Search

Objective To examine the effect of intrathecal application of nusinersen on the respiratory function in terms of vital capacity in pediatric patients with spinal muscular atrophy (SMA). SMA is characterized by on-going muscular atrophy and weakness that lead to respiratory insufficiency. In recent years therapy with nusinersen has been shown to improve motor function in patients with SMA. Methods We retrospectively analyzed data from 12 pediatric patients (aged 4–12 years) with SMA II or III (7 walkers, 5 sitters) treated with nusinersen. We examined forced vital capacity (FVC) at baseline (i.e., before treatment) and 180 and 300 days after initiation of treatment. Results No significant difference in the ranks of FVC of patients with SMA at baseline and day 300 was found and, thus, stable FVCs are implied (n = 6; Z = - 0.105, pexact = 1.000; Medianbaseline = 96.0%, 95%-CI [86.5, 110.5]; Medianday300 = 96.0%, 95%-CI [92.0, 109.5]; s. Table 1). This also applied to the comparison between baseline and day 180 (n = 7; Z = 0.00, pexact = 1.00; Medianbaseline = 93.0%, 95%-CI [85.0, 110.0]; Medianday180 = 91.0%, 95%-CI [72.0, 118.0]) and day 180 and 300 (n = 9; Z = - 0.533, pexact = .652; Medianday180 = 95.0%, 95%-CI [72.0, 118.0]; Medianday300 = 90.0%, 95%-CI [74.0, 105.0]). Conclusion Nusinersen therapy alone may not improve lung function of pediatric patients with SMA type II or III.

Background: Diagnosis and treatment of paediatric tuberculosis resistant to both isoniazid and rifampicin (MDR-pTB) remain challenging due to paucibacillary disease, low sensitivity and specificity of diagnostic tools and frequently changing guidelines Aims and objective: This study aimed to describe epidemiology, clinical characteristics and outcome of MDR-TB among children and adolescents in Germany. Methods: We collected all cases of MDR-pTB registered in Germany from 2010 to 2020 and compared their data to an adequate control sample with drug-sensitive TB. Results: 52 subjects with MDR-pTB (24 active MDR-TB, 28 MDR-LTBI) and 56 controls were included. The annual incidence of MDR-TB rose from two in 2010 to nine in 2020. Time to diagnosis was longer in MDR-pTB compared to drug-sensitive TB (43 vs. 8 days, p Conclusions: Early diagnosis, identification of potential MDR index, appropriate treatment and follow-up are essential in MDR-pTB. Therefore, better cooperation between clinics and public health care is required in Germany. In children with an MDR-TB index case or in those born in a MDR high-incidence country, bacteriological confirmation including PCR-based susceptibility testing should always be initiated. The individual drug regimen has to be adapted to the patients’ or index’ susceptibility testing results.

BACKGROUND: Sleep disturbances and poor sleep quality are a known phenomenon in patients with Cystic Fibrosis (CF). Habitual physical activity (HPA) plays an important role in the treatment of CF patients due to its positive influence on progression of disease and quality of life. The aim of this work is to create a home-based sleep and activity profile and to investigate the influence of habitual physical activity (HPA) on sleep quality of children, adolescents and adults with CF. METHODS: One hundred and nine CF patients (64 male, mean age 22.7±12.0 years; mean ppFEV1 63.0±26.7) were equipped with an actigraph (Actigraph Corp., Pensacola, FL, United States) for home-based collection of activity and sleep data for a total of 4 weeks. Evaluation of recorded raw data was performed by ActiLife software, Version 6.11.9 (Actigraph Corp., Pensacola, FL, United States). RESULTS: CF patients under the age of 18 show the best sleep efficiency (92%±3%), the longest time in bed (TIB) (545±71 min) and Total Sleep Time (504±72 min) and the lowest Wake after sleep Onset (WASO) (39±15 min). With increasing age there is a decrease in Sleep efficiency (SE) (P0.05). In terms of lung function, CF patients with FEV1 values > 70%pred. have the best SE (92%±3%), the highest TST (490±72 min) and TIB (531±71 min) and the lowest WASO (39±13 min). As FEV1 deteriorates, a change in sleeping behavior can be detected. SE (P0.05) decrease, whereas WASO (P>0.05) increases. Interestingly, there is no difference in the number of awakenings between the different age and FEV1 groups (all P>0.05). Statistical analysis was performed using version 25 of the SPSS statistics package (SPSS Inc., Chicago, USA). CONCLUSIONS: Besides younger age and higher FEV1, daily activity in higher intensities influences sleep of CF patients in a positive way. Patients with poor quality and disturbances of sleep possibly benefit from an intensification of physical activity in the home environment.

Introduction: chILD comprises various rare respiratory conditions and partially overlaps with adult ILD. Lung fibrosis is the most common disease entity in adults; however, there are no data on the prevalence, clinical, radiological and histopathological presentation of pulmonary fibrosis in chILD. Aim: To assess the prevalence of fibrosis in lung biopsies from the international management platform, the European chILD registry (NCT02852928), and to correlate paediatric lung fibrosis with radiological findings. Methods: Features of fibrosis in biopsies were defined by the presence of any of the following: description of interstitial fibrosis, fibroblastic foci or honeycombing. A histological diagnosis of chronic pneumonitis of infancy (CPI) was also included. Fibrosis by chest computed tomography (CT) scans was defined by the presence of linear or reticular opacities, honeycombing, traction bronchiectasis or architectural distortion. Results: Lung biopsies were available for 149/825 chILD cases (18%); 46 biopsies (31%) had features of fibrosis and 11 were identified by CPI pattern alone. Mean age at biopsy was 6.4 years (range 0–26). Thirty cases were related to alveolar surfactant region (ABCA3: n=11; SFTPC: n=3), five to systemic disease processes (e.g. connective tissue disease: n=2) and three to immunodeficiency. Individual cases accounted for the other categories. Only 21/46 cases (46%) with biopsy-proven features of fibrosis had fibrosis features by CT. Conclusions: Features of fibrosis were already present in 31% of cases with a diagnostic lung biopsy. Concordance between biopsy- and CT-diagnosed fibrosis was lower than expected and requires further evaluation.

