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BACKGROUND: In cystic fibrosis (CF), renal base excretion is impaired. Accordingly, challenged urine bicarbonate excretion may be an in vivo biomarker of cystic fibrosis transmembrane conductance regulator (CFTR) function.OBJECTIVE: To evaluate the association between challenged bicarbonate excretion and clinical characteristics at baseline, quantify the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor-induced changes of challenged bicarbonate excretion after 6 months of treatment, and characterize the intraindividual variation in healthy adults.DESIGN: Prospective observational study.SETTING: Cystic fibrosis clinic, Aarhus University Hospital, Denmark.PATIENTS: Fifty adult patients with CF starting CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor between May 2020 and June 2021.MEASUREMENTS: Quantification of urine bicarbonate excretion after an acute oral sodium bicarbonate challenge before and 6 months after elexacaftor/tezacaftor/ivacaftor treatment.RESULTS: At baseline, challenged urine bicarbonate excretion was associated with several CF disease characteristics. Bicarbonate excretion was higher in patients with residual function mutations. A higher bicarbonate excretion was associated with better lung function, pancreatic sufficiency, and lower relative risk for chronic pseudomonas infections. Elexacaftor/tezacaftor/ivacaftor treatment increased bicarbonate excretion by 3.9 mmol/3 h (95% CI, 1.6 to 6.1 mmol/3 h), reaching about 70% of that seen in healthy control participants. In healthy control participants, individual bicarbonate excretion at each visit correlated with the individual mean bicarbonate excretion. The median coefficient of variation was 31%.LIMITATION: Single-center study without a placebo-controlled group.CONCLUSION: Although further studies are needed to address the performance and sensitivity of this approach, this early-stage evaluation shows that challenged urine bicarbonate excretion may offer a new, simple, and safe quantification of CFTR function and the extent of its pharmacologic improvement. Elexacaftor/tezacaftor/ivacaftor partially restores renal CFTR function in patients with CF, likely resulting in decreased risk for electrolyte disorders and metabolic alkalosis.PRIMARY FUNDING SOURCE: Innovation Fund Denmark.

Background: Several studies have assessed safety and efficacy outcomes for lumacaftor/ivacaftor therapy. We report on lumacaftor/ivacaftor's impact on lung function, physical performance, and health-related quality of life (HRQOL) in a subpopulation of Danish people with Cystic Fibrosis (CF; PWCF) with advanced pulmonary disease who would not fulfill inclusion criteria for these studies. Methods: This follow-up study examined lumacaftor/ivacaftor's effect in a highly selected CF population. Inclusion criteria included low percent predicted forced expiratory volume in one second (ppFEV1), fast deteriorating ppFEV1, low body mass index (BMI), and difficult-to-treat infections. Primary endpoints included change in ppFEV1 slope, cardiopulmonary exercise testing (CPET), and all domains of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Secondary outcomes included change in ppFEV1, BMI Z-score, and sweat chloride concentration. Results: A total of 21 patients homozygous for the F508del mutation and a median ppFEV1 of 38.7 were included. We found significant improvements in ppFEV1 (+4.2 p 1 after 3, 6, 9, and 12 months of treatment compared to baseline), ppFEV1 slope (+6.84 ppFEV1/year between the year before and the year after treatment initiation; p =.02), and saturation at CPET initiation (+1.4%, p

Background: Cystic fibrosis related diabetes (CFRD) has implications for morbidity and mortality with several risk factors identified. We studied the epidemiology of CFRD in the large dataset of the European Cystic Fibrosis Society Patient registry. Methods: Data on CF patients were investigated for the prevalence of CFRD as well as for any association with suggested risk factors and effects. Results: CFRD increased by approximately ten percentage points every decade from ten years of age. Prevalence was higher in females in the younger age groups. CFRD was associated with severe CF genotypes (OR = 3.11, 95%CI: 2.77–3.48), pancreatic insufficiency (OR = 1.46, 95%CI: 1.39–1.53) and female gender (OR = 1.28, 95%CI: 1.21–1.34). Patients with CFRD had higher odds of being chronically infected with Pseudomonas aeruginosa, Burkholderia cepacia complex and Stenotrophomonas maltophilia than patients without CFRD, higher odds of having FEV1% of predicted

