An unusual pattern of B‐cell immunological reconstitution after allogeneic stem cell transplantation: A possible correlation with CMV reactivation?

Abstract: IR after HSCT is a slow process that involves several components of the immune response, and, in allogeneic setting, it can be delayed by GvHD and immuno‐suppressive therapy. Our study on IR post‐HSCT included a child with FA who underwent MUD transplantation. To evaluate B, T and NK cell reconstitution and to investigate the differentiation of B lymphocyte repertoire, this patient was carefully monitored at various time points by IgHCDR3 (third complementarity determining region of the immunoglobulin heavy chain) fingerprinting and by FACS analysis. IgHCDR3 fingerprinting showed a strong oligoclonality of IgM and IgG profiles from day +60 to +180 post‐transplant. CMV reactivation was present at the same time points and overlapped the clonal pattern shown in IgHCDR3 fingerprinting. Immunophenotype analysis showed early repopulation of T and NK cells following HSCT, whereas B cells increased first at one yr post‐transplant. The overlapping of virus reactivation and B‐cell clonal expansion seems to suggest that B lymphocytes may be involved in the CMV immunological response, at least in the early time points after HSCT when the immune repertoire is still reconstituting.     

How do parents of 4‐ to 5‐year‐old children perceive the weight of their children?

Introduction: A heavier weight in adults is becoming the norm rather than an abnormal weight. Whether the same trend is happening in children is unknown. Objective: To assess the perception of the weight of 4‐ to 5‐year‐old children and the recognition of overweight by both parents. Design: Population‐based survey. Participants: A questionnaire was sent to parents of 1155 4‐ to 5‐year‐old children. Results: In total, 439 questionnaires (35%) were returned. Of all, 90% of the children had a normal weight, 9.3% were overweight and 4.1% were obese. For all weight classes, the parents depicted the child as lighter on both the verbal and visual scale. Of all, 75% of mothers of overweight children stated that the child had a normal weight. In obese children, 50% of the mothers believed that the child had a normal weight. Conclusion: Children with a weight in the normal range were considered by their parents as a little too light or too light. Overweight was considered as normal weight, and obesity as normal or a little too heavy. The perception of a normal weight in children at 4–5 years is distorted.     

Diagnosis of gastrointestinal graft‐versus‐host disease—Is rectal biopsy enough?

BACKGROUND: Graft-versus-host disease (GVHD) is an important cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). The clinical diagnosis of gastrointestinal GVHD can be difficult to establish and endoscopic diagnosis entails a procedural risk. The aim of this study was to determine whether rectal biopsy alone might be sufficient to establish or exclude the diagnosis of intestinal GVHD. METHODS: A retrospective chart review of children with histological evidence of gastrointestinal GVHD after allogeneic BMT at the Royal Children's Hospital in Melbourne, Australia, between January 1981 and July 2004. RESULTS: During the study period, 264 patients received allogeneic BMT. Thirty-three had either an upper or lower gastrointestinal endoscopy, or both. Of these, 14 (8 M: 6 F, mean age 9 years 5 months at the time of BMT) had histological features suggestive of GVHD in at least one gastrointestinal biopsy. Overall, 9 of 14 could have been diagnosed with GVHD on the basis of rectal biopsies alone (negative predictive value: 64%). Gastroscopy was needed to establish the diagnosis in a further five patients. Multiple biopsies obtained from each site in the lower gastrointestinal tract showed similar histological findings, but there was frequent non-agreement between biopsies obtained at differing sites within the upper gastrointestinal tract. CONCLUSIONS: Based on these results, we suggest that regardless of symptoms, rectal biopsy should initially be performed to identify gastrointestinal GVHD. Gastroscopy should be added only if the rectal biopsy is unhelpful and there is still good reason to suspect GVHD.     

Use of subcutaneous treprostinil in pediatric pulmonary arterial hypertension—Bridge‐to‐transplant or long‐term treatment?

PAH is a progressive life‐threatening disease in children. While parenteral prostacyclin therapy improves survival in patients with severe PAH, central line‐related complications are common. Our aim was to assess the efficacy, safety, and tolerability of subcutaneous treprostinil treatment in pediatric PAH patients. Eight patients were treated with subcutaneous treprostinil at the Pediatric Heart Center Budapest. Indications for subcutaneous treprostinil therapy were clinical worsening and/or echocardiographic progression or switch from intravenous to subcutaneous therapy. Following treprostinil initiation, clinical status improved or did not change in four of eight patients. Two patients were lost early during treprostinil therapy, parenteral treprostinil as a rescue therapy being insufficient in these cases. The final dose in long‐term treated patients was between 60 and 100 ng/kg/min. Aside from thrombocytopenia, other severe side effects were not observed. Potts shunt was performed as palliative treatment in two cases. Three patients had successful lung transplantation, and one died while on the waiting list. Long‐term subcutaneous treprostinil could be a safe and well‐tolerated therapy in children with severe PAH even at higher doses. It may serve as an alternative to intravenous prostacyclin treatment allowing to avoid the potential complications of permanent central line placement.     

