primary responsibility for each stage of a large prospective clinical research study. The project, which was integrated successfully into the residency program, enabled a large group of residents, with mentorship from a dedicated faculty member, to benefit from a structured clinical research experience while providing the flexibility necessary to meet the demands of a busy residency curriculum. Careful topic selection with a well-defined end point, faculty involvement, resident collegiality, and institutional support were factors identified by study leaders as central to the success of this model. [ABSTRACT FROM AUTHOR]

Background: Hyponatremia has emerged as an important cause of race-related death and life-threatening illness among marathon runners. We studied a cohort of marathon runners to estimate the incidence of hyponatremia and to identify the principal risk factors.Methods: Participants in the 2002 Boston Marathon were recruited one or two days before the race. Subjects completed a survey describing demographic information and training history. After the race, runners provided a blood sample and completed a questionnaire detailing their fluid consumption and urine output during the race. Prerace and postrace weights were recorded. Multivariate regression analyses were performed to identify risk factors associated with hyponatremia.Results: Of 766 runners enrolled, 488 runners (64 percent) provided a usable blood sample at the finish line. Thirteen percent had hyponatremia (a serum sodium concentration of 135 mmol per liter or less); 0.6 percent had critical hyponatremia (120 mmol per liter or less). On univariate analyses, hyponatremia was associated with substantial weight gain, consumption of more than 3 liters of fluids during the race, consumption of fluids every mile, a racing time of >4:00 hours, female sex, and low body-mass index. On multivariate analysis, hyponatremia was associated with weight gain (odds ratio, 4.2; 95 percent confidence interval, 2.2 to 8.2), a racing time of >4:00 hours (odds ratio for the comparison with a time of <3:30 hours, 7.4; 95 percent confidence interval, 2.9 to 23.1), and body-mass-index extremes.Conclusions: Hyponatremia occurs in a substantial fraction of nonelite marathon runners and can be severe. Considerable weight gain while running, a long racing time, and body-mass-index extremes were associated with hyponatremia, whereas female sex, composition of fluids ingested, and use of nonsteroidal antiinflammatory drugs were not. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) is a severe complication of hematopoietic stem cell transplant (HSCT). To determine incidence, risk factors and outcomes for patients who develop TMA following HSCT. All patients were prospectively screened for TMA at participating centers with daily CBC, renal panel, and blood pressure; twice weekly LDH; and weekly urine analysis, including urine protein to creatinine ratio, from the start of the preparative regimen through the first 30 days. All labs were transitioned to weekly from day +30 to +100. TMA was diagnosed if (1) pathologic evidence of TA-TMA (e.g., renal biopsy with evidence of TMA), or (2) if meeting laboratory/clinical markers diagnostic for TMA (Figure 1). Each site retrospectively reviewed the data from screened patients from their respective center, and these data were aggregated to determine outcomes. 589 consecutive patients received TMA screening at the 12 participating centers from May 1, 2016 through June 30, 2018. TMA was diagnosed in 10% (20 of 198) of autologous and 21% (85 of 391) of allogeneic HSCT recipients. Patients undergoing HSCT for an underlying immune deficiency or bone marrow failure syndrome had a significantly higher rate of TMA (p=<0.001) (Figure 2). TMA was diagnosed at a median of 32 (IQR 24-44) days post-HSCT. Patients with TMA had a higher need for intensive care admission (46% vs. 17%, p=0.0001); increased incidence of respiratory failure (19% vs. 7%, p=0.0001); and increased incidence of bloodstream infections (44% vs. 22%, p=0.0001) in the first 100 days versus patients not diagnosed with TMA. Patients with TMA averaged significantly more days inpatient during the first 100 days than those without TMA (65 +/-27 vs. 41 +/-22 days; p=0.001). Further, patients with TMA averaged significantly more days in the ICU during the first 100 days than those without TMA (10 +/-20 vs. 3 +/-11 days; p=0.001). Six-month non-relapse mortality was significantly higher in the TMA group (19/105,18% vs. 19/484,4%; p=0.0001). Finally, six-month overall survival was significantly decreased in patients with TMA (84/105, 80% vs. 453/484,94%; p=0.0001) (Figure 3). In patients diagnosed with TA-TMA, 49 (47%) were treated with eculizumab and 3 (3%) received plasmapheresis. In this multi-center cohort we demonstrate a high incidence of TMA after pediatric HSCT through prospective screening. Patients with TA-TMA have higher morbidity and mortality when compared to patients without TA-TMA. [ABSTRACT FROM AUTHOR]

