Cystic fibrosis newborn screening in Switzerland - evaluation and scenarios for improvement after 11 years of follow-up.

BACKGROUND: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance. METHODS: The Swiss CF-NBS is based on an IRT-DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net. RESULTS: The Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %. CONCLUSION: The Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity.

ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.

Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme.

More than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings.

[An unusual cause of a decline in general health in a very old person]. / Une cause inhabituelle d'altération de l'état général chez une personne très âgée.

Humans are accidental intermediate hosts and a dead-end for the echinococcosis parasite. No cases of hydatid echinococcosis (hydatid cyst) have ever been described in a French-born very elderly person, who has never been out of France. We report the case of a 90-year-old man hospitalised following a decline in his general health and the discovery of a liver mass on the CT-scan. The abdominal palpation was painless, and no mass was felt. Biological tests revealed hypereosinophilia, a mild inflammatory syndrome, a slight increase in the immunoglobulin E level, and positive serology for Echinococcus granulosus. A diagnosis of hydatid echinococcosis due to Echinococcus granulosus was made given the liver mass on the CT-scan, the positive serology and the hypereosinophilia. Management consisted of watch and wait. This observation is interesting because it was a case of an autochthonous hydatid cyst of an unexpected discovery in a very elderly patient. Indeed, even though the discovery was classical, the clinical presentation was singular because of the context.

L'être humain est un hôte intermédiaire accidentel et une impasse parasitaire pour l'échinococcose. Aucun cas de kyste hydatique (échinococcose hydatique) n'a été décrit chez une personne très âgée née en France et ne l'ayant jamais quittée. Nous rapportons ici le cas d'un patient âgé de 90 ans hospitalisé pour altération de l'état général et découverte d'une masse hépatique à la tomodensitométrie. La palpation abdominale était indolore sans masse perçue. Le bilan biologique révélait une hyperéosinophilie, un discret syndrome inflammatoire, une légère augmentation du taux d'immunoglobuline E et une sérologie de l'Echinococcus granulosus positive. Le diagnostic d'échinococcose hydatique (kyste hydatique) due à Echinococcus granulosus fut alors posé, compte tenu de la masse hépatique découverte à la tomodensitométrie, de la sérologie positive et de l'hyperéosinophilie. La prise en charge a consisté en une attitude «watch and wait¼. Cette observation est intéressante car il s'agissait d'un cas de kyste hydatique autochtone de découverte fortuite chez un patient très âgé. En effet, même si le mode de découverte était classique, le tableau clinique était singulier en raison du contexte.

[Iron deficiency in adults : to understand what biological evaluation should be carried out]. / Déficit en fer chez l'adulte : comprendre quel bilan biologique réaliser.

Iron is a major mineral in the human body. It participates in various metabolisms, including oxygen transport in hemoglobin. Iron deficiency (ID) is characterized by a deficit in circulating iron. There are two types of ID : 1) absolute ID (AID), in case of decrease in iron reserves and circulating iron, or 2) functional ID (FID), in case of decrease in circulating iron, while reserves are preserved or increased. AID is mainly due to bleeding, usually gastrointestinal, while FID is linked to the inflammatory syndrome. AID is characterized by low serum ferritin and transferrin saturation (TS). Hypochromic microcytic anemia is frequent. FID is characterized by elevated serum ferritin, normal or low TS, and normal sTfR levels. Furthermore, C-reactive protein levels are high, and there is non-regenerative non-macrocytic anemia. New biological tests (serum hepcidin) may be useful in case of doubt. However, they are not yet commonly used.

Le fer, oligoélément capital, participe à divers métabolismes chez l'être humain, dont le transport d'oxygène dans l'hémoglobine. La carence martiale (CM) peut être de deux types : 1) absolue (CMA), en cas de réduction des réserves martiales et du fer circulant, ou 2) fonctionnelle (CMF), avec une réduction du fer circulant et des réserves au contraire préservées ou augmentées. La CMA est principalement secondaire à un saignement, souvent digestif, tandis que la CMF est liée au syndrome inflammatoire. La CMA est attestée par une ferritinémie et un coefficient de saturation de la transferrine (CSTf) abaissés. Une anémie microcytaire hypochrome est fréquente. La CMF se caractérise par une ferritinémie normale ou élevée, un CSTf normal ou abaissé, un taux de récepteurs solubles de la transferrine non élevé, une C-réactive protéine élevée et une possible anémie non macrocytaire arégénérative. De nouveaux biomarqueurs (hepcidine sérique) peuvent être utiles en cas de doute. Cependant, ils ne sont pas encore couramment réalisés.

