A Swiss database and biobank to better understand and manage congenital lung anomalies.

Congenital lung anomalies are a group of rare malformations, often diagnosed during the prenatal period. Guidelines on how to manage these patients are currently under debate, especially with regard to prophylactic surgery in asymptomatic patients, or how to proceed with conservative follow-up. Currently, there is no clear consensus on management strategies. A Swiss congenital lung anomaly national database and biobank was created in 2016 to enable data recording and collection of surgical lung samples in order to help define the most appropriate management strategies. This national observational cohort study represents an important step towards a better understanding of the pathophysiology and clinical course of the diseases included under congenital lung anomalies, especially in the context of a small country like Switzerland.

Comparison of two sweat test systems for the diagnosis of cystic fibrosis in newborns.

OBJECTIVES: In the national newborn screening programme for CF in Switzerland, we compared the performance of two sweat test methods, by investigating the feasibility and diagnostic performance of the Macroduct® collection method (with chloride mesurement) and Nanoduct® test (measuring conductivity) for diagnosing CF. STUDY-DESIGN: We included all newborns with a positive screening result between 2011 and 2015 who were referred to a CF-centre for sweat testing. In the CF-centre, a Macroduct and Nanoduct sweat test were performed simultaneously. If sweat test results were positive or borderline, a DNA analysis was performed. Final diagnosis was based on genetic mutations. RESULTS: Over 5 years, 445 children were screened positive and in 413 (114 with CF) at least one sweat test was performed (median age at first test, 22 days); both tests were performed in 371 children. A sweat test result was more often available with the Nanoduct compared to the Macroduct (79 vs 60%, P < 0.001). The Nanoduct was equally sensitive as the Macroduct in identifying newborns with CF (sensitivity 98 vs 99%) but less specific (specificity 79 vs 93%; P-value comparing ROC curves = 0.033). CONCLUSIONS: This national multicentre study revealed high failure rates for Macroduct and Nanoduct in newborns in real life practice. While this needs to be addressed, our results suggested that performing the Nanoduct in addition to the Macroduct might speed up the diagnostic process because it more often yields valid results with comparable diagnostic performance. The addition of the Nanoduct sweat test can therefore help to reduce the stressful time of uncertainty for parents and to start appropriate treatment earlier.

Feasibility and normal values of an integrated conductivity (Nanoduct™) sweat test system in healthy newborns.

BACKGROUND: Nanoduct™ is a simple and practical sweat analysis system measuring conductivity in situ. It requires only three microlitres of sweat, making it especially applicable to newborns. METHODS: We measured conductivity in 260 healthy term infants at the age of four days, and again at four weeks to determine the proportion of successful tests, test duration, and normal values for sweat conductivity in newborns. RESULTS: Sufficient sweat was collected in 159/260 of four-day olds (61%), and in 225/239 of four-week olds (94%). Mean (sd) test duration was 27 (5) and 25 (5) min. Mean (sd, range) conductivity was 53mmol/l (16, 8-114) at age four days, and 36 (9, 12-64) at four weeks. CONCLUSIONS: Determination of sweat conductivity using Nanoduct™ cannot be recommended for four-day old newborns. However, at the age of four weeks the success rate is high (94%), and conductivity values at that age are comparable to older healthy children.

Measurement of fecal elastase improves performance of newborn screening for cystic fibrosis.

