RESUMO
BACKGROUND AND PURPOSE: Pompe disease is a rare, inheritable, progressive metabolic myopathy. This study aimed to estimate the minimal clinically important difference (MCID) for an improvement in forced vital capacity in the upright seated position (FVCup) and the 6-min walk test (6MWT) after a year of treatment with enzyme replacement therapy. METHODS: Data were obtained from two prospective follow-up studies. Between-group and within-group MCIDs were estimated using anchor-based methods. Additionally, a distribution-based method was used to generate supportive evidence. As anchors, self-reported change in health and in physical functioning, shortness of breath and a categorization of the Short-Form 36 Physical Component Summary score were used. Anchor appropriateness was assessed using Spearman correlations (absolute values ≥0.29) and a sufficient number of observations in each category. RESULTS: In all, 102 patients had at least one FVCup or 6MWT measurement during enzyme replacement therapy. Based on the anchors assessed as appropriate, the between-group MCID for an improvement in FVCup ranged from 2.47% to 4.83% points. For the 6MWT, it ranged from 0.35% to 7.47% points which is equivalent to a distance of 2.18-46.61 m and 1.97-42.13 m for, respectively, a man and a woman of age 50, height 1.75 m and weight 80 kg. The results of the distribution-based method were within these ranges when applied to change in the outcome values. CONCLUSION: The MCIDs for FVCup and 6MWT derived in this study can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort studies.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Masculino , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Estudos Prospectivos , Teste de Caminhada , Seguimentos , Pulmão , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. METHODS: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. RESULTS: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. CONCLUSIONS: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.
Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Terapia de Reposição de Enzimas/métodos , Europa (Continente)RESUMO
Pompe disease is a rare, progressive, and metabolic myopathy. Reduced pulmonary function is one of the main problems seen in adult patients with late-onset Pompe disease (LOPD). We aimed to explore the association between changes over time in pulmonary function and in patient-reported outcome measures (PROMs), in these patients treated with enzyme replacement therapy (ERT). This is a post hoc analysis of two cohort studies. Pulmonary function was assessed as forced vital capacity in the upright position (FVCup ). As PROMs, we assessed the physical component summary score (PCS) of the Medical Outcome Study 36-item Short-Form Health Survey (SF-36) and daily life activities (Rasch-Built Pompe-Specific Activity [R-PACT] scale). We fitted Bayesian multivariate mixed-effects models. In the models of PROMs, we assumed a linear association with FVCup , and adjusted for time (nonlinear), sex, and age and disease duration at the start of ERT. One hundred and one patients were eligible for analysis. PCS and R-PAct were positively associated with FVCup , while their relation with time was nonlinear (initial increase then decrease). A 1%-point increase in FVCup is expected to increase PCS by 0.14 points (95% Credible Interval: [0.09;0.19]) and R-PACT by 0.41 points [0.33;0.49] at the same time point. In the first year of ERT, we expect a change of PCS and R-PAct scores by +0.42 and +0.80 points, and in the 5th year of +0.16 and +0.45, respectively. We conclude that the physical domain of quality of life and daily life activities improve when FVCup increases during ERT.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Humanos , Adulto , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Qualidade de Vida , Teorema de Bayes , Terapia de Reposição de Enzimas , Medidas de Resultados Relatados pelo Paciente , alfa-Glucosidases/uso terapêuticoRESUMO
OBJECTIVES: Pompe disease is a progressive metabolic myopathy for which enzyme replacement therapy (ERT) was approved in 2006. While various publications have examined the effects of ERT in classic-infantile patients and in adults, little has been published on ERT in children with non-classic presentations. STUDY DESIGN: This prospective study was conducted from June 1999 to May 2015. Seventeen patients from various countries participated. Outcome measures comprised muscle function (6-minute walk test, quick motor-function test (QMFT)), muscle strength (hand-held dynamometry; manual muscle testing), and lung function (FVC sitting and supine). For each outcome measure, we used linear mixed-effects models to calculate the difference at group level between the start of therapy and 7 years of ERT. Patients' individual responses over time were also evaluated. RESULTS: Eleven males and six females started ERT at ages between 1.1 and 16.4 years (median 11.9 years); 82% of them carried the common c.-32-13T > G GAA gene variant on one allele. At group level, distance walked increased by 7.4 percentage points (p < 0.001) and QMFT scores increased by 9.2 percentage points (p = 0.006). Muscle strength scores seemed to remain stable. Results on lung function were more variable. Patients' individual data show that the proportion of patients who stabilized or improved during treatment ranged between 56 and 69% for lung function outcomes and between 71 and 93% for muscle strength and muscle function outcomes. CONCLUSIONS: We report a positive effect of ERT in patients with childhood Pompe disease at group level. For some patients, new or personalized treatments should be considered.
Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/terapia , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Seguimentos , Doença de Depósito de Glicogênio Tipo II/enzimologia , Humanos , Lactente , Internacionalidade , Modelos Lineares , Masculino , Força Muscular/efeitos dos fármacos , Estudos Prospectivos , Coelhos , Testes de Função Respiratória , Resultado do Tratamento , Teste de Caminhada , alfa-Glucosidases/uso terapêuticoRESUMO
PURPOSE: To determine the effect of antibodies against recombinant human acid α-glucosidase (rhGAA) on treatment efficacy and safety, and to test whether the GAA genotype is involved in antibody formation. METHODS: We used enzyme-linked immunosorbent assay (ELISA) to determine anti-rhGAA antibody titers at baseline and at 6, 12, and 36 months of rhGAA treatment. We measured the capacity of antibodies to neutralize rhGAA enzymatic activity or cellular uptake and the effects on infusion-associated reactions (IARs), muscle strength, and pulmonary function. RESULTS: Of 73 patients, 45 developed antibodies. Maximal titers were high (≥1:31,250) in 22% of patients, intermediate (1:1,250-1:31,250) in 40%, and none or low (0-1:1,250) in 38%. The common IVS1/delex18 GAA genotype was absent only in the high-titer group. The height of the titer positively correlated with the occurrence and number of IARs (P ≤ 0.001). On the group level, antibody titers did not correlate with treatment efficacy. Eight patients (11%) developed very high maximal titers (≥156,250), but only one patient showed high sustained neutralizing antibodies that probably interfered with treatment efficacy. CONCLUSIONS: In adults with Pompe disease, antibody formation does not interfere with rhGAA efficacy in the majority of patients, is associated with IARs, and may be attenuated by the IVS1/delex18 GAA genotype.Genet Med 19 1, 90-97.
Assuntos
Formação de Anticorpos/imunologia , Doença de Depósito de Glicogênio Tipo II/imunologia , Proteínas Recombinantes/administração & dosagem , alfa-Glucosidases/administração & dosagem , Adulto , Idoso , Formação de Anticorpos/genética , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Genótipo , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/genética , alfa-Glucosidases/imunologiaRESUMO
BACKGROUND: Pompe disease is an inheritable metabolic disorder for which enzyme replacement therapy (ERT) has been available since 2006. Effects of ERT have been shown on distance walked, pulmonary function and survival. We investigated whether it also improves quality of life and participation in daily life in adult patients with the disease. METHODS: In an international survey, we assessed quality of life (Short Form 36, SF-36) and participation (Rotterdam Handicap Scale, RHS) annually between 2002 and 2012. Repeated measurements mixed effects models were used to describe the data over time. RESULTS: Responses were available for 174 adult patients. In the periods before and after start of ERT, the median follow-up times were 4 years each (range 0.5-8). The SF-36 Physical Component Summary measure (PCS) deteriorated before ERT (-0.73 score points per year (sp/y); CI 95 % -1.07 to -0.39), while it improved in the first 2 years of ERT (1.49 sp/y; CI 0.76 to 2.21), and remained stable thereafter. The Mental Component Summary measure (MCS) remained stable before and during ERT. After declining beforehand (-0.49 sp/year; CI -0.64 to-0.34), the RHS stabilized under ERT. CONCLUSION: In adult patients with Pompe disease, ERT positively affects quality of life and participation in daily life. Our results reinforce previous findings regarding the effect of ERT on muscle strength, pulmonary function and survival.