International approaches for delivery of positive newborn bloodspot screening results for CF.

BACKGROUND: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. A European survey demonstrated considerable variability in approach to delivering a positive NBS result. We used a mixed methods approach to explore healthcare systems and beliefs around this process. METHODS: We used semi-structured interviews and online questionnaires with a purposive, international sample of health professionals involved in communicating positive NBS results to parents. Data were analysed using thematic analysis and Qualtrics Survey Software. RESULTS: In total, 63 healthcare professionals were approached; 25 interviews were conducted with delegates at the 2017 ECFS conference, 4 online questionnaires were subsequently completed by participants in the EU, 1 from Australia and 33 from the US. Methods used to communicate positive NBS results to families varied considerably. This influenced the quality and quantity of information provided which had the potential to heighten anxiety and affect timely diagnostic testing. Participants identified positive practices including systems to improve the timeliness of screening and processing of results, as well as areas for improvement. Respondents stated that knowledge of CF and familiarity with the family were both important when deciding who should communicate positive NBS results. CONCLUSIONS: Guidance and practice regarding communication of positive NBS results for CF to families varies considerably internationally. Further research is needed to ensure information received is accurate, up-to-date and from the most appropriate person. Also, that all children are followed up in a timely manner to minimise potential negative outcomes for the child and family.

Real life practice of sweat testing in Europe.

Evidence based guidelines exist for sweat testing, which remains a key component of a diagnosis of cystic fibrosis (CF), especially following newborn bloodspot screening (NBS). There are emerging challenges with respect to maintaining a valid sweat test service, notably a smaller number of sweat tests ordered in regions with established NBS programmes where Pediatricians refer less children for sweat testing, younger patients and equipment becoming obsolete. The ECFS Diagnostic Network Working Group has undertaken a comprehensive survey to better define sweat test practice across Europe. The survey was completed by 136 European respondents representing a CF center or laboratory providing a sweat test service (65% from regions with NBS for CF). There was considerable variance in practice, often not consistent with guidelines. In particular collection of sweat from two sites was rarely reported in European centres in contrast to US guidelines. There was a range of different references quoted for cut-off for both a positive and intermediate test. Most responses suggest cost is becoming an increasing issue and is not sufficiently reimbursed. This work will inform best practice guidelines and resources to sustain and improve sweat testing in Europe.

Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) results in the recognition of a number of infants with a positive NBS result, but an inconclusive diagnosis. Varied practice exists with respect to the management of these infants. METHODS: A Delphi consensus approach was used to determine agreement on statements generated by a core group of specialists. A designation (naming) exercise was required after Round 1 and further expert opinion was sought to guide that process. After Round 2, a sensitivity analysis was undertaken to assess the impact of attrition on subsequent agreement levels. RESULTS: Infants were divided into group A (normal sweat chloride and two CFTR mutations, at least one of which has unclear phenotypic consequences) and group B (intermediate sweat chloride and one or no CFTR mutations). 32 statements were produced for Round 1 and 24 achieved consensus. After Round 1, a designation exercise was undertaken and the term "CF Screen Positive, Inconclusive Diagnosis (CFSPID)" was suggested for Round 2. Agreement was achieved for this statement and for all other statements aside from the need for routine respiratory culture, on which there was divided opinion. The core group advocated local practice for this issue. A sensitivity analysis demonstrated that consensus for Round 2 was achieved by change in opinion rather than attrition. CONCLUSION: We have generated a new designation and statements to guide the management of infants with CFSPID through a robust international Delphi process. These statements will be a valuable tool for CF teams and will improve the consistency of management of these infants.

Management of acute bronchiolitis: can evidence based guidelines alter clinical practice?

BACKGROUND: Acute bronchiolitis is the most common lower respiratory tract infection in infants and there is no evidence that drug treatment alters its natural course. Despite this, most Swiss paediatricians reported in 2001 prescribing bronchodilators and inhaled corticosteroids (ICS). This situation led to the creation of national guidelines followed by a tailored implementation programme. The aim of this study was to examine if treatment practices changed after the implementation of the new guidelines. METHODS: A questionnaire on treatment of bronchiolitis was sent to all Swiss paediatricians before (2001) and after (2006) creation and implementation of national guidelines (2003-2005). Guidelines were created in collaboration with all paediatric pulmonologists and implemented carefully using a multifaceted approach. RESULTS: Questionnaires were returned by 541 paediatricians (58%) in 2001 and by 639 (54%) in 2006. While both surveys showed a wide variation in the treatment of bronchiolitis between physicians, reported drug prescription decreased significantly between the two surveys. For outpatients, general use (for all patients) of bronchodilators dropped from 60% to 23%, and general use of ICS from 34% to 6%. For inpatients, general use of bronchodilators and ICS dropped from 55% to 18% and from 26% to 6%, respectively (all p<0.001). The decrease was evident in all regions, among hospital and primary care physicians, and among general paediatricians and paediatric pulmonologists. CONCLUSIONS: National guidelines together with a tailored implementation programme can have a major impact on medical management practices in a country.

