Diarrhea in pediatric recipients of solid organ or bone marrow transplants

Diarrhea is common in adults after solid organ transplantation (SOT) and bone marrow transplantation (BMT), but data in children are limited. Therefore, we aimed to determine the incidence and etiology of pediatric early-onset diarrhea in post SOT and BMT.We reviewed children aged 6 months to 18 years who underwent liver transplantation, kidney transplantation or BMT between January 2015 and December 2019 with duration of diarrhea > 72 hours within the first 6 months after transplantation. Clinical data and diarrheal course were collected. Regression analyses were performed to define factors associated with the interested outcomes.Among 252 transplanted patients, 168 patients (66.6%) had 289 documented episodes of diarrhea. A diagnosis of 68.2% of post-transplant diarrhea remained ‘indefinite’. Enteric infection in SOT and gastrointestinal acute graft-versus-host disease (GI-aGVHD) in BMT were the commonly identified etiologies. Among 182 episodes among BMT children, skin rash was more pronounced when compared the ones with diarrhea > 7 days vs ≤ 7 days (odds ratio [OR] 13.9; 95% CI 1.8, 107.6). Males were more likely to develop GI-aGVHD as compared to females (OR 8.9). We found that GI-aGVHD was more common in the ones with skin rash and the presence of white blood cells in stool examination (OR 8.4 and 3.1, respectively). Deaths occurred in 7.7%.Two-thirds of post-transplant children experienced at least one episode of early-onset diarrhea, of which the etiology mainly remains undefined. Various clinical factors of prolonged/chronic diarrhea and GI-aGVHD may help clinicians when managing these children.     

Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3

Background

Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%–70% of the Asian affected population.

Methods

We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3).

Results

Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6–18 months and the age at HSCT was 3.8–15 years in the patients with GD3. The latest age at follow-up was 8–22 years, with a post-HSCT duration of 3–14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment.

Conclusions

ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.     

Cytomegalovirus,adenovirus, and polyomavirus co‐infection among pediatric recipients of allogeneic stem cell transplantation: Characteristics and outcome

Watcharananan SP, Kiertiburanakul S, Piyatuctsanawong W, Anurathapan U, Sungkanuparph S, Pakakasama S, Chantratita W, Hongeng S. Cytomegalovirus, adenovirus, and polyomavirus co‐infection among pediatric recipients of allogeneic stem cell transplantation: Characteristics and outcome.
Pediatr Transplantation 2010: 14:675–681. © 2010 John Wiley & Sons A/S. Abstract: ADV and PMV infection have increasingly been documented as significant complications following allo‐HSCT. Despite increasing recognition, characteristics and outcome of CMV, ADV, and PMV viral co‐infection remain obscured. In this study, a retrospective quantitative PCR analysis of ADV, PMV (BKV and JCV) was performed from pediatric patients’ stored blood samples previously tested for CMV viremia after allo‐HSCT. Clinical and virological characteristics and outcome among patients with and without viral co‐infection were analyzed and compared. From 2001 to 2006, 219 blood samples from 69 patients were studied. Viral DNA was present in 119 samples (52.9%).The proportion of viremia was highest for BKV (30.6%), followed by CMV (20.9%), ADV (9.1%), and JCV (0.5%). Viral co‐infection occurred in 17 patients (24.6%), with CMV/BKV as the most common type (11.6%), followed by CMV/ADV (4.3%) and ADV/BKV (2.9%). From multivariate analysis, factors associated with viral co‐infection were acute GVHD (OR 4.57; 95% CI 1.9–10.96, p = 0.001), level of blood CMV viral load (OR 1.53; 95% CI 1.24–1.89, p < 0.001), and level of blood ADV viral load (OR 1.56; 95% CI 1.05–2.32, p = 0.027). Higher probability of developing viral disease was strongly associated with more types of virus detected in blood (p < 0.001). Significant difference in the causes of death was observed among patients with and without viral co‐infection (p = 0.014). Infection (87.5%) was the major cause of death of patients with viral co‐infection, whereas relapse of hematologic disease (70%) was the major cause of death of patients with mono‐viral infection. Viral co‐infection is a common and significant infectious complication in pediatric recipients of allo‐HSCT. Blood monitoring of CMV, ADV, and BKV is suggested among pediatric patients who develop GvHD or who have rising of CMV or ADV viremia following allo‐HSCT.     

