Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF.The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF.Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy

Cystic fibrosis. Disease on the way to personalized therapy

By the introduction of newborn screening it has become possible in most patients to implement symptomatic therapy for cystic fibrosis in the first weeks of life. The life expectancy and the quality of life of patients and their families will be improved by this implementation. Many mutation-specific therapies as well as mutation-agnostic treatments are in preclinical and clinical development and two have already been approved. Because of the difficulties in evaluating the individual effectiveness of these therapies by using clinical parameters alone, measurement of improved chloride channel function in vivo and in vitro is becoming more important

Cystic Fibrosis as a Rare Cause of Apple Peel Syndrome

Apple peel atresia is a special form of intestinal atresia with absence of mesentery. It is most likely due to an intrauterine intestinal vascular accident and has been described with other anomalies. Meconium ileus can compromise blood supply causing intestinal atresia. Therefore, cystic fibrosis needs to be ruled out in apple peel syndrome

Prevalence and molecular characterization of azole resistance in Aspergillus spp. isolates from German cystic fibrosis patients

Aspergillus spp. are the most frequently isolated filamentous fungi in the sputum of patients with cystic fibrosis (CF). Resistance to the azoles, the mainstay of current antifungal therapy, has been increasingly observed worldwide, but few data are available on the resistance of Aspergillus spp. in German CF patients. This study investigated the epidemiology of Aspergillus spp. and the molecular origin of azole resistance in a large German CF centre. In total, 2677 respiratory samples from 221 CF patients collected between April 2010 and April 2013 were analysed; of these, 573 yielded Aspergillus spp., which were screened for azole resistance. Isolates with reduced susceptibility to itraconazole and/or voriconazole were tested according to the EUCAST reference procedure. Sequencing of cyp51A, the target of azole antifungals, was performed in all resistant isolates. Six isolates obtained from four patients were highly resistant to itraconazole (all identified as Aspergillus fumigatus sensu stricto); five of them were pan-azole resistant. The TR34/L98H mutation was the most frequent mutation identified in azole-resistant isolates (naEuroS=aEuroS4), followed by M220L and TR46/Y121F/T289A, a mutation previously reported from Belgium and the Netherlands only. Three of four patients harbouring azole-resistant A. fumigatus had not received any prior azole treatment. Resistance to azoles in Aspergillus spp. is still infrequent in German CF patients and is mainly caused by the TR34/L98H mutation. Worryingly, pan-azole-resistant TR46/Y121F/T289A has spread to Germany. Azole resistance has to be considered also in azole-naive CF patients and susceptibility testing of Aspergillus spp. isolates should be performed in all patients requiring treatment

6-month approval of Kaftrio (R) in Germany-First experiences from real life of people with CF

Background By advancement of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators therapy and the approval of Kaftrio (R), for the majority of people with CF a further promising therapeutic option for the causal treatment of CF in addition to the established symptomatic therapy is now available. Objective The aim of this investigation was to analyze the first effects of Kaftrio (R) therapy on the clinical phenotype of people with CF 6 months after approval as well as to put the results into the context of new challenges and questions for future treatment of CF patients. Material and methods Clinical data (ppFEV(1), BMI, HbA(1c), sweat chloride, liver enzymes) from 56 CF patients were collected before and after receiving Kaftrio (R) for more than 4 weeks. The analysis of data was anonymized and retrospective. The paired t-test was used to compare the changes of the different parameters, a p-value Results Treatment with Kaftrio (R) was associated with an increase in ppFEV(1) (+11.3% predicted), an increased body mass index (+0.89 kg/m(2)), a decreased sweat chloride concentration (-58.8 mmol/l) and an increase of liver enzymes. Discussion Our retrospective data collection confirms the positive effect of Kaftrio (R) therapy on the clinical phenotype of people with CF as described in previous clinical trials. The improvement of lung function and nutritional status as well as the resulting increased life expectancy, will lead to the need for a re-evaluation of previous treatment standards and the future focus should also be on maintaining the quality of life through early diagnosis and efficient treatment of possible concomitant diseases

Pharmacokinetics and safety of an 8 week continuous treatment with once-daily versus twice-daily inhalation of tobramycin in cystic fibrosis patients

This randomized, multicentre, open-label, two-period crossover study showed that inhaling tobramycin either once daily or twice daily for 8 weeks appears to be safe and tolerable for treating patients with cystic fibrosis and chronic P. aeruginosa infection.We evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. In this randomized, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow(A (R)) rapid once daily and twice daily each for 8 weeks. Serum pharmacokinetics of these two regimens was analysed. Tobramycin levels were determined before the morning dose and at 30, 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle. At these timepoints, trough and peak serum tobramycin concentrations (C-max, mg/L) as well as the area under the curve for 0-90 min of tobramycin (AUC(0-90min)) were assessed in order to evaluate the risk of systemic toxicity. Safety parameters and forced expiratory volume in 1 s (FEV1) were assessed. For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC(0-90min) ratioaEuroS=aEuroS1.096, 90% CIaEuroS=aEuroS0.860-1.396, PaEuroS=aEuroS0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC(0-90min) ratioaEuroS=aEuroS0.608, 90% CIaEuroS=aEuroS0.461-0.802, PaEuroS=aEuroS0.0055). The AUC(0-90min) ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC(0-90min) ratioaEuroS=aEuroS0.749, 90% CIaEuroS=aEuroS0.514-1.092, PaEuroS=aEuroS0.2009). The mean FEV1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted. Continuous treatment with TIS (once daily or twice daily) over 8 weeks appears to be safe and tolerable