RATIONAL: People with cystic fibrosis carrying residual function (RF) mutations are considered to have a mild disease course. This may influence caregivers and patients on how intensive the treatments should be.OBJECTIVES: Characterize disease severity of patients carrying RF mutations, using the European CF Society Patient Registry (ECFSPR) data.METHODS: Demographic, clinical characteristics, lung function and death probability of patients carrying at least one RF mutation were analyzed and compared to patients homozygous to minimal function mutations (MF).MAIN RESULTS: Of the 44,594 eligible patients (median age 19.5 years, IQR 10-29.8), 6,636 (14.6%) carried RF mutations, and 37,958 (85.1%) MF mutations. Patients carrying RF mutations were older, diagnosed at a later age, had lower sweat chloride at diagnosis and better FEV1pp at each age group. However, their FEV1pp declined with age and rates of chronic Pseudomonas aeruginosa increased with age. A significant number of patients with RF had FEV1pp similar to patients with MF at each age group. 4.5% of RF patients were treated with oxygen and 2.61% had a lung transplant. With increasing age, 26.6% of RF patients were treated with pancreatic enzymes associated with a more severe lung disease. RF patients had shortened life spans, with mortality starting around the age of 20 years.CONCLUSIONS: Patients carrying an RF mutations experience a decline of pulmonary function with age, leading to life-shortening. Standard of care therapies and augmenting CFTR function may improve their survival and quality of life.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes.MethodsIn 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.ResultsUp 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).ConclusionSARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s

BACKGROUND: Since 2015, when the first cystic fibrosis transmembrane conductance regulator (CFTR) modulators were approved for people with cystic fibrosis (CF) homozygous for F508del-CFTR, studies have shown improved lung function after initiation of the treatment and patients experience improved physical capacity. The aim of this study was to investigate change in exercise capacity after initiation of Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor treatment (LUM/IVA, TEZ/IVA).METHODS: We performed a single group prospective observational cohort study with follow-up at six and 12 months. The study examined change in exercise capacity in people with CF initiating treatment with LUM/IVA and TEZ/IVA, measured by cardio-pulmonary exercise testing (CPET). Inclusion criteria were people with CF homozygous for F508del-CFTR aged 12 years or older eligible for LUM/IVA and TEZ/IVA treatment from June 2017 until June 2019. Primary outcomes were change in VO 2peak and maximal workload. Secondary outcomes were change in muscle strength, muscle power and body composition in a subgroup of the study population. RESULTS: A total of 91 patients were included in the analysis. The mean change in VO 2peak and VO 2peak divided by body weight from baseline to 12-months follow-up was 145.7 (91.2;200.2) ml/min and 1.07 (95% CI 0.19;1.95) ml/min/kg, respectively. The mean change in maximal workload between baseline and 12 months was 14.2 Watt (95% CI 9.1;19.2). All improvements in exercise capacity were statistically significant. CONCLUSIONS: Patients in this study improved their exercise capacity by a statistically significant increase in VO 2peak and maximal workload 12 months after initiation of treatment with LUM/IVA and TEZ/IVA.

Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/10 0 0 pwCF. Incidence was higher in lung-transplanted patients (n = 23) versus non transplanted patients (n = 107) (8.43 versus 2.36 cases/10 0 0). Incidence was higher in pwCF versus the age-matched general population in the age groups < 15, 15-24, and 25-49 years (p < 0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p = 0.133). Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Paediatric early warning score (PEWS) assessment tools can assist healthcare providers in the timely detection and recognition of subtle patient condition changes signalling clinical deterioration. However, PEWS tools instrument data are only as reliable and accurate as the caregivers who obtain and document the parameters.The aim of this study is to evaluate inter-rater reliability among nurses using PEWS systems.The study was carried out in five paediatrics departments in the Central Denmark Region. Inter-rater reliability was investigated through parallel observations. A total of 108 children and 69 nurses participated. Two nurses simultaneously performed a PEWS assessment on the same patient. Before the assessment, the two participating nurses drew lots to decide who would be the active observer. Intraclass correlation coefficient, Fleiss' κ and Bland-Altman limits of agreement were used to determine inter-rater reliability.The intraclass correlation coefficients for the aggregated PEWS score of the two PEWS models were 0.98 and 0.95, respectively. The κ value on the individual PEWS measurements ranged from 0.70 to 1.0, indicating good to very good agreement. The nurses assigned the exact same aggregated score for both PEWS models in 76% of the cases. In 98% of the PEWS assessments, the aggregated PEWS scores assigned by the nurses were equal to or below 1 point in both models.The study showed good to very good inter-rater reliability in the two PEWS models used in the Central Denmark Region.

