RESUMO
INTRODUCTION/AIMS: Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD. METHODS: An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 1014 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests. RESULTS: Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125). DISCUSSION: Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.
Assuntos
Distrofia Muscular de Duchenne , Criança , Pré-Escolar , Humanos , Masculino , Progressão da Doença , Terapia Genética/efeitos adversos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/metabolismo , Prednisona/uso terapêuticoRESUMO
BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. METHODS: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts). RESULTS: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone. CONCLUSIONS: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).
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Terapia Genética , Atrofias Musculares Espinais da Infância/terapia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Estudos de Coortes , Dependovirus , Intervalo Livre de Doença , Feminino , Terapia Genética/efeitos adversos , Vetores Genéticos , Estudo Historicamente Controlado , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Hepatopatias/etiologia , Masculino , Destreza Motora , Apoio Nutricional , Respiração Artificial , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/fisiopatologiaRESUMO
OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.
Assuntos
Atrofias Musculares Espinais da Infância/sangue , Atrofias Musculares Espinais da Infância/diagnóstico , Biomarcadores/sangue , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos , Atrofias Musculares Espinais da Infância/genética , Proteína 1 de Sobrevivência do Neurônio Motor/sangue , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/sangue , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8-year-old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well-controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations. Whole exome sequencing revealed compound heterozygosity for two EPG5 variants, inherited in trans. One was a known pathogenic mutation in exon 13 (c.2461C > T, p.Arg821X). The second was reported as a variant of unknown significance found within intron 16, six nucleotides before the exon 17 splice acceptor site (c.3099-6C > G). Reverse transcription-polymerase chain reaction of the EPG5 mRNA showed skipping of exon 17-which maintains an open reading frame-in 77% of the transcript, along with 23% expression of wild-type mRNA suggesting that intronic mutations may affect splicing of the EPG5 gene and result in symptoms. However, the expression of 23% wild-type mRNA may result in a significantly attenuated Vici syndrome phenotype.
Assuntos
Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Catarata/diagnóstico , Catarata/genética , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Proteínas/genética , Proteínas Relacionadas à Autofagia , Biópsia , Regulação para Baixo , Éxons , Heterozigoto , Humanos , Proteínas de Membrana Lisossomal , Masculino , Músculos/metabolismo , Músculos/patologia , Mutação , RNA Mensageiro , Análise de Sequência de DNA , Proteínas de Transporte Vesicular , Sequenciamento do ExomaRESUMO
Background Pre-lung transplant (LTx) panel reactive antibody (PRA) levels are associated with adverse outcomes in adult LTx recipients, but their impact in pediatric LTx recipients is unknown. Methods The United Network for Organ Sharing registry was queried from 2004 to 2013 to compare survival between pediatric LTx recipients with PRA class I and II levels = 0 versus > 0. Results Overall, 333 pediatric LTx recipients had data on class I or II PRA and were included in the analysis. Univariate analysis demonstrated that PRA > 0 was not associated with survival benefit for class I (hazard ratio [HR] = 0.985; 95% confidence interval [CI]: 0.623, 1.555; p = 0.947) or class II (HR = 1.080; 95% CI: 0.657, 1.774; p = 0.762) PRA. Multivariate Cox models confirmed no significant association with mortality hazard for both class I (HR = 1.230; 95% CI: 0.641, 2.363; p = 0.533) and class II (HR = 0.847; 95% CI: 0.359, 1.997; p = 0.704) PRA. Multivariate logistic regression models identified no association between class I or class II and acute rejection within 3 years of LTx. Conclusions Pretransplant class I and II PRA levels > 0 were not associated with mortality or acute rejection in pediatric LTx recipients.