BACKGROUND: The aim of newborn screening (NBS) for CF is to detect children with 'classic' CF where early treatment is possible and improves prognosis. Children with inconclusive CF diagnosis (CFSPID) should not be detected, as there is no evidence for improvement through early treatment. No algorithm in current NBS guidelines explains what to do when sweat test (ST) fails. This study compares the performance of three different algorithms for further diagnostic evaluations when first ST is unsuccessful, regarding the numbers of children detected with CF and CFSPID, and the time until a definite diagnosis. METHODS: In Switzerland, CF-NBS was introduced in January 2011 using an IRT-DNA-IRT algorithm followed by a ST. In children, in whom ST was not possible (no or insufficient sweat), 3 different protocols were applied between 2011 and 2014: in 2011, ST was repeated until it was successful (protocol A), in 2012 we proceeded directly to diagnostic DNA testing (protocol B), and 2013-2014, fecal elastase (FE) was measured in the stool, in order to determine a pancreas insufficiency needing immediate treatment (protocol C). RESULTS: The ratio CF:CFSPID was 7:1 (27/4) with protocol A, 2:1 (22/10) with protocol B, and 14:1 (54/4) with protocol C. The mean time to definite diagnosis was significantly shorter with protocol C (33days) compared to protocol A or B (42 and 40days; p=0.014 compared to A, and p=0.036 compared to B). CONCLUSIONS: The algorithm for the diagnostic part of the newborn screening used in the CF centers is important and affects the performance of a CF-NBS program with regard to the ratio CF:CFSPID and the time until definite diagnosis. Our results suggest to include FE after initial sweat test failure in the CF-NBS guidelines to keep the proportion of CFSPID low and the time until definite diagnosis short.

Ventilatory response to nitrogen multiple-breath washout in infants.

BACKGROUND: Nitrogen multiple-breath washout (N2 MBW) using 100% oxygen (O2) has regained interest to assess efficiency of tracer gas clearance in, for example, children with Cystic Fibrosis (CF). However, the influence of hyperoxia on the infants' respiratory control is unclear. We assessed safety and impact on breathing pattern from hyperoxia, and if exposure to 40% O2 first induces tolerance to subsequent 100% O2 for N2 MBW. METHODS: We prospectively enrolled 39 infants aged 3-57 weeks: 15 infants with CF (8 sedated for testing) and 24 healthy controls. Infants were consecutively allocated to the protocols comprising of 100% O2 or 40/100% O2 administered for 30 breaths. Lung function was measured using an ultrasonic flowmeter setup. Primary outcome was tidal volume (VT). RESULTS: None of the infants experienced apnea, desaturation, or bradycardia. Both protocols initially induced hypoventilation. VT temporarily declined in 33/39 infants across 10-25 breaths. Hypoventilation occurred independent of age, disease, and sedation. In the new 40/100% O2 protocol, VT returned to baseline during 40% O2 and remained stable during 100% O2 exposure. End-tidal carbon dioxide monitored online did not change. CONCLUSION: The classical N2 MBW protocol with 100% O2 may change breathing patterns of the infants. The new protocol with 40% O2 induces hyperoxia-tolerance and does not lead to changes in breathing patterns during later N2 washout using 100% O2. Both protocols are safe, the new protocol seems an attractive option for N2 MBW in infants.

One-year evaluation of a neonatal screening program for cystic fibrosis in Switzerland.

BACKGROUND: From January 2011 onward, the Swiss newborn screening (NBS) program has included a test for cystic fibrosis (CF). In this study, we evaluate the first year of implementation of the CF-NBS program. METHODS: The CF-NBS program consists of testing in two steps: a heel prick sample is drawn (= Guthrie test) for measurement of immunoreactive trypsinogen (IRT) and for DNA screening. All children with a positive screening test are referred to a CF center for further diagnostic testing (sweat test and genetic analysis). After assessment in the CF center, the parents are given a questionnaire. All the results of the screening process and the parent questionnaires were centrally collected and evaluated. RESULTS: In 2011, 83 198 neonates were screened, 84 of whom (0.1%) had a positive screening result and were referred to a CF center. 30 of these 84 infants were finally diagnosed with CF (positive predictive value: 35.7%). There was an additional infant with CF and meconium ileus whose IRT value was normal. The 31 diagnosed children with CF correspond to an incidence of 1 : 2683. The average time from birth to genetically confirmed diagnosis was 34 days (range: 13-135). 91% of the parents were satisfied that their child had undergone screening. All infants receiving a diagnosis of CF went on to receive further professional care in a CF center. CONCLUSION: The suggested procedure for CF-NBS has been found effective in practice; there were no major problems with its implementation. It reached high acceptance among physicians and parents.