Pompe disease is a rare metabolic myopathy caused by deficiency of lysosomal α-glucosidase. Reduced enzyme activity results in abnormal intra- and extralysosomal glycogen deposition as well as impaired cellular function and autophagy. Age at manifestation and severity of disease depend on residual enzyme activity. Enzyme replacement therapy (ERT) is available since 2006. In infantile onset Pompe disease, the most severe form, markedly prolonged survival has resulted in a new phenotype with symptoms and problems not encountered previously. In addition, it became apparent that antibody formation against the recombinant human enzyme may adversely affect the response to ERT. This review summarizes new knowledge gained in the last years concerning care of pediatric patients with Pompe disease and gives recommendations for diagnostics, treatment, and follow-up.Morbus Pompe ist eine seltene metabolische Myopathie, bei der ein Mangel an lysosomaler Alpha-Glukosidase zur pathologischen intra- und extralysosomalen Speicherung von Glykogen sowie zu gestörter Autophagie führt. Je nach Alter bei Beginn können klassisch infantile sowie kindliche, juvenile und adulte Formen unterschieden werden. Alter bei Manifestation und Schweregrad hängen von der Enzym-Restaktivität ab. Seit 2006 ist eine Enzymersatztherapie (EET) verfügbar. Das verlängerte Überleben von Patienten mit infantiler Verlaufsform führt zum Auftreten neuer Symptome, die bisher bei diesen Kindern nicht beschrieben wurden. Zudem hat sich gezeigt, dass eine Antikörperbildung gegen das rekombinante humane Enzym den Erfolg der EET negativ beeinflussen kann. Dieser Artikel fasst neue Erkenntnisse zusammen, die in den letzten Jahren hinsichtlich neuer klinischer Symptome und therapeutischer Probleme gewonnen wurden, und gibt Empfehlungen für Initialdiagnostik, Behandlung und Verlaufserfassung des Morbus Pompe im Kindesalter.

BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).

The aim of this study was to examine motor performance and trainability in youths with cystic fibrosis (CF).Twenty-two children and adolescents (11 f/11 m), age range 6-17 years (11.3 ± 3.3 years), mean FEV1 91.0 ± 21.7% pred.finished the partially monitored 12-months exercise program. Patients performed the Deutsche Motorik Test (DMT) to assess flexibility, balance, strength, power and totalmotor performance. An incremental ergometer cycle test was used to assess maximal exercise capacity (Wpeak). All tests were performed before (T1), after 6 months of monitored exercise training (T3) and another 6 months without monitoring (T4).Motor Competence in total and test-items of the DMT (except foreward bend) improved to T3 (p .05). No further improvement could be observed after the end of the monitoring (T3). However, the values remained stable at the improved level (T4). Girls scored lower in test items depending on strength/power but scored higher in balancing compared to boys (p .05). Wpeak and FEV1 were not influenced by the training program. From T3 to T4 a slight decrease was observed (p ≤ .05).The findings demonstrate benefits of an individualizedmonitored long-term exercise intervention on motor performance in CF with improvements of test-tasks to predicted normal. Monitoringseems to be a facilitator in maintaining motivation toward physical activity as no further increase in motor performance was observed after stopping supervision. The results suggest that an individually tailored monitoredregular exercise program should include all aspects of physical fitness with a variety of movement experiences.

Objective While out-of-center testing was introduced as an alternative for the diagnosis of obstructive sleep apnea in adults, polysomnography (PSG) is still considered mandatory in the diagnosis of sleep-disordered breathing (SDB) in children. The purpose of this study was to validate the outpatient screening device ApneaLink ® in comparison to PSG in children and adolescents for the diagnosis of SDB. Methods Sixty consecutive children and adolescents (10.4 ± 6.2, 0–22 years) with suspected SDB admitted to the sleep laboratory underwent simultaneous recording with full PSG and the screening device ApneaLink ® based on flow measurement and oxygen saturation. Results The mean apnea–hypopnea index (AHI) was 11.8 ± 19.7 in PSG and 10.3 ± 12.0 in ApneaLink ® . When the AHI threshold was set to 5/h to diagnose SDB, the overall sensitivity for ApneaLink ® was 79% and the specificity was 63%. After reducing the AHI threshold to 1/h, the sensitivity and specificity were 94% and 29%. In children older than 10 years, the performance of ApneaLink ® improved (AHI 5/h: sensitivity 80%, specificity 64%; AHI 1/h: sensitivity 100%, specificity 50%). Conclusion These results show that the outpatient screening device ApneaLink ® reliably identifies SDB in preselected children older than 10 years. In contrast, it may not be used for the exclusion of SDB.

OBJECTIVES The lung clearance index (LCI) is determined by multiple-breath washout lung function (MBW). It is increasingly used as an endpoint in clinical trials. Chest physiotherapy (CP) is part of routine cystic fibrosis (CF) care. Whether the LCI is useful in detecting short-term treatment effects of CP has not been sufficiently investigated. We assessed the short-term influence of CP with highly standardized high-frequency chest wall oscillation (HFCWO) on the LCI in CF patients. METHODS In this randomized controlled study, the LCI was obtained in 20 CF patients (7-34 years) hospitalized for infective pulmonary exacerbation prior to and immediately after a single treatment of HFCWO. Twenty-one control group CF patients (7-51 years) received no treatment. We calculated the coefficient of repeatability (CR) to estimate the clinical relevance of possible treatment effects. RESULTS HFCWO improved (ie, decreased) the LCI by a median of 0.9 (range −0.45; 3.47; P = 0.002); the LCI decreased in 15 of 20 intervention group patients. In five patients the decrease in LCI exceeded the CR (2.15), indicating a clinically relevant treatment effect; in five patients the LCI increased but did not exceed the CR. The LCI did not change significantly in the control group patients. CONCLUSIONS HFCWO can have a short-term decreasing effect on the LCI, but the treatment response is heterogeneous. In future trials using LCI as an endpoint, the timing of CP in relation to MBW should be considered a possible bias.

