Allergies, allergic comorbidities and the home environment in pediatric asthma in Southern Florida

Background: Environmental exposure is critical in sensitization to environmental allergens and pediatric asthma morbidity, especially in tropical climates where children are perennially exposed to bioaerosols, such as pollen and mold spores, and endotoxins. Objective: This cross-sectional study examines the association of allergies, associated allergic comorbidities, and the home environment separately and synergistically in pediatric asthma, including in asthma prevalence, severity of asthma, and undiagnosed asthma, in South Florida. Methods: An online survey was administered to the parents of children attending two of the University of Miami pediatric clinics from June to October 2016. Descriptive, factor, and multivariate regression analyses were used to analyze the data. Results: Of 163 children, 22% (36) children had physician-diagnosed asthma; 10% and 32% had allergic rhinitis diagnosis and rhinitis symptoms, respectively, in the past. The allergy diagnosis age was 2.3 years higher than the asthma diagnosis age (p \u3c 0.01). Children with ≥ 2 allergies were 12.8 times more likely to have physician-diagnosed asthma than those without allergies (p \u3c 0.01). Children with allergies and allergic rhinitis were 4.3 (p \u3c 0.05) times more likely to have asthma, and those with asthma were 15 (p \u3c 0.05) times more likely to have an asthma attack than those without known allergies and allergic rhinitis. Conclusion: Allergies and associated comorbidities are risk factors of asthma, asthma persistence, and multiple allergies exacerbate their effects. Early screening for allergies and treatment are warranted to manage asthma. Since the home environment plays an important role in sensitization to allergens, further research is needed to assess home-environmentmediated allergic conditions in the onset and persistence of asthma

CITRULINA SÉRICA COMO MARCADOR DE REJEIÇÃO CELULAR AGUDA EM TRANSPLANTE INTESTINAL EM RATOS

Introdução: O objetivo deste estudo foi relacionar os níveis de citrulina sérica à rejeição celular aguda após transplante intestinal, avaliando a citrulina como método laboratorial menos invasivo e de menor custo que a biópsia endoscópica para diagnosticar a mais importante complicação após transplante intestinal. Métodos: Estudo aprovado pelo Comitê de Ética em Pesquisa com Animais e realizado em caráter experimental no Batchelor Research Institute da Universidade de Miami, no período de agosto a dezembro de 2004. Foram realizados cinco transplantes heterotópicos de intestino, com duas estomias e vascularização da artéria mesentérica superior na aorta e drenagem venosa do mesentério na veia cava. Amostras de sangue foram colhidas no 3º, 5º e 7º dias pré- e pós-operatórios. Resultados: Os níveis de citrulina sérica variaram de 78 a 99 µmol/L no pré-transplante, de 44 a 54 µmol/L no pós-transplante 3, de 62 a 73 µmol/L no pós-transplante 5 e de 36 a 60 µmol/L no pós-transplante 7. Os níveis médios de citrulina sérica nos pós-transplante 3,5 e 7 foram significativamente menores comparados ao correspondente no pré-transplante. Conclusão: Os níveis séricos diminuíram durante a rejeição celular aguda, o que pode indicar a citrulina como marcadora precoce de episódios de rejeição celular aguda no transplante intestinal

Efficacy and Safety of Ex Vivo Cultured Adult Human Mesenchymal Stem Cells (Prochymal™) in Pediatric Patients with Severe Refractory Acute Graft-Versus-Host Disease in a Compassionate Use Study

Preliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 10 6cells/kg/dose in 2 patients and 2 × 10 6cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients

Use of Mesenchymal Stem Cells To Treat Pediatric Patients with Severe (Grade III–IV) Acute Graft Versus Host Disease Refractory to Steroid and Other Agents on a Compassionate Use Basis

Abstract Background: Severe acute Graft versus Host Disease (aGvHD) refractory to steroids and other immunosuppressive agents carries a high mortality and very poor prognosis. Preliminary studies have shown that mesenchymal stem cells (MSC; Prochymal™ Osiris Therapeutics Inc.) can have immunosuppressive and tissue regenerative properties. We hypothesized that MSC might have efficacy in the treatment of GvHD. Methods: Between July 2005 and June 2007, 12 children (10 boys, 9 Caucasian) at 5 centers with aGvHD who failed steroid and additional immunosuppressive agents (median exposure 3 others) were treated with MSC provided by Osiris for compassionate use after FDA and local IRB approval. MSCs were administered per manufacturer’s instructions, without HLA or other matching, to eligible patients in a median of 30 days (range 16–181) from diagnosis of aGvHD. The cell dose for “induction therapy” was 8×106 cells/kg/dose in first 2 patients and 2×106 cells/kg/dose in all subsequent patients. Cells were given by IV infusion over 1 hour 2×/week for 4 weeks and initial response was assessed at the end of this induction therapy. “Maintenance therapy” 1×/week was continued in patients showing response. Results: The median patient age was 6 yrs (range 0.4–15) and all but one had received unrelated donor transplant (8 UCB, 3 adult MUD). GvHD Grade III and IV was present in 7 and 5 patients respectively. All patients had advanced (stage 3 or 4) gut disease, and 6 also had liver and/or skin involvement. Acute GvHD was diagnosed a median of 81 days (range 22–98) post-transplant and MSC were started at a median of 119 days (range 38–279) post-transplant. Three patients had renal failure requiring dialysis which had developed prior to MSC therapy. Patients received a median of 8 doses (range 3–21) of MSC. A total of 124 doses of MSCs were administered. No infusional or other identifiable toxicity was seen in any patient. One osteopetrosis patient developed ectopic lesions in the scalp and foot, however biopsy showed that no MSC DNA was present. With a median follow-up of 102 days (range 36–756) all 12 patients responded to therapy, with 6 patients having a complete response (CR), and the remainder having a partial response (PR) as defined by an improvement of at least one stage in one system without any worsening in another. Two of the PR patients are still being treated. Two patients responded, stopped therapy and later relapsed, requiring further MSC therapy to which they partially responded. Of 12, 6 patients died a median of 68 days (range 36–185) from the start of therapy. Three each died of multi-system organ failure and infection. Three of these were on dialysis pre-therapy. Conclusion: With short term follow-up in young children, MSC appears to be safe and likely have beneficial activity in severe treatment refractory aGvHD. Additional studies are underway to evaluate the efficacy of this agent in this clinical setting

Utilization of dried blood spot citrulline level as a noninvasive method for monitoring graft function following intestinal transplantation

Citrulline concentrations have been proposed as a marker for intestinal allograft rejection. We instituted dried blood spot (DBS) specimen monitoring of citrulline to simplify sample collection posttransplant. This study demonstrates the correlation between plasma and dried blood spot specimen citrulline concentrations after intestinal transplantation. Plasma and DBS samples were analyzed by hydrophilic interaction chromatography tandem mass spectrometry. Comparison of the strength of linear correlation was made according to the type of surgery, sonication time, DBS citrulline levels, and the time interval between the blood sample collection and the assay date. A very strong linear correlation exists between the plasma and DBS citrulline concentrations (r=0.87; P<0.001). The correlation between plasma and DBS citrulline concentrations was maintained when evaluating only the intestinal transplant recipients. There was no significant difference in the strength of linear correlation according to sonication time, cirtrulline concentrations, or length of time to assay date. DBS citrulline monitoring will ease sample collection following intestinal transplantation and improve the ability to detect intestinal dysfunction and rejection by a noninvasive means