Sweat test in patients with glucose-6-phosphate-1-dehydrogenase deficiency.

BACKGROUND: A false-positive sweat test in patients with deficiency of glucose-6-phosphate-1-dehydrogenase (EC 1.1.1.49; G6PD) is repeatedly reported. METHODS: Sweat chloride or conductivity was measured in 11 patients with G6PD deficiency. RESULTS: Mean (SD) chloride level (n = 8, median age 9.2 years, range 1.9-48.5) was 18.8 (9.6 mmol/l) and, mean (SD) sodium level was 26.0 (10.0 mmol/l), respectively, and mean (SD) conductivity (n = 3, median age 6.6 years, range 1.9-40.5) was 34.3 (6.5 mmol/l). CONCLUSION: In sweat of 11 patients with G6PD deficiency we did not find any abnormality. The reason for alleged false-positive sweat test in patients with G6PD deficiency is not known and we were unable to identify any original reference. It appears that tables of putative false-positive sweat tests in several disease states have been directly "copied and pasted" from one paper or textbook to another without verifying the original literature, a phenomenon one can call "chain citation".

Large deletions in the CFTR gene: clinics and genetics in Swiss patients with CF.

Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disorder in Caucasians, and is associated with at least one mutation on each CF transmembrane conductance regulator (CFTR) allele. Some patients, however, with only one identifiable point mutation carry on the other allele, a large deletion that is not detected by conventional screening methods. The overall frequency of large deletions in patients with CF is estimated to be 1-3%. Using the CFTR Multiplex Ligation dependent Probe Amplification Kit (MRC-Holland, Amsterdam, Netherlands) that allows the exact detection of copy numbers from all 27 exons in the CFTR gene, we screened 50 patients with only one identified mutation for large deletions in the CFTR gene. Each detected deletion was confirmed using our real-time polymerase chain reaction (PCR) assay and deletion-specific PCR reactions using junction fragment primers. We detected large deletions in eight patients (16%). These eight CF alleles belong to four different deletion types (CFTRindel2, CFTRdele14b-17b, CFTRdele17a-17b and CFTRdele 2-9) whereof the last is novel. Comparing detailed clinical data of all these patients with CF and the molecular genetic findings, we were able to elaborate criteria for deletion screenings and possible genotype-phenotype associations. In conclusion, we agree with other authors that deletion screenings should be implemented in routine genetic diagnostics of CF.

Administrative monitoring of tuberculosis treatment in Switzerland.

SETTING: Treatment of tuberculosis (TB) is critically dependent on adherence. Directly observed treatment (DOT) has been shown to be effective. OBJECTIVE: To determine operational treatment outcome using administrative treatment monitoring (ATM) to assess the need for more vigorous promotion of DOT. DESIGN: Cohort study in eastern Switzerland, where ATM was started in 2002. Bi-monthly progress forms and a treatment outcome form (after 6 months) were sent to the treating doctors. Forms not returned within 6 weeks were followed up with phone calls. RESULTS: Between 2002 and 2004, 98 (87.5%) of 112 new TB patients completed a 6-month treatment course. Eight elderly patients died of causes other than TB while on treatment, four travelled out of the region and two were lost to follow-up. Treating doctors opted for DOT in only seven cases. CONCLUSION: Given the high success rate of 87.5% in our cohort, more vigorous promotion of DOT is not a priority for TB case management in eastern Switzerland. In our setting, ATM in collaboration with the family doctors offers a valuable alternative to the more time-consuming universal DOT.

Effect of detergent-coated versus non-coated spacers on bronchodilator response in children with asthma.