Newborn screening for cystic fibrosis in Switzerland--consequences after analysis of a 4 months pilot study.

BACKGROUND: Switzerland introduced newborn screening (NBS) for CF in 2011, using an IRT/DNA/IRT protocol. This paper describes the results of the first year and compares two versions of the protocol with different IRT cut-offs, particularly effects on recall rate, sensitivity and specificity. METHODS: IRT cut-offs were >45 ng/ml (99.0th percentile) in period 1 (months 1-4) and >50 ng/ml (99.2nd percentile) in period 2 (months 5-12). In period 2 we abstained from recalls when none of the 7 most common CF mutations were detected and IRT was <60 ng/ml. RESULTS: In periods 1 and 2, 26,535 and 56,663 tests were performed. Recall rates were 0.94% and 0.48%, respectively (p<0.001), PPV increased from 23% to 47% (p=0.024) and sensitivity was 90% and 100%. CONCLUSIONS: Raising initial IRT cut-off from the 99.0th to the 99.2nd percentile and abstaining from recalls for children with an IRT<60 ng/ml and carrying no major CFTR mutation significantly reduced the recall rate without affecting sensitivity.

Retrospective analysis of stored dried blood spots from children with cystic fibrosis and matched controls to assess the performance of a proposed newborn screening protocol in Switzerland.

BACKGROUND: Newborn screening (NBS) for Cystic Fibrosis (CF) has been introduced in many countries, but there is no ideal protocol suitable for all countries. This retrospective study was conducted to evaluate whether the planned two step CF NBS with immunoreactive trypsinogen (IRT) and 7 CFTR mutations would have detected all clinically diagnosed children with CF in Switzerland. METHODS: IRT was measured using AutoDELFIA Neonatal IRT-Kit in stored NBS cards. RESULTS: Between 2006 and 2009, 66 children with CF were reported, 4 of which were excluded for various reasons (born in another country, NBS at 6 months, no informed consent). 98% (61/62) had significantly higher IRT compared to matched control group. There was one false negative IRT result in an asymptomatic child with atypical CF (normal pancreatic function and sweat test). CONCLUSIONS: All children but one with atypical CF would have been detected with the planned two step protocol.

Pseudomonas aeruginosa in public swimming pools and bathroom water of patients with cystic fibrosis.

INTRODUCTION: Acquisition of Pseudomonas aeruginosa (PA) in the lungs of patients with cystic fibrosis (CF) is a marker of poor survival. PA is a ubiquitous pathogen prevalent in humid conditions. This study aimed to identify the prevalence of PA in public swimming pools, as well as from water taps. METHODS: Water was collected from public indoor and outdoor pools in the area of St. Gallen, Switzerland. In addition, standing and running water was sampled from bathroom water taps of 50 patients with CF. RESULTS: Outdoor pools: In 2002, none of the 72 specimens from 28 pools revealed PA. In 2003, three specimens from 46 pools (7%) revealed PA, each were from a different paddling pool. Indoor pools: two of 128 specimens from 56 pools (4%) identified PA, both were from non-public hydrotherapy pools. Water taps: in winter, none of the 102 specimens was colonized with PA. in summer, only two out of 50 specimens of the standing water were positive for PA but none of the running water revealed PA. CONCLUSION: The prevalence of PA in public swimming pools and bathroom water taps in the eastern part of Switzerland is very low. On hot summer days, outdoor paddling pools and standing tap water can contain PA. This study does not support recommendations to avoid public swimming pools or running tap water if the water is maintained according to hygiene guidelines.

Conductivity determined by a new sweat analyzer compared with chloride concentrations for the diagnosis of cystic fibrosis.

