Nationwide lung function monitoring from infancy in newborn-screened children with cystic fibrosis.

Background: Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor. Methods: This was a nationwide observational cohort study (2018-2021) using data collected as part of the routine clinical surveillance programme (including MBW and monthly endo-laryngeal suction sampling for bacterial pathogens) in children born after implementation of newborn screening for CF (May 2016). Lumacaftor/ivacaftor commenced from age 2 years in children homozygous for F508del. Ventilation distribution efficiency (VDE), recently described to have advantages over lung clearance index (LCI), was reported as the primary MBW outcome after z-score calculations based on published reference data. Mixed effect linear regression models were the main statistical analyses performed in this study. Results: 59 children, aged 2-45 months, contributed with 211 MBW occasions (median (interquartile range (IQR)) 3 (2-5) MBW occasions per child) with a median (IQR) follow-up time of 10.8 (5.2-22.3) months. An overall mean annual deterioration rate of -0.50 (95% CI -0.78- -0.22) z-VDE was observed, starting from an estimated mean z-VDE of -1.68 (95% CI -2.15- -1.22) at age 0.0 years (intercept). Pseudomonas aeruginosa "ever" (n=14, MBWs 50) had a significantly worse z-VDE trajectory versus P. aeruginosa "never" (mean difference 0.53 (95% CI 0.16-0.89) per year; p=0.0047) and lumacaftor/ivacaftor treatment (n=22, MBWs 46) significantly improved the trajectory of z-VDE (mean difference 1.72 (95% CI 0.79-2.66) per year; p=0.0004), leading to a stable mean z-VDE trajectory after start of treatment. Conclusions: Infants and toddlers with CF demonstrated progressive deterioration in z-VDE over the first years of life. P. aeruginosa isolation "ever" was associated with an accelerated deterioration in lung function, while lumacaftor/ivacaftor therapy significantly improved and stabilised the trajectory.

Cryotherapy in the paediatric airway: Indications, success and safety.

BACKGROUND AND OBJECTIVE: Cryotherapy in interventional bronchoscopy is a new treatment modality, which has recently been made available for the paediatric airway. Lack of experience and safety concerns have led to hesitant adaptation. The aim of this study was to assess indications, success rates and complications of airway cryotherapy in children. METHODS: Bronchoscopists from medical centre performing cryotherapy in patients between 0 and 18 years were invited to participate in a prospective study based on an online questionnaire. Patient and participant data were collected between June 2020 and June 2021. RESULTS: A total of 69 cryotherapy procedures were performed in 57 patients a for three main indications: Biopsy (30), restoration of airway patency (23) and foreign body aspiration (16). The overall success rate was 93%, the remaining 7% were performed for foreign body removal and required a switch of technique. Restoration of airway patency was successfully applied in various pathologies, including mucus plugs, bronchial casts and post traumatic stenosis. The diagnostic yield of transbronchial biopsies was 96%. No severe complications were encountered; one pneumothorax following a cryobiopsy required a chest drain for 48 h. No child was admitted to intensive care or died from a procedural complication. CONCLUSION: In this largest paediatric case collection to date, cryotherapy was safe and carried a high success rate. Cryobiopsy compares favourably to the widely used forceps biopsy and could replace it in the future. Paediatric bronchoscopists are encouraged to add cryotherapy to their armamentarium of airway interventions.

Validation of nasal tracheal aspiration in children with lung disease.