Assuntos
Atividades Cotidianas/psicologia , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/métodos , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Gravidez , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: The impact of TB disease on survival in people living with HIV in high resource settings is not well documented in the antiretroviral treatment (ART) era. We calculated TB incidence rates and compared the mortality of persons with and without HIV-TB in a UK HIV cohort in the post-ART era, to determine the impact of HIV-TB on survival in the UK. METHODS: We linked the national cohort of persons (aged ≥15â years) diagnosed with HIV between 2000 and 2008 in England, Wales and Northern Ireland with the national TB register and deaths from the Office of National Statistics. We compared all-cause and AIDS-specific mortality in patients with and without TB by estimating HRs using Cox regression modelling allowing for potential predictors. RESULTS: Overall, 3188 (7.2%) individuals developed TB infection among a cohort of 44â 050 HIV-diagnosed persons and 149â 663 person-years. The cumulative TB incidence rate was 2.13 per 100 person-years with a spike within the first 6â months after HIV diagnosis. TB coinfected patients comprised 18% of the 1880 deaths during follow-up and 79% of deaths (n=967) in the year following HIV diagnosis. TB coinfection (HR 4.77, 95% CI 4.11 to 5.54) was significantly associated with increased all-cause mortality. Analysis of AIDS-related survival showed similar results. DISCUSSION: The unexpected high mortality in patients with HIV-TB in a population with good healthcare access and ART availability highlights the importance of improving active and latent TB case-finding among patients with HIV, and HIV-testing among patients with TB, to ensure appropriate and prompt treatment initiation for both diseases.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Infecções por HIV/mortalidade , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/complicações , Adolescente , Adulto , Inglaterra/epidemiologia , Feminino , Seguimentos , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Irlanda do Norte/epidemiologia , Modelos de Riscos Proporcionais , Tuberculose Pulmonar/complicações , País de Gales/epidemiologiaRESUMO
OBJECTIVE: To assess if a 12-week exercise intervention to improve aerobic fitness, muscle strength, and core stability also had an impact on fatigue, pain, activity, and participation in adults with Pompe disease, an inherited neuromuscular disorder. DESIGN: Open-label trial. Change was assessed by the chi-square test and Wilcoxon signed-rank test. SETTING: Physiotherapy practices. PARTICIPANTS: Mildly affected adult patients with Pompe disease who were not dependent on ventilators and/or walking devices and were receiving enzyme replacement therapy. INTERVENTION: Patients participated in a 12-week exercise program, which included 36 sessions of standardized aerobic, resistance, and core stability exercises. MAIN OUTCOME MEASURES: Before and after the training program we evaluated fatigue (Fatigue Severity Scale), pain (yes/no), motor function (Quantitative Muscle Function Test, Rasch-built Pompe-specific Activity Scale), amount of physical activity (activity monitor), and health status (Medical Outcomes Study 36-Item Short-Form Health Survey). RESULTS: Of the 25 patients enrolled, 23 completed the program. At the end of the program, levels of fatigue (median, 5.33 to 4.78, P=.01) and pain (56.5% to 21.7%, P=.04) improved. The quality of motor function and the amount of physical activity patients engaged in did not change. Changes in pain and fatigue were not related to improvements in aerobic fitness or muscle strength. CONCLUSIONS: This study in mildly affected adult patients with Pompe disease suggests that a combined training program aiming to increase aerobic fitness, muscle strength, and core stability also leads to improvements in fatigue and pain.
Assuntos
Terapia por Exercício/métodos , Fadiga/fisiopatologia , Doença de Depósito de Glicogênio Tipo II/reabilitação , Dor/fisiopatologia , Aptidão Física/fisiologia , Adulto , Idoso , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Qualidade de Vida , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Pompe disease is a progressive metabolic myopathy. Involvement of respiratory muscles leads to progressive pulmonary dysfunction, particularly in supine position. Diaphragmatic weakness is considered to be the most important component. Standard spirometry is to some extent indicative but provides too little insight into diaphragmatic dynamics. We used lung MRI to study diaphragmatic and chest-wall movements in Pompe disease. METHODS: In ten adult Pompe patients and six volunteers, we acquired two static spirometer-controlled MRI scans during maximum inspiration and expiration. Images were manually segmented. After normalization for lung size, changes in lung dimensions between inspiration and expiration were used for analysis; normalization was based on the cranial-caudal length ratio (representing vertical diaphragmatic displacement), and the anterior-posterior and left-right length ratios (representing chest-wall movements due to thoracic muscles). RESULTS: We observed striking dysfunction of the diaphragm in Pompe patients; in some patients the diaphragm did not show any displacement. Patients had smaller cranial-caudal length ratios than volunteers (p < 0.001), indicating diaphragmatic weakness. This variable strongly correlated with forced vital capacity in supine position (r = 0.88) and postural drop (r = 0.89). While anterior-posterior length ratios also differed between patients and volunteers (p = 0.04), left-right length ratios did not (p = 0.1). CONCLUSIONS: MRI is an innovative tool to visualize diaphragmatic dynamics in Pompe patients and to study chest-walland diaphragmatic movements in more detail. Our data indicate that diaphragmatic displacement may be severely disturbed in patients with Pompe disease.