Background: Life expectancy in Cystic Fibrosis (CF) patients is low which may rise personal questions regarding spiritual issues to cope. Aims and Objectives: Aims of our study were to explore which spiritual needs are of relevance and their association with indicators of quality of life or disease progression in adolescents and adults with CF. Methods: Cross-sectional multi-center survey using standardized questionnaires (i.e., SpNQ, BMLSS, GrAw-7). Descriptive statistics, analyses of variance, first order correlations and regression analyses were applied. Results: 115 patients (20 adolescents, 95 adults) with a mean age of 30.4±13.1 years participated in the survey. Needs for Attention/Affirmation (AA) (1.59±.86) and for inner peace (IP) (1,39±.97) scored highest, while religious needs (RN) (.51±.78) and existential needs (EN) (.69±.75) scored low. Usage of a respirator was associated with higher AA (F=10.1; p=.002) and IP (F=6.2; p=.015), and being on the waiting list for lung transplantation (LTX) was associated with higher AA (F=4.8, p=.030), higher EN (F=5.3; p=.023) and higher RN (F=15.5 (p Conclusions: Needs for AA and IP are important for patients with CF; RN become more relevant for patients on a waiting list for LTX. Evaluation of patient´s needs can provide clinicians with useful information to further support them in difficult life situations.

Home non-invasive ventilation improves morbidity and mortality patients with respiratory insufficiency due to neuromuscular disease. Evidence-based information on adequate ventilator settings for paediatric patients is missing. In a single-centre retrospective study, we analysed ventilator settings for 128 patients aged 0-17 years with home non-invasive ventilation on account of respiratory insufficiency due to neuromuscular disease. In four defined age groups (

BACKGROUND: Culturing of bronchoalveolar lavage (BAL) fluid is a commonly used method for pathogen detection in pneumonia. However, the sensitivity is low, especially in patients pre-treated with anti-infective agents. The early detection of a pathogen is crucial for the outcome of respiratory tract infections. For bloodstream infections, a multiplex polymerase chain reaction (PCR) assay (SeptiFast®, SF) is available for improved pathogen detection from blood. OBJECTIVE: The aim of the present study was to determine whether the SF assay is applicable to the BAL of children with pulmonary infections and whether the frequency of pathogen detection is enhanced by the use of this multiplex PCR method. METHODS: We investigated 70 BAL samples of 70 children simultaneously by culture and multiplex PCR. The frequency of pathogen detection was compared. RESULTS: Pathogens were detected more frequently by SF than by culture (83% vs. 31%; p

Background In patients with severe neurological impairment, recurrent respiratory tract infections frequently occur as a result of impaired clearance of airway secretions and microbial airway colonisation. We hypothesised that inhaled antibiotic therapy may improve the morbidity of these patients. Methods A retrospective data analysis of 20 patients (11 nontracheotomised and nine tracheotomised) with neurological impairment and microbial airway colonisation was carried out at a children's university hospital. Two questionnaires that asked about the number of respiratory tract infections, antibiotic therapies and hospitalisations were distributed to the patients/caregivers: a first questionnaire representing the 12 months prior to the initiation of inhaled antibiotics and a second questionnaire describing the first 12 months under therapy. Results During the first 12 months of therapy, the frequency of respiratory tract infections among all participants was reduced from a mean of 6.8 episodes (median (interquartile range (IQR)) 6.0 (4.0–10.0) episodes) to a mean of 2.5 episodes (median (IQR) 2.0 (1.0–3.0) episodes; p, Inhaled antibiotic therapy offers a novel approach to the prevention of respiratory tract infections in patients with severe neurological impairment who have chronic microbial airway colonisation and recurrent respiratory tract infections http://bit.ly/2HQRyz0

Background and objective Inherited neuromuscular disorders (NMD) inevitably result in severe lung volume restriction and cough insufficiency associated with high morbidity and mortality. The aim of this retrospective study was to evaluate whether the airways of patients with NMD are colonized with potential pathogenic microorganisms that might contribute to the pulmonary morbidity in NMD. Methods In this cross-sectional study, cough swabs were obtained and cultured for microbiological analyses from 77 patients with NMD and different degrees of lung volume restriction and cough insufficiency. Upper airway microbial colonization was compared to lung function parameters and cough peak flow values. Results Upper airway microbial colonization with potential pathogenic pathogens was identified in 39/77 (51%) of the subjects. Upper airway microbial colonization was associated with lower forced vital capacity (% pred.) 26.6 ± 19.7 versus 41.8 ± 20.4, P

Objectives: Aspergillus fumigatus is the most prevalent filamentous fungus in the respiratory tract of patients with cystic fibrosis (CF). The aim of this prospective multicentre study was to investigate the prevalence of azole-resistant A. fumigatus (ARAF) in respiratory secretions from CF patients across Germany and to characterize ARAF isolates by phenotypic and molecular methods. Methods: Twelve tertiary care centres from Germany participated in the study. In total, 2888 A. fumigatus isolates from 961 CF patients were screened for ARAF by using azole-containing agar plates. Antifungal susceptibility testing of isolates was performed by broth microdilution according to EUCAST guidelines. Analysis of mutations mediating resistance was performed using PCR and sequencing of the cyp51A gene. Furthermore, genotyping by microsatellite PCR was performed. Results: Of a total of 2888 A. fumigatus isolates, 101 isolates from 51 CF patients were found to be azole resistant (prevalence per patient 5.3%). The Essen centre had the highest prevalence (9.1%) followed by Munich (7.8%), Munster (6.0%) and Hannover (5.2%). Most ARAF isolates (n = 89) carried the TR34/L98H mutation followed by eight G54E/R, one TR46/Y121F/T289A and one F219S mutation. In two isolates no mutation was found. Genotyping results showed no major clustering. Forty-five percent of CF patients with ARAF had previously received azole therapy. Conclusions: This is the first multicentre study analysing the prevalence of ARAF isolates in German CF patients. Because of a resistance rate of up to 9%, susceptibility testing of A. fumigatus isolates from CF patients receiving antifungal treatment should be part of standard diagnostic work-up.

