Observational study of health utilities in adult primary ciliary dyskinesia patients: preliminary data on associations with molecular diagnosis, clinical phenotype and HRQOL measures.

Background: Primary ciliary dyskinesia (PCD) is a congenital disorder characterized by chronic respiratory morbidity. To date, there is no information on PCD-specific preference-based quality of life measures such as health utilities (HU). We cross-sectionally assessed HU in adult PCD patients and explored relationships with genotype, phenotype and quality of life (QOL)-PCD scales. Methods: Diagnostic testing was performed according to international guidelines, while participants completed the visual analog scale (VAS), time trade off (TTO), standard gamble (SG), and EuroQol 5 dimensions (EQ5D) HU instruments, as well as the QOL-PCD questionnaire. Hierarchical regression was used to identify the QOL-PCD scales that are most predictive of HU. Results: Among 31 patients, median HU are 0.75 (VAS), 0.86 (EQ5D), 0.91 (TTO) and 0.99 (SG). The underlying genotype is not associated with HU measures. VAS and EQ5D are associated with lung function, while TTO and SG values are not sensitive to any of the examined factors. Among the QOL-PCD scales, physical functioning and lower respiratory symptoms explained much of VAS (R2= 0.419) and EQ5D (R2= 0.538) variability. Conclusions: Our study demonstrates that HU elicitation in PCD is feasible using both direct and indirect methods. Overall, HU scores are relatively high among adult patients, with higher scores observed in SG and TTO, followed by EQ5D and VAS. VAS and EQ5D HU values are sensitive to lung function as well as to QOL-PCD physical functioning and lower respiratory symptom scores.

Demographic characteristics, clinical and laboratory features, and the distribution of pathogenic variants in the CFTR gene in the Cypriot cystic fibrosis (CF) population demonstrate the utility of a national CF patient registry.

BACKGROUND: Specialized clinical care for cystic fibrosis (CF) in Cyprus, a small island country, has been implemented since the 1990s. However, only recently, a national CF patient registry has been established for the systematic recording of patients' data. In this study, we aim to present data on the epidemiological, genotypic and phenotypic features of CF patients in the country from the most recent data collection in 2019, with particular emphasis on notable rare or unique cases. RESULTS: Overall, data from 52 patients are presented, 5 of whom have deceased and 13 have been lost to follow-up in previous years. The mean age at diagnosis was 7.2 ± 12.3 years, and the mean age of 34 alive patients by the end of 2019 was 22.6 ± 13.2 years. Patients most commonly presented at diagnosis with acute or persistent respiratory symptoms (46.2%), failure to thrive or malnutrition (40.4%), and dehydration or electrolyte imbalance (32.7%). Sweat chloride levels were diagnostic (above 60 mmol/L) in 81.8% of examined patients. The most common identified mutation was p.Phe508del (F508del) (45.2%), followed by p.Leu346Pro (L346P) (6.7%), a mutation detected solely in individuals of Cypriot descent. The mean BMI and FEV1 z-scores were 0.2 ± 1.3 and - 2.1 ± 1.7 across all age groups, respectively, whereas chronic Pseudomonas aeruginosa colonization was noted in 26.9% of patients. The majority of patients (74.5%) were eligible to receive at least one of the available CFTR modulator therapies. In 25% of patients we recovered rare or unique genotypic profiles, including the endemic p.Leu346Pro (L346P), the rare CFTR-dup2, the co-segregated c.4200_4201delTG/c.489 + 3A > G, and the polymorphism p.Ser877Ala. CONCLUSIONS: CF patient registries are particularly important in small or isolated populations, such as in Cyprus, with rare or unique disease cases. Their operation is necessary for the optimization of clinical care provided to CF patients, enabling their majority to benefit from evolving advances in precision medicine.

Health related quality of life in adult primary Ciliary dyskinesia patients in Cyprus: development and validation of the Greek version of the QOL-PCD questionnaire.

