Attenuation of exacerbation.

J Cyst Fibros. 2018 11;17(6):692-693

Authors: Ranganathan SC

PMID: 30314936 [PubMed - indexed for MEDLINE]

N1303K: Leaving no stone unturned in the search for transformational therapeutics.

J Cyst Fibros. 2018 09;17(5):555-557

Authors: Noel S, Sermet-Gaudelus I, Sheppard DN

PMID: 30126793 [PubMed - indexed for MEDLINE]

Patient-reported outcomes: Time for a new approach?

J Cyst Fibros. 2018 09;17(5):560-561

Authors: Abbott J

PMID: 30089531 [PubMed - indexed for MEDLINE]

The BRICS (Bronchiectasis Radiologically Indexed CT Score): A Multicenter Study Score for Use in Idiopathic and Postinfective Bronchiectasis.

Chest. 2018 05;153(5):1177-1186

Authors: Bedi P, Chalmers JD, Goeminne PC, Mai C, Saravanamuthu P, Velu PP, Cartlidge MK, Loebinger MR, Jacob J, Kamal F, Schembri N, Aliberti S, Hill U, Harrison M, Johnson C, Screaton N, Haworth C, Polverino E, Rosales E, Torres A, Benegas MN, Rossi AG, Patel D, Hill AT

Abstract
OBJECTIVES: The goal of this study was to develop a simplified radiological score that could assess clinical disease severity in bronchiectasis.
METHODS: The Bronchiectasis Radiologically Indexed CT Score (BRICS) was devised based on a multivariable analysis of the Bhalla score and its ability in predicting clinical parameters of severity. The score was then externally validated in six centers in 302 patients.
RESULTS: A total of 184 high-resolution CT scans were scored for the validation cohort. In a multiple logistic regression model, disease severity markers significantly associated with the Bhalla score were percent predicted FEV1, sputum purulence, and exacerbations requiring hospital admission. Components of the Bhalla score that were significantly associated with the disease severity markers were bronchial dilatation and number of bronchopulmonary segments with emphysema. The BRICS was developed with these two parameters. The receiver operating-characteristic curve values for BRICS in the derivation cohort were 0.79 for percent predicted FEV1, 0.71 for sputum purulence, and 0.75 for hospital admissions per year; these values were 0.81, 0.70, and 0.70, respectively, in the validation cohort. Sputum free neutrophil elastase activity was significantly elevated in the group with emphysema on CT imaging.
CONCLUSIONS: A simplified CT scoring system can be used as an adjunct to clinical parameters to predict disease severity in patients with idiopathic and postinfective bronchiectasis.

PMID: 29247616 [PubMed - indexed for MEDLINE]

Upper versus lower airway microbiome and metagenome in children with cystic fibrosis and their correlation with lung inflammation.

PLoS One. 2019;14(9):e0222323

Authors: Kirst ME, Baker D, Li E, Abu-Hasan M, Wang GP

Abstract
OBJECTIVE: Airways of children with cystic fibrosis (CF) harbor complex polymicrobial communities which correlates with pulmonary disease progression and use of antibiotics. Throat swabs are widely used in young CF children as a surrogate to detect potentially pathogenic microorganisms in lower airways. However, the relationship between upper and lower airway microbial communities remains poorly understood. This study aims to determine (1) to what extent oropharyngeal microbiome resembles the lung microbiome in CF children and (2) if lung microbiome composition correlates with airway inflammation.
METHOD: Throat swabs and bronchoalveolar lavage (BAL) were obtained concurrently from 21 CF children and 26 disease controls. Oropharyngeal and lung microbiota were analyzed using 16S rRNA deep sequencing and correlated with neutrophil counts in BAL and antibiotic exposure.
RESULTS: Oropharyngeal microbial communities clustered separately from lung communities and had higher microbial diversity (p < 0.001). CF microbiome differed significantly from non-CF controls, with a higher abundance of Proteobacteria in both upper and lower CF airways. Neutrophil count in the BAL correlated negatively with the diversity but not richness of the lung microbiome. In CF children, microbial genes involved in bacterial motility proteins, two-component system, flagella assembly, and secretion system were enriched in both oropharyngeal and lung microbiome, whereas genes associated with synthesis and metabolism of nucleic acids and protein dominated the non-CF controls.
CONCLUSIONS: This study identified a unique microbial profile with altered microbial diversity and metabolic functions in CF airways which is significantly affected by airway inflammation. These results highlight the limitations of using throat swabs as a surrogate to study lower airway microbiome and metagenome in CF children.

