RESUMO
Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.
Assuntos
Bronquiolite Obliterante , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/terapia , Criança , Estados Unidos , Testes de Função Respiratória , Pré-Escolar , Síndrome de Bronquiolite ObliteranteRESUMO
Improvements in medical care have allowed many children with neuromuscular disease and chronic respiratory failure to survive into adulthood. There are currently no published guidelines to facilitate transition from pediatric to adult respiratory care in this population. The transition process in neuromuscular disease and chronic respiratory failure is uniquely challenging in that the patients are often declining in health and losing independence as they approach adulthood. Barriers to transition include lack of access to adult providers, incompatible health insurance, loss of resources within patients' medical structures, absence of transition preparation, and patient and family insecurity with a new healthcare system. The six core elements and optimal time frame of transition should be applied, with special consideration of the psychosocial aspects associated with neuromuscular disease. Successful transition revolves around information, open communication between young adults and their medical care team, and individualized planning to ensure optimal health and quality of life.
Assuntos
Acessibilidade aos Serviços de Saúde , Seguro Saúde , Doenças Neuromusculares/terapia , Planejamento de Assistência ao Paciente , Pneumologia/métodos , Respiração Artificial , Insuficiência Respiratória/terapia , Transição para Assistência do Adulto/organização & administração , Paralisia Cerebral/complicações , Paralisia Cerebral/terapia , Família , Serviços de Saúde , Hospitais Pediátricos/organização & administração , Humanos , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/terapia , Doenças Neuromusculares/complicações , Ventilação não Invasiva , Política Organizacional , Pneumologia/organização & administração , Insuficiência Respiratória/etiologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/terapia , Atrofias Musculares Espinais da Infância/complicações , Atrofias Musculares Espinais da Infância/terapia , TraqueostomiaRESUMO
Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.
Assuntos
Síndrome de Bronquiolite Obliterante , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Síndrome de Bronquiolite Obliterante/diagnóstico , Síndrome de Bronquiolite Obliterante/etiologia , Síndrome de Bronquiolite Obliterante/terapia , Volume Expiratório Forçado , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Guias de Prática Clínica como Assunto , Testes de Função RespiratóriaRESUMO
BACKGROUND: Severe primary graft dysfunction (PGD) is associated with the development of bronchiolitis obliterans syndrome (BOS), the most common form of chronic lung allograft dysfunction (CLAD), in adults. However, PGD associations with long-term outcomes following pediatric lung transplantation are unknown. We hypothesized that PGD grade 3 (PGD 3) at 48- or 72-hours would be associated with shorter CLAD-free survival following pediatric lung transplantation. METHODS: This was a single center retrospective cohort study of patients ≤ 21 years of age who underwent bilateral lung transplantation between 2005 and 2019 with ≥ 1 year of follow-up. PGD and CLAD were defined by published criteria. We evaluated the association of PGD 3 at 48- or 72-hours with CLAD-free survival by using time-to-event analyses. RESULTS: Fifty-one patients were included (median age 12.7 years; 51% female). The most common transplant indications were cystic fibrosis (29%) and pulmonary hypertension (20%). Seventeen patients (33%) had PGD 3 at either 48- or 72-hours. In unadjusted analysis, PGD 3 was associated with an increased risk of CLAD or mortality (HR 2.10, 95% CI 1.01-4.37, p=0.047). This association remained when adjusting individually for multiple potential confounders. There was evidence of effect modification by sex (interaction p = 0.055) with the association of PGD 3 and shorter CLAD-free survival driven predominantly by males (HR 4.73, 95% CI 1.44-15.6) rather than females (HR 1.23, 95% CI 0.47-3.20). CONCLUSIONS: PGD 3 at 48- or 72-hours following pediatric lung transplantation was associated with shorter CLAD-free survival. Sex may be a modifier of this association.
Assuntos
Bronquiolite Obliterante , Transplante de Pulmão , Disfunção Primária do Enxerto , Adulto , Masculino , Humanos , Feminino , Criança , Estudos Retrospectivos , Disfunção Primária do Enxerto/epidemiologia , Disfunção Primária do Enxerto/etiologia , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/cirurgia , Pulmão , Transplante de Pulmão/efeitos adversos , AloenxertosRESUMO
INTRODUCTION: Cystic fibrosis (CF) is the most common autosomal recessive disorder among Caucasians affecting ~70,000 people worldwide. The lack of functional cystic fibrosis transmembrane conductance regulator (CFTR) causes dysregulation of epithelial fluid transport in the lungs, gastrointestinal tract, and sweat glands. Areas covered: The most common disease-causing CFTR mutation, F508del, is present in over 75% of those affected;. therapies targeting F508del function have the promise to reduce morbidity and mortality in the majority of patients with CF. The combination of lumacaftor, which corrects the aberrant intracellular trafficking of F508del, and ivacaftor, which potentiates CFTR function, is known as OrkambiTM, and is the first drug approved for the treatment of CF in patients who are F508del-homozygotes. OrkambiTM is currently approved for use in children aged 2 and older based on recent data from open-label Phase 3 clinical safety studies. Expert opinion: OrkambiTM modestly improves clinical outcomes for people with CF who are F508del-homozygotes, and does so with a reasonable safety profile. This is a major advance in therapy for CF, but further advances are needed, perhaps with the addition of a third agent to this combination small molecule therapy, in order to expand both the targeted population and beneficial effects.
Assuntos
Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Aminofenóis/efeitos adversos , Aminopiridinas/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Humanos , Mutação , Quinolonas/efeitos adversos , Resultado do TratamentoRESUMO
Development of facile, sensitive, specific, and economical assays for the analysis of methylated alleles is crucial to the use of methylated biomarkers for cancer detection. We hereby report a novel method, MethySYBR, a SYBR green-based PCR assay for the dual analysis of DNA methylation and CpG methylation density. MethySYBR begins with multiplex PCR to enable the simultaneous amplification of many discrete target alleles in a single reaction using as little as 3 pg of bisulfite-converted DNA. In the second round of PCR, the specific methylated target is quantified from multiplex products using both nested methylation-independent and methylation-specific primer sets. Moreover, the use of SYBR green dye during quantitative PCR enables melting curve analysis of target amplicons to determine the methylation density of CpG sites on target alleles. To establish proof of principle, two cancer-specific methylated genes, RASSF1A and OGDHL, were assessed by MethySYBR. We demonstrated that MethySYBR sensitively detected methylated alleles in the presence of a 100,000-fold excess of unmethylated allele. Furthermore, MethySYBR was shown to be capable of analyzing minute amounts of DNA from paraffin-embedded tissue. Therefore, the MethySYBR assay is a simple, highly specific, highly sensitive, high-throughput, and cost-effective method that is widely applicable to basic and clinical studies of DNA methylation.