BackgroundPaediatric track and trigger tools (PTTTs) based on vital parameters have been implemented in hospitals worldwide to help healthcare professionals identify signs of critical illness and incipient deterioration in hospitalised children. It has been documented that nurses do not use PTTT as intended, but deviate from PTTT protocols because, in some situations, PTTT observations make little sense to them. The present study aimed to reach consensus on whether automatically generated PTTT scores that are higher than deemed reasonable by healthcare professionals according to their professional experience and clinical expertise may be downgraded.MethodsA two-round modified Delphi technique was used to explore consensus on 14 patient cases for hospitalised children with a high PTTT score that did not raise concerns by systematically collating questionnaire responses. Participants rated their level of agreement on a 9-point Likert scale. IQR and median were calculated for each case.FindingsA total of 221 participants completed round 1 and 101 participants completed round 2. Across the two rounds, majority of the participants were from paediatric departments, nurses and women. In round 1, consensus on inclusion was reached on 2 of the 14 cases. In round 2, consensus was reached on one additional patient case. Three of the 11 non-consensus cases remaining after rounds 1 and 2 were included by the research group based on predefined criteria.ConclusionIn conclusion, a consensus opinion was achieved on six patient cases where the child had a high PTTT score but where the healthcare professionals were not as concerned as indicated by the PTTT score.

Background Monitoring changes in the epidemiology of cystic fibrosis (CF) pathogens is essential for clinical research, quality improvement, and clinical management. Methods We analyzed data reported to the European Cystic Fibrosis Society Patient Registry (ECFSPR) from 2011 to 2016 to determine the overall and the age-specific annual prevalence and incidence of selected CF pathogens and their trends during these years. The ECFSPR collects data on three chronic infections: Pseudomonas aeruginosa (PsA), Burkholderia cepacia complex Species (BCC) and Staphylococcus aureus (SA), as well as on the occurrence of non-tuberculous mycobacteria (NTM) and Stenotrophomonas maltophilia (SM). The same analyses were performed for different country groups, according to their gross national income (GNI). Results The pathogens with the highest prevalence were SA and PsA, with prevalence, in 2016, equal to 38.3% and 29.8% respectively, followed by SM (8.1%). The pathogens with the lowest prevalence were NTM (3.3%) and BCC (3.1%). The overall prevalence and incidence significantly decreased for PsA; they also decreased for BCC, while they increased significantly for SA. The overall prevalence of NTM and SM increased significantly. The most considerable prevalence changes were observed for PsA, which decreased across all income country groups and all age strata (with the exception of 0–1 years) The prevalence and incidence of pathogens differed significantly according to GNI. Conclusions The epidemiology of CF pathogens in Europe has changed; epidemiologic data differ significantly among countries with different socio-economic status. The causes of these observations are multifactorial and include improvements in clinical care and infection control.

BACKGROUND: In Denmark, newborn screening (NBS) for cystic fibrosis (CF) was introduced on 1 May 2016. The implementation and results from the first 2 years of the national newborn CF screening program are presented.METHODS: The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed.RESULTS: Of 126 522 newborn infants 126 338 were tested (99.85%), and 4730 samples (3.7%) were assessed for CFTR mutations. Twenty-six infants were screen-positive and referred for diagnostic follow-up of whom 22 were confirmed to have a CF diagnosis, four had one known and one CFTR allele with unknown pathogenicity, classified as cystic fibrosis screening positive inconclusive diagnosis (CFSPID), PPV 84.6%. One of the four children classified as CFSPID was later found to carry the two identified CFTR variants in cis and was reclassified as a carrier of CF. We found two false negatives; one exhibited an IRT level above the 50 ng/mL cutoff but was below the 145 ng/mL very high cutoff and with no F508del mutation present. The second false-negative fell below the 50 ng/mL IRT cutoff but was diagnosed shortly after birth on the basis of meconium ileus. Screening sensitivity, 91.7%. Two hundred thirty-two children were identified as carriers of CF, which is twofold above the estimated annual number of carriers. All but one carrier were heterozygous for the F508del CFTR mutation. Sixteen percent of the sequenced samples revealed rare CFTR variants, which were classified as nonpathogenic in relation to CF.CONCLUSIONS: During the first 2 years of NBS CF screening in Denmark, we identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis. CFSPID accounted for only a small minority, despite comprehensive CFTR sequencing, whereas more carriers than initially expected were identified.