Medication‐induced diabetes during induction treatment for ALL,an early marker for future metabolic risk?

Medication‐induced diabetes (MID) is seen in children treated for acute lymphoblastic leukemia (ALL) mostly during induction, due to the use of l ‐asparaginase and glucocorticoids. Our objective was to assess whether MID during induction, is a risk factor for future impaired glucose tolerance (IGT), diabetes, or metabolic syndrome. Ninety survivors of pediatric ALL, ages 10 yr and older were recruited, 30 with history of MID and 60 controls. Waist/height ratio >0.5 was considered as an increased risk for central adiposity and insulin resistance. Lipid profile and an oral glucose tolerance test (OGTT) were performed. Study patients were older than controls (17.2 vs. 14.9, p < 0.05). The groups had similar sex distribution, body mass index (BMI) z‐score, and Tanner staging. A waist/height ratio of >0.5 was seen in 60 and 31.7% of the study and control groups, respectively (p = 0.01). Increased frequency of IGT in the study group compared with the control group was seen (13.3 and 1%, respectively) (p = 0.07). We observed a trend toward higher proportion of patients with multiple features of metabolic syndrome in the study compared with control group (16.7 vs. 5%, p = 0.09). In conclusion, MID during induction may be an early marker for metabolic disturbances later in life. The higher rates of increased waist/height ratio, and subjects with multiple metabolic syndrome features, may predict a metabolic risk in children with history of MID. Rates of IGT were four fold higher in the study group although not statistically significant. MID may be a ‘red flag’ indicating the need for ongoing metabolic screening and lifestyle modifications to prevent future metabolic disease.     

Preservation of C‐peptide secretion in subjects at high risk of developing type 1 diabetes mellitus – a new surrogate measure of non‐progression?

Individuals at high risk of developing type 1 diabetes mellitus can be identified using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention Trial-1 (DPT-1), annual intravenous infusions of low doses of regular insulin, together with daily subcutaneous injection of a single low dose of Ultralente insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in high-risk non-diabetic relatives. In our study, we attempted to achieve beta-cell rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin twice daily to high-risk non-diabetic subjects in an effort to prevent or delay the onset of the disease. The maximum tolerable dose was given with the dose reduced for any hypoglycemia (mean dose 0.33 +/- 0.15; range 0.09-0.66 units/kg/d). We treated 26 subjects who were confirmed to have islet cell antibodies (ICAs) and a low first-phase insulin response (FPIR) to intravenous glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance (IGT). The median duration of follow-up was 5.5 yr. Diabetes occurred in 10 of 12 subjects with IGT and five of 14 subjects with normal glucose tolerance. The cumulative incidence of diabetes was the same as with that seen in a matched, observation group (subjects followed prospectively as part of the University of Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the rate of progression (p = 0.79). There was a higher rate of progression to diabetes in the group with abnormal glucose tolerance at baseline than in those with normal baseline glucose tolerance (p = 0.003). Interestingly, in non-progressors, as opposed to progressors, there was no fall in C-peptide (peak and area under the curve) production regardless of the type of tolerance testing (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the dose and regimen of NPH insulin used, insulin did not delay or prevent the development of type 1 diabetes. However, preservation of C-peptide production in the prediabetic period appears to indicate non-progression to clinical disease and may serve as a new surrogate for determining response to preventative efforts.     

A developmental analysis of self‐reported fears in late childhood through mid‐adolescence: social‐evaluative fears on the rise?