Assuntos
Teste de Histocompatibilidade , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Pulmão , Doença Aguda , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/mortalidade , Masculino , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Obtenção de Tecidos e Órgãos , Resultado do Tratamento , Estados UnidosRESUMO
5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023. In our cohort, onasemnogene abeparvovec treatment remained safe and no child experienced any significant adverse events, including thrombotic microangiopathy, liver failure or death. All children experienced benefit, although the benefit in those with 2 copies of SMN2 was variable. 79 % of the children treated when symptomatic had a SMN2 modifying therapy added on. With careful screening and post treatment monitoring, onasemnogene abeparvovec is safe and effective for children with SMA in the state of Ohio, but more work needs to be done to ensure optimal outcomes for all children with 2 copies of SMN2.
Assuntos
Produtos Biológicos , Atrofia Muscular Espinal , Doenças Neurodegenerativas , Proteínas Recombinantes de Fusão , Atrofias Musculares Espinais da Infância , Criança , Humanos , Ohio , Terapia GenéticaRESUMO
Right ventricular (RV) dysfunction may occur in patients with cystic fibrosis (CF). Tissue Doppler imaging (TDI) and strain and strain rate analysis are new echocardiographic tools that can quantitate RV function. This study aimed to compare the RV function between healthy CF patients and non-CF patients to determine whether differences exist. Healthy CF children and age-matched non-CF children were enrolled in the study. In this study, TDI analysis of the RV free wall was performed at the level of the tricuspid valve annulus. Two-dimensional speckle echocardiography was used to measure global strain and strain rates in a six-segment model of the RV. Independent t tests were used to compare the groups. The study enrolled 18 CF patients (age, 7.7 ± 2.0 years) and 15 non-CF patients (age, 6.4 ± 2.5 years). The age difference was not significant. The forced expiratory volume in the first second (FEV(1)) for the CF patients was 91 ± 15 %. The systolic annular velocity by TDI was significantly lower in the CF group. The RV strain values in the CF group were significantly lower in four of the six segments (RV free-wall base, RV free-wall mid, RV septal apex, and RV septal mid). The global strain value, the systolic strain rate, and the early diastolic strain rate were significantly lower in the CF group. Decreased systolic and diastolic RV properties were present in young healthy CF patients. Further studies with longitudinal follow-up evaluation are needed to determine the significance of these findings for the pediatric CF population.
Assuntos
Fibrose Cística/fisiopatologia , Ecocardiografia/métodos , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Direita/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Fibrose Cística/diagnóstico por imagem , Ecocardiografia Doppler/métodos , Feminino , Humanos , Masculino , Estudos Prospectivos , Testes de Função Respiratória , Disfunção Ventricular Direita/diagnóstico por imagemRESUMO
Chronic respiratory failure is a common endpoint in the loss of respiratory muscle function in patients with progressive neuromuscular disease (NMD). Identifying the onset of hypoventilation is critical to allow for the timely introduction of ventilator support and effectively manage respiratory failure [1-3]. While there are accepted criteria governing the diagnosis of hypoventilation during polysomnography (PSG) [4], there is concern that criteria are insufficient for identifying hypoventilation in the earlier stages of respiratory insufficiency related to NMD. The purpose of this project was to identify more sensitive criteria for identifying hypoventilation. METHODS: Fifteen pediatric pulmonologists with broad experience in managing patients with NMD, 10 of whom were board certified in and practice sleep medicine, were assembled and performed a review of the pertinent literature and a two-round Delphi process with 6 domains (Table 1). RESULTS: Within the 6 domains there were three pertinent items per domain (Table 2). There was clear agreement on findings on history (morning headaches) and pulmonary function testing (FVC <â50% or awake TcCO2 >â45âmmHg) indicating a high concern for nocturnal hypoventilation. There was close agreement on the definitions for nocturnal hypercapnia and hypoxemia. PSG criteria were identified that indicate a patient is likely in the transitional phase from adequate ventilation to hypoventilation. DISCUSSION: We identified a set of clinical criteria that may allow for more sensitive diagnosis of hypoventilation in NMD and earlier initiation of non-invasive ventilation leading to a reduction in the respiratory morbidity in progressive NMD. These criteria need to be further and more broadly validated prospectively to confirm their utility.
