Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis.

Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1 decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of 'normal' (FEV1≥90% predicted) and 'mild lung disease' (FEV1 70%-89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lung function techniques. The state and readiness of two imaging (CT and MRI) and two functional (multiple breath washout and oscillometry) tools for the detection and monitoring of early lung disease in children and adults with CF are discussed in this article.Prospective research programmes and technological advances in these techniques mean that well-designed interventional trials in early lung disease, particularly in young children and infants, are possible. Age appropriate, randomised controlled trials are critical to determine the safety, efficacy and best use of new therapies in young children. Regulatory bodies continue to approve medications in young children based on safety data alone and extrapolation of efficacy results from older age groups. Harnessing the complementary information from structural and functional tools, with measures of inflammation and infection, will significantly advance our understanding of early CF lung disease pathophysiology and responses to therapy. Defining clinical utility for these novel techniques will require effective collaboration across multiple disciplines to address important remaining research questions. Future impact on existing management burden for patients with CF and their family must be considered, assessed and minimised.To address the possible role of these techniques in early lung disease, a meeting of international leaders and experts in the field was convened in August 2019 at the Australiasian Cystic Fibrosis Conference. The meeting entitiled 'Shaping imaging and functional testing for early disease detection of lung disease in Cystic Fibrosis', was attended by representatives across the range of disciplines involved in modern CF care. This document summarises the proceedings, key priorities and important research questions highlighted.

Early disease surveillance in young children with cystic fibrosis: A qualitative analysis of parent experiences.

BACKGROUND: Sensitive measures of early lung disease are being integrated into therapeutic trials and clinical practice in cystic fibrosis (CF). The impact of early disease surveillance (EDS) using these novel and often intensive techniques on young children and their families is not well researched. METHODS: The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has operated a combined clinical and research early disease surveillance program, based around annual chest CT scan, bronchoscopy and lung function from newborn screening diagnosis until age 6 years, for over two-decades. To explore parental experiences of EDS in their child, a qualitative study was conducted using audio-recorded, semi-structured interviews in n=46 mothers and n=21 fathers of children (aged 3-months to six years) attending CF centres in Perth and Melbourne, Australia. Themes were developed iteratively using thematic analysis and assessed for validity and confirmability. RESULTS: Parents' experiences were positive overall; affording a sense of control over CF, disease knowledge, and belief that EDS was in the best interests of their child. Challenges included poor understanding about EDS measures leading to anxiety and distress, self-blame surrounding adverse findings, and emotional burden of surveillance visits. Tailored information regarding the practical and psychosocial aspects of EDS were endorsed. CONCLUSION: While experiences were generally positive there is need for information and psychosocial support for parents to mitigate anxiety and develop positive coping strategies surrounding surveillance procedures and results. Managing expectations regarding risks and benefits of disease surveillance in clinical and research settings are important aspects of care.

Health-related quality-of-life in children with cystic fibrosis aged 5-years and associations with health outcomes.

BACKGROUND: The impact of early cystic fibrosis (CF) on health-related quality-of-life (HRQOL) in preschool children is poorly characterised, and data on relationships between HRQOL and health outcomes in young children with CF are limited. We aimed to characterise and compare parent-proxy and child-reported HRQOL and evaluate relationships with clinical outcomes at age 5-years. METHODS: Subjects were participating in the multi-centre Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial investigating BAL-directed versus standard CF therapy. Children aged 5-years and their parents rated HRQOL using the Pediatric Quality of Life Inventory (PedsQL™) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaires. RESULTS: PedsQL and CFQ-R questionnaires were completed by 141 primary caregivers and 135 and 130 children, respectively. There were no differences in HRQOL between children randomised to BAL-directed versus standard CF therapy. Children with CF rated worse HRQOL than healthy children and there was poor parent-child concordance across HRQOL domains. Nutritional status, CF-CT scan score, forced expiratory volume in 1-second (FEV1), and pulmonary exacerbations correlated with HRQOL at age 5-years. FEV1 z-scores positively correlated with parent-proxy HRQOL in CFQ-R Respiratory (p = 0.018), Physical (<0.001), Emotional (p = 0.007) subscales and PedsQL Total-score (p = 0.021), Physical (p = 0.019) domains. Pulmonary exacerbation rates were inversely associated with parent-proxy CFQ-R Respiratory (p = 0.004), Physical (p = 0.022), PedsQL Total (p = 0.009) and Physical (p = 0.009) scores. CONCLUSION: Parent-reported HRQOL is a meaningful clinical endpoint to evaluate interventions in young children. Parent and child HRQOL reports provide different, complementary information. A preschool version of the CFQ-R is needed to assess relationships between HRQOL and clinical outcomes in young children.

Early Lung Disease in Infants and Preschool Children with Cystic Fibrosis. What Have We Learned and What Should We Do about It?

The past decade has seen significant advances in understanding of the pathogenesis and progression of lung disease in cystic fibrosis (CF). Pulmonary inflammation, infection, and structural lung damage manifest very early in life and are prevalent among preschool children and infants, often in the absence of symptoms or signs. Early childhood represents a pivotal period amenable to intervention strategies that could delay or prevent the onset of lung damage and alter the longer-term clinical trajectory for individuals with CF. This review summarizes what we have learned about early lung disease in children with CF and discusses the implications for future clinical practice and research.

Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis.

BACKGROUND: Early detection of Pseudomonas aeruginosa is essential for successful eradication. The accuracy of serum antibodies against specific and multiple P aeruginosa antigens at predicting lower airway infection in young children with cystic fibrosis (CF) was investigated. METHODS: A commercial P aeruginosa multiple antigen (MAg) ELISA and an in-house exotoxin A (ExoA) ELISA were compared in two populations: a discovery population of 76 children (0.1-7.1 years) undergoing annual bronchoalveolar lavage (BAL)-based microbiological surveillance and a test population of 55 children (0.1-5.6 years) participating in the Australasian CF Bronchoalveolar Lavage Trial. RESULTS: In the discovery population, P aeruginosa was cultured from BAL fluid (≥10(5) colony-forming units (cfu)/ml) in 15/76 (19.7%) children (median age 1.88 years). Positive MAg and ExoA serological results were found in 38 (50.0%) and 30 (39.5%) children, respectively. Positive (PPV) and negative (NPV) predictive values for serology at diagnosing P aeruginosa infection (≥10(5) cfu/ml) were 0.14 and 0.99 respectively (MAg assay) and 0.11 and 0.98 (ExoA assay). In the test population, P aeruginosa was cultured from BAL fluid (≥10(5) cfu/ml) in 16/55 (29.1%) children (median age 1.86 years) and from oropharyngeal swabs in 32/36 (88.9%). Positive MAg and ExoA serology was detected in 19 (34.5%) and 33 (60.0%) children, respectively. The PPV and NPV of serology were 0.26 and 0.94 respectively (MAg assay) and 0.19 and 0.98 (ExoA assay) and were marginally higher for oropharyngeal cultures. CONCLUSIONS: Measuring serum antibody responses against P aeruginosa is of limited value for detecting early P aeruginosa infection in young children with CF.