OBJECTIVE: Previous studies have demonstrated that coating spacers with ionic detergents minimizes the static charge and thereby improves in vivo drug deposition. The present study aims to examine the effect of coated spacers versus non-coated spacers in the clinical situation. METHODS: A randomized, double-blind study in children with asthma and a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of < or =72% predicted was carried out. Spirometry was performed at baseline and at 10 min and 20 min after inhalation of two puffs of salbutamol (100 microg/puff) through either a detergent-coated or a non-coated spacer. RESULTS: Fifty children were studied (mean age 11.6 years, range 7-18 years): 26 in the group using coated spacers (CG); and 24 in the group using non-coated spacers (NCG). The mean percentage change in FEV1 from baseline 10 min after inhalation was 18.8% (range 5-50%) in the CG versus 18.5% (range 3-35%) in the NCG. At 20 min after inhalation, the per cent increase in FEV1 was 19.8% (range 0-50%) in the CG versus 19.5% (range 9-35%) in the NCG. There was no significant difference between groups in the percentage change in FEV1 after 10 min (P = 0.91), or after 20 min (P = 0.93). CONCLUSIONS: There was no improvement in bronchodilatation from detergent-coated spacers in the present study, possibly because a maximal bronchodilator response was achieved with the lower output.

Current management of acute bronchiolitis in Switzerland.

INTRODUCTION: Acute bronchiolitis is the most common lower respiratory tract infection in the first year of life. Current expert opinion and scientific data suggest that pharmaceutical agents have little impact on the natural course of the disease. METHODS: Postal questionnaires were sent to all Swiss paediatricians to assess their current practice for treating acute bronchiolitis in children. RESULTS: Of a total of 937 questionnaires, 541 (58%) were returned. Of the respondents, 422 (78%) treat children with acute bronchiolitis. Up to 99% of paediatricians used bronchodilators in the outpatient and inpatient management, either routinely (up to 62%) or occasionally (37%). Steroids were used by 41% of the respondents in outpatient management and by 57% in inpatient management. The paediatric respiratory physicians tended to use bronchodilators and corticosteroids less frequently than the general paediatricians. CONCLUSIONS: A wide variation in the treatment of bronchiolitis was noted. Despite lack of evidence of benefit most Swiss paediatricians use pharmaceutical agents in the management of acute bronchiolitis. In particular, bronchodilators and corticosteroids were used in inpatient management in Switzerland much more frequently than recently reported for Australian paediatricians. National guidelines could be helpful in reducing the variations in the management of acute bronchiolitis in our country.

Implementation of evidence-based management of acute bronchiolitis.

OBJECTIVE: Implementation of clinical guidelines is frequently delayed well beyond their dissemination and the publication of clinical evidence. The recently published Australian guidelines for the management of acute viral bronchiolitis (AVB) have been evaluated by assessing the current practice of Australian paediatricians. METHODS: Questionnaire survey of all Australian paediatricians and a review of the literature. RESULTS: Of a total of 891 questionnaires, 555 (62%) were returned. Of the respondents, 373 (67%) treated children with AVB and, of these, 232 (67%) treated 10-50 children per year. A wide variation in management practice for both outpatient and inpatient treatment of AVB was identified. Up to 70% of paediatricians who treated AVB indicated using pharmaceutical agents in their outpatient management (88% in inpatient management), most using these agents 'sometimes' or in high-risk children. Paediatric respiratory physicians tended to use bronchodilators less frequently than general paediatricians. Compared with many countries in Europe, few Australian paediatricians routinely use supplementary drugs in the inpatient managenment of AVB; in particular, bronchodilators (61 vs 7%) and corticosteroids (11 vs 1%) are used far less often. A review of the literature demonstrated that pharmaceutical agents do not influence the course of AVB. CONCLUSIONS: Despite a lack of evidence for their efficacy and the recommendation of the Australian guidelines, pharmaceutical agents are frequently used in the management of AVB by paediatricians in Australia, although far less than reported in a recently published European survey. Guidelines alone are not sufficient to implement change and there is a need for more specific strategies to ensure that children receive appropriate management for this common condition.

Bronchial granuloma - where's the foreign body?

Airway masses are uncommon in children. The majority of bronchial tumors are granulomata secondary to an inhaled foreign body. However, other rare diseases like primary bronchopulmonary tumors should always be considered in the evaluation of a bronchial granuloma in children. The differential diagnosis of bronchial granuloma is presented. We report a 7-year-old girl with a 3-year history of recurrent cough and fevers who was found to have a bronchial granuloma in the left upper lobe bronchus. The diagnosis of foreign body-related granuloma was eventually made after combined and repeated rigid and flexible bronchoscopy. This case highlights the need to search aggressively for a foreign body in the presence of an airway granuloma in children, even in the absence of a history of aspiration.