Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Airway clearance physiotherapy and health-related quality of life in cystic fibrosis.

OBJECTIVE: Airway clearance physiotherapy is recommended in cystic fibrosis, but limited evidence exists to suggest how much treatment is enough. As a secondary analysis of a prior study investigating the safety, efficacy, and participants' perceptions of a novel airway clearance technique, specific cough technique (SCT) compared to forced expiration technique (FET), we aimed to evaluate whether the intervention was associated with changes in health-related quality of life (HRQoL). METHODS: We conducted randomised, controlled individual trials with six adults (N-of-1 RCTs). Each trial included eight weeks of treatment, twice a week, using saline inhalation in horizontal positions, one with SCT and one with FET, in random order. Efficacy was measured by sputum wet weight (g) after each session. Perceived usefulness and preference were self-reported at the end of the study. Lung function was assessed at baseline and at the end of study. HRQoL was measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at baseline (week 1) and at completion of the study (week 8). Individual HRQoL scores (0-100) were coded and analysed using CFQ-R Software Program, version 2.0. RESULTS: Patient-reported outcomes were completed by all subjects. Individual CFQ-R-Respiratory Symptoms Scores (CFQ-R-RSS) showed a positive change, meeting the minimal important difference (MID) ≥ 4 points in five participants and a negative change in one individual. A strong correlation (r = 0.94 (p<0.01) was found between total sputum weight (g) and the positive changes in CFQ-R-RSS, and between changes in lung function and CFQ-R-RSS (r = 0.84 (p = 0.04). CONCLUSION: The airway clearance intervention was associated with clinically meaningful changes in patient-reported symptoms on the CFQ-R in the majority of the participants. This finding warrants further investigation regarding treatment, duration and frequency. A long-term study may reveal beneficial effects on other clinically meaningful endpoints, such as pulmonary exacerbations, high-resolution computed tomography scores and HRQoL. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov, under the number NCT0 1266473.

Maternal Stress, Early Life Factors and Infant Salivary Cortisol Levels.

BACKGROUND: Salivary cortisol (SC), a commonly used biomarker for stress, may be disrupted by negative events in pregnancy, at birth and in infancy. We aimed to explore if maternal perceived stress (PSS) in or after pregnancy and SC levels in pregnancy were associated with SC in early infancy, and, secondly, to identify early life factors associated with infants' SC levels (iSC). METHODS: At 3 months of age, SC was analyzed in 1057 infants participating in a Nordic prospective mother-child birth cohort study. Maternal PSS was available from questionnaires at 18- and 34-week gestational age (GA) and 3-month post-partum, and SC was analyzed at 18-week GA. Early life factors included sociodemographic and infant feeding from questionnaires, and birth data from medical charts. Associations to iSC were analyzed by Spearman correlation and multinomial logistic regression analyses. RESULTS: In this exploratory study neither PSS at any time point nor maternal SC (mSC) were associated with iSC. Higher birth weight was associated with higher levels of iSC, while inverse associations were observed in infants to a mother not living with a partner and mixed bottle/breastfeeding. CONCLUSIONS: Maternal stress was not associated with iSC levels, while birth weight, single motherhood and infant feeding may influence iSC levels.

Factors for severe outcomes following SARS-CoV-2 infection in people with cystic fibrosis in Europe.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. METHODS: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. RESULTS: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). CONCLUSION: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes.

Virus, allergic sensitisation and cortisol in infant bronchiolitis and risk of early asthma.

BACKGROUND: Acute bronchiolitis during infancy and human rhinovirus (HRV) lower respiratory tract infections increases the risk of asthma in atopic children. We aimed to explore whether specific viruses, allergic sensitisation or cortisol levels during acute bronchiolitis in infancy increase the risk of early asthma, using recurrent wheeze as a proxy. METHODS: In 294 children with a mean (range) age of 4.2 (0-12) months enrolled during hospitalisation for acute infant bronchiolitis, we analysed virus in nasopharyngeal aspirates, serum specific immunoglobulin E against food and inhalant allergens, and salivary morning cortisol. These factors were assessed by regression analyses, adjusted for age, sex and parental atopy, for risk of recurrent wheeze, defined as a minimum of three parentally reported episodes of wheeze at the 2-year follow-up investigation. RESULTS: At 2 years, children with, compared to without, recurrent wheeze had similar rates of respiratory syncytial virus (RSV) (82.9% versus 81.8%) and HRV (34.9% versus 35.0%) at the acute bronchiolitis, respectively. During infancy, 6.9% of children with and 9.2% of children without recurrent wheeze at 2 years were sensitised to at least one allergen (p=0.5). Neither recurrent wheeze nor incidence rate ratios for the number of wheeze episodes at 2 years were significantly associated with specific viruses, high viral load of RSV or HRV, allergic sensitisation, or morning salivary cortisol level during acute bronchiolitis in infancy. CONCLUSION: In children hospitalised with acute infant bronchiolitis, specific viruses, viral load, allergic sensitisation and salivary morning cortisol did not increase the risk of early asthma by 2 years of age.