OBJECTIVES: The aim of the study was to determine if a new conductivity measuring sweat test system (Nanoduct) could reliably identify patients with cystic fibrosis (CF) and differentiate them from healthy subjects. STUDY DESIGN: On the same day and in the same patient, the new system was tested in comparison with the Macroduct sweat collection system measuring chloride concentration and osmolality. RESULTS: Subjects (n = 111) 3 weeks to 60 years of age were investigated. Three children had no sweat production, and in 14 children, only conductivity could be measured. In the remaining 94 subjects, the new system identified all patients with classic CF (mean conductivity, 115 mmol/L; range, 92 to 137) and differentiated them from healthy subjects (mean conductivity, 36 mmol/L; range, 17 to 59) within a mean time of 20 minutes. CONCLUSIONS: Measuring sweat conductivity using the new test system reliably differentiated between patients with and those without CF. This suggests that the new system could be used as a diagnostic test in addition to its suggested screening value.

Major haemoptysis in children with cystic fibrosis: a 20-year retrospective study.

BACKGROUND: Major haemoptysis occurs in approximately 1% of children with cystic fibrosis (CF). This report describes management and follow-up of these children at a tertiary centre in Australia. METHODS: Retrospective review of medical records from 1980-1999. RESULTS: Fifty-one children (45% female) had major haemoptysis (102 episodes). Mean age at first episode was 15 years (range 7-19) and mean FEV(1) was 56% predicted (range 14-98). Massive life-threatening haemoptysis was not confined to those with severe lung disease (FEV1 < 50% predicted). Bronchial artery embolisation (BAE) was more likely to be the initial treatment for those with massive haemoptysis and chronic recurrent bleeding tended to be treated conservatively (P = 0.01). Overall, 52 BAE were performed in 28 children with an immediate success rate of 98%; 13 children (46%) had repeated BAE. Four patients died as a direct result of severe haemoptysis. Mean follow-up was 54 months (range 0.5-183). Median survival time (Kaplan-Meier estimate) after first haemoptysis was 70 months, with a significantly longer survival for male patients independent of age (RR 3.8; 95% CI 1.7-8.8; P = 0.001). Median survival time following initial treatment with BAE was longer (103 months) compared to conservative treatment (52 months, P = 0.09). CONCLUSIONS: Massive haemoptysis was unrelated to the severity of lung disease and was more likely to be treated with embolisation. BAE was highly effective, however, 46% of the children required re-embolisation at some time, which is similar to the recurrence risk for major hemoptysis treated conservatively on longer term follow-up.

Bronchial artery embolization for hemoptysis in young patients with cystic fibrosis.

PURPOSE: To review the authors' 15-year experience with bronchial artery embolization (BAE) for treatment of hemoptysis in young patients with cystic fibrosis. MATERIALS AND METHODS: By searching the 1985-1999 radiology database, the authors identified 23 young patients who had been referred to the radiology department for angiography. Twenty of these patients underwent BAE. The 23 medical records were retrospectively reviewed with regard to embolization agents used, embolization success rates, number of repeat embolizations, survival times, and causes of death. RESULTS: BAE was performed on 38 occasions in 20 patients. The mean age of patients at first BAE was 15 years (age range, 7-19 years). The majority (n = 34 [89%]) of BAEs were performed by using polyvinyl alcohol. The immediate success rate after BAE (ie, no recurrent bleeding within 24 hours) was 95% (36 of 38 BAEs). Eleven (55%) patients required more than one BAE, and the median time between first and second embolizations was 4 months (range, 5 days to 61 months). Three patients died as a consequence of severe hemoptysis during induction of anesthesia with intermittent positive pressure ventilation in preparation for BAE. The median survival duration after the first BAE (Kaplan-Meier estimate) was 84 months (average follow-up, 61 months; range, 5 days to 169 months). CONCLUSION: BAE had a high success rate for short-term control of bleeding; however, more than half the patients required repeat embolization during the long-term follow-up.