Auto-immune haemolytic anaemia concurrent with Plasmodium vivax infection: a case report

A 7-month-old Myanmar boy was admitted with a 3-day history of fever. He was markedly pale and his temperature was 38·2°C. Peripheral blood smear demonstrated Plasmodium vivax infection with spherocytosis and auto-agglutination of red blood cells. Haematocrit was 16% and reticulocyte count 14·9%. Direct and indirect antiglobulin tests were positive. Antibody analysis was positive for auto-antigen I. P. vivax malaria with auto-immune haemolytic anaemia (AIHA) was diagnosed. He was treated with chloroquine and primaquine for the P. vivax infection, and oral prednisolone for the AIHA. Because of the clinical symptoms of anaemia and mild dyspnoea, blood with the least incompatible red blood cells was transfused. The clinical symptoms and signs improved. At follow-up 3 and 7 weeks after treatment, his haematocrit, reticulocyte count and peripheral blood smear results were within normal limits. Prednisolone was then tapered and stopped. The patient has since been well with no detectable recurrence of AIHA.     

Clinical practice guidelines for children with cancer presenting with fever to the emergency room

Background: Patients with febrile neutropenia (FN) may develop severe infection, septic shock, and death. To improve the outcome of pediatric oncology patients with suspected FN, clinical practice guidelines were developed for these patients at the emergency room (ER). The objective of the present study was to evaluate compliance of the clinical practice guidelines for children with cancer presenting with fever to the ER and adverse outcomes after using the guidelines. Methods: A retrospective cohort study was undertaken of children with cancer presenting with fever to the ER from January 2007 to December 2008 after the clinical guidelines were implemented. The control group was the children with cancer who presented with fever during January 2005–December 2006. Guideline compliance was evaluated by recording the time of initial clinical and laboratory assessment and door‐to‐antibiotic time. The adverse outcomes, including septic shock and death, were determined. Results: There were 170 febrile episodes after using the guidelines. Approximately half (49.4%) of the patients received clinical assessment and laboratory results within 60 min, whereas the antibiotics were administered within 120 min in 80%. Prevalence of septic shock and intensive care unit admission were significantly reduced compared to controls (P = 0.011 and 0.016, respectively). No infection‐associated mortality was found after the implementation of the guidelines. Conclusions: Using the clinical practice guidelines for pediatric oncology patients with fever was found to reduce the adverse outcomes and improve survival.     

Kinetics of Tumor Destruction by Chimeric Antigen Receptor-modified T Cells

The use of chimeric antigen receptor (CAR)–modified T cells as a therapy for hematologic malignancies and solid tumors is becoming more widespread. However, the infusion of a T-cell product targeting a single tumor-associated antigen may lead to target antigen modulation under this selective pressure, with subsequent tumor immune escape. With the purpose of preventing this phenomenon, we have studied the impact of simultaneously targeting two distinct antigens present on tumor cells: namely mucin 1 and prostate stem cell antigen, both of which are expressed in a variety of solid tumors, including pancreatic and prostate cancer. When used individually, CAR T cells directed against either tumor antigen were able to kill target-expressing cancer cells, but tumor heterogeneity led to immune escape. As a combination therapy, we demonstrate superior antitumor effects using both CARs simultaneously, but this was nevertheless insufficient to achieve a complete response. To understand the mechanism of escape, we studied the kinetics of T-cell killing and found that the magnitude of tumor destruction depended not only on the presence of target antigens but also on the intensity of expression—a feature that could be altered by administering epigenetic modulators that upregulated target expression and enhanced CAR T-cell potency.     

Reversal of Tumor Immune Inhibition Using a Chimeric Cytokine Receptor

The success of adoptively transferred tumor-directed T cells requires them to survive and expand in vivo. Most tumors, however, employ immune evasion mechanisms, including the production of inhibitory cytokines that limit in vivo T-cell persistence and effector function. To protect tumor-directed T cells from such negative influences, we generated a chimeric cytokine receptor in which the interleukin (IL) 4 receptor exodomain was fused to the IL7 receptor endodomain. We thereby inverted the effects of tumor-derived IL4 so that the proliferation and activation of tumor directed cytotoxic T cells was enhanced rather than inhibited in the tumor microenvironment, resulting in superior antitumor activity. These transgenic T cells were only activated in the tumor environment since triggering required exposure to both tumor antigen (signal 1) and tumor-derived IL4 (signal 2). This selectivity supports future clinical adaptation.     

The second mini-transplant for unstable mixed chimerism within the first 100 days after hematopoietic stem cell transplant in severe thalassemia

Allogeneic HSCT is the only curative treatment for severe thalassemia disease. MC occurs in one-third of these patients within the first two months after HSCT; this is a major risk factor of graft rejection, especially when RHCs are more than 25%. There is still no consensus for the management of MC, especially in the early phase of HSCT. The DLI has also been described in the treatment of MC following HSCT for hemoglobinopathies, but its success is still not guaranteed. The second HSCT has been an approach used in an attempt to cure patients who reject their graft. Concern about toxicity of conditioning regimen, the second HSCT is usually delayed for at least a year after the first HSCT. We would like to demonstrate the successful use of the second mini-allogeneic HSCT in hemoglobin E/β-thalassemia with evidence of unstable MC in the first 100 days after allogeneic HSCT to prevent further graft loss after allogeneic HSCT.