PMID: 31536536 [PubMed - in process]

Minimal detectable change in six-minute walk test in children and adolescents with cystic fibrosis.

Disabil Rehabil. 2019 Sep 19;:1-6

Authors: López-de-Uralde-Villanueva I, Sarría Visa T, Moscardó Marichalar P, Del Corral T

Abstract
Purpose: To provide test-retest reliability for the 6-min walk test and the physiological variables obtained during the test, and to establish the minimal detectable change for the distance walked in children and adolescents with cystic fibrosis. Methods: 40 patients performed two 6-min walk tests on the same day (separated by 30-min of rest). The perceived breathlessness and fatigue in the legs were assessed with the modified Borg scale. The peripheral muscle strength was assessed using a hand dynamometer device, the medicine ball throw test and the horizontal jump test. Results: The test-retest reliability of the distance walked, dyspnea and fatigue in the legs were good for children (minimal detectable change90-95: 59.39-70.55 m) and for adolescents (minimal detectable change90-95: 47.81-56.8 m) with cystic fibrosis. Exercise tolerance is more related to 6-min walk work (distance walked x body weight) than to the distance walked alone and showed a positive association with peripheral muscle strength and forced vital capacity. Conclusions: The 6-min walk test is a reproducible and reliable tool to measure exercise tolerance for children and adolescents with cystic fibrosis. The minimal detectable changes reported for the distances achieved by these patients will be useful to identify the effectiveness of therapies aimed at alleviating or improving impaired physical capacity. IMPLICATIONS FOR REHABILITATION The 6-min walk test could be used to measure exercise tolerance for children and adolescents with cystic fibrosis, as it is a reliable test over time. An increase in the distance covered in the 6-min walk test that exceeds the minimum detectable change is recommended to determine improved exercise tolerance for children and adolescents with cystic fibrosis. The use of the 6-min walk work (distance walked x body weight) is recommended because it correlates better with exercise tolerance than the distance alone in children and adolescents with cystic fibrosis.

PMID: 31536381 [PubMed - as supplied by publisher]

The emerging role of regulatory T cells following lung transplantation.

Immunol Rev. 2019 Sep 19;:

Authors: Gauthier JM, Harrison MS, Krupnick AS, Gelman AE, Kreisel D

Abstract
Regulatory T cells (Treg) have proven to be a powerful immunologic force in nearly every organ system and hold therapeutic potential for a wide range of diseases. Insights gained from non-transplant pathologies, such as infection, cancer, and autoimmunity, are now being translated to the field of solid organ transplantation, particularly for livers and kidneys. Recent insights from animal models of lung transplantation have established that Tregs play a vital role in suppressing rejection and facilitating tolerance of lung allografts, and such discoveries are being validated in human studies and preclinical trials. Given that long-term outcomes following lung transplantation remain profoundly limited by chronic rejection, Treg therapy holds the potential to significantly improve patient outcomes and should be aggressively investigated.

PMID: 31536165 [PubMed - as supplied by publisher]

The Prevalence of Pseudomonas Aeruginosa Infection Over a Ten-Year Period in Children with Cystic Fibrosis

Ir Med J. 2019 Jun 17;112(6):946

Authors: Al Shidhani K, O’Reilly R, Javadpour S, O’Sullivan N, McNally P, Cox DW

Abstract
Background Pseudomonas aeruginosa (PA) infection is associated with an increased morbidity and adverse prognosis in children with Cystic Fibrosis(CF). The aim of the study was to evaluate the prevalence and characteristics of PA over a ten year period at a single paediatric tertiary referral centre in Ireland. Methods This was a retrospective cross-sectional study. Patient’s case notes, microbiology laboratory results and CF Registry of Ireland(CFRI) data were used to collect the data. Results The overall chronic PA infection prevalence was 28.1%(45/160) in 2004 and 21.3%(35/164) in 2014. In 2004, 54/160(33.8%) patients were never infected with PA, 27/160(16.9%) were free for 12 months and 34/160(21.3%) were intermittently infected. In 2014; 80/164(49%) patients, 38/164(23.2%) and 11/164(6.7%) were never infected, free for 12 months and intermittently infected respectively. Conclusion There has been a decline in the overall prevalence of PA infection and a change in the pattern of prevalence over the last decade at our Centre.

