Effects of higher and more frequent dosing of alglucosidase alfa and immunomodulation on long-term clinical outcome of classic infantile Pompe patients.

The aim of this study was to compare the long-term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross-reactive immunologic material (CRIM)-negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator-free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)-naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator-free survival was 50% and 92%. Both CRIM-negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk. Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM-negative also received immunomodulation. B-cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B-cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250-1:800 000 and 1:250-1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator-free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.

Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop.

Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy.

A long term follow-up study of the development of hip disease in Mucopolysaccharidosis type VI.

Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lack of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology). Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance. A total of 157 pelvic radiographs of 14 ERT treated MPS VI patients were evaluated. Age at first image ranged from 2.0 to 21.1years. Median follow up duration was 6.8years. In all patients, even in the youngest, the acetabulum and os ilium were dysplastic. Coverage of the femoral head by the acetabulum improved over time, but remained insufficient. While the femoral head appeared normal in the radiographs at young age, the ossification pattern became abnormal in all patients over time. In all patients the distance covered in the 6MWT was reduced (median Z scores -3.3). Twelve patients had a waddling gait. Four patients were partially wheelchair-dependent and ten patients had limitations in their maximum walking distance. In conclusion, clinically significant hip abnormalities develop in all MPS VI patients from very early in life, starting with deformities of the os ilium and acetabulum. Femoral head abnormalities occur later, most likely due to altered mechanical forces in combination with epiphyseal abnormalities due to glycosaminoglycan storage. The final shape and angle of the femoral head differs significantly between individual MPS VI patients and is difficult to predict.

The effectiveness of physiotherapy in patients with asthma: a systematic review of the literature.

Since the introduction of medical therapy for asthma the interest in non-medical treatments deteriorated. Physiotherapy could have beneficial effects in asthmatics. This review investigates the effectiveness of physiotherapy in the treatment of patients with asthma. A review was performed on the terms breathing exercises (BE), inspiratory muscle training (IMT), physical training (PhT) and airway clearance (AC) in patients with asthma. The search resulted in 237 potentially relevant articles, after exclusion 23 articles remained. BE (n = 9) may improve disease specific quality of life (QoL), reduce symptoms, hyperventilation, anxiety and depression, lower respiratory rate and medication use. IMT (n = 3) can improve inspiratory pressure and may reduce medication use and symptoms. PhT (n = 12) can reduce symptoms, improve QoL and improve cardiopulmonary endurance and fitness. In conclusion, physiotherapy may improve QoL, cardiopulmonary fitness and inspiratory pressure and reduce symptoms and medication use. Further studies, investigating combinations of techniques, are needed to confirm these findings.

Nocturnal oxygen saturation in children with stable cystic fibrosis.

BACKGROUND: Hypoxemia during sleep is a common finding in Cystic Fibrosis (CF) patients with more advanced lung disease. Nocturnal hypoxemia is associated with frequent awakenings and poor sleep quality. For children with CF, data of nocturnal oxygen saturation are sparse. OBJECTIVE: To assess the oxygen saturation profile during sleep in 25 clinically stable children with CF lung disease and to correlate these data with spirometry, cough frequency, sleep quality, and CT-scan scores. METHOD: During two nights cough was recorded with a digital audio recorder in 25 clinically stable CF patients. In addition oxygen saturation was measured. The day following the recording spirometry was carried out. CT scores were obtained from the most recent routine CT scan. RESULTS: Twenty-two patients were included in the study. Mean age (range) was 13 (6-18) years. Spirometry was FVC% 84 (range 52-114), FEV(1) % 77 (range 43-115), and FEF(75) % 50 (range 12-112). The mean SO(2) was 95.6% for the first and 96.2% for the second night. Mean SO(2) between the two nights correlated strongly (r(s) = 0.84, P < 0.001). Positive correlation was observed between mean SO(2) of the two nights (mean × SO(2)) and FVC, FEV(1) and FEF(75). Correlations were found between mean × SO(2) and the total CT score (r(s) = -0.45, P = 0.05) and the bronchiectasis subscore (r(s) = -0.48, P = 0.03). CONCLUSION: Nocturnal oxygen saturation in children with stable CF is lower than that in healthy children, and is correlated with lung function parameters and CT scores. Monitoring oxygen saturation during one night is sufficient to get a representative recording.