Assuntos
Hipoventilação , Doenças Neuromusculares , Humanos , Criança , Hipoventilação/diagnóstico , Hipoventilação/etiologia , Consenso , Técnica Delphi , Doenças Neuromusculares/complicações , Doenças Neuromusculares/diagnóstico , Respiração ArtificialRESUMO
BACKGROUND: Improvement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care. OBJECTIVE: A multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec. METHODS: We defined bulbar function as the ability to meet nutritional needs while maintaining airway protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion. RESULTS: Overall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint. CONCLUSIONS: In these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation.
Assuntos
Transtornos de Deglutição , Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Lactente , Humanos , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Atrofia Muscular Espinal/genética , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Deglutição , Terapia GenéticaRESUMO
Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function.
Assuntos
Transtornos de Deglutição , Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Criança , Humanos , Lactente , Atrofia Muscular Espinal/genética , Neurônios Motores , Terapia Genética , Deglutição , Atrofias Musculares Espinais da Infância/terapia , Atrofias Musculares Espinais da Infância/tratamento farmacológicoRESUMO
PURPOSE: To review the results of a postoperative respiratory pathway for patients with muscular dystrophy (MD) and spinal muscular atrophy (SMA) undergoing spinal surgery. METHODS: With IRB approval, a retrospective review was done on all patients with SMA and MD undergoing spinal surgery on a neuromuscular protocol. Baseline demographics, perioperative results, and long-term outcomes were collected. Per the protocol, patients remained intubated after surgery and were transported to the intensive care unit (ICU) for extubation. We present the results of protocol implementation and compare patients with MD to those with SMA. RESULTS: Twenty-four patients were treated using the protocol. Average age was 13.1 years. Severe restrictive lung disease was present in 75% of patients. Nocturnal BiPAP was required in 68% of patients. Average number of instrumented levels was 17. All patients were immediately extubated upon entering the ICU. There were three respiratory complications and only was patient was re-intubated. Average ICU stay was 1.8 days and average hospital length of stay was 6.7 days. No differences in postoperative inspiratory or expiratory positive airway pressures were observed between the MD and SMA groups. CONCLUSION: Through a multidisciplinary neuromuscular protocol, excellent clinical outcomes were achieved in patients with neuromuscular scoliosis and restrictive lung disease, with complication rates and length of stay significantly lower than previously published data. LEVEL OF EVIDENCE: IV.
Assuntos
Pneumopatias , Atrofia Muscular Espinal , Doenças Neuromusculares , Escoliose , Fusão Vertebral , Adolescente , Extubação/efeitos adversos , Humanos , Pneumopatias/complicações , Pneumopatias/cirurgia , Atrofia Muscular Espinal/cirurgia , Doenças Neuromusculares/complicações , Escoliose/complicações , Escoliose/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Resultado do TratamentoRESUMO
Statistical analysis and logistic regression (LR) in particular are among the most popular tools being used by safety professionals and practitioners to assess the association between exposures and possible occupational disorders or diseases and predict the outcome. Recently, artificial neural network (ANN) models are gradually finding their way into safety field. It has been shown that they are capable of predicting outcomes more accurately than LR, but they are incapable of demonstrating the direct correlation between exposure variables and a possible outcome variable. The objective of this study was to develop a mathematical function that can use the result of ANN models to produce a measure for evaluating the direct association between exposure and possible outcome variables. This function was referred to as the function of Magnitude-of-Effect (MoE). Safety experts and practitioners can use the MoE function to interpret how strongly an exposure variable can affect the outcome variable, similar to an odds ratio, which can be calculated by using estimated parameters in LR models. The significance of such achievement is that it can eliminate one of the ANN model's shortcoming and make them more applicable in the occupational safety and health engineering field.