We report the case of a 19-years-old patient who presented with a perplexing variety of symptoms which included remarkable facial features, intellectual disability, granulomatous upper lip swelling (previously diagnosed as Melkersson–Rosenthal syndrome), Crohn’s-like disease, non-productive cough, and a granulomatous mass localized in the left lung. Chronic granulomatous disease (CGD) was diagnosed using dihydrorhodamine 123 assay that showed low levels of phagocytic NADPH-oxidase. DNA sequencing revealed a heterozygous mutation in the NCF-1 gene on chromosome 7. As remarkable facial features and psychomotor retardation are not associated with CGD, a more detailed genetic work-up using fluorescence in situ hybridization was performed. A microdeletion in 7q11.23 on one allele indicated Williams–Beuren syndrome (WBS). The NCF-1 gene and its two pseudogenes are part of a highly repetitive region within 7q11.23 and are prone to recombination events and deletions. Such deletions can involve both the WBS critical region and the NCF-1 wildtype gene, as was the case for our patient. The second allele of the NCF-1 gene was affected by the frequent c.75.76delGT mutation that stems from a recombination of the NCF-1 wildtype gene with one of its pseudogenes. In conclusion, patients with NCF-1-deficient CGD may also harbor microdeletions that result in WBS or other hereditary disorders; therefore, it is important to perform a thorough genetic analysis in order to initiate appropriate therapy for these patients. CA Soukup

Inherited neuromuscular disorders inevitably result in severe lung volume restriction associated with high morbidity and mortality. The aim of this retrospective study was to evaluate the long-term effects of the regular use of mechanical insufflation/exsufflation on the course of the vital capacity. This retrospective data analysis included 21 patients (16.1 ± 6.5 years) with neuromuscular disorders and severe lung volume restriction using nocturnal noninvasive ventilation. The patients were advised to regularly use the mechanical insufflation/exsufflation twice a day for 10 minutes applying sets of three insufflation/exsufflation breath via face mask irrespective of respiratory tract infection. Data on the course of vital capacity were collected 2 years prior and 2 years after the introduction of regular use of mechanical insufflation/exsufflation. Before the introduction of mechanical insufflation/exsufflation vital capacity decreased from 0.71 ± 0.38 L to 0.50 ± 0.24 L in the last year and from 0.88 ± 0.45 L to 0.71 ± 0.38 L in the next to last year. In the first year, after regular use of mechanical insufflation/exsufflation vital capacity significantly increased by 28% (from 0.50 L to 0.64 L)—after the second year the vital capacity increase remained stable (0.64 vs. 0.65 L). These data suggest that the regular use of mechanical insufflation/exsufflation improves vital capacity in patients with neuromuscular disorders and severe lung volume restriction.

Background: Bloodstream pathogens can be identified by multiplex PCR (SeptiFast (SF)) or blood culture (BC); whether these pathogens are present in cystic fibrosis (CF) patients during febrile pulmonary exacerbations (FPE) has not been sufficiently studied. Methods: In this prospective observational study, blood from CF patients experiencing FPE was tested with SF and BC before the initiation of antibiotic treatment. Results: After contaminants had been excluded, 9 of 72 blood samples tested positive by BC or SF. SF exclusively detected four pathogens; BC, one. Pulmonary pathogen transmission was likely in all cases except for 2 cases of candidaemia, which were believed to be caused by catheter-related infections. For three cases, test results caused us to change the antibiotic regimen. Sensitivity (85.7% vs. 42.9%) and negative predictive value (98.4% vs. 87.0%) tended to be higher for SF than for BC. Conclusions: The results of SF and BC show that bacteraemia and fungaemia are present in CF patients during FPE and may affect antibiotic therapy. SF can help rule out catheter-related bloodstream infections. OA gold

While out-of-center testing was introduced as an alternative for the diagnosis of obstructive sleep apnea in adults, polysomnography (PSG) is still considered mandatory in the diagnosis of sleep-disordered breathing (SDB) in children. The purpose of this study was to validate the outpatient screening device ApneaLinkSixty consecutive children and adolescents (10.4 ± 6.2, 0-22 years) with suspected SDB admitted to the sleep laboratory underwent simultaneous recording with full PSG and the screening device ApneaLinkThe mean apnea-hypopnea index (AHI) was 11.8 ± 19.7 in PSG and 10.3 ± 12.0 in ApneaLinkThese results show that the outpatient screening device ApneaLink

Introduction. Antibiotic treatment regimens againstPseudomonas aeruginosalung infection in cystic fibrosis (CF) patients often include aminoglycoside antibiotics that may cause chronic renal failure after repeated courses. Aminoaciduria is an early marker of acute aminoglycoside-induced renal tubular dysfunction. We hypothesized that urinary amino acid reabsorption is decreased after repeated once-daily tobramycin therapies.Methods. In this prospective cross-sectional study creatinine clearance was estimated by the Schwartz and the Cockcroft-Gault formula. Tubular amino acid reabsorption was determined by ion exchange chromatography in 46 patients with CF who received multiple tobramycin courses (6.3±10.1(1–57)) in a once-daily dosing regimen and 10 who did not.Results. Estimated creatinine clearance employing the Cockcroft-Gault was mildly reduced in 17/46 (37%) of the patients who received tobramycin and 5/10 (50%) of the patients who did not but in none using the Schwartz formula. No association with lifetime tobramycin courses was found. Tubular amino acid reabsorption was not influenced by the amount of once-daily tobramycin courses.Conclusion. Clinically not significant reduction of eCCL occurred in a minority of CF patients. However, chronic tubular dysfunction was not present in patients with CF repeatedly treated with tobramycin in the once-daily dosing scheme.

