Insights into the Adolescent Cystic Fibrosis Airway Microbiome Using Shotgun Metagenomics.

Cystic fibrosis (CF) is an inherited genetic disorder which manifests primarily in airway disease. Recent advances in molecular technologies have unearthed the diverse polymicrobial nature of the CF airway. Numerous studies have characterised the genus-level composition of this airway community using targeted 16S rDNA sequencing. Here, we employed whole-genome shotgun metagenomics to provide a more comprehensive understanding of the early CF airway microbiome. We collected 48 sputum samples from 11 adolescents and children with CF over a 12-month period and performed shotgun metagenomics on the Illumina NextSeq platform. We carried out functional and taxonomic analysis of the lung microbiome at the species and strain levels. Correlations between microbial diversity measures and independent demographic and clinical variables were performed. Shotgun metagenomics detected a greater diversity of bacteria than culture-based methods. A large proportion of the top 25 most-dominant species were anaerobes. Samples dominated by Staphylococcus aureus and Prevotella melaninogenica had significantly higher microbiome diversity, while no CF pathogen was associated with reduced microbial diversity. There was a diverse resistome present in all samples in this study, with 57.8% agreement between shotgun metagenomics and culture-based methods for detection of resistance. Pathogenic sequence types (STs) of S. aureus, Pseudomonas aeruginosa, Haemophilus influenzae and Stenotrophomonas maltophilia were observed to persist in young CF patients, while STs of S. aureus were both persistent and shared between patients. This study provides new insight into the temporal changes in strain level composition of the microbiome and the landscape of the resistome in young people with CF. Shotgun metagenomics could provide a very useful one-stop assay for detecting pathogens, emergence of resistance and conversion to persistent colonisation in early CF disease.

Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism.

Introduction: Data suggest a potential role for vitamin D in autism spectrum disorder (ASD) prevention and treatment. It is likely that the serum response to vitamin D supplementation contributes to its effectiveness. Multiple factors affect serum vitamin D 25(OH)D response to supplementation. Methods: We conducted post-hoc analysis of two double-blind, randomized, placebo-controlled trials (RCT) of vitamin D3 supplementation, one RCT involving children with ASD and another involving children with asthma. Both trials were conducted in the same geographic location (Dublin, Ireland, 53°N), conducted over Winter season and utilized the same vitamin D3 dose (2000 IU/day). Results: We included 18 children with ASD and 17 children with asthma. There was no significant difference in 25(OH)D or age at baseline, however, BMI was significantly lower in ASD (P = 0.03). Compliance with vitamin D supplementation was high in both trials. Despite a significantly longer intervention period (20w vs. 15w; P < 0.0001), ASD children had a significantly lower absolute increase (+26 vs. +45 nmol/l) in 25(OH)D (P = 0.04). Conclusions: Despite similar demographics, children with ASD had a lower increase in 25(OH)D levels with supplementation. Potential mechanisms include altered absorption/metabolism as well as well genetic factors. Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses.

Multiorgan involvement and management in children with Down syndrome.

AIM: To review multiorgan involvement and management in children with Down syndrome (DS). METHODS: A literature review of articles from 1980 to 2019 using the MEDLINE interface of PubMed was performed using the following search terms- [Down syndrome] or [Trisomy 21] AND [Cardiology] or [Respiratory] or [neurodevelopment] or [epilepsy] or [musculoskeletal] or [immune system] or [haematological] or [endocrine] or [gastrointestinal] or [ophthalmological] or [Ear Nose Throat] or [dermatology] or [renal]. RESULTS: Congenital heart disease particularly septal defects occur in over 60% of infants with DS and 5%-34% of infants develop persistent pulmonary hypertension of the newborn irrespective of a diagnosis of congenital heart disease. Early recognition and management of aspiration, obstructive sleep apnoea and recurrent lower respiratory tract infections (LRTI) could reduce risk of developing pulmonary hypertension in later childhood. Children with DS have an increased risk of autistic spectrum disorder, attention deficit disorder and epilepsy particularly infantile spasms, which are associated with poor neurodevelopmental outcomes. Congenital anomalies of the gastrointestinal and renal system as well as autoimmune diseases, coeliac disease, arthropathy, thyroid dysfunction fold diabetes mellitus and dermatological conditions are more common. Hearing and visual anomalies are also well recognised association with DS (Table 1). CONCLUSION: Children with DS are at an increased risk of multiorgan comorbidities. Organ-specific health surveillance may provide holistic care for the children and families with DS throughout childhood.