Assuntos
Diafragma/fisiopatologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Pulmão/fisiopatologia , Adulto , Idoso , Estudos de Casos e Controles , Diafragma/patologia , Expiração , Feminino , Volume Expiratório Forçado , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Inalação , Pulmão/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Espirometria , Capacidade VitalRESUMO
Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s, p < 0.001). This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p = 0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p = 0.004) and 60+ years age group (p = 0.01), but not to younger age groups (p = 0.99). Except for a shorter aortic reflexion time (p = 0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20%), more Pompe patients had a history of hypertension (36%, p = 0.005), and the MAP was higher than in volunteers (100 versus 92 mmHg, p < 0.001). This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly.
Assuntos
Doença de Depósito de Glicogênio Tipo II/complicações , Hipertensão/etiologia , Rigidez Vascular , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Estudos Transversais , Terapia de Reposição de Enzimas , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Análise de Onda de PulsoRESUMO
BACKGROUND: Patients with Pompe disease, a rare metabolic myopathy, were thought to be at increased risk of severe COVID-19 disease during the pandemic. In addition, the lockdown may have affected their regular treatment. OBJECTIVE: To assess the perceived effect of COVID-19 infection and of the pandemic on the treatment, and physical and mental health of patients with Pompe disease. METHODS: Patients with Pompe disease over 16 years of age participated in an international, cross-sectional, online survey (September 20, 2022-November 7, 2022). The questionnaire, available in eight languages, consisted of 89 questions divided into 3 parts: (A) severity of Pompe disease, (B) COVID-19 precautions and infection(s) and (C) effects of the COVID-19 pandemic. RESULTS: Among 342 respondents, originating from 25 different countries, 47.6% experienced one or more COVID-19 infections. While most recovered within 4 weeks (69.7%) and only eight patients needed to be admitted to the hospital, 42.2% of patients experienced an impact of the infection on their overall condition, respiratory status and/or mobility status. More severely affected patients took more stringent control measures. The pandemic additionally caused interruptions in medical care in many patients (56.0%) and 17.2% of patients experienced interruptions of enzyme replacement therapy. The pandemic also affected many patients' disease severity (27.7%), mental health (55.4%) and feeling of loneliness (43.4%). CONCLUSION: COVID-19 infection(s) and the pandemic affected the treatment, physical health and mental health of patients with Pompe disease, emphasizing the importance of continued patient centered care during a difficult time such as the COVID-19 pandemic.
Assuntos
COVID-19 , Doença de Depósito de Glicogênio Tipo II , Humanos , COVID-19/complicações , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Doença de Depósito de Glicogênio Tipo II/terapia , Doença de Depósito de Glicogênio Tipo II/complicações , Pandemias , Estudos Transversais , Controle de Doenças TransmissíveisRESUMO
Active tuberculosis (TB) in the UK predominantly affects the non-UK born, but is generally not manifest at the time of UK entry. Strategies to detect latent TB infection (LTBI) in this population are, therefore, important. To date, targeted screening has focused on TB risk estimates based on the incidence in the country of origin. Using TB incidence in the UK and migration data, we estimated the numbers needed to be tested and treated for LTBI to prevent one case of TB disease. Numbers were the lowest in Somalian and the highest in South African and Filipino migrants, which contrasts with TB rates in these countries. Targeting screening on the basis of incidence in the UK may thus improve effectiveness.
Assuntos
Emigração e Imigração/estatística & dados numéricos , Tuberculose Latente/diagnóstico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/etnologia , África Subsaariana/etnologia , Bangladesh/etnologia , Humanos , Incidência , Testes de Liberação de Interferon-gama , Programas de Rastreamento , Paquistão/etnologia , Filipinas/etnologia , Tuberculose Pulmonar/prevenção & controle , Reino Unido/epidemiologiaRESUMO
BACKGROUND: Pompe disease is a hereditary metabolic myopathy, for which enzyme replacement therapy (ERT) has been available since 2006. We investigated whether ERT reduces fatigue in adult patients with Pompe disease. METHODS: In this prospective international observational survey, we used the Fatigue Severity Scale (FSS) to measure fatigue. Repeated measures ANOVA was used to analyze the data over time. In a subgroup of patients, we also evaluated muscle strength using the Medical Research Council Scale, measured pulmonary function as Forced Vital Capacity, and assessed depression using the Hospital Anxiety and Depression Scale. RESULTS: We followed 163 patients for a median period of 4 years before ERT and for 3 years during ERT. Before ERT, the mean FSS score remained stable at around 5.3 score points; during ERT, scores improved significantly by 0.13 score points per year (p < 0.001). Fatigue decreased mainly in women, in older patients and in those with shorter disease duration. Patients' improvements in fatigue were moderately correlated with the effect of ERT on depression (r 0.55; CI 95% 0.07 to 0.70) but not with the effect of ERT on muscle strength or pulmonary function. CONCLUSIONS: Fatigue is a common and disabling problem in patients with early and advanced stages of Pompe disease. Our finding that ERT helps to reduce fatigue is therefore important for this patient population, irrespective of the mechanisms underlying this effect.