PMID: 31535835 [PubMed - as supplied by publisher]

Management of Exocrine Pancreatic Insufficiency in Children.

Nutr Clin Pract. 2019 Oct;34 Suppl 1:S27-S42

Authors: Sankararaman S, Schindler T, Sferra TJ

Abstract
The diagnosis of exocrine pancreatic insufficiency (EPI) can be difficult, as symptoms may be nonspecific. A delayed diagnosis of EPI can negatively impact health through poor weight gain, impaired growth, and malabsorption of nutrients. Because of active growth and development, children are more vulnerable to the consequences of untreated EPI. Pancreatic enzyme replacement therapy is the cornerstone of management and offers both symptomatic relief and improvement in clinical outcomes. Additionally, a high-energy diet with unrestricted fat and supplementation with fat-soluble vitamins is often required to optimize growth and prevent nutrition deficiencies. Cystic fibrosis (CF) is the most common condition in children that causes EPI, and improvement in nutrition management is associated with improved pulmonary function and increased survival. Currently, the management of other conditions leading to EPI in children is not well studied, and inferences from the CF literature are often necessary in caring for these patients.

PMID: 31535732 [PubMed - in process]

ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in Cystic Fibrosis.

Elife. 2019 Sep 18;8:

Authors: Scambler T, Jarosz-Griffiths HH, Lara-Reyna S, Pathak S, Wong C, Holbrook J, Martinon F, Savic S, Peckham D, McDermott MF

Abstract
Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3-inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1b, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3-inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na+) channels. Overexpression of b-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3-inflammasome activation.

PMID: 31532390 [PubMed - as supplied by publisher]

Social complexity negatively influences lung function in cystic fibrosis after transfer to adult care.

Pediatr Pulmonol. 2019 Sep 17;:

Authors: Crowley EM, Bosslet GT, Khan B, Ciccarelli M, Brown CD

Abstract
BACKGROUND: Several nongenetic factors, such as socioeconomic status, environmental exposures, and adherence have been described to have an impact on outcomes in cystic fibrosis (CF).
OBJECTIVE: To determine the effect of social complexity on the % predicted forced expiratory volume (ppFEV1 ) before and after transfer to adult care among adolescents with CF.
METHODS: Retrospective, single center, cohort study included all patients with CF who were transitioned into adult care between 2005 and 2015 at Indiana University. Social complexity (Bob's level of social support, [BLSS]) was collected at transfer. Linear mixed regression models assessed the relationship between ppFEV1 decline over time and BLSS with other covariates.
RESULTS: The median age of the patients (N = 133) at the time of transfer was 20 years (interquartile range: 19-23). Overall, there was a decline in lung function over time in our population (ppFEV1 at 24 months pretransfer 77 ± 20%, ppFEV1 at 24 months, posttransfer 66 ± 24%; P < .001). The relationship between BLSS and ppFEV1 became more negative over time, even after adjusting for other covariates.
CONCLUSION: Social complexity is strongly associated with lung function decline after transfer to adult care.

PMID: 31531964 [PubMed - as supplied by publisher]

VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level.