Co-colonisation with Aspergillus fumigatus and Pseudomonas aeruginosa is associated with poorer health in cystic fibrosis patients: an Irish registry analysis.

BACKGROUND: Pulmonary infection is the main cause of death in cystic fibrosis (CF). Aspergillus fumigatus (AF) and Pseudomonas aeruginosa (PA) are the most prevalent fungal and bacterial pathogens isolated from the CF airway, respectively. Our aim was to determine the effect of different colonisation profiles of AF and PA on the clinical status of patients with CF. METHODS: A retrospective analysis of data from the Cystic Fibrosis Registry of Ireland from 2013 was performed to determine the effect of intermittent and persistent colonisation with AF or PA or co-colonisation with both microorganisms on clinical outcome measures in patients with CF. Key outcomes measured included forced expiratory volume in one second (FEV1), number of hospitalisations, respiratory exacerbations and antimicrobials prescribed, and complications of CF, including CF related diabetes (CFRD) and allergic bronchopulmonary aspergillosis (ABPA). RESULTS: The prevalence of AF and PA colonisation were 11% (5% persistent, 6% intermittent) and 31% (19% persistent, 12% intermittent) in the Irish CF population, respectively. Co-colonisation with both pathogens was associated with a 13.8% reduction in FEV1 (p = 0.016), higher levels of exacerbations (p = 0.042), hospitalisations (p = 0.023) and antimicrobial usage (p = 0.014) compared to non-colonised patients and these clinical outcomes were comparable to those persistently colonised with PA. Intermittent and persistent AF colonisation were not associated with poorer clinical outcomes or ABPA. Patients with persistent PA had a higher prevalence of CFRD diagnosis (p = 0.012). CONCLUSIONS: CF patients co-colonised with AF and PA had poor clinical outcomes comparable to patients persistently colonised with PA, emphasising the clinical significance of co-colonisation with these microorganisms.

Vitamin D3 for uncontrolled childhood asthma: A pilot study.

BACKGROUND: Observational and mechanistic data suggest a role for vitamin D in childhood asthma. However, subsequent interventional trials have been inconsistent. We aimed to assess the effect of 15 weeks of vitamin D3 supplementation compared with placebo (PL) in Irish children with asthma. METHODS: We conducted a double-blind, randomized, PL-controlled trial of vitamin D supplementation (2000 IU/day) in 44 urban, Caucasian children at high latitude. Assessments were completed at baseline and after 15 weeks of supplementation. Outcome measures were lung function, subjective asthma control and biochemical parameters of total vitamin D, allergy, immunity, airway inflammation, and systemic inflammation. Finally, parents/guardians completed a weekly diary during the trial. RESULTS: There was no significant difference in baseline 25(OH)D levels, but there was a significant increase in median 25(OH)D in the vitamin D3 group (57.5-105 nmol/l) compared with the PL group (52.5-57.5 nmol/l) (p < 0.0001). There was no significant difference between groups regarding subjective asthma control. Compared with PL, there was a significant decrease in school days missed due to asthma (1 vs. 5 days, p = 0.04) and alkaline phosphatase (-3.4 vs. +16; p = 0.037) in the vitamin D3 group, but there were no beneficial effects regarding several other secondary end-points. However, there were non-significant, advantageous changes in the PL group compared with the vitamin D3 group in subjective asthma control and lung function, particularly percentage of predicted forced expiratory volume in 1 s (+2.5 vs. -4; p = 0.06). CONCLUSION: Vitamin D3 supplementation led to a significant increase in serum 25(OH)D and decreased school days missed (p = 0.04), but no other advantageous changes in asthma parameters compared with PL. The potential adverse effect of vitamin D deficiency on growth and the potential negative effect of high serum 25(OH)D on pulmonary function warrant further investigation.