Assuntos
Fadiga/terapia , Doença de Depósito de Glicogênio Tipo II/terapia , alfa-Glucosidases/uso terapêutico , Adulto , Idoso , Terapia de Reposição de Enzimas , Fadiga/fisiopatologia , Feminino , Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Estudos Prospectivos , Resultado do Tratamento , Capacidade Vital , Adulto JovemRESUMO
OBJECTIVES: Tuberculosis (TB) disease adversely affects mother and child, and strategies to control TB in this group are important. The aim of this study was to analyze the epidemiology of TB in pregnancy, and to establish whether pregnancy is an independent risk factor for TB. METHODS: The United Kingdom-wide cohort study was based on the General Practitioner Research Database (GPRD), enrolling all women with pregnancies between 1996 and 2008. Incidence rates and incidence rate ratios (IRRs) of TB events during pregnancy, 6 months postpartum, and outside pregnancy were calculated and compared by Poisson regression. A nested self-controlled case series compared the risk of TB in these periods, adjusting for individual and time-bound confounders. MEASUREMENTS AND MAIN RESULTS: The crude TB rate for the combined pregnancy and postpartum period was 15.4 per 100,000 person-years, significantly higher than outside of pregnancy (9.1 per 100,000 person-years; P = 0.02). Adjusting for age, region, and socioeconomic status the postpartum TB risk was significantly higher than outside pregnancy (IRR, 1.95; 95% confidence interval [CI], 1.24-3.07), whereas there was no significant increase during pregnancy (IRR, 1.29; 95% CI, 0.82-2.03). These observations were confirmed in the self-controlled case series (IRR, 1.62; 95% CI, 1.01-2.58 and IRR, 1.03; 95% CI, 0.64-1.65, respectively). CONCLUSIONS: The incidence of TB diagnosis is significantly increased postpartum. Although we did not find an increase during pregnancy, the postpartum incidence may reflect an increase during pregnancy given diagnostic, immunological and administrative delays. Clinicians' awareness should be improved and the effectiveness of public health policy measures such as targeted screening of pregnant and postpartum women in high-risk groups should be evaluated.
Assuntos
Complicações Infecciosas na Gravidez/microbiologia , Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Distribuição de Poisson , Período Pós-Parto , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/etiologia , Resultado da Gravidez , Fatores de Risco , Tuberculose Pulmonar/etiologia , Reino Unido/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. OBJECTIVES: This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. METHOD: We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. RESULTS: We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. CONCLUSION: Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Humanos , Adulto , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/efeitos adversos , Terapia de Reposição de Enzimas/efeitos adversos , Rotulagem de MedicamentosRESUMO
WHO standards for tuberculosis (TB) control require monitoring and evaluation of TB control programmes. In London, TB rates have stabilised at 44 per 100,000 since 2005. In 38 urban areas outside London with TB rates above the national average, these continued to rise after 2004, to 28 per 100,000 in 2008 (15% increase). London has the highest proportion of TB cases in certain risk groups, but these are increasing rapidly outside London. Many TB control efforts focus on the capital, but with rates rising elsewhere in the country, this strategy is likely to fail in the long term.
Assuntos
Tuberculose/epidemiologia , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Londres/epidemiologia , Masculino , Vigilância da População , Tuberculose/etnologia , Tuberculose/prevenção & controle , Saúde da População Urbana/estatística & dados numéricos , Saúde da População Urbana/tendências , País de Gales/epidemiologia , Adulto JovemRESUMO
Pompe disease is an inherited metabolic, neuromuscular disorder. With the introduction of enzyme replacement therapy skeletal muscle and respiratory function can be stabilized or improved. Additional physiotherapy to advance physical functioning of patients might be beneficial, but evidence and guidelines are lacking. In order to get an insight into current practices of referral and treatment, and perceived benefit, we performed a survey among 88 Dutch adult Pompe patients and 31 physiotherapists. Sixty percent of patients were ever referred for physiotherapy, whereas currently less than 40% receive physiotherapy. Approximately 50% of patients were referred for loss of muscle strength; while 74% received muscle strengthening exercises, often combined with aerobic endurance training. In 47% of patients the intervention did not match the referral reason. More than two-thirds of patients and physiotherapists perceived physiotherapy as beneficial, and the majority highlighted the need for guidance. Physiotherapeutic care can be improved by tailoring interventions to referral reasons and treatment objectives. More high quality studies are urgently needed to assess which interventions are most useful in this patient group.
