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.

Drug desensitization to lumacaftor/ivacaftor: A fast lane to drug tolerance.

We present the case of a girl (now 11 years and 9 months old) with cystic fibrosis (F508del homozygote), who developed pruritic rash and urticaria six days after the first dose of the CFTR modulators lumacaftor/ivacaftor. The treatment was paused and had to be interrupted due to an immediate recurrence of the urticarial rash after rechallenge. We developed a drug desensitization protocol, aligned to protocols used for desensitization against oral antibiotics. In contrast to other published protocols, it was performed by rapidly increasing the dose of lumacaftor/ivacaftor granulate at 15 min intervals. The medication was continued without interruption, the rash did not reappear during follow-up of two years. This drug desensitization protocol provides a potential new therapeutic option for patients with drug hypersensitivity reactions to CFTR modulators, especially when there are no alternative treatments. Lumacaftor/ivacaftor is available as granulate, doses can be titrated during desensitization and used for long-term treatment.

Chronic inhaled antibiotic therapy in people with cystic fibrosis with Pseudomonas aeruginosa infection in Germany.

BACKGROUND: Several clinical guidelines recommend chronic inhaled therapy for pwCF (people with cystic fibrosis) and chronic Pseudomonas aeruginosa infection of the lungs. METHODS: To demonstrate what kind of therapy regimens are used in Germany, we retrospectively analysed chronic inhaled antibiotic therapy within the cohort of the German CF Registry in 2020. For comparison we also analysed the use of inhaled antibiotics in pwCF with intermittent Pseudomonas or without Pseudomonas infection. RESULTS: A total of 1960 pwCF had chronic P. aeruginosa infection and were retrospectively evaluated. Almost 90% (n = 1751) received at least one inhaled antibiotic. The most commonly used inhaled antibiotic was colistin solution for inhalation (55.2%), followed by aztreonam solution for inhalation (32.6%) and tobramycin solution for Inhalation (30%). Almost 56% of adults and 44% of children alternated two antibiotics for inhalation. In children, alternating colistin + tobramycin was the most often used regimen. In adults, only 23% used colistin + tobramycin; there was a wide range of treatment regimens among adults using two inhaled antibiotics alternately. 2456 pwCF had no Pseudomonas infection, but almost 24% had a chronic inhaled antibiotic therapy, while 56% of 361 pwCF and intermittent chronic Pseudomonas infection had a chronic inhaled antibiotic therapy. CONCLUSION: In all three groups the most commonly used inhaled antibiotic was colistin solution for inhalation. Almost 56% of adults and 44% of children with chronic Pseudomonas infection alternated two antibiotics for inhalation. It will be interesting to see how the introduction of the highly effective modulator elexacaftor/tezacaftor/ivacaftor will change the use of inhaled antibiotics.

Risk factors for cystic fibrosis arthropathy: Data from the German cystic fibrosis registry.

BACKGROUND: Epidemiology and potential risk factors for cystic fibrosis arthropathy (CFA) were studied in a relevant cystic fibrosis (CF) patient cohort. METHODS: Cohort study of patients included in the German CF registry in 2016-2017. Descriptive analysis, exploratory tests and multivariable logistic regression were used to assess prevalence of CFA and associated potential risk factors for adult patients with/without chronic Pseudomonas aeruginosa infection. RESULTS: 6069 CF patients aged from 0 to 78 years were analysed. CFA was observed in 4.9% of the patients. Prevalence was significantly higher in adult patients (8.4%) compared to patients <18 years (0.7%; p<0.0001). Logistic regression analyses in adult patients (n=3319) showed that CFA was significantly associated with increasing age (OR=1.04; 95% CI: 1.02-1.05; p<0.0001), female gender (OR=2.10; 95%CI:1.52-2.90; p<0.0001), number of hospitalizations (OR=1.24; 95%CI:1.12-1.36; p<0.0001), chronic P. aeruginosa infection (OR=1.83; 95%CI:1.28-2.61; p=0.0009), CF-related diabetes (OR=1.69; 95%CI:1.23-2.33; p=0.0013), pancreatic insufficiency (OR=2.39; 95%CI:1.28-4.46; p=0.0060) and sinusitis/polyps (OR=1.91; 95%CI:1.39-2.62; p<0.0001). In a subgroup analysis of adults without chronic P. aeruginosa infection (n=1550) CFA was also significantly associated with increasing age, female gender, increasing number of hospitalizations, pancreatic insufficiency as well as sinusitis/polyps; antimycotic treatment associated only in this subgroup while association with CF-related diabetes was not significant. CONCLUSION: CFA is a frequent and clinically relevant co-morbidity particularly in adult CF patients. CFA is significantly more common in patients with chronic P. aeruginosa colonization but associations with other indicators for a more severe disease course were identified regardless of P. aeruginosa colonization status.