Quality of life, salivary cortisol and atopic diseases in young children.

BACKGROUND: Children with atopic disease may have reduced health-related quality of life (QoL) and morning cortisol. Possible links between QoL, morning cortisol and atopic disease are unclear. We aimed to determine if QoL was associated with morning salivary cortisol at two years of age, and if asthma, atopic dermatitis and/or allergic sensitisation influenced this association. Secondarily, we aimed to determine if QoL at one year of age was associated with salivary cortisol one year later. METHODS AND FINDINGS: The Bronchiolitis All SE-Norway study included infants during hospitalisation for acute bronchiolitis in infancy (bronchiolitis group) and population-based control infants (controls). The present study included all 358 subjects with available Infant Toddler Quality of Life Questionnaire (ITQOL) from parents, consisting of 13 domains and morning salivary cortisol at two years of age. Answers from the same 0-100 score questionnaire, with optimal score 100 nine months after enrolment, was also available for 289 of these children at about one year of age. Recurrent bronchial obstruction was used as an asthma proxy. Atopic dermatitis was defined by Hanifin and Rajka criteria and allergic sensitisation by a positive skin prick test. Due to different inclusion criteria, we tested possible interactions with affiliation groups. Associations between QoL and cortisol were analysed by multivariate analyses, stratified by bronchiolitis and control groups due to interaction from affiliation grouping on results. At two years of age, QoL decreased significantly with decreasing cortisol in 8/13 QoL domains in the bronchiolitis group, but only with General health in the controls. The associations in the bronchiolitis group showed 0.06-0.19 percentage points changes per nmol/L cortisol for each of the eight domains (p-values 0.0001-0.034). The associations remained significant but diminished by independently including recurrent bronchial obstruction and atopic dermatitis, but remained unchanged by allergic sensitisation. In the bronchiolitis group only, 7/13 age and gender adjusted QoL domains in one-year old children were lower with lower cortisol levels at two years of age (p = 0.0005-0.04). CONCLUSIONS: At two years, most QoL domains decreased with lower salivary cortisol among children who had been hospitalised for acute bronchiolitis in infancy, but for one domain only among controls. Recurrent bronchial obstruction and to a lesser extent atopic dermatitis, weakened these associations that nevertheless remained significant. After bronchiolitis, lower QoL in one-year old children was associated with lower salivary cortisol at two years.

Evaluation of a novel technique in airway clearance therapy - Specific Cough Technique (SCT) in cystic fibrosis: A pilot study of a series of N-of-1 randomised controlled trials.

OBJECTIVES: The aim of this pilot study was to evaluate the efficacy, safety and participants' perception of a novel technique in airway clearance therapy - specific cough technique in cystic fibrosis. METHODS: We conducted randomised controlled individual trials (N-of-1 randomised controlled trials) in six adults. Each trial included 8 weeks of treatment with two interventions each week, one with specific cough technique and one with forced expiration technique. The efficacy was investigated by a blinded assessor measuring wet weight of sputum (g) after each session. Perceived usefulness and preference was self-reported at the end of study. Additional measurements included oxygen saturation and heart rate before and after each session and lung function (week 2). RESULTS: Three of six participants produced significantly higher mean sputum weight when using specific cough technique, differences being 21%, 38% and 23%, respectively. In three of the six participants, mean sputum weight was lower after forced expiration technique than after specific cough technique in each of the eight treatment pairs. Participant-reported outcomes were completed in all participants. Specific cough technique was reported to be easier to use in daily treatments and more normalising in everyday life. CONCLUSION: Specific cough technique was well tolerated and accepted by the participants with cystic fibrosis. Specific cough technique was non-inferior to forced expiration technique in terms of sputum production, thus specific cough technique appears to represent a promising alternative for clearing sputum in airway clearance therapy.

Morning Salivary Cortisol in Young Children: Reference Values and the Effects of Age, Sex, and Acute Bronchiolitis.