Background In pediatric neuromuscular disorders (NMD), respiratory muscle weakness parallels respiratory failure. The objectives of this study are (1) to evaluate respiratory muscle capacity in neuromuscular children and (2) to assess the relationship between vital capacity, respiratory muscle performance, and alveolar ventilation during sleep and wakefulness. Methods Inspiratory vital capacity (IVC), peak inspiratory pressure (PIP), mouth occlusion pressure (P 0.1 ), and noninvasive tension-time index of the respiratory muscles (TTImus) were studied in 80 NMD subjects (12.1 ± 3.3 years) and 80 healthy children (11.1 ± 2.2 years). Subjects' results were compared with arterial blood gases and polysomnography. Results In 15 NMD subjects with normal ventilation IVC and PIP were reduced to 70% predicted but TTImus was normal. In 50 NMD subjects with nocturnal hypoventilation IVC and PIP were lower than 50% predicted, TTImus was doubled compared with the control group. In 15 NMD subjects with diurnal and nocturnal hypoventilation IVC and PIP were below 30% predicted, TTImus was increased fourfold, and thus the main determinant of respiratory failure. Conclusions In NMD children, reduced IVC and PIP result in increased respiratory muscle load and disturbed ventilation. TTImus is an important noninvasive determinant of disturbed ventilation in children with NMD.

Background There is only sparse data on the use of non-invasive ventilation (NIV) in acute respiratory failure (ARF) in infants and children. For this setting we investigated feasibility and efficacy of NIV and aimed to identify early predictors for treatment failure. Patients and Methods Retrospective chart review was performed for all patients treated with NIV for ARF from 2003 to 2010 on an 8-bed pediatric intensive care unit of a tertiary university hospital. Results Seventy-four patients were treated with NIV. One patient did not tolerate mask ventilation and needed immediate invasive ventilation. Intubation rate of the remaining patients was 23% and mortality 15%. Institution of NIV led to significant improvement of both respiratory and heart rate in all patients within the first hour and to further stabilization within the next 8–10 hr. In patients with NIV success blood gases improved significantly 1–2 hr after starting NIV. Multivariate analysis identified low pH after 1–2 hr to be an individual risk factor for NIV failure. Other factors tested were age, underlying disease, acute respiratory insufficiency versus post-extubation failure (PEF), and 1–2 hr after starting NIV oxygen saturation, respiratory rate, PCO2, and FiO2. Patients with PEF tended to show better outcomes compared to those with acute respiratory insufficiency. Conclusion NIV can be effective in infants and children with ARF. Low pH 1–2 hr after start of NIV is associated with NIV failure. It may therefore be useful in the decision to continue or stop mask ventilation. Pediatr. Pulmonol. 2011; 46:1114–1120. © 2011 Wiley Periodicals, Inc.

Thrombolysis is the only effective pharmaceutical therapy in acute ischemic stroke in humans but has a high risk of intracerebral hemorrhage. We aimed to establish an animal model to study changes of coagulation and fibrinolytic parameters during thromboembolic ischemic stroke and thrombolysis with recombinant tissue plasminogen activator (rt-PA). We used a thromboembolic stroke model in the rat. Animals were treated with rt-PA thrombolysis (n=10) and compared with untreated (n=10), sham operated (n=10) and control animals (n=20). Coagulation parameters (APTT, PT, TT, fibrinogen, AT III, TAT) and fibrinolytic parameters (t-PA antigen concentration, t-PA activity, PAI-1 concentration, PAI activity, plasminogen, antiplasmin) were measured at two time points (2.5 and 5h after stroke induction) with a battery of commercially available test kits. We observed an (1) initiation of coagulation and inhibition of fibrinolysis by the operation procedure itself, (2) simultaneous activation of fibrinolysis and its inhibitors after stroke induction and (3) potent initiation of fibrinolysis and consumption of fibrinolysis inhibitors after rt-PA therapy of stroke. We established a model system to monitor coagulation and fibrinolysis during thrombolytic therapy of stroke in the rat. This model may be used to study the influence of these parameters on hemorrhagic stroke transformation and outcome in experimental stroke in future.

ZusammenfassungIm letzten Jahrzehnt wurden große Fortschritte in der Diagnostik und Therapie neuromuskulärer Erkrankungen gemacht. Insbesondere die Therapie des chronischen Atemmuskelversagens mit der nicht-invasiven Beatmung konnte Morbidität und Mortalität senken und die Lebensqualität verbessern. Rezidivierende Atemweginfekte und Atelektasen komplizieren den Verlauf bei Patienten mit fortgeschrittenen Erkrankungen und sind Folgen eines insuffizienten Hustens. Ein wichtiger, aber noch nicht ausreichend angewandter Bestandteil der Therapie ist die Technik des assistierten Hustens. Mit steigender Lebenserwartung rückt die Herzbeteiligung als lebenslimitierender Faktor weiter in den Vordergrund. In dieser Übersichtsarbeit wird die aktuelle Datenlage zum Atemmuskelversagen und der Herzbeteiligung bei neuromuskulären Erkrankungen diskutiert.