[Life-threatening subcutaneous emphysema after minor blow to the neck]. / Lebensbedrohliches Hautemphysem nach banalem Stoß gegen den Hals.

After a minor blow to the neck from the handlebars of a bike, a 5-year-old boy developed a massive subcutaneous emphysema with respiratory distress. Orotracheal intubation was performed. A computed tomography (CT) scan of the neck and thorax showed a pneumomediastinum and a bilateral pneumothorax. No injury to the large airways was identified. The patient was stabilized by insertion of chest tubes and controlled ventilation. The endoscopic examination of the trachea revealed a tear of the pars membranacea, which was successfully treated conservatively. The specific features of the injury and the airway management are discussed based on a review of the current literature.

Importance to question sinonasal symptoms and to perform rhinoscopy and rhinomanometry in cystic fibrosis patients.

OBJECTIVES: Cystic fibrosis (CF) patients almost regularly reveal sinonasal pathology. The purpose of this study was to assess association between objective and subjective measurements of sinonasal involvement comparing nasal airflow obtained by active anterior rhinomanometry (AAR), nasal endoscopic findings, and symptoms assessed with the Sino-Nasal Outcome Test-20 (SNOT-20). METHODS: Nasal cavities were explored by anterior rigid rhinoscopy and findings were compared to inspiratory nasal airflow measured by AAR to quantify nasal patency and subjective health-related quality of life in sinonasal disease obtained with the SNOT-20 questionnaire. Relations to upper and lower airway colonization with Pseudomonas aeruginosa, medical treatment, and sinonasal surgery were analysed. RESULTS: A total of 124 CF patients were enrolled (mean age 19.9 ± 10.4 years, range 4-65 years). A significant association of detection of nasal polyposis (NP) in rhinoscopy was found with increased primary nasal symptoms (PNS) which include "nasal obstruction," "sneezing," "runny nose," "thick nasal discharge," and "reduced sense of smell." At the same time patients with pathologically decreased airflow neither showed elevated SNOT-20 scores nor abnormal rhinoscopic findings. Altogether, rhinomanometric and rhinoscopic findings are not significantly related. CONCLUSIONS: Among SNOT-20 scores the PNS subscore is related to rhinoscopically detected polyposis and sinonasal secretion. Therefore, we recommend including short questions regarding PNS into CF-routine care. At the same time our results show that a high inspiratory airflow is not associated with a good sensation of nasal patency. Altogether, rhinomanometry is not required within routine CF-care, but it can be interesting as an outcome parameter within clinical trials. Pediatr Pulmonol. 2017;52:167-174. © 2016 Wiley Periodicals, Inc.

Concordant genotype of upper and lower airways P aeruginosa and S aureus isolates in cystic fibrosis.

