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.

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.

Clinical and Functional Characteristics of the E92K CFTR Gene Variant in the Russian and Turkish Population of People with Cystic Fibrosis.

The pathogenic variant E92K (c.274G > A) of the CFTR gene is rare in America and Europe, but it is common for people with cystic fibrosis from Russia and Turkey. We studied the effect of the E92K genetic variant on the CFTR function. The function of the CFTR channel was studied using the intestinal current measurements (ICM) method. The effects of CFTR modulators on the restoration of the CFTR function were studied in the model of intestinal organoids. To assess the effect of E92K on pre-mRNA splicing, the RT-PCR products obtained from patients' intestinal organoid cultures were analyzed. Patients with the genetic variant E92K are characterized by an older age of diagnosis compared to homozygotes F508del and a high frequency of pancreatic sufficiency. The results of the sweat test and the ICM method showed partial preservation of the function of the CFTR channel. Functional analysis of CFTR gene expression revealed a weak effect of the E92K variant on mRNA-CFTR splicing. Lumacaftor (VX-809) has been shown to restore CFTR function in an intestinal organoid model, which allows us to consider the E92K variant as a promising target for therapy with CFTR correctors.

Molecular Epidemiology of Mycobacterium abscessus Isolates Recovered from German Cystic Fibrosis Patients.

Infections due to Mycobacterium abscessus are a major cause of mortality and morbidity in cystic fibrosis (CF) patients. Furthermore, M. abscessus has been suspected to be involved in person-to-person transmissions. In 2016, dominant global clonal complexes (DCCs) that occur worldwide among CF patients have been described. To elucidate the epidemiological situation of M. abscessus among CF patients in Germany and to put these data into a global context, we performed whole-genome sequencing of a set of 154 M. abscessus isolates from 123 German patients treated in 14 CF centers. We used MTBseq pipeline to identify clusters of closely related isolates and correlate those with global findings. Genotypic drug susceptibility for macrolides and aminoglycosides was assessed by characterization of the erm(41), rrl, and rrs genes. By this approach, we could identify representatives of all major DCCs (Absc 1, Absc 2, and Mass 1) in our cohort. Intrapersonal isolates showed higher genetic relatedness than interpersonal isolates (median 3 SNPs versus 16 SNPs; P < 0.001). We further identified four clusters with German patients from same centers clustering with less than 25 SNPs distance (range 3 to 18 SNPs) but did not find any hint for in-hospital person-to-person transmission. This is the largest study investigating phylogenetic relations of M. abscessus isolates in Germany. We identified representatives of all reported DCCs but evidence for nosocomial transmission remained inconclusive. Thus, the occurrence of genetically closely related isolates of M. abscessus has to be interpreted with care, as a direct interhuman transmission cannot be directly deduced. IMPORTANCE Mycobacterium abscessus is a major respiratory pathogen in cystic fibrosis (CF) patients. Recently it has been shown that dominant global clonal complexes (DCCs) have spread worldwide among CF patients. This study investigated the epidemiological situation of M. abscessus among CF patients in Germany by performing whole-genome sequencing (WGS) of a set of 154 M. abscessus from 123 German patients treated in 14 CF centers. This is the largest study investigating the phylogenetic relationship of M. abscessus CF isolates in Germany.

What can the CF registry tell us about rare CFTR-mutations? A Belgian study.

BACKGROUND: CFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented. METHODS: Belgian CF-Registry 2013 data were analyzed to identify CF with at least 1 RM (CF+RM). Clinical data and sweat chloride of CF+RM were compared to CF-controls, carrying 2 class 1 to 3 mutations (CFclassic). Disease severity was compared between both groups. To avoid bias in the comparison, transplanted patients were excluded from each group. RESULTS: Seventy-seven CF+RM were identified (77/1183 = 6.5%). Sixty-four different RM were detected, of which 21 had not been previously reported. All RMs, corresponding to HGVS (Human Genome Variation Society) nomenclature, were listed in supplementary data. Seven transplanted CF+RM were excluded for further analysis. CF+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3-18.3) vs. 0.3y (0.1-2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64-107) vs. 104 mmol/L (97-115) (p < 0.0001)], higher FEV1%pred [77%pred (58-96) vs. 68%pred (48-86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CFclassic. However, a wide spectrum of disease severity was seen amongst CF+RM. CONCLUSIONS: CF-patients with a RM cover 6.5% of the Belgian CF-population. Rare mutations can be found in severely ill patients, but more often in late diagnosed, pancreatic sufficient patients.

Ethnicity impacts the cystic fibrosis diagnosis: A note of caution.

BACKGROUND: The diagnosis of Cystic Fibrosis (CF) is by consensus based on the same parameters in all patients, yet the influence of ethnicity has only scarcely been studied. We aimed at elucidating the impact of Asian descent on the diagnosis of CF. METHODS: We performed a retrospective analysis of the CFTR2 and UK CF databases for clinical phenotype, sweat chloride values and CFTR mutations and compared the diagnostic characteristics of Asian to non-Asian patients with CF. RESULTS: Asian patients with CF do not have a worse clinical phenotype. The repeatedly reported lower FEV1 of Asian patients with CF is attributable to the influence of ethnicity on lung function in general. However, pancreatic sufficiency is more common in Asian patients with CF. The diagnosis of CF in people with Asian ancestry is heterogeneous as mean sweat chloride values are lower (92±26 versus 99±22mmol/L in controls) and 14% have sweat chloride values below 60mmol/L (versus 6% in non-Asians). Also, CFTR mutations differ from those in Caucasians: 55% of British Asian patients with CF do not have one mutation included in the routine newborn screening panel. CONCLUSIONS: Bringing together the largest cohort of patients with CF and Asian ethnicity, we demonstrate that Asian roots impact on all three CF diagnostic pillars. These findings have implications for clinical practice in the increasingly ethnically diverse Western population.