Health‐related quality of life in pediatric intestinal transplantation

To determine HRQOL after pediatric intestinal transplantation. Thirty‐four IT survivors from 1999 to 2012 were asked to complete age‐specific HRQOL non‐disease‐specific questionnaires: TAPQOL (0–4 yr), KINDL‐R (5–7 yr; 8–12 yr; 13–17 yr), and SF‐36v2 (>18 yr), all validated with Spanish population. Primary caregiver completed a SF‐36 questionnaire and CBI. Thirty‐one participants were included. Median age was 10.2 yr (1–29) and time after transplant 4.4 yr (0–13). Overall patient scores were 78.2 ± 10.6 (n = 8), 83.3 ± 9.7 (n = 6), 72.2 ± 9.21 (n = 6), 80.5 ± 12.4 (n = 7), and 82.2 ± 12.4 (n = 4) for each age group. Highest scores were obtained for vitality (group I), self‐esteem (group IV), and physical and social functioning and emotions (group V). Lowest scores were obtained in appetite and behavior (I), family and school (III), and chronic disease perception (III, IV). No significant differences were found between caregivers and their children. CBI showed stress in 52%. SF‐36 for caregivers was lower than general population. No significant differences were found depending on relevant clinical and sociodemographic data. HRQOL was acceptable and improved with age and time since transplantation. Parents had a slighter own QOL and worse perception of health than their children. When successful, intestinal transplantation allows a normal life in most patients and can be offered as an attractive option.     

Acute graft‐versus‐host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single‐center experience during 10 yr

a‐GvHD may complicate allogeneic HSCT. In this retrospective single‐center study, we evaluated incidence and risk factors of a‐GvHD in 197 consecutive allogeneic pediatric HSCTs applying Glucksberg and NIH a‐GvHD classifications. Among 179 eligible transplants, the cumulative incidence of grade 0–I a‐GvHD was 48% and grade II–IV was 52%. None of the considered variables significantly influenced the incidence of grade II–IV a‐GvHD. Malignancy and myeloablation were associated with an increased risk of classic a‐GvHD (p < 0.01). Seventy‐two percentage of children are alive, with a significant difference in OS and TRM between grade 0 and I vs. grade II and IV a‐GvHD; this observation was reproduced in the non‐malignant setting, while only a disparity in TRM was evidenced in children with malignancy. In our experience, the incidence of a‐GvHD was similar, regardless of donor type. Myeloablation and malignant disease represented the only risk factors for classic a‐GvHD. Our results highlight the need for a better prevention of this complication in the non‐malignant setting.     

Health‐related and diabetes‐related quality of life in Japanese children and adolescents with type 1 and type 2 diabetes

Background: The aim of this study was to assess (i) the health‐related quality of life (HR‐QOL) of primary, junior and high school children with type 1 and type 2 diabetes and to compare it with that of healthy school children; and (ii) to compare the diabetes‐related QOL (DR‐QOL) and the QOL of parents of children with diabetes, between type 1 and type 2 diabetes in Japan. Methods: Overall, 471 patients aged 9–18 years (368 with type 1 and 103 with type 2 diabetes) and their parents were involved. QOL was assessed using a self‐administered questionnaire. Results: The total score for HR‐QOL of primary and junior school children with type 1 diabetes was significantly higher than that of those with type 2 diabetes and healthy controls. However, there were no significant differences in high school children. Some subscales regarding HR‐QOL were significantly lower for children with type 2 diabetes than for children with type 1 diabetes or healthy controls. The DR‐QOL of children with type 1 and type 2 diabetes did not significantly differ. The Family Burden and Family Involvement were significantly greater in parents of children with type 1 diabetes. There were significantly positive correlations between HR‐QOL and DR‐QOL in both groups. In type 1 diabetes only, there were significant negative correlations between glycated hemoglobin and some subscales of the HR‐QOL and QOL of parents of children with diabetes, and weak positive correlation between glycated hemoglobin and Family Burden. Conclusions: The HR‐QOL of school children with type 1 diabetes was higher than that of those with type 2 diabetes and healthy school children. The QOL of school children with type 1 diabetes was not impaired.     