Dietary Nitrate Acutely and Markedly Increased Exhaled Nitric Oxide in a Cystic Fibrosis Case.

Airway nitric oxide (NO) is a ubiquitous signaling molecule with bronchoprotective, anti-inflammatory and anti-infective roles. Cystic fibrosis (CF) is a chronic lung condition associated with deceased exhaled NO. Strategies to increase exhaled NO in CF have yielded inconsistent results. A potential new method of increasing systemic NO involves ingestion of dietary, inorganic nitrate which is reduced to nitrite and NO. We present the case of a 12-year-old, athletic boy with CF who demonstrated acute but marked increases in exhaled NO following dietary nitrate consumption compared to placebo.

Girl with xanthogranulomatous pyelonephritis and bronchiectasis: case report.

Xanthogranulomatous pyelonephritis (XGP) is a rare chronic inflammatory disorder of the kidney. Infiltration to lung and liver can occur. We present a rare complication of locally invasive XGP extending beyond the diaphragm to the lung to cause bronchiectasis in an adolescent girl with chronic productive cough, weight loss and no urinary symptoms. The patient underwent open left radical nephrectomy, where it was noted that the left kidney lay very high with significant perinephric inflammation and was densely adherent to the diaphragm and partially adherent to the spleen. XGP was confirmed on histology.

IL-8 dictates glycosaminoglycan binding and stability of IL-18 in cystic fibrosis.

Dysregulation of airway inflammation contributes to lung disease in cystic fibrosis (CF). Inflammation is mediated by inflammatory cytokines, including IL-8, which illustrates an increase in biological half-life and proinflammatory activity when bound to glycosaminoglycans (GAGs). The aim of this project was to compare IL-8 and IL-18 for their relative stability, activity, and interaction with GAGs, including chondroitin sulfate, hyaluronic acid, and heparan sulfate, present in high quantities in the lungs of patients with CF. Bronchoalveolar lavage fluid was collected from patients with CF (n = 28), non-CF controls (n = 14), and patients with chronic obstructive pulmonary disease (n = 12). Increased levels of IL-8 and reduced concentrations of IL-18 were detected in bronchial samples obtained from CF individuals. The low level of IL-18 was not a defect in IL-18 production, as the pro- and mature forms of the molecule were expressed and produced by CF epithelial cells and monocytes. There was, however, a marked competition between IL-8 and IL-18 for binding to GAGs. A pronounced loss of IL-18 binding capacity occurred in the presence of IL-8, which displaced IL-18 from these anionic-matrices, rendering the cytokine susceptible to proteolytic degradation by neutrophil elastase. As a biological consequence of IL-18 degradation, reduced levels of IL-2 were secreted by Jurkat T lymphocytes. In conclusion, a novel mechanism has been identified highlighting the potential of IL-8 to determine the fate of other inflammatory molecules, such as IL-18, within the inflammatory milieu of the CF lung.

Nebulized hypertonic saline decreases IL-8 in sputum of patients with cystic fibrosis.