BACKGROUND: Nasal tracheal aspiration (NTA) is a frequently used diagnostic method to assess of infections in the lower airways. However, the validity of the method has not previously been compared to bronchoalveolar lavage (BAL) in non-intubated children with a lung disease. We hypothesised that NTA performed by health professionals using the nares vocal cord distance to be placed at the entrance of the trachea, will result in same finding of bacteria in the lower airways as the gold standard of BAL. METHODS: In a prospective study, 173 paired samples of NTA and BAL were obtained between June 2016 to August 2018. Samples were collected from all patients undergoing bronchoscopy with spontaneous breathing during general anaesthesia. This study compares the microbiological results from the cultures obtained by investigating complete concordance i.e. identical pathogenic bacteria and coherence i.e. absence or presence of pathogenic bacteria growth between NTA and BAL. RESULTS: Samples were collected in 164 patients, 158 children between 21 days and 18 years of age and six young adults still treated at the paediatric department. The overall similarity (complete agreement) was found in 49% [41-56], sensitivity was 35% [27-45], specificity was 66% [55-76], positive predictive value was 36% [27-46] and negative predictive value was 64% [54-64] concerning complete pathogenic bacteria concordance. If we only considered coherence growth of pathogenic bacteria, similarity was 71% [63-79], sensitivity was 74% [64-81], specificity was 66% [55-76], positive predictive value was 75% [65-82] and negative predictive value was 65% [54-75]. Patients with cystic fibrosis showed a similarity of 88% [73-95], a sensitivity of 92% [76-99], a specificity of 71% [36-95], a positive predictive value of 92% [76-99] and a negative predictive value of 71% [36-95] concerning coherence growth of pathogenic bacteria. CONCLUSION: The study indicates that NTA compared to BAL as the gold standard is not clinically useful to assess positive findings of specific bacteria in the lower airway tract. Statistically significantly increased sensitivity and positive predictive value were found in cystic fibrosis patients concerning coherence growth. The clinical usage of NTA remains important as negative findings are of clinical value. However, BAL continues to be preferred as a significantly superior diagnostic tool.

National multi-centre study found a low prevalence of severely impaired lung function in children and adolescents.

AIM: As no data to our knowledge exist, the aim of the study was to describe the national prevalence and characteristics of Danish children and adolescents with severely impaired lung function. METHODS: We performed a descriptive, cross-sectional Danish multi-centre study. Children and adolescents between 6 and 18 years old demonstrating severely impaired lung function from 2015 to 2018, defined by forced expiratory volume in 1 second (FEV1 ) <60% or who had lung transplantation, were eligible for inclusion. RESULTS: This study included 113 children with a mean age (standard deviation) of 12.9 years (3.5 years). The prevalence of severely impaired lung function was approximately 13 in 100,000. The mean (standard deviation) FEV1 was 46.1% (10.1%) of predicted, and z-score was -4.5 (0.8). The most frequent diagnosis was cystic fibrosis (20.4%), followed by asthma (19.5%) and bronchiolitis obliterans (16.8%), while almost 25% had different elements of airway malformations or non-pulmonary conditions. Two adolescents with cystic fibrosis underwent lung transplantation. CONCLUSION: The estimated prevalence of severely impaired lung function in Danish children and adolescents was low, and extremely, few children underwent lung transplantation. The most frequent diagnosis was cystic fibrosis, while almost 25% had different elements of airway malformations or non-pulmonary conditions, which may require clinical attention.

Contemporary N2 and SF6 multiple breath washout in infants and toddlers with cystic fibrosis.

INTRODUCTION: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF6 MBW commonly viewed as the reference method. The use of N2 MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N2  signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF6 and N2 MBW,corrected-such as tidal volume reduction during N2 washout with pure O2 . METHOD: This was a longitudinal multicenter cohort study. SF6 MBW and N2 MBW were performed prospectively at three CF centers in the same visits on 154 test occasions across 62 children with CF (mean age: 22.7 months). Offline analysis using identical algorithms to the commercially available program provided outcomes of N2,original and N2,corrected for comparison with SF6 MBW. RESULTS: Mean functional residual capacity, FRCN2,corrected was 14.3% lower than FRCN2, original , and 1.0% different from FRCSF6 . Lung clearance index, LCIN2,corrected was 25.2% lower than LCIN2,original , and 7.3% higher than LCISF6 . Mean (SD) tidal volume decreased significantly during N2 MBWcorrected , compared to SF6 MBW (-13.1 ml [-30.7; 4.6], p < 0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCIN2,corrected and LCISF6 . The absolute differences in LCI increased significantly with higher LCISF6 (0.63/LCISF6 ) and (0.23/LCISF6 ), respectively, for N2,original and N2,corrected , but the relative differences were stable across disease severity for N2,corrected , but not for N2,original . CONCLUSION: Only minor residual differences between FRCN2,corrected and FRCSF6 remained to show that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N2 MBW did not affect differences. The corrected N2 MBW can now be used with confidence in young children with CF, although not interchangeably with SF6 .