Advanced stages of Duchenne muscular dystrophy (DMD) result in severe lung volume decline and are associated with high respiratory morbidity and mortality. The aim of this study was to investigate whether lung volume decline in subjects with DMD is associated with ventilation inhomogeneity measured with the multiple-breath washout technique.This cross-sectional study of lung function included 45 subjects with DMD and 16 healthy controls using multiple-breath washout, spirometry, and cough peak flow.Subjects with DMD exhibited an elevated lung clearance index (> 7.0) defined as the cumulative exhaled volume divided by the functional residual capacity to lower the sulfur hexafluoride concentration below 2.5% compared with controls (8.16 ± 2.55 vs 6.23 ± 0.46, P < .001). Lung clearance index elevation was negatively correlated with vital capacity (% predicted: r = -0.79, P < .001) and cough peak flow (L/min: r = -0.41, P = .005). Furthermore, dead-space ventilation (dead-space-to-tidal-volume ratio) and functional residual capacity showed a positive correlation with lung clearance index elevation (r = 0.81 and 0.48, P < .001). An FVC of < 24% predicted lung clearance index elevation with a sensitivity of 96% and a specificity of 80%.Moderate-to-severe lung volume decline in subjects with DMD is associated with ventilation inhomogeneity. Lung clearance index elevation may be the result of altered ventilation geometry or retention of airway secretions in the infection-free DMD subject. OA embargo

Sleep disordered breathing is a common but under-diagnosed complication causing sleep disturbance and daytime symptoms in children with spinal muscular atrophy. Non-invasive (positive pressure) ventilation is an established treatment of respiratory failure; its role in treatment of sleep disordered breathing though remains controversial. Aim of this study was to verify the hypothesis that nocturnal non-invasive ventilation has beneficial impact on breathing during sleep, sleep quality and daytime complaints in children with spinal muscular atrophy. Twelve children with spinal muscular atrophy type I or II (7.8+/-1.9 years) underwent polysomnography and were asked to fill out a symptom questionnaire. Seven patients (six with spinal muscular atrophy I and one with spinal muscular atrophy II) had sleep disordered breathing and received non-invasive ventilation during sleep. Five less severely affected patients (one with spinal muscular atrophy I and four with spinal muscular atrophy II) had no sleep disordered breathing and served as reference group. Patients were restudied after 6-12 months. In patients with sleep disordered breathing both sleep architecture and disease related symptoms were significantly worse than in the reference-group. Non-invasive ventilation during sleep completely eliminated disordered breathing, normalized sleep architecture and improved symptoms (P

Assessment of inspiratory muscle function (IMF) is limited in children with neuromuscular disorders, because respiratory muscle tests are poorly standardized and valid normative data are unavailable. We investigated maximum inspiratory pressure after exhalation to residual volume (MIP), mouth occlusion pressure (P0.1) and time of inspiration during quiet breathing and derived inspiratory muscle load (P0.1/MIP), and tension time index (TTI) in 301 healthy schoolchildren 6-16 years old. Gender-specific and age-dependent percentile curves for MIP were drawn with the median, 5%, 10%, 25%, 75% and 95% percentile. P0.1 was equal in boys and girls (0.23 ± 0.11 kPa), while MIP was significantly higher in boys (6.8 ± 2.2 versus 5.8 ± 2.4 kPa). Consequently, P0.1/MIP (4.8% ± 3.2% versus 4.0% ± 3.1%) and TTI (0.2 ± 0.14 versus 0.16 ± 0.14) were significantly higher in girls. MIP was 2.90 + 0.36 × age (kPa) and 3.19 + 0.24 × age (kPa) in boys and girls, respectively. The 95% confidence intervals for boys and girls, respectively, were MIP, 6.3-7.3 kPA and 5.4-6.2 kPa; P0.1/MIP, 3.5%-4.5% and 4.3%-5.3%; TTI, 0.14-0.18 and 0.18-0.22; and P0.1, 0.20-0.24 kPa for both. IMF in children has a wide interindividual variability; however percentile curves facilitate a longitudinal assessment of individual patients. Furthermore, narrow confidence intervals allow for comparisons of study populations, making IMF an appropriate endpoint for clinical trials.

BackgroundTo describe a simple quantitative immunofluorescence assay (IFA) for the detection of specific Stenotrophomonas maltophilia antibodies in serum of CF patients.MethodsA total of 100 sera (64 CF patients and 36 healthy subjects) were collected over a period of 2years at the University Hospital Essen, Germany. Sputum culture status classified CF patients into groups. Serologic response was determined after Pseudomonas aeruginosa absorption by indirect IFA to Sm whole cell.ResultsCF patients with “chronic S. maltophilia” showed significantly higher S. maltophilia antibody levels compared with healthy individuals (P1:120 titre was established to differentiate “CF chronic S. maltophilia” from the other groups. For “CF chronic S. maltophilia”, the IFA showed sensitivity and specificity values of 70.7% and 84.7%, respectively.ConclusionOur data demonstrated that quantitative IFA is a simple serological assay for the detection of specific S. maltophilia antibodies, which could be useful as a diagnostic tool for monitoring immune response of CF patients to S. maltophilia.