RATIONALE: Inflammation within the cystic fibrosis (CF) lung is mediated by inflammatory chemokines, such as IL-8. IL-8 is protected from proteolytic degradation in the airways by binding to glycosaminoglycans, while remaining active. Evidence that increased hypertonicity of airway secretions induced by hypertonic saline treatment alters levels of IL-8 is lacking. OBJECTIVES: To investigate the antiinflammatory effect of hypertonic saline (HTS) treatment within the CF lung by focusing on IL-8. METHODS: Degradation of IL-8 in CF lung secretions after treatment with glycosaminoglycan lyases and HTS was analyzed by Western blot analysis and ELISA. The ex vivo chemotactic activity of purified neutrophils in response to CF airway secretions was evaluated post nebulization of HTS (7% saline). MEASUREMENTS AND MAIN RESULTS: In vivo CF bronchoalveolar lavage fluid (BALF) IL-8 levels were significantly higher than the control group (P < 0.05). Digesting glycosaminoglycans in CF BALF displaced IL-8 from glycosaminoglycan matrices, rendering the chemokine susceptible to proteolytic cleavage. High sodium concentrations also liberate IL-8 in CF BALF in vitro, and in vivo in CF sputum from patients receiving aerosolized HTS, resulting in degradation of IL-8 and decreased neutrophil chemotactic efficiency. CONCLUSIONS: Glycosaminoglycans possess the ability to influence the chemokine profile of the CF lung by binding and stabilizing IL-8, which promotes neutrophil chemotaxis and activation. Nebulized hypertonic saline treatment disrupts the interaction between glycosaminoglycans and IL-8, rendering IL-8 susceptible to proteolytic degradation with subsequent decrease in neutrophil chemotaxis, thereby facilitating resolution of inflammation.

Omalizumab for the treatment of severe allergic asthma in children: A tale of two.

Omalizumab is a monoclonal antibody which targets immunoglobulin E. It is approved as an add-on therapy for children with severe allergic asthma. Assessment of endotype and phenotype is necessary in order to correctly identify those patients who are most likely to respond to omalizumab. Children with severe asthma represent a complex heterogeneous group. This report outlines the background, management, and outcomes for two children initiated on omalizumab for severe allergic asthma in Children's Health Ireland at Tallaght. It demonstrates the difficulties faced by this cohort and the positive impact targeted biological therapy can have. Given the substantial cohort of children with asthma attending our tertiary center, it also indicates that comprehensive stepwise care can achieve adequate control in the vast majority of cases without the requirement for additional therapies.

Outcome in cystic fibrosis liver disease.

OBJECTIVES: Evidence suggests that cystic fibrosis liver disease (CFLD) does not affect mortality or morbidity in patients with cystic fibrosis (CF). The importance of gender and age in outcome in CF makes selection of an appropriate comparison group central to the interpretation of any differences in mortality and morbidity in patients with CFLD. METHODS: This is a 7-year follow-up of 42 children with CFLD and their age- and sex-matched controls. Participants were reviewed clinically, biochemically, and radiologically at follow-up. RESULTS: Overall, 85% (72 of 84) of the original cohort were included, 36 CFLD participants and 36 CF controls. There was no significant difference in the number of deaths/transplants between groups (7 of 36 (19.4%) CFLD participants, 3 of 36 (8.3%) CF controls). There was a tendency for participants with CFLD to die younger than their respective CF controls. There was no difference in height, weight, body mass index, or pulmonary function between the groups. Nutritional parameters (sum skinfold thickness 31.6 vs. 42.3, P=0.03; mean upper arm fat area 15.08 vs. 10.59, P=0.001; Shwachman score 43.7 vs. 32.1, P=0.001) were worse among CFLD participants than among CF controls. Cystic fibrosis-related diabetes was more common in CFLD participants (11 of 27 (40.7%) vs. 5 of 33 (15.2%), P=0.02). Eight children (22.2%) with evidence of CFLD at baseline had no clinical evidence of liver disease as adults. CONCLUSIONS: Patients with CFLD have a more severe CF phenotype than do CF patients without liver disease. However, a subgroup of children with CFLD will not manifest clinically significant liver disease as adults.

LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline.

There is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan-LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan-LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.

Early Interleukin-22 and Neutrophil Proteins Are Correlated to Future Lung Damage in Children With Cystic Fibrosis.

Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan®. High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0.0041 and p = 0.0182, respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.0026), X-ray repair CCP 6 (p = 0.0059), C3a anaphylatoxin des Arginine (p = 0.0129) and cytokine receptor common subunit gamma (p = 0.0214) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.0243). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies.

Neonatal screening programme for CF: Results from the Irish Comparative Outcomes Study (ICOS).

The introduction of NBS in Ireland in July 2011, provided a unique opportunity to investigate clinical outcomes using a comparative historical cohort study. Clinical cohort: children clinically diagnosed with CF born 1 July 2008 to 30 June 2011, and NBS cohort: children diagnosed with CF through NBS born 1 July 2011 to 30 June 2016. Clinical data were collected from the CF Registry of Ireland, medical charts, and data on weight/height before diagnosis from public health nurses and family doctors. SPSS was used for analysis. A total of 232 patients were recruited (response 93%) (93 clinically diagnosed, 139 NBS-detected). Following exclusions of meconium ileus (MI) (40), diagnosis outside Ireland (4), and being designated as CFSPID (2), a total of 77 clinically diagnosed patients and 109 NBS detected children were included in analysis. Over half were homozygous for F508del mutation. Being clinically diagnosed was independently associated with hospitalization for infective exacerbation of CF < 36 months (OR, 2.80; 95%CI 1.24-6.29). Diagnosis to first acquisition of Pseudomonas aeruginosa was significantly longer in NBS than clinically detected; from birth there was no significant difference. Weight and length/height were significantly greater in NBS cohort at 6 and 12 months. We provide evidence of improved growth, reduced hospitalization for acute exacerbations, and delayed P. aeruginosa acquisition (from diagnosis) to age 3 for the NBS cohort. Screening practices likely account for the non-significant difference in P. aeruginosa acquisition from birth.

The prevalence of Aspergillus fumigatus in early cystic fibrosis disease is underestimated by culture-based diagnostic methods.

Aspergillus fumigatus is the most common fungus infecting/colonising people with cystic fibrosis (CF) and can negatively impact clinical status. Diagnostic laboratories rely on culture to detect A. fumigatus which is known to be less sensitive than molecular approaches. Therefore, A. fumigatus colonisation in the CF population may be underestimated. Sputum (n = 60) from 25 children with CF were collected and A. fumigatus was detected using routine culture (CM1), enhanced culture (CM2) and ITS1 qPCR. The prevalence of A. fumigatus in this young CF population was 68% by qPCR and only 16% by CM1. CM1, CM2 and qPCR detected A. fumigatus in 8%, 22% and 53% of samples, respectively. qPCR had a 94.2% and 77.4% increased odds of detecting A. fumigatus over CM1 and CM2, respectively. Molecular methods proved superior for detecting A. fumigatus in CF sputum. A. fumigatus is likely more prevalent in early CF disease than is currently reported.

Longitudinal Trends in Real-World Outcomes after Initiation of Ivacaftor. A Cohort Study from the Cystic Fibrosis Registry of Ireland.