Sci Rep. 2019 Sep 17;9(1):13460

Authors: Cui G, Stauffer BB, Imhoff BR, Rab A, Hong JS, Sorscher EJ, McCarty NA

Abstract
VX-770 (ivacaftor) is approved for clinical use in CF patients bearing multiple CFTR mutations. VX-770 potentiated wildtype CFTR and several disease mutants expressed in oocytes in a manner modulated by PKA-mediated phosphorylation. Potentiation of some other mutants, including G551D-CFTR, was less dependent upon the level of phosphorylation, likely related to the severe gating defects in these mutants exhibited in part by a shift in PKA sensitivity to activation, possibly due to an electrostatic interaction of D551 with K1250. Phosphorylation-dependent potentiation of wildtype CFTR and other variants also was observed in epithelial cells. Hence, the efficacy of potentiators may be obscured by a ceiling effect when drug screening is performed under strongly phosphorylating conditions. These results should be considered in campaigns for CFTR potentiator discovery, and may enable the expansion of VX-770 to CF patients bearing ultra-orphan CFTR mutations.

PMID: 31530897 [PubMed - in process]

NHS England explores funding options for cystic fibrosis drug.

BMJ. 2019 Sep 17;366:l5600

Authors: Cohen D

PMID: 31530544 [PubMed - in process]

Micronutrient intake in children with cystic fibrosis in Sydney, Australia.

J Cyst Fibros. 2019 Sep 14;:

Authors: Tham A, Katz TE, Sutherland RE, Garg M, Liu V, Tong CW, Brunner R, Quintano J, Collins C, Ooi CY

Abstract
BACKGROUND: Children with CF have been reported to consume significantly more energy-dense, nutrient-poor foods than controls where there are now concerns of inadequate micronutrient intake. There are no current or comprehensive dietary studies assessing micronutrient intake in CF children.
OBJECTIVES: To evaluate micronutrient intake in children with CF compared to recommended dietary intakes (RDIs).
METHODS: Dietary intake of 13 micronutrients was measured in CF children aged 2-18 years and age- and sex-matched controls using a validated food frequency questionnaire (The Australian Child and Adolescent Eating Survey).
RESULTS: CF children (n = 82) consumed significantly more energy than controls (n = 82) [3142(2531-3822) kcal vs 2216(1660-2941) kcal; p < .001]. Absolute intake in CF children was significantly higher in all micronutrients except vitamin C and folate, however energy-adjusted intake was significantly lower for all micronutrients except vitamin A, sodium, calcium and phosphorous. Energy-adjusted intake in primary school CF children was significantly less than controls in 8/13 micronutrients. Overall, median intakes exceeded the RDIs for all micronutrients however CF children fell short of the RDIs for folate (26.8%), iron (15.9%) and calcium (9.8%). In pre-school, 50% of CF children and 91.7% of controls did not meet the iron RDI. High school CF and control children failed to meet RDIs for 7/13 and 9/13 micronutrients respectively.
CONCLUSION: Increased intake of most micronutrients in CF children was largely attributed to higher energy consumption. However, micronutrient density of the diet declined with increasing age, where high school children failed to meet RDIs for most key micronutrients.

PMID: 31530443 [PubMed - as supplied by publisher]

Targeting airway inflammation in cystic fibrosis.

Expert Rev Respir Med. 2019 Sep 18;:

Authors: McElvaney OJ, Wade P, Murphy M, Reeves EP, McElvaney NG

Abstract
Introduction: The major cause of morbidity and mortality in patients with cystic fibrosis (CF) is lung disease. Inflammation in the CF airways occurs from a young age and contributes significantly to disease progression and shortened life expectancy. Areas covered: In this review, we discuss the key immune cells involved in airway inflammation in CF, the contribution of the intrinsic genetic defect to the CF inflammatory phenotype, and anti-inflammatory strategies designed to overcome what is a critical factor in the pathogenesis of CF lung disease. Review of the literature was carried out using the MEDLINE (from 1975 to 2017), Google Scholar and The Cochrane Library databases. Expert opinion: Therapeutic interventions specifically targeting the defective CF transmembrane conductance regulator (CFTR) protein have changed the clinical landscape and significantly improved the outlook for CF. As survival estimates for people with CF increase, long-term management has become an important focus, with an increased need for therapies targeted at specific elements of inflammation, to complement CFTR modulator therapies.

PMID: 31530195 [PubMed - as supplied by publisher]

A Metacognitive Intervention of Narrative Imagery for young people with cystic fibrosis: A feasibility study.

