Cystic fibrosis in Iceland and the high prevalence of the N1303K variant.

BACKGROUND: Cystic fibrosis (CF) is most common in populations of Northern European ancestry where the F508del variant predominates. In 2020, Iceland became a member of the European Cystic Fibrosis Society Patient Registry, and we launched an epidemiological study of CF in Iceland. The study aimed to determine the prevalence and the genetic variants present in the country. Furthermore, we aimed to describe the previous and the current situation regarding lung function, infections, complications, treatment, and follow-up to understand the strengths and weaknesses of CF care in Iceland. METHODS: This retrospective study included all individuals in Iceland with a confirmed CF diagnosis between 1955 and 2021. We conducted a medical records search for CF diagnosis codes and found 30 people with CF who were included in the study. Two hundred sixteen clinical variables were registered. A descriptive analysis of these was performed. RESULTS: The prevalence of CF in Iceland is 0.372:10,000 inhabitants. The F508del is the most common CF transmembrane conductance regulator (CFTR) variant (46.4%), closely followed by N1303K (44.6%). Staphylococcus aureus was the most common airway pathogen, followed by Pseudomonas aeruginosa. Nasal polyps and CF-related diabetes were the most common complications. Modern CF medications, including the recent CFTR modulators, are available. CONCLUSION: Even though Iceland has a relatively low prevalence of CF, it holds the highest known prevalence of the N1303K variant in Europe. Access to necessary treatment is satisfactory, but improvements are advisable for some aspects of the routine assessments by best practice guidelines.

ST2 Predicts Mortality In Patients With Acute Hypercapnic Respiratory Failure Treated With Noninvasive Positive Pressure Ventilation.

Background: Patients with Acute Hypercapnic Respiratory Failure (AHRF) are often treated with Noninvasive Positive Pressure Ventilation (NPPV). In this heterogeneous patient group, there is a lack of clinical tools for predicting mortality and outcome. Aims: In order to facilitate the choice of treatment in patients with AHRF we evaluated the protein ST2, an established biomarker for cardiac stress, and its role in predicting mortality in patients with AHRF treated with NPPV. We also examined if ST2 baseline levels and changes during the first 12 hrs of treatment were predictive of treatment outcome. Methods: The study population consisted of 46 patients treated with NPPV for AHRF. Background data and clinical parameters were obtained and blood samples taken at various time points during the treatment. During the follow-up period of 18 months, the prognostic value of ST2 with regards to mortality was evaluated using Cox proportional hazard model. Results: Of the 46 patients, there were 3 subgroups in regards to primary diagnosis: Acute Exacerbation of COPD (n=34), Acute Heart Failure (n=8) and Acute Exacerbation in Obesity Hypoventilation Syndrome (n=4). We found that ST2 was an independent predictor of both short-term and long-term mortality during the follow-up period. The Hazard Ratio (HR) per 1-SD increment of ST2 for 28-day mortality was 11.00 (95% CI 1.8-67.2, p 0.009) and for 18-month mortality 2.11 (95% CI 1.4-3.2, p 0.001). The results seem to be driven by the largest subgroup of patients, with Acute Exacerbation of COPD, and deaths within the first 28 days. Furthermore, changes in ST2 values during the first 12 hrs of treatment were not predictive of treatment outcome. Conclusion: Our results show that ST2 is a target to explore further as a predictor of short-term mortality in patients with AHRF treated with NPPV.

IL-8 predicts early mortality in patients with acute hypercapnic respiratory failure treated with noninvasive positive pressure ventilation.

BACKGROUND: Patients with Acute Hypercapnic Respiratory Failure (AHRF) who are unresponsive to appropriate medical treatment, are often treated with Noninvasive Positive Pressure Ventilation (NPPV). Clinical predictors of the outcome of this treatment are scarce. Therefore, we evaluated the role of the biomarkers IL-8 and GDF-15 in predicting 28-day mortality in patients with AHRF who receive treatment with NPPV. METHODS: The study population were 46 patients treated with NPPV for AHRF. Clinical and background data was registered and blood samples taken for analysis of inflammatory biomarkers. IL-8 and GDF-15 were selected for analysis, and related to risk of 28-day mortality (primary endpoint) using Cox proportional hazard models adjusted for gender, age and various clinical parameters. RESULTS: Of the 46 patients, there were 3 subgroup in regards to primary diagnosis: Acute Exacerbation of COPD (AECOPD, n = 34), Acute Heart Failure (AHF, n = 8) and Acute Exacerbation in Obesity Hypoventilation Syndrome (AEOHS, n = 4). There was significant difference in the basic characteristic of the subgroups, but not in the clinical parameters that were used in treatment decisions. 13 patients died within 28 days of admission (28%). The Hazard Ratio for 28-days mortality per 1-SD increment of IL-8 was 3.88 (95% CI 1.86-8.06, p < 0.001). When IL-8 values were divided into tertiles, the highest tertile had a significant association with 28 days mortality, HR 10.02 (95% CI 1.24-80.77, p for trend 0.03), compared with the lowest tertile. This correlation was maintained when the largest subgroup with AECOPD was analyzed. GDF-15 was correlated in the same way, but when put into the same model as IL-8, the significance disappeared. CONCLUSION: IL-8 is a target to explore further as a predictor of 28 days mortality, in patients with AHRF treated with NPPV.

A sequence variant on 17q21 is associated with age at onset and severity of asthma.

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

[Cystic fibrosis--review]. / Slímseigjusjúkdómur (cystic fibrosis): meingerd, greining og medferd--Yfirlitsgrein.

The purpose of this paper is to give a brief overview of cystic fibrosis; its pathogenesis, diagnosis, treatment and prognosis. Cystic fibrosis is an autosomal recessive disorder, which is caused by a mutation in the CFTR protein, a chloride channel in epithelial cell membranes. More than 1500 mutations are known. The incidence is 1/2.000-3.000 in nations of European origin. The CFTR mutation influences the secretion and absorption by epithelium in various organs. The consequences are different depending on the organ, but there is a global tendency for obstruction of secretory glands. The primary organs affected are the respiratory tract, pancreas, gastrointestinal tract and sweat glands. The disease is most often diagnosed during the first months of life, with a common presentation of salty tasting sweat, failure to thrive and diverse faecal problems. Possible diagnostic tools are sweat test and DNA testing. Respiratory symptoms cause most morbidity, with chronic infections and an exaggerated inflammatory response. Abnormal water and electrolyte composition leads to thicker respiratory secretions compared to that of healthy individuals. The interaction of pathogens with the epithelium causes S. aureus, and later P. aeuruginosa, to transform into a mucoid form which is much more difficult to eradicate with antibiotics, making them a significant part of the disease burden of cystic fibrosis. The main respiratory medications are antibiotics, bronchodilators, mucolytic agents and anti-inflammatory agents. 90% of cystic fibrosis patients have pancreas insufficiency which is treated with pancreas enzymes. A good nutritional status is a necessary basis for any further treatment. The prognosis of cystic fibrosis patients has improved greatly over the last few decades in parallel with increased knowledge, and the average survival is currently 37 years in the United States.