Assuntos
Modelos Teóricos , Redes Neurais de Computação , Exposição Ocupacional , Medicina do Trabalho/métodos , Previsões , Humanos , Modelos LogísticosRESUMO
Safety professionals and practitioners are always searching for methods to accurately assess the association between exposures and possible occupational disorders or diseases and predict the outcome of any variable. Statistical analysis and logistic regression (LR) in particular are among the most popular tools being used today. Artificial neural network (ANN) models are another method of predicting outcomes, which are gradually finding their way into the safety field. Limited studies have shown that they are capable of predicting outcomes more accurately than LR, but they have been tested either on continuous or on dichotomous variables or combinations of them. The objective of this research was to demonstrate that ANN models can perform better than LR models with data sets comprised of all ordinal variables, which has not been done so far. The data set used in this research was collected from construction workers using the Work Compatibility questionnaire. The data set contained only ordinal variables both as input (exposure) and as output (outcome) variables. LR models and ANN models were constructed using the same data set and the performance of all models was compared by using the log-likelihood ratio. The result of this study showed that ANN models performed significantly better than LR models with a data set of all ordinal variables as well as other types of variables such as dichotomous and continuous.
Assuntos
Redes Neurais de Computação , Medicina do Trabalho/métodos , Gestão da Segurança/métodos , Previsões/métodos , Humanos , Medição de Risco/métodosRESUMO
The phenotype of spinal muscular atrophy (SMA) has been changing with the recent availability of three FDA-approved treatments: intrathecal nusinersen, intravenous onasemnogene abeparvovec-xioi, and enteral risdiplam. The degree of improvement in muscle strength and respiratory health varies with SMA genotype, severity of baseline neuromuscular and pulmonary impairment, medication used, and timing of the first dose. A spectrum of pulmonary outcomes has been reported with these novel medications when used early and in conjunction with proactive multidisciplinary management of comorbidities. In this review, we summarize the reported impact of these novel therapies on pulmonary well-being and the improving trajectory of pulmonary morbidity, compared to the natural history of SMA. The importance of ongoing clinical monitoring albeit the improved phenotype is reiterated. We also discuss the limitations of the current SMA-therapy trials and offer suggestions for future clinical-outcome studies and long-term monitoring.
Assuntos
Atrofia Muscular Espinal , Produtos Biológicos , Terapia Genética , Genótipo , Humanos , Atrofia Muscular Espinal/tratamento farmacológico , Fenótipo , Proteínas Recombinantes de Fusão , Atrofias Musculares Espinais da Infância/terapiaRESUMO
CASE PRESENTATION: A 17-year-old male patient who was diagnosed with Becker muscular dystrophy (nonsense mutation [c.3822C>A] within exon 28 of the DMD gene) at 6 years of age was evaluated in the multidisciplinary neuromuscular clinic for loss of ambulation for 1 year. From a pulmonary perspective, there were no acute or chronic respiratory symptoms, and no history of pneumonia or aspiration. Clinical examination revealed a nonambulant teenager, with normal oxygen saturation and end-tidal CO2 when awake, no respiratory distress, and symmetrically diminished aeration due to obesity (BMI 40 kg/m2). Results of pulmonary function testing revealed FVC of 83% predicted with actual volume of 3.5 L and peak cough flow of 445 L/min (all within normal limits).
Assuntos
Distrofia Muscular de Duchenne/complicações , Apneia do Sono Tipo Central/diagnóstico , Apneia do Sono Tipo Central/etiologia , Adolescente , Humanos , Masculino , PolissonografiaRESUMO
We describe six teenagers presenting with fever and severe abdominal symptoms admitted with concerns for multisystem inflammatory syndrome in children (MIS-C). Laboratory evaluation revealed elevated markers of inflammation, lymphopenia, and increased D-dimers. Imaging studies revealed multifocal airspace disease and ground-glass opacities. SARS-CoV-2 polymerase chain reaction and serologies were negative. All patients reported a history of vaping, prompting E-cigarette, or vaping, product use-associated lung injury (EVALI) diagnosis. MIS-C has overlapping clinical and laboratory features highlighting the added challenge of diagnosing EVALI during the COVID-19 pandemic. Keywords COVID-19 pandemic, EVALI, MIS-C.