Nocturnal cough in children with stable cystic fibrosis.

INTRODUCTION: To date no studies have been published on nocturnal cough frequency in children with stable CF. Aim of the study was to assess nocturnal cough frequency in children with CF. In addition nocturnal cough frequency was correlated with parameters of disease severity. METHODS: During two nights cough was recorded with a digital audio recorder in 25 patients (mean age 13 years; range 6-19) with clinically stable CF. In addition oxygen saturation was measured. The day following the recording spirometry was carried out. CT scores were obtained from the most recent routine CT scan. Cough was expressed in cough seconds (csec) and in cough seconds per hour (csec/hr). RESULTS: Data shown are median values and interquartile range (IQR). First night: 8 csec (IQR 3-52); 0.9 csec/hr (IQR 0.3-6.1) Second night: 6 csec (IQR 2-32); 0.6 csec/hr (IQR 0.1-3.4). Csec in the 1st night did not correlate significantly with csec in the 2nd night. Only for the 2nd night a strong correlation was found between csec/hr and the FEV1%pred (r(s) = -0.75, P < 0.001) and FEF(75) %pred (r(s) = -0.71, P < 0.001). Bronchiectasis score correlated borderline with the mean csec/hr of both nights (r(s) = 0.39, P = 0.08). During both nights cough was significantly higher in the first hour of sleep (P < or = 0.04). CONCLUSION: Frequency of nocturnal coughing in children with CF was higher than that described for normal children. Nocturnal cough tended to be more severe in children with more advanced CF lung disease. Nocturnal cough was more severe in the first hour of sleep and varied from night-to-night.

Does the timing of inhaled dornase alfa matter?

In CF patients with mild or moderate lung disease, the most sensitive spirometric measure of response to dornase alfa is peripheral airflow. Cross-over studies in patients, already stabilised on dornase alfa, indicate that peripheral airflow shows greater improvement when it is administered 30 minutes before airway clearance therapy (ACT) rather than shortly after ACT. These results are consistent with the hypothesis that the major role of dornase alfa is to facilitate expectoration of sputum during ACT. When ACT is performed in the morning, efficacy and safety are similar when dornase alfa is inhaled before bedtime or upon awakening. Most patients may therefore choose the most convenient time of day to inhale dornase alfa provided that they wait at least 30 minutes before performing ACT. Further research is necessary to establish the optimum regimen in patients with more advanced lung disease.

RhDNase before airway clearance therapy improves airway patency in children with CF.

INTRODUCTION: Little is known about the optimal timing of rhDNase nebulization in relation to airway clearance therapy (ACT). OBJECTIVE: To compare the effects of rhDNase before ACT versus rhDNase after ACT in children with CF. DESIGN: randomized, double blind, double dummy, cross over study. INCLUSION CRITERIA: CF, stable clinical condition, rhDNase maintenance therapy. Children in Group I inhaled rhDNase 30 minutes before ACT, and placebo directly after ACT in week 1-3. The protocol was reversed during week 4-6. Group II performed the reversed sequence. Patients continued their daily routine ACT. Primary endpoint: MEF(25) %pred. Pulmonary functions tests were performed on days 0, 14, 21, 35 and 42. In weeks 3 and 6 children scored cough and sputum production on daily diary cards. RESULTS: 24 patients completed the study. Mean age = 12 years (range 7-19). Mean MEF(25) %pred was 5.8% higher after 3 weeks of rhDNase before ACT, compared to rhDNase after ACT (58.3% vs 52.5%, p=0.01). There were no significant differences for any of the other variables. CONCLUSION: Inhalation of rhDNase before ACT improves peripheral airway patency in children with cystic fibrosis. Since all children were already on maintenance rhDNase therapy before the study, this effect is additional to any existing effect of regular rhDNase.