BACKGROUND: The frequently reported decline in the overall frequency and intensity of fears during late childhood and adolescence may mask different developmental patterns for two broad subclasses of fears: fears concerning physical danger and fears concerning social evaluation. It was investigated if physical fears decrease between late childhood and mid-adolescence, while social-evaluative fears increase during this period. It was also studied if changes in both sets of fears are more strongly related to socio-cognitive maturity than to age, which itself is only a proxy measure of maturity. METHODS: A non-clinical sample of 882 children and adolescents (ages 8-18) was recruited for study. Fears were assessed using the Ollendick Fear Survey Schedule for Children-Revised (FSSC-R). A Principal Components Analysis (PCA) was conducted to study the factor structure of the Failure and Criticism subscale of the FSSC-R. Level of development was assessed using the Sentence Completion Test for Youth (SCT-Y), a measure of socio-cognitive maturity that is based on Loevinger's model, and measure, of ego development. RESULTS: The PCA of the Failure and Criticism subscale revealed three factors: Social Evaluation, Achievement Evaluation, and Punishment. As predicted, the significant decrease of overall fearfulness obscured two contradictory developmental patterns: (a) fears of physical danger and punishment decreased with age, whereas (b) fears of social and achievement evaluation increased with age. Hierarchical regression analyses showed that the age effect for social-evaluative fears was explained entirely on the basis of developmental differences in socio-cognitive maturity (controlling for verbal ability). In contrast, age was a better predictor of the decrease of physical and punishment fears (although socio-cognitive maturity still added to the predictive value of age). CONCLUSION: The expression of social evaluation fears during adolescence appears not atypical and might be a corollary of socio-cognitive maturation. At the same time, the natural presence of those fears during adolescence appears to constitute a vulnerability for developing a social anxiety disorder.     

Does the choice of bottle nipple affect the oral feeding performance of very‐low‐birthweight (VLBW) infants?

Background: There is a continuous debate regarding the best bottle nipple to be used to enhance the bottle-feeding performance of a preterm infant. Aim: To verify that feeding performance can be improved by using the bottle nipple with the physical characteristics that enhance infants' sucking skills. Methods: Ten “healthy” VLBW infants (941±273 g) were recruited. Feeding performance was monitored at two time periods, when taking 1-2 and 6-8 oral feedings/d. At each time and within 24 h, performance was monitored using three different bottle nipples offered in a randomized order. Rate of milk transfer (ml/min) was the primary outcome measure. The sucking skills monitored comprised stage of sucking, suction amplitude, and duration of the generated negative intraoral suction pressure. Results: At both times, infants demonstrated a similar rate of milk transfer among all three nipples. However, the stage of sucking, suction amplitude, and duration of the generated suction were significantly different between nipples at 1-2, but not 6-8 oral feedings/d.

Conclusion: We did not identify a particular bottle nipple that enhanced bottle feeding in healthy VLBW infants. Based on the notion that afferent sensory feedback may allow infants to adapt to changing conditions, we speculate that infants can modify their sucking skills in order to maintain a rate of milk transfer that is appropriate with the level of suck-swallow-breathe coordination achieved at a particular time. Therefore, it is proposed that caretakers should be more concerned over monitoring the coordination of suck-swallow-breathe than over the selection of bottle nipples.     

Primary mediastinal B‐cell lymphoma in the pediatric patient: Can a rational approach to therapy be based on adult studies?

The literature on adult and pediatric primary mediastinal B‐cell lymphoma (PMBCL) was reviewed and compared. Biologically, adult PMBCL has more similarities to Hodgkin Lymphoma (HL) than diffuse large B‐cell lymphoma (DLBCL). Pediatric studies suggest that the biology is similar to that in adults. Median age of children is 14.3 years and the overall survival (OS) is reported as 78.6% and event‐free survival (EFS) as 67.4%. Adverse prognostic factors included LDH >500 and mass size over 10 cm, with a trend towards better survival in younger patients. Studies in adults show better survival with intensified chemotherapy and the addition of rituximab. Data on the use of radiation therapy show improved CR rates and survival with addition of involved field radiation therapy (IFRT). Positron emission tomography (PET) with computerized tomography (CT) imaging response‐assessment after two courses and at therapy‐end may allow for the rational use of IFRT in pediatric/adolescent patients who are more susceptible to development of adverse late effects. Pediatr Blood Cancer 2009;52:566–570. © 2008 Wiley‐Liss, Inc.     

Repeated detection of gas in the portal vein after liver transplantation: A sign of EBV‐associated post‐transplant lymphoproliferation?

A 1-yr-old child presented with intractable right sided pleural effusion and progressive clinical deterioration 3 weeks after liver transplantation for Alagille Syndrome. He had been treated successfully for severe acute rejection before. Ultrasound and Doppler mode studies repeatedly demonstrated air in the portal vein. Intra-abdominal and intra-thoracic lymphoproliferation was detected, and EBV virus load and serology were suggestive of primary EBV infection. Liver biopsy revealed blast-like infiltrates of B-cells, considered diagnostic for post-transplant lymphoproliferative disease. The disease resolved upon reduction of immunosuppression. We suggest that the detection of portal vein gas in pediatric liver transplant recipients beyond the early post-operative period may be a sign of intra-abdominal post-transplant lymphoproliferative disease.