Trends in the off‐label use of β‐blockers in pediatric patients

The use of US Food and Drug Administration (FDA)‐approved drugs for the treatment of an unapproved indication or in an unapproved age group, or at doses or route of administration not indicated on the label is known as off‐label use. Off‐label use may be beneficial in circumstances when the standard‐of‐care treatment has failed, and/or no other FDA‐approved medications are available for a particular condition. In pediatric patients, off‐label use may increase the risk of adverse events as pharmacokinetic and pharmacodynamic data are limited in children. Approximately 73% of off‐label drugs currently prescribed for various conditions do not have sufficient scientific evidence for safety and efficacy. For example, β‐blockers are a class of drugs with FDA‐approval for very few indications in pediatrics but are commonly used for various off‐label indications. Interestingly, the proportion of off‐label use of β‐blockers in adults is at about 52% (66.2 million) of the total number of β‐blockers prescribed. The frequency of off‐label use of β‐blockers in children is also high with limited data on the indications as well as safety and efficacy. We present trends in off‐label use of β‐blockers in children to discuss drug safety and efficacy and include recommendations for pediatric providers.     

Health-related quality of life in paediatric patients with inflammatory bowel disease related to disease activity

Aim: Impaired health‐related quality of life (HRQoL) and an increased risk of psychosocial problems may encounter children and adolescents with inflammatory bowel disease (IBD). Generic HRQoL questionnaires, 15D designed for subjects over 16 years of age, 16D for adolescents aged 12–15 and 17D for younger children, allow comparison to healthy peers and have not been used in children with IBD before. Further, in paediatric IBD patients, HRQoL has not been related to disease activity. We evaluated the applicability of 15D, 16D and 17D questionnaires in the paediatric IBD population and examined how HRQoL is influenced by changes in clinical activity of IBD. Methods: The study subjects recruited at their scheduled, routine appointment in the outpatient clinic of the children's hospital completed the HRQoL questionnaire at baseline and again after 3–5 months. Disease activity was estimated by a three‐level scale. The HRQoL of the study population was compared with that of the age‐standardised general population. Results: Fifty‐five children, aged 7–19 years, were recruited. The HRQoL scores strongly correlated with the activity of the disease (P < 0.001). The two oldest age groups with IBD had lower HRQoL scores than age‐standardised peers (P= 0.001/0.04). There was no gender difference in HRQoL scores. Conclusions: IBD has a considerable impact on the HRQoL of children and adolescents. The generic HRQoL instruments used appeared to be promising tools for examining HRQoL in paediatric IBD patients in different age groups, but larger studies to establish their usefulness in the follow‐up of young patients are still warranted.     

Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients

Tacrolimus has become an effective alternative to cyclosporine as a component of primary immunosuppression in pediatric renal transplant patients, but the information on the pharmacokinetic characteristics of tacrolimus in young patients is still limited. The primary objective of this study was to determine the effect of patient age, ethnicity, and concurrent steroid administration on tacrolimus pharmacokinetics in pediatric renal transplant patients. The study population consisted of 30 pediatric patients, age 1.5-18.6 yr, who received a kidney transplant between July 1999 and February 2004. After twice daily dosing was stabilized based on clinical judgment, at least 5 days postoperatively, tacrolimus levels were drawn prior to, and 1, 2, 4, 8, and 12 h after the morning dose. The mean dose of tacrolimus was 0.12 mg/kg/dose. Mean trough level was 11.9 +/- 5.0 ng/mL. Mean area under the curve (AUC) was 192 +/- 84 with a range of 78-360 h x (ng/mL). The correlation between trough level and AUC was only fair (r = 0.74); later time points correlated better with AUC, and an excellent correlation (r = 0.96) was obtained between the mean of trough and 2-h level (C(2)) and AUC. There was a negative correlation between age and dose per body weight (r = -0.68). African-American patients had marginally lower drug exposure with similar dosing. Three age groups (<5, 5-12, and >12 yr) were compared with respect to dosing and AUC. Despite similar AUC in all three groups, the mean dose per kg required to achieve the AUC was 2.7- and 1.9-fold higher in the <5 and 5-12-yr groups, respectively, compared with the >12-yr group. Nine of the 30 patients were on a totally steroid-free regimen. Their tacrolimus dose and trough levels were similar to those of steroid-exposed patients, but their mean AUC was 41% higher. Our results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid-free regimen despite no change in trough level.     