National, clinical cohort study of late effects among survivors of acute lymphoblastic leukaemia: the ALL-STAR study protocol.

INTRODUCTION: More than 90% of patients diagnosed with childhood acute lymphoblastic leukaemia (ALL) today will survive. However, half of the survivors are expected to experience therapy-related chronic or late occurring adverse effects, reducing quality of life. Insight into underlying risk trajectories is warranted. The aim of this study is to establish a Nordic, national childhood ALL survivor cohort, to be investigated for the total somatic and psychosocial treatment-related burden as well as associated risk factors, allowing subsequent linkage to nation-wide public health registers. METHODS AND ANALYSIS: This population-based observational cohort study includes clinical follow-up of a retrospective childhood ALL survivor cohort (n=475), treated according to a common Nordic ALL protocol during 2008-2018 in Denmark. The study includes matched controls. Primary endpoints are the cumulative incidence and cumulative burden of 197 health conditions, assessed through self-report and proxy-report questionnaires, medical chart validation, and clinical examinations. Secondary endpoints include organ-specific outcome, including cardiovascular and pulmonary function, physical performance, neuropathy, metabolic disturbances, hepatic and pancreatic function, bone health, oral and dental health, kidney function, puberty and fertility, fatigue, and psychosocial outcome. Therapy exposure, acute toxicities, and host genome variants are explored as risk factors. ETHICS AND DISSEMINATION: The study is approved by the Regional Ethics Committee for the Capital Region in Denmark (H-18035090/H-20006359) and by the Danish Data Protection Agency (VD-2018-519). Results will be published in peer-reviewed journals and are expected to guide interventions that will ameliorate the burden of therapy without compromising the chance of cure.

Reversible lung fibrosis in a 6-year-old girl after long term nitrofurantoin treatment.

BACKGROUND: Pulmonary side effects are well known, including lung fibrosis, in elderly patients treated with long-term nitrofurantoin to prevent urinary tract infections and secondary renal injury. However, pulmonary side effects have only been reported rarely in paediatric cases, despite nitrofurantoin being a first line prophylactic treatment of recurrent childhood urinary tract infection. CASE PRESENTATIONS: A 6-year-old girl was admitted to the hospital with dyspnea, general fatigue, loss of appetite and need for nasal oxygen treatment after long-term nitrofurantoin treatment. A computed tomography scan of the chest showed lung fibrosis. A biopsy confirmed this diagnosis. We suspected the fibrosis to be caused by the nitrofurantoin treatment. Thorough examinations reveal no other explanations. Nitrofurantoin was discontinued and the girl was treated with methylprednisolone. After 17 month a new scan and lung function test showed total regression of the lung fibrosis. CONCLUSIONS: This case underlines that risk of severe side effects should be taken in to account before initiation of long-term nitrofurantoin treatment in children.

Lymphocytic interstitial pneumonia and follicular bronchiolitis in children: A registry-based case series.