Assuntos
COVID-19/complicações , Síndrome de Resposta Inflamatória Sistêmica , Adolescente , Humanos , Lesão Pulmonar/epidemiologia , Lesão Pulmonar/etiologia , Pandemias , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/complicaçõesRESUMO
Importance: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy. Objective: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. Design, Setting, and Participants: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020. Exposures: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. Main Outcomes and Measures: The primary outcome measure was the incidence of serious adverse events (SAEs). Results: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen. Conclusions and Relevance: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose. Trial Registration: ClinicalTrials.gov Identifier: NCT03421977.
Assuntos
Produtos Biológicos/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Seguimentos , Terapia Genética/métodos , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities. METHODS: Patients with genetically confirmed SMA completed functional testing at each visit including the Neuromuscular GRO and other appropriate gross motor outcomes. RESULTS: We enrolled 91 patients with SMA types 1 to 3 between 8 days and 32.1 years. The GRO utilizes a 0- to 2-point scale with scores in our cohort ranging from 1 to 95 points with no floor or ceiling effect. GRO scores were significantly different across functional categories (P < 0.001) and treatment status (P = 0.01) and correlated to other functional assessments (P ≤ 0.001). All patients were measured using the GRO, whereas traditional outcomes were only appropriate on 36% to 59% of our cohort. CONCLUSION: The Neuromuscular GRO quantifies function across the span of age and abilities included in our cohort, allowing for continuous longitudinal monitoring on one scale to reduce the burden of testing in our heterogeneous clinic population.
Assuntos
Técnicas de Diagnóstico Neurológico/normas , Progressão da Doença , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Bronchiectasis (BE) is defined as a permanent, irreversible dilation of the bronchial tree. In the pediatric population, this disease process is most commonly associated with patients with cystic fibrosis (CF). However, BE unrelated to CF is increasingly noted as a cause of chronic respiratory related morbidity worldwide. Chronic inflammation and recurrent infection result in cellular cascades that lead to irreversible structural changes of the airways. When these architectural changes occur, they confer extensive risks to morbidity usually due to continued infections. In the adult population, BE has been associated with chronic obstructive pulmonary disease, which is mainly caused by cigarette smoking. In this report, the authors reviewed various cases of BE in the pediatric population at our institution. After a comprehensive case by case review, we compiled details of three cases of newly diagnosed BE where the most likely inciting factor was the electronic cigarette use. Common features of the three cases included at least a year of e-cigarette use with conjunction of tetrahydrocannabinol and radiologic findings of BE, ground glass opacities, and nodule formation.
Assuntos
Bronquiectasia/induzido quimicamente , Sistemas Eletrônicos de Liberação de Nicotina , Adulto , Criança , Fibrose Cística/complicações , Humanos , Pulmão/fisiopatologia , Masculino , VapingRESUMO
Idiopathic acute eosinophilic pneumonia is a rare and potentially life-threatening condition that is defined by bilateral pulmonary infiltrates and fever in the presence of pulmonary eosinophilia. It often presents acutely in previously healthy individuals and can be difficult to distinguish from infectious pneumonia. Although the exact etiology of idiopathic acute eosinophilic pneumonia remains unknown, an acute hypersensitivity reaction to an inhaled antigen is suggested, which is further supported by recent public health risks of vaping (electronic cigarette) use and the development of lung disease. In this case, a patient with a year-long history of vaping in conjunction with tetrahydrocannabinol cartridge use who was diagnosed with idiopathic acute eosinophilic pneumonia with associated bilateral hilar lymphadenopathy is described.