J Health Psychol. 2019 Sep 18;:1359105319876336

Authors: Russell JK, Strodl E, Connolly J, Kavanagh DJ

Abstract
Cystic fibrosis and its treatment can have substantial functional and emotional impacts on patients and their families. This feasibility study assessed a new cystic fibrosis treatment, Metacognitive Intervention of Narrative Imagery, integrating narrative and meta-cognitive therapies with mental imagery. A total of 13 patients, aged 10-17 years, received three 1-hour sessions and were assessed on emotional functioning, anxiety, and depression at baseline and 4 and 8 weeks post-baseline. Participants had significant improvements in anxiety, and changes in emotional functioning and anxiety had a medium effect size. Participants and parents rated Metacognitive Intervention of Narrative Imagery highly on usability and favourability. Further clinical trials are indicated.

PMID: 31530184 [PubMed - as supplied by publisher]

Splenectomy for people with thalassaemia major or intermedia.

Cochrane Database Syst Rev. 2019 Sep 17;9:CD010517

Authors: Sharma A, Easow Mathew M, Puri L

Abstract
BACKGROUND: Thalassaemia is a genetic disorder of the haemoglobin protein in red blood cells. It has been historically classified into thalassaemia minor, intermedia and major, depending on the genetic defect and severity of the disease. The clinical presentation of β-thalassaemia varies widely from a mild asymptomatic form in thalassaemia minor, to a severe disease in thalassaemia major where individuals are dependant on life-long blood transfusions. The hallmark of thalassaemia syndromes is the production of defective red blood cells that are removed by the spleen resulting in an enlarged hyperfunctioning spleen (splenomegaly). Removal of the spleen may thus prolong red blood cell survival by reducing the amount of red blood cells removed from circulation and may ultimately result in the reduced need for blood transfusions.
OBJECTIVES: To assess the efficacy and safety of splenectomy in people with β-thalassaemia major or intermedia.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Review Group's Haemoglobinopathies Trials Register, compiled from searches of electronic databases and the handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews (27 July 2018).Date of the most recent search of the Group's trials register: 02 August 2019.
SELECTION CRITERIA: We included randomised controlled and quasi-randomised controlled studies of people of any age with thalassaemia major or intermedia, evaluating splenectomy in comparison to conservative treatment (transfusion therapy and iron chelation) or other forms of splenectomy compared to each other (laparoscopic, open, radio-frequency).
DATA COLLECTION AND ANALYSIS: Two authors independently selected and extracted data from the single included study using a customised data extraction form and assessed the risk of bias. The quality of the evidence was assessed using GRADE.
MAIN RESULTS: One study, including 28 participants was included in the review; the results were described, primarily, in a narrative manner. This study assessed the feasibility of splenectomy using a laparoscopic approach versus open surgery. Given the lack of detail regarding the study methods beyond randomisation, the overall risk of bias for this study was unclear. The study was carried out over a period of 3.5 years, with each participant followed up only until discharge (less than one week after the intervention); it did not assess the majority of the outcomes outlined in this review (including two of the three primary outcomes, frequency of transfusion and quality of life). A total of three serious post-operative adverse events (the review's third primary outcome) were reported in the laparoscopic splenectomy group (one case of atelectasis and two cases of bleeding), compared to two events of atelectasis in the open surgery group; however, there were no significant differences between the groups for either atelectasis, risk ratio (RR) 0.50 (95% confidence interval (CI) 0.05 to 4.90) or for bleeding, RR 5.00 (95% CI 0.26 to 95.61) (very low-quality evidence). In addition, the study also reported three serious cases of intra-operative bleeding in the laparoscopic group which mandated conversion to open surgery, although the difference between groups was not statistically significant, RR 7.00 (95% CI 0.39 to 124.14) (very low-quality evidence). These effect estimates are based on very small numbers and hence are unreliable and imprecise. From this small study, there appeared to be an advantage for the laparoscopic approach, in terms of post-operative hospital stay, although the group difference was not large (median difference of 1.5 days, P = 0.03).
AUTHORS' CONCLUSIONS: The review was unable to find good quality evidence, in the form of randomised controlled studies, regarding the efficacy of splenectomy for treating thalassaemia major or intermedia. The single included study provided little information about the efficacy of splenectomy, and compared open surgery and laparoscopic methods. Further studies need to evaluate the long-term effectiveness of splenectomy and the comparative advantages of surgical methods. Due to a lack of high quality evidence from randomised controlled studies, well-conducted observational studies may be used to answer this question.