OBJECTIVE: To identify morning salivary cortisol reference values in infancy and at 2 years of age and to investigate the influence of age, sex and acute bronchiolitis. STUDY DESIGN: In this South-East Norwegian cohort study, 308 children hospitalized with moderate to severe acute bronchiolitis in infancy in 2010-2011 were compared with 223 healthy controls included in 2012 by measuring morning salivary cortisol levels at inclusion and at 2 years of age. Samples were collected shortly after awakening after 6 am. The influences of age, sex, and acute bronchiolitis were assessed by regression analysis. RESULTS: In infancy, cortisol values were higher in acute bronchiolitis, with an age- and sex-adjusted weighted mean group difference of 13.9 nmol/L (95% CI 8.1-19.7; P < .0001). The median level in reference group was 23.7 nmol/L (95% CI 9.7-119.6). At 2 years of age, sex but not inclusion groups differed, with significantly higher values in girls. The weighted mean of all boys' cortisol levels was 32.4 nmol/L, (95% CI 30.5-34.3), and all girls' levels were 36.9 nmol/L (95% CI 34.7-39.2; P < .003). CONCLUSIONS: Salivary cortisol levels were higher at 2 years of age than in infancy in the reference group, were higher in girls than in boys at 2 years of age, and were higher in infants at the time of acute bronchiolitis than in healthy infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00817466.

The severity of acute bronchiolitis in infants was associated with quality of life nine months later.

AIM: Acute bronchiolitis in infancy increases the risk of later asthma and reduced health-related quality of life (QoL). We aimed to see whether the severity of acute bronchiolitis in the first year of life was associated with QoL nine months later. METHODS: The parents of 209 of 404 of children hospitalised for acute bronchiolitis in eight paediatric departments in south-east Norway at a mean four months of age (range 0-12 months) completed the Infant/Toddler Quality of Life Questionnaire sent by mail nine months after the acute illness. Disease severity was measured by length of stay and the need for supportive treatment. Interactions with gender, inclusion age, prematurity, maternal ethnicity and maternal education were examined. RESULTS: Reduced QoL in four domains was associated with increased length of stay and need for ventilatory support. Physical abilities and general health were associated with both severity markers, whereas bodily pain and discomfort and change in health were associated with length of stay. Ventilatory support was more negatively associated with QoL than atopic eczema and also associated with reduced parental emotions and parental time. CONCLUSION: The severity of acute bronchiolitis in infants was associated with reduced QoL nine months later.

Implementation of newborn screening for cystic fibrosis in Norway. Results from the first three years.

BACKGROUND: Norway introduced newborn screening for cystic fibrosis (CF) March 1, 2012. We present results from the first three years of the national newborn CF screening program. METHODS: Positive primary screening of immunoreactive trypsinogen (IRT) was followed by DNA testing of the Cystic fibrosis transmembrane conductance regulator (CFTR) gene. Infants with two CFTR mutations were reported for diagnostic follow-up. RESULTS: Of 181,859 infants tested, 1454 samples (0.80%) were assessed for CFTR mutations. Forty children (1:4546) had two CFTR mutations, of which only 21 (1:8660) were confirmed to have a CF diagnosis. The CFTR mutations differed from previously clinically diagnosed CF patients, and p.R117H outnumbered p.F508del as the most frequent mutation. One child with a negative IRT screening test was later clinically diagnosed with CF. CONCLUSIONS: The CF screening program identified fewer children with a conclusive CF diagnosis than expected. Our data suggest a revision of the IRT/DNA protocol.

Children hospitalised with bronchiolitis in the first year of life have a lower quality of life nine months later.

AIM: Acute bronchiolitis increases the risk of asthma, and reduced quality of life (QoL) is reported in children with asthma and allergy. However, the impact of asthma risk factors on QoL is unclear. This study investigated whether bronchiolitis and common asthma risk factors in infancy had an influence on later QoL. METHODS: The parents of 209 infants recruited during hospitalisation for bronchiolitis at a mean age of 4 months, and 206 controls responded to the generic Infant Toddler Quality of Life Questionnaire 9 months later. We used robust regression analyses to assess the association between four asthma risk factors, atopic eczema, parental asthma, parental allergic rhinoconjunctivitis and second-hand smoke and QoL in the two groups. RESULTS: QoL was lower among children with previous bronchiolitis in the overall health and general health domains and lower in six of 13 domains in children with atopic eczema. Compared with no risk factors, children with previous bronchiolitis and three risk factors had lower scores in four domains, and control children with three risk factors had lower scores in three domains. CONCLUSION: Having acute bronchiolitis, atopic eczema and three asthma risk factors were negatively associated with later QoL in early childhood.

Altered oxidative state in schoolchildren with asthma and allergic rhinitis.