To prospectively investigate the prevalence of hepatopulmonary syndrome (HPS), the importance of pulse oximetry in diagnosing HPS, and the longitudinal course after liver transplantation in children with cirrhosis referred for liver transplantation.Fifty-six patients aged 1-17 years (mean age, 4.6 ± 5.0 years) with liver cirrhosis were screened for HPS by hyperemic capillary blood gas (CBG) analysis and contrast-enhanced transthoracic echocardiography. Eleven patients were excluded owing to conditions that can produce cardiopulmonary dysfunction, including 5 with cystic fibrosis, 1 with pulmonary arterial hypertension, and 5 with an intracardial shunt. HPS was classified in accordance with the European Respiratory Society Task Force criteria on pulmonary-hepatic disorders. Patient groups were compared for biochemical and clinical characteristics.Eighteen children (40%) with cirrhosis were intrapulmonary vasodilatation (IPVD)-positive and had a pulse oximetry oxygen saturation level98%. Two of these patients (11%) exhibited moderate HPS with an elevated alveolar arterial oxygen gradient15 mm Hg and PaO270 mm Hg; they died before undergoing liver transplantation. The sensitivity and specificity of CBG analysis for detecting elevated alveolar arterial oxygen gradient in children with IPVD was 94% and 53%, respectively. HPS was associated with late hepatoportoenterostomy (P.04). Liver transplantation led to resolution of HPS in all patients.IPVD is frequent in children with liver cirrhosis (40%). Pulse oximetry is insufficient for timely HPS diagnosis. Pathological CBG analysis data indicate IPVD in the majority of cases, but are imprecise in children aged2 years. Contrast-enhanced transthoracic echocardiography and CBG analysis are recommended for evaluation of HPS in children with cirrhosis, regardless of liver synthesis capacity and clinical chemistry data.

Der plotzliche Sauglingstod oder Sudden Infant Death (SID) wird definiert als der plotzliche Tod eines Sauglings, der aufgrund der Anamnese unerwartet ist und bei dem eine grundliche postmortale Untersuchung – einschlieslich einer Beurteilung der Auffindesituation – keine adaquate Todesursache zu zeigen vermag.

Der M.Pompe ist eine seltene Stoffwechselerkrankung, bei der es durch Defizienz der lysosomalen α-Glukosidase zur pathologischen Speicherung von Glykogen zunachst in den Lysosomen, spater auch im Zytoplasma der Zelle kommt. Je nach Alter bei Beginn und Art der klinischen Symptomatik konnen klassisch infantile und spater beginnende kindliche, juvenile und adulte Formen unterschieden werden. Der Schweregrad der Erkrankung hangt wesentlich von der In-vivo-Restaktivitat des Enzyms ab, die wiederum durch die Art der GAA-Gen-Veranderung bestimmt wird. Seit 2006 ist eine Enzymersatztherapie verfugbar, doch ist das Ansprechen sehr variabel. Zudem fuhrt das verlangerte Uberleben von Patienten mit infantiler Verlaufsform zu Symptomen und Problemen, die bisher bei dieser Erkrankung nicht bekannt waren. Im Folgenden werden Empfehlungen fur ein sinnvolles diagnostisches und therapeutisches Vorgehen gegeben. Dies soll es behandelnden Arzten erlauben, betroffene Kinder trotz der Seltenheit der Erkrankung auf hochstem fachlichem Niveau zu behandeln. Die Komplexitat des Krankheitsbildes und die immer noch hohe Morbiditat und Mortalitat erfordern ein multidisziplinares Behandlungskonzept und machen die Anbindung an ein Zentrum mit Erfahrung in der Betreuung von Kindern mit M.Pompe sinnvoll.

Summary Background Duchenne muscular dystrophy is a rare X-linked progressive disease characterised by loss of ambulation at about age 10 years, with death in early adulthood due to respiratory and cardiac insufficiency. Steroids are effective at slowing the progression of muscle weakness; however, their use is limited by side-effects, prompting the search for alternatives. We assessed the effect of ciclosporin A as monotherapy and in combination with intermittent prednisone for the treatment of ambulant patients with this disorder. Methods Our study was a parallel-group, placebo-controlled, double-blind, multicentre trial at trial sites of the German muscular dystrophy network, MD-NET, over 36 months. Ambulant patients with Duchenne muscular dystrophy who were aged 5 years or older were randomly assigned to receive either ciclosporin A (3·5–4·0 mg/kg per day) or matching placebo. Allocation was done centrally with computer-generated random numbers. Patients and investigators were masked to the allocated treatment. After 3 months of treatment, both groups were also given intermittent prednisone for a further 12 months (0·75 mg/kg, alternating 10 days on with 10 days off). All patients who received at least one dose of study drug or placebo were included in the primary analysis. The primary outcome measure was manual muscle strength measured on the Medical Research Council (MRC) scale. This trial is registered with the German clinical trial register DRKS, number DRKS00000445. Findings 77 patients were randomly assigned to the ciclosporin A group and 76 to the placebo group; 73 patients on ciclosporin A and 73 on placebo received at least one dose and were available for efficacy analyses. 3 months of treatment with ciclosporin A alone did not show any significant improvement in primary outcome measures (mean change in the proportion of a possible total MRC score [%MRC] was −2·6 [SD 6·0] for patients on ciclosporin A and −0·8 [4·9] for patients on placebo; adjusted group difference estimate −0·88, 97·5% CI −2·6 to 0·9; p=0·26). The combination of ciclosporin A with intermittent steroids was not better than intermittent steroids alone over 12 months (mean change in %MRC was 0·7 [7·1] for patients on ciclosporin A and −0·3 [7·9] for patients on placebo; adjusted group difference estimate −0·85, −3·6 to 1·9; p=0·48). Numbers of adverse events (75 in patients on ciclosporin A and 74 on placebo) and serious adverse events (four with ciclosporin A and four with placebo) did not differ significantly between groups. Interpretation Ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated. Funding German Federal Ministry of Education and Research, Action Benni and co eV, Novartis Pharma AG, and Deutsche Gesellschaft fur Muskelkranke eV.