Background: Standardized patient registries provide a unique basis to get insight into cystic fibrosis (CF)-related diabetes (CFRD), the most common comorbidity in CF. Methods: A total of 3853 CFRD patients from the European CF Society Patient Registry (ECFSPR) and 752 from the German/Austrian diabetes prospective follow-up (diabetes patienten verlaufsdokumentation [DPV]) were studied. To adjust for age and sex, multivariable regression was used (SAS 9.4). Results: DPV subjects were younger (26.5 [20.2-32.6] vs 28.3 [21.7-36.0] years, P < 0.001) and more often female (59.6 vs 50.9%, P < 0.001). In both registries, F508del homozygotes were most frequent, with higher proportion in DPV (80.9 vs 57.8%, P = 0.003). After adjustment, lung-transplantation (LTX) was more common in ECFSPR (18.9 vs 4.9%, P < 0.001), although duration since LTX (4.8 ± 0.2 vs 5.5 ± 0.7 years, P = 0.33) did not differ. In DPV patients without LTX, a lower BMI (19.6 ± 0.1 vs 21.0 ± 0.1 kg/m 2 , P < 0.001), higher proportion of underweight (41.2 vs 20.2%, P < 0.001) and a tendency towards worse lung function (%FEV 1 : 42.3 ± 4.2 vs 48.3 ± 0.5%, P = 0.16) were observed. Conclusions: Between both registries, demographic and clinical differences of CFRD were present. Besides different kind of data sources, diverse treatment structures between countries may play a role. The results may further indicate a more serious illness in patients treated in specialized diabetes clinics, documenting their data in DPV.

AIM: Denmark has a high standard cystic fibrosis care. However, newborn screening was not implemented until 2016. This article describes the clinical status of cystic fibrosis patients at time of diagnosis prior to newborn screening.METHODS: Patients diagnosed with cystic fibrosis in Denmark in 2010-2014 were reviewed using the Danish Cystic Fibrosis Registry as well as patient files. Parameters collected were age at diagnosis, gender, weight, height, forced expiratory volume at 1 second, cystic fibrosis transmembrane regulator-genotype, lung bacteriology at diagnosis and previous diagnoses.RESULTS: A total of 63 patients were diagnosed in the study period. The most typical pre-cystic fibrosis diagnoses were asthma and pneumonia. The median age at diagnosis was 1.4 years for the pancreatic insufficient and 27.3 years for the pancreatic sufficient patients. Of the pancreatic insufficient patients, 21% had moderate to severe malnutrition with BMI below minus 2 SD and 40% had moderate to severe stunting with height below minus 2 SD.CONCLUSION: Diagnosis was delayed considerably compared to diagnosis by newborn screening in other countries. Many cystic fibrosis patients diagnosed due to clinical symptoms were moderately to severely underweight or stunted at diagnosis.

Few studies have described the various reasons for unplanned transfer to a higher level of care due to clinical deterioration and the clinical profile of those paediatric patients. However, an understanding of the nature of illness is important to patient safety. This study aimed to describe the frequency and clinical characteristics of children who experience unplanned transfer to a higher level of care due to clinical deterioration. A retrospective, descriptive registry study design was used. Of the 92 paediatric patients included, 69% ( n = 64) was male. The median age was 2.1 years (interquartile range 0.4–6.9) with 33% being infants under 1 year. The highest number (61.3%) of transfers occurred between 8 and 16 hours. In the 24 hours leading up to a transfer due to clinical deterioration, 15 patients had no vital parameters documented, and 77 patients had least one vital parameter measured. Physiological abnormalities were present in 19 (37.7%) of the 77 patients where vital parameters were documented. This study provides essential baseline data to inform further research to improve care and treatment for critically ill children in paediatric wards. This study’s findings suggest reporting of vital parameters is incomplete and infrequent.

Purpose Pediatric early warning systems (PEWS) are used to detect clinical deterioration in hospitalized children. Few PEWSs have been validated in multicenter studies and the performance in many single-center studies varies. We wanted to compare two PEWS in a multicenter study. Design and Methods Randomized multicenter unblinded trial conducted at all pediatric departments in the Central Denmark Region. A random sample of 16,213 pediatric patients (31,337 admissions) were enrolled from November 2014 to March 2017. Patients were randomized to The Bedside PEWS or CDR PEWS. The primary outcome was the sum of hospitalized children experiencing in-hospital clinical deterioration requiring transfer to a higher level of care. Results Of the 21,077 pediatric patients who met the inclusion criteria, 16,213 (from 31,337 admissions) were enrolled. 22 unplanned transfers to a higher level of care were identified: 14 in The Bedside PEWS group and 8 in the CDR PEWS group, a non-statistical difference (P = 0.20). No significant difference in predicting unplanned transfer to a higher level of care (P = 0.78) were detected and no significant difference was observed in the secondary outcomes. Conclusions The CDR PEWS prevents as many critical events as The Bedside PEWS. Shorter median time to PEWS reassessment when CDR PEWS was used and fewer reassessments being done to late could reflect that the CDR PEWS was more acceptable to staff. Practice Implications The results from this study should be interpreted with caution as very few patients experiencing clinical deterioration and further studies should also focus on challenges trying to evaluate PEWS.