RATIONALE: Patient registries have the potential to collect and analyze high-quality postauthorization data on new medicines. OBJECTIVES: We used cystic fibrosis (CF) registry data to assess outcomes after the initiation of ivacaftor, a CF transmembrane conductance regulator (CFTR) potentiator approved for the treatment of CF with a defective gating CFTR mutation. METHODS: Longitudinal trends were examined using mixed-effects regression analysis in 80 ivacaftor-treated patients with CF aged 6 to 56 years registered with the CF Registry of Ireland with at least 36 months of before and after commencement data. The effects of ivacaftor treatment on forced expiratory volume in 1 second (FEV1) % predicted, body mass index (BMI), hospitalization for pulmonary exacerbation, and oral and intravenous antibiotic use were assessed. RESULTS: In the 36 months after ivacaftor initiation, FEV1% predicted improved by 2.26% per annum (95% confidence interval [CI], 0.2 to 4.3) for patients aged younger than 12 years, remained unchanged for 12- to younger than 18-year-olds (95% CI, -1.9 to 2.9), and declined in adults by 1.74% per annum (95% CI, -3.1 to -0.4). BMI in adults increased 0.28 kg/m2 per annum (95% CI, 0.03 to 0.5), and there was no significant change in BMI z-score in children (95% CI, -0.01 to 0.1). In the year after ivacaftor initiation, intravenous antibiotic treatment reduced by 46% (95% CI, -62.5% to -23.3%, oral antibiotic treatment reduced by 49% (95% CI, -61.1% to -32.1%), and there was no significant reduction in hospitalization (95% CI, -59.2% to 9.7%). CONCLUSIONS: In this study of real-world CF registry data, clinical outcomes improved and healthcare resource utilization decreased after commencing ivacaftor.

Aspergillus fumigatus Inhibits Pseudomonas aeruginosa in Co-culture: Implications of a Mutually Antagonistic Relationship on Virulence and Inflammation in the CF Airway.

Many cystic fibrosis (CF) airway infections are considered to be polymicrobial and microbe-microbe interactions may play an important role in disease pathology. Pseudomonas aeruginosa and Aspergillus fumigatus are the most prevalent bacterial and fungal pathogens isolated from the CF airway, respectively. We have previously shown that patients co-colonized with these pathogens had comparable outcomes to those chronically colonized with P. aeruginosa. Our objective was to examine the interactions between A. fumigatus and P. aeruginosa, specifically the effects of co-colonization on biofilm formation, virulence and host pro-inflammatory responses. Our findings suggest that co-infections of A. fumigatus and P. aeruginosa in the Galleria mellonella acute infection model showed that pre-exposure of larvae to sub-lethal inocula of A. fumigatus increased the mortality caused by subsequent P. aeruginosa infection. Co-infection of human bronchial epithelial cells (CFBE41o-) with both pathogens did not enhance IL-6 and IL-8 production beyond the levels observed following single infections. In addition, both pathogens stimulated cytokine secretion via the same two mitogen-activated protein kinases (MAPKs) signaling pathways, ERK and p38. Mixed species biofilms showed overall reduced biofilm development with crystal violet staining. Quantification by species-specific qPCR revealed that both pathogens had mutually antagonistic effects on each other. A. fumigatus supernatants showed strong anti-Pseudomonal activity and gliotoxin was the main active agent. Gliotoxin resulted in varying levels of anti-biofilm activity toward other bacteria commonly found in the CF airways. Gliotoxin produced by A. fumigatus colonizing the CF airways may have a significant impact on the CF airway microbiome composition with potential clinical implications.

Outcome in patients with cystic fibrosis liver disease.

BACKGROUND: Liver disease is an important complication in CF. AIMS: To determine if CFLD is a risk factor for mortality in CF, and which baseline characteristics predict all-cause mortality. METHODS: Irish children with CFLD, and their age and gender matched controls were enrolled at baseline and reviewed after 10years to determine which characteristics predict mortality. RESULTS: 72/84 (85.71%) participants were followed, (mean age Cases 21.71yrs SD 6.5, CF controls 23.62 SD 5.6, 22 (61%) males), with no difference in duration of follow-up. Nineteen participants (26.4%) died, 38.9% (14/36) with CFLD and 13.89% (5/36) CF controls (Odds Ratio (OR) 3.94 95% CI:1.23-12.56 p=0.005). In logistic regression, liver disease (OR 4.28 95% CI 1.07-17.16) female gender (OR 12.25 95% CI 2.37-63.24), reduced pulmonary function, (OR 5.11 95% CI 1.09-23.81) were each independent risk factors for mortality in CF. CONCLUSIONS: Liver disease is an independent risk factor for mortality in CF.