BACKGROUND: The QOL-PCD questionnaire is a recently developed Health Related Quality of Life (HRQoL) instrument for Primary Ciliary Dyskinesia. The aim of this study was to translate the adult QOL-PCD questionnaire into Greek language and to conduct psychometric validation to assess its performance. METHODS: Forward translations to Greek and backward translation to English were performed, followed by cognitive interviews in 12 adult PCD patients. The finalized translated version was administered to a consecutive sample of 31 adult, Greek speaking PCD patients in Cyprus for psychometric validation, which included assessment of internal consistency, test-retest reliability, construct and convergent validity. Internal consistency was assessed by Cronbach's alpha test in terms of the overall and sub-scales. Test-retest reliability was assessed by repeat administration of the questionnaire within 2 weeks and calculation of the intra-class correlation (ICC). Construct validity was assessed by comparing different groups of patients based on a-priori hypotheses and convergent validity was evaluated by examining associations between the QOL-PCD and SF-36 questionnaires. RESULTS: Moderate to good internal consistency was observed (Cronbach's α: 0.46-0.88 across sub-scales) and test-retest reliability assessment demonstrated good repeatability for most scales (ICC: 0.67-0.91 across subscales). Patients of female gender, older age and lower lung function exhibited lower QOL-PCD scores in general, while high correlations for most QOL-PCD scales with corresponding SF-36 scales were observed, in particular for physical functioning (r = 0.78, p < 0.05). CONCLUSION: The adult version of QoL-PCD questionnaire has been translated according to international guidelines resulting to a cross-culturally validated Greek version which exhibited moderate to good metric properties in terms of internal consistency, stability, known-group and convergent validity.

Clinical features of primary ciliary dyskinesia in Cyprus with emphasis on lobectomized patients.

BACKGROUND: Despite the manifestations of primary ciliary dyskinesia (PCD) in early life, the diagnosis is often much delayed. Since 1998 in Cyprus, we have established the only national diagnostic and clinical referral center for PCD. OBJECTIVE: To review the phenotypic features at presentation of PCD patients in Cyprus in relation to age at diagnosis, with emphasis on previously lobectomised patients. METHODS: The medical records of the diagnosed PCD patients were retrospectively reviewed to obtain clinical data on presentation. RESULTS: Thirty patients, aged 13.9 years (range 0.1, 58.4 years), were diagnosed with PCD. Twelve of them presented after the age of 18. The most common manifestations were chronic cough (100%), chronic rhinorrhea (96.7%), sputum production (92.9%), laterality defects (63.3%), a history of pneumonia (53.3%) and neonatal respiratory distress (50%). A history of lobectomy in the past was recorded in 16.7% (5 patients). Patients who presented in adulthood had significantly higher frequency of lobectomy (41.7% vs 0%, p-value = 0.006) and had more frequently low FEV1 (58.3% vs 0%, p-value = 0.015) than those who presented before. Serial measurements of FEV1 and FVC indicated significantly lower intercepts in lobectomised compared to the adult non-lobectomised patients both in terms of FEV1 (-4.90 vs -1.80, p-value = 0.022) and FVC (-5.43 vs -1.91, p-value = 0.029) z-score levels. Change in FEV1 and FVC across time was not statistically significant in either group. CONCLUSIONS: PCD often remains undiagnosed up to adulthood accompanied by appearance of advanced lung disease. Performance of lobectomies seems to be a poor prognostic factor for PCD in adulthood.

Gender differences in objectively assessed physical activity in asthmatic and non-asthmatic children.