Oxidative stress may be defined as a disruption of the balance between the level of oxidants and reductants (antioxidants), and oxidative state in children may influence the risk of asthma and allergic disease. We investigated serum antioxidant levels: selenium, vitamin E, bilirubin, albumin, uric acid and transferrin as well as the oxidant ferritin and their association with asthma and allergic rhinitis. Children of 7-12 yr with asthma (n = 50) and no asthma (controls) (n = 52) underwent skin prick test, lung function, fractional exhaled nitric oxide (FeNO) measurements and blood sampling. Allergic rhinitis was found in 23 children, 19 with asthma and four controls. Healthy children were controls without rhinitis. Asthma was associated with reduced albumin (g/l), adjusted odds ratio (aOR) (95% CI) 0.81 (0.66, 0.99) (p = 0.048) compared with healthy children in a regression analysis adjusted for age and gender. Asthma with high FeNO ≥20 ppb was associated with reduced albumin, aOR 0.60 (0.40, 0.89) (p = 0.012) compared to controls with FeNO <20. Asthma with allergic rhinitis had reduced albumin, aOR = 0.70 (0.50, 0.99) (p = 0.04), and higher ferritin levels (mg/l) [aOR = 1.04 (1.00, 1.09) p = 0.03] compared to healthy children. Poorly controlled asthma was associated with lower vitamin E levels, aOR 0.79 (0.65, 0.95) (p = 0.02), lower transferrin levels, aOR 0.72 (0.57, 0.92) (p < 0.01), and higher albumin levels, aOR 1.53 (1.03, 2.28) (p = 0.04), compared to well controlled asthma. In conclusion, schoolchildren with asthma and rhinitis had reduced levels of the major serum antioxidant albumin, and poorly controlled asthma was associated with decreased vitamin E and transferrin levels. Reduced albumin was associated with increased FeNO, a marker of allergic inflammation in asthma, although the discriminatory value of this finding should be further assessed in population studies.

Paracetamol in early infancy: the risk of childhood allergy and asthma.

AIM: We investigated whether paracetamol exposure in pregnancy and until 6 months of age was associated with allergic disease in school children. METHODS: In a prospective birth cohort study in Oslo, 1016 children included at birth were re-investigated at 10 years. Paracetamol exposure in pregnancy and until 6 months of age was registered. Outcomes at 10 years included current asthma, a history of asthma, allergic sensitization and allergic rhinitis. RESULTS: Maternal paracetamol use in the first trimester increased the risk for allergic rhinitis at 10 years OR (odds ratio) (95%CI) 2.30 (1.06, 4.97) in boys and girls. Paracetamol use until 6 months in girls increased the risk for allergic sensitization OR 2.20 (1.15, 4.22) and a history of asthma OR 2.20 (1.13, 4.30). The ORs for allergic sensitization and history of asthma in girls remained unchanged adjusting for upper or lower airway infections during the first 6 months of life. CONCLUSION: Paracetamol exposure in pregnancy was associated with allergic rhinitis, but not with asthma or allergic sensitization at 10 years of age. Paracetamol used until 6 months of age was associated with allergic sensitization and having a history of asthma in girls at 10 years of age, even considering concomitant airway infections.

Maternal IgG anti-A and anti-B titres predict outcome in ABO-incompatibility in the neonate.

AIM: To evaluate predictors for risk of severe hyperbilirubinaemia and kernicterus in ABO-incompatible neonates with emphasize on maternal IgG anti-A/-B titres. METHODS: Blood group O women in labour at Oslo University Hospital, Ullevål, were included in the years 2004-2006. Offspring with blood group A or B had direct antiglobulin test performed and IgG anti-A/-B levels measured in maternal plasma. Blood group A or B infants developing severe hyperbilirubinaemia, received in addition to phototherapy, immunoglobulin treatment and/or exchange transfusion (EXT). RESULTS: Of 253 neonates, 61.3% had blood group O, 29.6% blood group A and 9.1% blood group B. Twenty neonates with blood group A or B received at least one immunoglobulin treatment. In multivariate analysis, maternal antibody-titres were the only significant predictors for immunoglobulin treatment (p < 0.0001), EXTs (p < 0.05) and duration of phototherapy (p < 0.0001). The need for invasive treatment increased sharply for antibody titres > or =512. Receiver operating characteristic analyses demonstrated that titres > or =512 had a sensitivity of 90% and a specificity of 72% for predicting immunoglobulin treatment and thus severe hyperbilirubinaemia. CONCLUSION: Maternal IgG anti-A/-B titres contribute to the prediction of risk of severe hyperbilirubinaemia in ABO-incompatible neonates, in addition to blood-grouping and direct antiglobulin-testing, especially following early discharge after delivery.