OBJECTIVES: Pediatric lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis (FB) are poorly characterized lymphoproliferative disorders. We present and quantify demographics, radiological and histopathologic patterns, treatments and their responses, and outcomes in non-HIV-infected children with LIP and FB. METHODS: This structured registry-based study included a retrospective chart review, blinded analysis of imaging studies and lung biopsies, genetic testing, and evaluation of treatments and outcomes. RESULTS: Of the 13 patients (eight females) studied, eight had FB, four had combined LIP/FB, and one had isolated LIP; diagnoses were highly concordant between the pathologists. Most patients became symptomatic during the first 2 years of life, with a mean lag time to diagnosis of 4 years. The most common symptoms were coughing and respiratory infections (11 out of 13 each), dyspnea (10 out of 13), and wheezing (eight out of 13). Autoantibodies were found in eight out of 13 patients. In three patients, disease-causing mutations in the COPA gene were identified. CT revealed hilar lymphadenopathy (five out of 12), ground-glass opacity (eight out of 12), consolidation (five out of 12), and cysts (four out of 13). Systemic steroids as intravenous pulses (11 out of 13) or oral intake (10 out of 13) were the main treatments and showed high response rates of 100% and 90%, respectively. Within the mean observation period of 68 months, all children had chronic courses, eight out of 13 had severe diseases, two died, and one worsened. CONCLUSIONS: Children with LIP/FB have chronic diseases that occurred in early childhood and were commonly associated with immune dysregulation as well as high morbidity and mortality. Early diagnosis and treatment may be crucial to improve the outcome.

Effect of "motivational interviewing" on quality of care measures in screen detected type 2 diabetes patients: a one-year follow-up of an RCT, ADDITION Denmark.

OBJECTIVE. "Motivational interviewing" (MI) has shown to be broadly applicable in the management of behavioural problems and diseases. Only a few studies have evaluated the effect of MI on type 2 diabetes treatment and none has explored the effect of MI on target-driven intensive treatment. METHODS. Patients were cluster-randomized by GPs, who were randomized to training in MI or not. Both groups received training in target-driven intensive treatment of type 2 diabetes. The intervention consisted of a 1½-day residential course in MI with half-day follow-up twice during the first year. Blood samples, case record forms, national registry files, and validated questionnaires from patients were obtained. RESULTS. After one year significantly improved metabolic status measured by HbA1c (p < 0.01) was achieved in both groups. There was no difference between groups. Medication adherence was close to 100% within both treatment groups. GPs in the intervention group did not use more than an average of 1.7 out of three possible MI consultations. CONCLUSION. The study found no effect of MI on metabolic status or on adherence of medication in people with screen detected type 2 diabetes. However, there was a significantly improved metabolic status and excellent medication adherence after one year within both study groups. An explanation may be that GPs in the control group may have taken up core elements of MI, and that GPs trained in MI used less than two out of three planned MI consultations. The five-year follow-up of this study will reveal whether MI has an effect over a longer period.

A controlled study of the short- and long-term effects of a Train the Trainers course.

Objectives This study aimed to establish the longterm effects of a 3-day 'Training for Trainers' course (TTC) on doctors' knowledge, teaching behaviour and clinical learning climate. Methods The study was designed as an intervention study with pre-, post- and long-term measurements. The intervention group (I-group) included 118 doctors from the departments of internal medicine and orthopaedic surgery at one university hospital. The control group (C-group) consisted of 125 doctors from the corresponding departments at another university hospital. Gains in knowledge about teaching skills were assessed by a written test. Teaching behaviour and learning climate were evaluated by questionnaires. Results In the I-group, 98.4% of doctors, both specialists and trainees, participated in a TTC. Response rates on the written test varied from 90% at baseline to 70% at 6 months after the intervention. Knowledge about teaching skills increased in the I-group by 25% after the TTC and was sustained at 6 months. Questionnaire response rates varied from 98.4% at baseline to 84.8% at 6 months. Post-course, the teaching behaviour of the I-group significantly changed and its learning climate improved compared with the C-group. Scores for use of feedback and supervision in the I-group increased from 4-5 to 6-7 (maximum score = 9). This was significantly higher than in the C-group. Conclusions A 3-day residential TTC has a significant impact in terms of gains of knowledge concerning teaching skills, teaching behaviour and learning climate after 6 months. The positive effects demonstrated in this study were rooted in both the specialists and trainees who attended the course.