Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition.
To examine the safety and efficacy of 28 days of once-daily ...Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa.
105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R).
The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49).
Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.
•We report 130 SARS-CoV-2 cases in people with CF (pwCF) to June 2020 across Europe.•Reported incidence was higher in pwCF versus the age-matched general population.•pwCF had more hospital and ...intensive care admissions than the general population.•Lung-transplanted pwCF had more severe illness and needed more care.•SARS-CoV-2 can cause severe disease in pwCF justifying priority vaccination.
Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF).
We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection.
Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant.
Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133).
SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination.
There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and ...reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530
. 1:1284).
Abstract The most prevalent "rare" disease worldwide, cystic fibrosis (CF), is an autosomal recessive multisystem disease, caused by mutations in the CFTR gene. The knowledge of CFTR mutations ...present in certain population is important for designing a simple, fast and cost-effective genetic testing approach, also for better management of CF patients, including the administration of novel targeted therapies. Here, we present genetic results of 158 unrelated CF patients from the National CF Registry of the Republic of North Macedonia. Initially, patients were screened for the 11 most common CF mutations. Additional CF mutations and large deletions/duplications in the CFTR gene were analyzed using commercial kits. If the genotype was undetermined, all CFTR exons were analyzed using Sanger DNA sequencing or next generation sequencing (NGS) (since 2014). The most common CF mutation, c.l521_ 1523del (legacy name F508del), was found with an overall incidence of 75.9%. Additionally, 26 other pathogenic variants and three large deletions were identified in the CFTR gene as a genetic cause of CF. Two of these, c.1070 C>T (p.Ala357Val) and c.2779_2788dup CTTGCTATGG (p.Gly930AlafsTer48), were novel. According to the distribution and prevalence of the pathogenic variants detected in our patients, a fast and cost-effective method, based on a single base extension was designed as a first-line CF genetic test with a 90.0% detection rate within our population. Furthermore, the knowledge of CFTR mutation classes in our CF patients represents the first step toward personalized therapy for CF in our country.
Objectives Due to the increased losses of chloride and sodium in the sweat, CF infants are predisposed to develop episodes of hyponatremic/hypochloremic dehydration with hypokalemia and metabolic ...alkalosis, the condition sometimes referred to as pseudo-Bartter's syndrome in CF. The aims of study were to estimate the prevalence of this metabolic disorder among CF infants in our region and the influence of some clinical and genetic factors on its developing. Methods The records of all 90 newly diagnosed infants with CF in the period from 1998 to 2014 were reviewed. Laboratory, clinical and CFTR genotype data of patients with pseudo-Bartter's syndrome were analyzed. Results Nineteen infants had manifestations of electrolyte depletion with metabolic alkalosis, therefore the prevalence of pseudo-Bartter's syndrome among newly diagnosed infants with CF was 21%. Mean age of patients was 4.2 months (range 1–8). Most of them were breastfed. Mean values of blood pH, serum bicarbonate, sodium, chloride and potassium (mmol/L) were: 7.57±0.06, 43.71±7.23, 118.2±4.98, 67.7±8.23 and 2.7±0.46, respectively. Concerning CFTR genotypes of these patients, a great variability was found: F508del/F508del (8), F508del/G542X (3), F508del/621+G→T (1), F508del/457TAT→G (1), F508del/711+3A→G (1), G126D/V456F (1), G126D/E585X (1), F508del/Unknown (2) and Unknown/Unknown (1). Five of them were pancreatic sufficient. Conclusion This metabolic disorder is a common presenting manifestation of CF in infancy in our region. The possibility of CF should be seriously considered in any infant with metabolic alkalosis and hypoelectrolytemia, whether or not there are associated pulmonary and/or gastrointestinal symptoms.
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