Objectives: Acute respiratory failure is common in pediatric hematopoietic cell transplant recipients and has a high mortality. However, respiratory prognostic markers have not been adequately evaluated for this population. Our objectives are to assess respiratory support strategies and indices of oxygenation and ventilation in pediatric allogeneic hematopoietic cell transplant patients receiving invasive mechanical ventilation and investigate how these strategies are associated with mortality.Design: Retrospective, multicenter investigation.Setting: Twelve U.S. pediatric centers.Patients: Pediatric allogeneic hematopoietic cell transplant recipients with respiratory failure.Interventions: None.Measurements and Main Results: Two-hundred twenty-two subjects were identified. PICU mortality was 60.4%. Nonsurvivors had higher peak oxygenation index (38.3 [21.3-57.6] vs 15.0 [7.0-30.7]; p < 0.0001) and oxygen saturation index (24.7 [13.8-38.7] vs 10.3 [4.6-21.6]; p < 0.0001), greater days with FIO2 greater than or equal to 0.6 (2.4 [1.0-8.5] vs 0.8 [0.3-1.6]; p < 0.0001), and more days with oxygenation index greater than 18 (1.4 [0-6.0] vs 0 [0-0.3]; p < 0.0001) and oxygen saturation index greater than 11 (2.0 [0.5-8.8] vs 0 [0-1.0]; p < 0.0001). Nonsurvivors had higher maximum peak inspiratory pressures (36.0 cm H2O [32.0-41.0 cm H2O] vs 30.0 cm H2O [27.0-35.0 cm H2O]; p < 0.0001) and more days with peak inspiratory pressure greater than 31 cm H2O (1.0 d [0-4.0 d] vs 0 d [0-1.0 d]; p < 0.0001). Tidal volume per kilogram was not different between survivors and nonsurvivors.Conclusions: In this cohort of pediatric hematopoietic cell transplant recipients with respiratory failure in the PICU, impaired oxygenation and use of elevated ventilator pressures were common and associated with increased mortality. [ABSTRACT FROM AUTHOR]

Background: Hyponatremia has emerged as an important cause of race-related death and life-threatening illness among marathon runners. We studied a cohort of marathon runners to estimate the incidence of hyponatremia and to identify the principal risk factors. Methods: Participants in the 2002 Boston Marathon were recruited one or two days before the race. Subjects completed a survey describing demographic information and training history. After the race, runners provided a blood sample and completed a questionnaire detailing their fluid consumption and urine output during the race. Prerace and postrace weights were recorded. Multivariate regression analyses were performed to identify risk factors associated with hyponatremia. Results: Of 766 runners enrolled, 488 runners (64 percent) provided a usable blood sample at the finish line. Thirteen percent had hyponatremia (a serum sodium concentration of 135 mmol per liter or less); 0.6 percent had critical hyponatremia (120 mmol per liter or less). On univariate analyses, hyponatremia was associated with substantial weight gain, consumption of more than 3 liters of fluids during the race, consumption of fluids every mile, a racing time of >4:00 hours, female sex, and low body-mass index. On multivariate analysis, hyponatremia was associated with weight gain (odds ratio, 4.2; 95 percent confidence interval, 2.2 to 8.2), a racing time of >4:00 hours (odds ratio for the comparison with a time of <3:30 hours, 7.4; 95 percent confidence interval, 2.9 to 23.1), and body-mass-index extremes. Conclusions: Hyponatremia occurs in a substantial fraction of nonelite marathon runners and can be severe. Considerable weight gain while running, a long racing time, and body-mass-index extremes were associated with hyponatremia, whereas female sex, composition of fluids ingested, and use of nonsteroidal antiinflammatory drugs were not. N Engl J Med 2005;352:1550-6. [ABSTRACT FROM AUTHOR]