PMID: 31529486 [PubMed - as supplied by publisher]

A critical review of definitions used to describe Pseudomonas aeruginosa microbiological status in patients with cystic fibrosis for application in clinical trials.

J Cyst Fibros. 2019 Sep 13;:

Authors: Taccetti G, Denton M, Hayes K, ECFS-CTN Microbiology Group, Drevinek P, Sermet-Gaudelus I

Abstract
BACKGROUND: Definition of Pseudomonas aeruginosa (Pa) microbiological status is essential for patients' inclusion in clinical trials. The aim of this study was to agree on the definitions of Pa infection status for initial infection, eradication and chronic infection to be used in clinical trials and to propose additional future study areas.
METHODS: An exhaustive literature search was performed. The clinimetric properties of different definitions of Pa microbiological status were evaluated.
RESULTS: Historical studies have mostly used culture-based definitions, although some have also involved complementary anti-Pa antibodies. Clinimetric analysis showed great variability in the definitions used, leading to differences in reliability, validity, responsiveness to treatment and correlation with outcome measures. Use of serology for initial Pa infection and successful Pa eradication introduced a greater level of complexity as antibody tests are not standardised. Moreover, the chronology of the immune response to Pa antigenic determinants was not completely clear. Chronic Pa infection was characterized by high levels of antibodies and good concordance between culture results and serology.
CONCLUSIONS: Microbiological monitoring, regular sampling from the airways and standardization of culture methods remain essential requisites for microbiological definitions. Despite limitations, serology should be incorporated in the definitions of initial infection and eradication used in clinical trials to better classify patients at enrolment, mainly in non-expectorating children. This requires standardization of serological testing.

PMID: 31526710 [PubMed - as supplied by publisher]

Influence of sex gap on muscle strength and functional mobility in patients with cystic fibrosis.

Appl Physiol Nutr Metab. 2019 Sep 17;:

Authors: Martínez-García MDM, Rodríguez-Juan JJ, Ruiz-Cárdenas JD

Abstract
The aims were to determine whether there were differences in handgrip strength and functional mobility between cystic fibrosis (CF) patients and healthy controls with regard to sex, and to ascertain whether these differences were related to lung function. Thirty-eight CF patients (twenty-one women) aged 18-65 and thirty-eight healthy controls were included. Muscle weakness and functional mobility were assessed through handgrip strength; walking speed; time, velocity and power derived from a single sit-to-stand (STS) test. CF patients showed differences for STS variables and walking speed but not for handgrip strength, compared to healthy controls. Considering sex differences, female patients showed differences for all variables analyzed while CF males only exhibited differences for STS variables, compared to healthy controls. CF females showed moderate relationship between muscle weakness, functional mobility, and lung function (|r| = 0.45 - 0.49; p ≤ 0.05) whereas no relationships were observed for CF males. The influence of chronic infection with Pseudomonas aeruginosa and pancreatic insufficiency on muscle weakness and functional mobility was similar in both sexes. Differences in muscle strength and functional mobility were predominantly observed in CF females. These results suggest an important effect of sex gap on muscle weakness and functional mobility in CF patients. NCT03524859 ●The influence of sex gap on muscle weakness in cystic fibrosis (CF) has been shown. ●Muscle weakness was predominantly observed in CF females.

PMID: 31526325 [PubMed - as supplied by publisher]

Cystic Fibrosis Mutation Spectrum in North Macedonia: A Step Toward Personalized Therapy.

Balkan J Med Genet. 2019 Jun;22(1):35-40

Authors: Terzic M, Jakimovska M, Fustik S, Jakovska T, Sukarova-Stefanovska E, Plaseska-Karanfilska D

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.

PMID: 31523618 [PubMed]