OBJECTIVE: To compare objectively assessed physical activity levels, between asthmatic children and non-asthmatic controls. METHODS: From a random community sample of 794 children aged 8-9 years, in a case-control design, 104 children with ever doctor's diagnosis of asthma and 99 non-asthmatic controls were recruited and had assessment of physical activity with biaxial accelerometers for 7 days. RESULTS: Children with active (also reporting at least one episode of wheezing in the last 12 months) and inactive (no wheezing in past 12 months) asthma appeared to have similar physical activity and sedentary activity levels compared to non-asthmatic children. However, girls with active asthma had significantly lower moderate-to-vigorous physical activity (MVPA) levels than their peers with adjusted geometric mean ratio of 0.59 (95% CI: 0.369, 0.929, P-value = 0.024). No difference in physical and sedentary activity levels was observed between asthmatic and non-asthmatic boys. The difference between genders in the comparison of MVPA levels in asthmatics and controls was statistically significant (P-value of likelihood ratio test [LRT] for effect modification by gender = 0.034). CONCLUSIONS: Unlike boys, girls with active asthma appear to be less active than their healthy peers, and this gender difference might explain the inconsistent evidence from previous reports on physical activity levels in asthmatic children. Further studies are needed to confirm the gender interaction in the childhood asthma-physical activity relation and the implications on current guidelines for physical exercise prescriptions in asthmatic children.

Apparent Homozygosity of p.Phe508del in CFTR due to a Large Gene Deletion of Exons 4-11.

We report a classic cystic fibrosis (CF) boy with a large deletion of exons 4-11 in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on one allele and p.Phe508del in exon 10 on the second allele. Both parents of Georgian and Ukrainian background had no personal or family history of the disease. The initial molecular diagnostic investigation identified the patient as homozygous for the p.Phe508del and not compatible with his parent's genetic status. The possibility of nonpaternity or uniparental disomy (UPD7) was investigated and excluded using microsatellite analysis of highly polymorphic markers on chromosome 7. Array-CGH was also performed on the patient and revealed a male profile with a subtle deletion within the CFTR gene on the long arm (q-arm) of chromosome 7 (7q31.2). The deletion was confirmed by MLPA extending from probe L02380 to probe L14978 (28.7 kb) and that was inherited from his father, while p.PheF508del was inherited from his mother. These data highlight the need for additional testing for large deletions in patients with apparent homozygosity for a mutated CFTR allele that do not match the carrier status of the parents. Not testing can lead to misdiagnosis and misinterpretation of mutation carrier status and the expected penetrance of the disorder.

Domestic allergen and endotoxin exposure and allergic sensitization in Cyprus.

We investigated the relationship between domestic allergen and endotoxin exposure and allergic sensitization among children in Cyprus. We skin prick tested 128 children aged 15-16 yr (random samples of 85 children with self-reported asthma and 43 healthy controls) and measured their domestic exposure to endotoxin and allergens (mite, cat, and dog). We analyzed the data using multivariate logistic regression (adjusting for gender, area of residence and parental history) and presented the outcomes as odds ratios (OR) and 95% confidence intervals (CI). Among this selected population, 19% of children were sensitized to mite, 15% to cat and 7% to dog. Male gender (OR 2.74, 95% CI 1.18-6.38, p = 0.02), maternal history of allergic disease (OR 3.53, 95% CI 1.13-11.00, p = 0.03), increasing endotoxin (OR 1.58, 95% CI 1.00-2.49, p = 0.05) and residence in the district of Nicosia (OR 2.48, 95% CI 1.01-6.08, p = 0.05) were independent associates of allergic sensitization. Factors associated with mite sensitization were increasing Der p 1 and endotoxin exposure (OR 1.28, 95% CI 1.01-1.62, p = 0.04 and OR 1.76, 95% CI 1.01-3.08, p = 0.05, respectively) and living in an urban area (OR 6.80, 95% CI 1.37-33.67, p = 0.02). Sensitization to domestic pets was associated only with paternal allergic disease (cat: OR 5.68, 95% CI 1.57-23.56, p = 0.02; dog: OR 13.5, 95% CI 1.79-101.73, p = 0.01), but not with pet ownership or specific allergen or endotoxin exposure. In conclusion, mite allergen exposure was associated with sensitization to mite, but there was no association between cat and dog allergen exposure and specific sensitizations. Surprisingly, in this area, increasing endotoxin exposure was associated with an increased risk of sensitization.