Assuntos
Doença de Depósito de Glicogênio Tipo II/terapia , Modalidades de Fisioterapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing progressive proximal muscular, respiratory, and bulbar weakness. We present outcome data on motor function, ventilation, nutrition, and language development of SMA patients treated with nusinersen in Switzerland. This multicenter, observational study included 44 patients. At treatment initiation, after 2 months and then every 4 months we assessed motor function with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale expanded (HFMSE) and 6-Minute Walk Test (6MWT). At treatment initiation, patients were 0.1-44.6 years old, treatment duration ranged from 6 to 41 months. All 11 SMA type 1 children achieved higher CHOP-INTEND scores at the last assessment compared to treatment initiation, 4 acquired stable sitting. Six type 1 children were <18 months-old at treatment initiation. Two of them did not need ventilation or nutritional support at the last assessment; three had delayed language development and 3 articulation difficulties. 5/21 SMA type 2 patients achieved higher HFMSE scores. All ambulant type 3 patients showed a gain in the 6MWT. Nusinersen is an effective treatment, with gains in motor function occurring particularly in children and SMA type 1, but also in type 2 and 3, adolescents and adults.
Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Suíça , Adulto JovemRESUMO
BACKGROUND: Enzyme replacement therapy (ERT) with alglucosidase alfa has been found to improve outcomes in patients with classic infantile Pompe disease, who without treatment typically die before the age of 1 year. Variable responses to the standard recommended dosage have led to alternative dosing strategies. We aimed to assess the effect of real-world ERT regimens on survival and walking ability in these patients. METHODS: In this observational cohort study, we obtained data collected as part of a collaborative study within the European Pompe Consortium on patients with classic infantile Pompe disease from France, Germany, Italy, and the Netherlands diagnosed between Oct 26, 1998 and March 8, 2019. Eligible patients had classic infantile Pompe disease with a disease onset and proven diagnosis before age 12 months, and a hypertrophic cardiomyopathy. A proven diagnosis of classic infantile Pompe disease was defined as a confirmed deficiency of α-glucosidase in leukocytes or lymphocytes, fibroblasts or muscle, or two pathogenic GAA variants in trans, or both. We collected data on demographics, GAA variants, ERT dosage, age at death, and walking ability. We analysed the effects of ERT dosage on survival and walking ability using Cox regression, Kaplan-Meier curves, and log-rank tests. FINDINGS: We included 124 patients with classic infantile Pompe disease, of whom 116 were treated with ERT (median age at start of treatment 3·3 months [IQR 1·8-5·0, range 0·03-11·8]). During follow-up (mean duration 60·1 months [SD 57·3]; n=115), 36 (31%) of 116 patients died. 39 different ERT dosing regimens were applied. Among the 64 patients who remained on the same dosage, 16 (52%) of 31 patients on the standard dosage (20 mg/kg every other week), 12 (80%) of 15 patients on an intermediate dosage (20 mg/kg per week or 40 mg/kg every other week), and 16 (89%) of 18 patients on the high dosage (40 mg/kg per week) were alive at last follow-up. Survival was significantly improved in the high dosage group compared with the standard dosage group (hazard ratio [HR] 0·17 [95% CI 0·04-0·76], p=0·02). No significant difference in survival was identified between the intermediate dosage group and the standard dosage group (HR 0·44 [0·13-1·51], p=0·19). Of the 86 patients who reached 18 months of age, 44 (51%) learned to walk. Ten (53%) of 19 patients on the standard dosage regimen, six (67%) of nine patients on intermediate dosage regimens, and 14 (93%) of 15 patients on high dosage regimens learnt to walk, but the differences between groups were not statistically significant. INTERPRETATION: Patients with classic infantile Pompe disease treated with the high ERT dosage of 40 mg/kg per week had significantly improved survival when compared with patients treated with the standard recommended ERT dosage of 20 mg/kg every other week. Based on these results, we suggest that the currently registered dosage should be reconsidered. FUNDING: Prinses Beatrix Spierfonds and Wishdom Foundation.