There is only sparse data on the use of non-invasive ventilation (NIV) in acute respiratory failure (ARF) in infants and children. For this setting we investigated feasibility and efficacy of NIV and aimed to identify early predictors for treatment failure.Retrospective chart review was performed for all patients treated with NIV for ARF from 2003 to 2010 on an 8-bed pediatric intensive care unit of a tertiary university hospital.Seventy-four patients were treated with NIV. One patient did not tolerate mask ventilation and needed immediate invasive ventilation. Intubation rate of the remaining patients was 23% and mortality 15%. Institution of NIV led to significant improvement of both respiratory and heart rate in all patients within the first hour and to further stabilization within the next 8-10 hr. In patients with NIV success blood gases improved significantly 1-2 hr after starting NIV. Multivariate analysis identified low pH after 1-2 hr to be an individual risk factor for NIV failure. Other factors tested were age, underlying disease, acute respiratory insufficiency versus post-extubation failure (PEF), and 1-2 hr after starting NIV oxygen saturation, respiratory rate, PCO(2) , and FiO(2) . Patients with PEF tended to show better outcomes compared to those with acute respiratory insufficiency.NIV can be effective in infants and children with ARF. Low pH 1-2 hr after start of NIV is associated with NIV failure. It may therefore be useful in the decision to continue or stop mask ventilation.

Background In cystic fibrosis (CF) patients, the absence or dysfunction of the chloride channel CF transmembrane conductance regulator (CFTR) results in reduced chloride ion transport in respiratory epithelial cells. Moli1901 stimulates an alternative chloride channel and may thus compensate for the CFTR deficiency in the airway epithelium of CF patients. Methods A phase II, placebo-controlled, double-blinded, single-center, multiple (5 consecutive days), rising-dose (daily dose, 0.5, 1.5, or 2.5 mg of Moli1901) study was conducted to investigate the safety and tolerability of multiple doses of aerosolized inhaled Moli1901 in 24 patients with CF and stable lung disease. Results Moli1901 was well tolerated in all but one CF patient, in whom a transient significant decrease in FEV 1 developed following inhalation, which resolved spontaneously, and in a second patient in whom transient throat numbness developed during drug inhalation. A significant improvement of FEV 1 was observed in the group receiving treatment with 2.5 mg/d Moli1901 compared to the group receiving placebo (p = 0.01 [Wilcoxon test]). Moli1901 was not detected in the plasma of the highest dose group. Conclusions The inhalation of Moli1901 up to a total cumulative dose of 12.5 mg appears to be safe in adult patients with CF. In addition, Moli1901 had a sustained beneficial effect on pulmonary function, which supports further studies of its efficacy in CF patients.

Retrospective data suggest that approximately half of patients with primary ciliary dyskinesia (PCD) have symptoms of neonatal respiratory distress. Respiratory distress syndrome in a full term infant should therefore raise PCD as a potential underlying disease.1,2 The non-invasive measurement of nasal nitric oxide (NO) is of diagnostic value in adults and children with PCD,1,3 but similar information is not available for neonates with PCD. A 3550 g male infant was delivered after uncomplicated …

In this study, noninvasive ventilation (NIV) was prospectively applied to eight patients (35.8 +/- 11.4 years) with late-onset Pompe disease and respiratory failure apparent from severe restrictive lung disease, nocturnal hypoxemia (83 +/- 8%), and daytime hypercapnia (66.7 +/- 17.9 mm Hg). The impact of NIV on respiratory function was followed for 34 +/- 17 months. Despite further decrease of vital capacity and inspiratory muscle strength, NIV normalized oxygen saturation during sleep (96 +/- 1%), daytime carbon dioxide tensions (44.1 +/- 3.6 mm Hg), and symptoms.

Transient neonatal myasthenia gravis arises from antibody mediated maternal disease during pregnancy. Clinical findings vary from postnatal muscular weakness up to arthrogryposis multiplex congenita (AMC). If AMC is associated with polyhydramnios, pulmonary hypoplasia, dysmorphic facial features and central nervous abnormalities it belongs to a fetal akinesia, namely Pena-Shokeir-phenotype. Diagnosis allows therapy for the child and in further pregnancies for the mother. The boy was presented to our clinic as a “floppy infant” at the age of 8 months for adjustment of a nocturnal non-invasive ventilation. Extensive diagnostic procedures had been performed previously – including a muscle biopsy – overall not leading to diagnosis. The examination showed retrognathia, contractures of the fingers and pulmonary hypoplasia. Analyses revealed acetylcholinreceptor-antibodies (AChR-AB) elevated with >1 nmol/l, consequently a therapy with pyridostigmine was initiated leading to a significant improvement of respiratory situation and motor development. Now the boy is three years old, walks and eats independently, but lacks development of speech so far. The mother presented mild muscular weakness of the shoulder girdle and elevated AChR-AB of 5.6 nmol/l. She has clinically and neurophysiologically no myasthenic symptoms. Pyridostigmine treatment did not generate an amelioration. A specific analysis of AChR-AB from the mother in Oxford disclosed antibodies against the fetal subunit of the AChR. In patients presenting with a Pena-Shokeir-phenotype myasthenia must be considered, caused by maternal antibodies against the fetal subunit (gamma) of the AChR, which is expressed in fetuses until the 32nd week of gestation. The diagnosis is crucial for the treatment of the child and further pregnancies of the mother. Fetal impairment can be avoided through thymectomy before and immunosuppressive treatment during pregnancy to suppress the producing of the antibodies.

complications and when symptoms of sleep disordered breathing are present; a minority of the CPNG request consultation in these two situations (14.3% and 35.7%). While both groups request routine pulmonary function tests, 95.5% of Respirologists use maximal inspiratory and expiratory pressures to assess respiratory muscle strength, whereas 81.8% of CPNG members additionally use peak cough flow. Assessment for sleep disordered breathing is requested by both groups when pulmonary function is abnormal or patients are symptomatic. Respirologists favor polysomnography, whereas CPNG members use overnight pulse oximetry. Nocturnal noninvasive ventilation and lung volume recruitment are used in a minority of patients by both groups. Conclusions/Reflections: Respirologists and CPNG members provide similar respiratory management of DMD patients, but differ in their timing of initial respiratory consultation and choice of diagnostic tests for pulmonary function and sleep-disordered breathing. Opportunities exist for standardization of respiratory care practices for childhood DMD amongst care providers.