Evaluating pharmacokinetics and pharmacodynamics of intravenous busulfan in pediatric patients receiving bone marrow transplantation

Abstract: BU is a commonly used conditioning agent in BMT. However, it is a narrow therapeutic index drug which shows a strong correlation between AUC and both efficacy and toxicity. Studies in pediatric patients have suggested that children less than four yr of age have a greater clearance and thus lower AUC at standard adult doses. The goal of this retrospective analysis was to evaluate any age‐related pharmacokinetic and pharmacodynamic differences in pediatric patients who received BU as a conditioning agent. From 2003 to 2006, 21/77 pediatric patients who received BMT were reviewed. There were 15 males and six females with a mean age of six yr old. Diagnoses of leukemia (n = 11), Hodgkin’s lymphoma (n = 3), myelodysplastic syndrome (n = 2), and other (n = 5) were included. Sixteen patients received BU + cyclophosphamide while five patients received BU + another agent. There were 20 allogeneic and one autologous transplants among which 16 were human leukocyte antigen matched and five were mismatched. Average BU clearance in patients younger than four yr old (n = 8) was 4.1 ± 1.0 mL/min/kg vs. 3.1 ± 0.7 mL/min/kg in patients older than four yr old (n = 13) (p = 0.02). The corresponding averages for AUC were 998 ± 226 μm ·min vs. 1155 ± 183 μm ·min (p = 0.12). No patients younger than four yr old developed VOD while five of the older patients did (p = 0.044). There were no significant differences in terms of engraftment and acute GvHD. There were significant age‐related pharmacokinetic differences in pediatric patients less than four yr of age receiving BU for conditioning prior to BMT. There was a decrease in drug toxicity seen in these patients.     

Plasma‐derived C1‐INH for managing hereditary angioedema in pediatric patients: A systematic review

Presently, medications approved for children with Hereditary Angioedema (HAE) are extremely limited. This is especially the case for children under 12 years of age. For this reason we reviewed and summarized the data on treatment of children with HAE. Available data indicate that plasma derived C1‐inhibitor is a safe, effective treatment option for HAE in pediatric patients, including those below 12 years of age. Other therapies are also appear safe for the under 12 year of age, but less data are available. Importantly, home‐based treatment of HAE in this age group appears to be safe and effective and can improve quality of life. These findings support current HAE consensus guidelines which strongly recommend the use of plasma derived C1‐inhibitor as a first‐line treatment in children and encourage home and self‐treatment.     

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.     

Infusion‐related febrile reaction after haploidentical stem cell transplantation in children is associated with higher rates of engraftment syndrome and acute graft‐versus‐host disease

The clinical significance and prognostic impact of IRFR in pediatric recipients of haploidentical SCT are not clearly understood. Therefore, we attempted to determine how IRFR affects clinical outcomes in children. Clinical data from 100 consecutive pediatric patients (60 boys and 40 girls; median age, 12 yr [range, 2–18 yr] after haploidentical SCT between January 2010 and December 2012 were collected retrospectively. IRFR was described as unexplained fever (>38 °C) within 24 h after the infusion of haploidentical PBSCs. Thirty‐eight (38.0%) cases met the criteria for IRFR. ES was found in 24 (63.2%) of the 38 children with IRFR, with the median time of developing ES of +9 (7–16) days, while only 15 (25.4%) of the 59 children without IRFR were found with ES (p < 0.001). Similarly, the cumulative incidence rates of grade II–IV aGVHD were 50.0% in the IRFR group and 29.3% (p = 0.012) in the non‐febrile group. Multivariate analysis identified IRFR as the risk factor for ES and aGVHD. In the haploidentical setting, IRFR is associated with the development of ES and aGVHD. We attempted to determine how IRFR affects clinical outcomes in children after haploidentical SCT. Thirty‐eight children comprised the IRFR group, and 59 were in the control (non‐IRFR) group. High incidence of ES was observed in children with the occurrence of IRFR. Similarly, the incidence of stage I–IV and II–IV aGVHD was significantly higher in the febrile group. Multivariate analysis showed IRFR to be the risk factor for ES and aGVHD.