RATIONALE: Lower airway (LAW) infection with Pseudomonas aeruginosa and Staphylococcus aureus is the leading cause of morbidity in cystic fibrosis (CF). The upper airways (UAW) were shown to be a gateway for acquisition of opportunistic bacteria and to act as a reservoir for them. Therefore, tools for UAW assessment within CF routine care require evaluation. OBJECTIVES: The aims of the study were non-invasive assessment of UAW and LAW microbial colonisation, and genotyping of P aeruginosa and S aureus strains from both segments. METHODS: 182 patients with CF were evaluated (age 0.4-68 years, median 17 years). LAW specimens were preferably sampled as expectorated sputum and UAW specimens by nasal lavage. P aeruginosa and S aureus isolates were typed by informative single nucleotide polymorphisms (SNPs) or by spa typing, respectively. RESULTS: Of the typable S aureus and P aeruginosa isolates from concomitant UAW- and LAW-positive specimens, 31 of 36 patients were carrying identical S aureus spa types and 23 of 24 patients identical P aeruginosa SNP genotypes in both compartments. Detection of S aureus or P aeruginosa in LAW specimens was associated with a 15- or 88-fold higher likelihood also to identify S aureus or P aeruginosa in a UAW specimen from the same patient. CONCLUSIONS: The presence of identical genotypes in UAW and LAW suggests that the UAW play a role as a reservoir of S aureus and P aeruginosa in CF. Nasal lavage appears to be suitable for non-invasive UAW sampling, but further longitudinal analyses and comparison with invasive methods are required. While UAW bacterial colonisation is typically not assessed in regular CF care, the data challenge the need to discuss diagnostic and therapeutic standards for this airway compartment. TRIAL REGISTRATION NUMBER: NCT00266474.

[Sweat testing practices in German cystic fibrosis centres]. / Durchführung und Interpretation des Schweisstests in deutschen Mukoviszidoseambulanzen.

BACKGROUND: Surveys in USA and UK have shown inconsistencies between practice of sweat testing and guidelines of the National Committee for Clinical Laboratory Standards (NCCLS), which could increase the risk of false-positive and -negative results. To determine the current practice of sweat testing in German cystic fibrosis (CF)-centres a survey was performed. METHOD: A questionnaire was mailed to all 123 German CF-centres that join the German CF-register. The results were compared with the NCCLS-guidelines. RESULTS: 88 out of 113 responding centres perform 30-1100 (median 200) sweat tests by pilocarpine iontophoresis per year. The recommended sweat sample time of 20-30 min was accepted by 33% of all centres. Minimum acceptable sweat rates were quoted between 100 and 7500 (median 1000) mg/m (2)/min differing from the recommended 1000 mg/m (2)/min. Osmolality was measured in 3%, sodium in 24% and conductivity in 53% of the centres. Chloride, the only accepted diagnostic measurement by the NCCLS, was investigated by only 58% of all centres. The recommended chloride CF-reference value of >60 mmol/l was used in 78% of centres that perform chloride testing. CONCLUSIONS: Major areas of inconsistencies between sweat testing practice in German CF-centres and NCCLS-guidelines are sweat collection, analyzing method and reference values. Chloride, the only accepted diagnostic measurement by the NCCLS, was investigated only by 58% of all centres.

[Two rare complications of percutaneous endoscopic gastrostomy: obstruction of the pylorus and gastrocolic fistula occurring in one patient]. / Zwei seltene Komplikationen der perkutanen endoskopischen Gastrostomie: Pylorusobstruktion und gastrokolische Fistel bei einem Patienten.

UNLABELLED: We report an 10 month old male infant, who developed an obstruction of the pylorus by dislocation of the retention disk 5 months after percutaneous endoscopic gastrostomy (PEG). This could be corrected under endoscopic control. Two years after PEG insertion diarrhoe occurred immediately after feeding caused by a gastrocolic fistula with dislocation of the retention disk in the colon transversum. An excision of the fistula and a resection of the colon segment were performed successfully. CONCLUSION: In patients with PEG and unclear abdominal symptoms a tube dislocation has to be kept in mind at any time.

Balloon dilation of an esophageal stenosis in a patient with recessive dystrophic epidermolysis bullosa.

We report a 13-year-old boy with recessive dystrophic epidermolysis bullosa who had dysphagia due to esophageal stenosis. A balloon dilation was successfully performed under flexible endoscopic and fluoroscopic control. The early and long-term follow-up was characterized by the disappearance of dysphagia, weight gain, and improvement of his skin lesions.