PURPOSE: Pediatric early warning score (PEWS) systems are used to monitor pediatric patients' vital signs and facilitate the treatment of patients at risk of deteriorating. The aim of this study was to gain knowledge about nurses' experiences with PEWS and to highlight factors facilitating and impeding the use of PEWS tools in clinical practice.DESIGN AND METHODS: An exploratory qualitative design was chosen using focus group interviews to gain a deeper understanding of nurses' experiences with PEWS. A total of five focus group interviews were conducted at three hospitals, and a qualitative meaning condensation analysis as described by Kvale and Brinkmann was performed.RESULTS: Seven themes were identified, including i) lack of interdisciplinary awareness, ii) clinical judgment and PEWS-a multi-faceted approach, iii) PEWS supports a professional language, iv) monitoring the patient's - a challenge, v) PEWS helps to visualize the need for escalating care, vi) an inflexible and challenging tool, and vii) supportive tools enhance the nurses' experiences of PEWS positively.CONCLUSIONS: Our findings suggest that attention should be given to nurses' perceptions of how both clinical judgment and PEWS should be seen as essential in providing nurses with information about the patients' conditions. If not, the risk of failing to recognize patients' deteriorating conditions will remain as this can have an impeding influence on nurses' use of PEWS. From the nurses' perspective, medical doctors seemed unaware of their role in using PEWS.

Background Patients’ evolving critical illness can be predicted and prevented. However, failure to identify the signs of critical illness and subsequent lack of appropriate action for patients developing acute and critical illness remain a problem. Challenges in assessing whether a child is critically ill may be due to children’s often uncharacteristic symptoms of serious illness. Children may seem relatively unaffected until shortly before circulatory and respiratory failure and cardiac arrest. The Bedside Paediatric Early Warning Score has been validated in a large multinational study and is used in two regions in Denmark. However, healthcare professionals experience difficulties in relation to measuring blood pressure and to the lack of assessment of children’s level of consciousness. In addition, is it noteworthy that in 23,288-hour studies, all seven items of the Bedside Paediatric Early Warning Score were recorded in only 5.1% of patients. This trial aims to compare two Paediatric Early Warning Score (PEWS) models to identify the better model for identifying acutely and critically ill children. The hypothesis is that the Central Denmark Region PEWS model is superior to the Bedside PEWS in terms of reducing unplanned transfers to intensive care or transfers from regional hospitals to the university hospital among already hospitalised children. Methods/design This is a multicentre, randomised, controlled clinical trial where children are allocated to one of two different PEWS models. The study involves all paediatric departments and one emergency department in the Central Denmark Region. The primary outcome is unplanned transfer to the paediatric intensive care unit or transfer from regional hospitals to the university hospital. Based on preliminary data, 14,000 children should be included to gain a power of 80% (with a 5% significance level) and to detect a clinically significant difference of 30% of unplanned transfers to intensive care or from regional hospitals to the paediatric department at the university department. A safety interim analysis will be performed after inclusion of 7000 patients. Discussion This is the first randomised trial to investigate two different PEWS models. This study demonstrates the safety and effectiveness of a new PEWS model and contributes to knowledge of hospitalised children’s clinical deterioration. Trial registration ClinicalTrials.gov, NCT02433327. Registered on 27 April 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2011-7) contains supplementary material, which is available to authorized users.

Staphylococcus aureus is the most commonly isolated pathogen in respiratory tract secretions from young patients with cystic fibrosis (CF), and several treatment strategies are used to control the infection. However, it is not known whether intensified treatment with antimicrobial agents causes eradication of S. aureus clones. We retrospectively determined the impact of intravenous (IV) antimicrobial agents on the suppression and eradication of S. aureus clones. One thousand and sixty-one S. aureus isolates cultured from 2526 samples from 130 CF patients during a 2-year study period were subjected to spa typing. Intervals between positive samples and the occurrence of clone replacements were calculated in relation to courses of IV antimicrobial agents. Of 65 patients chronically infected with S. aureus , 37 received 139 courses of IV antimicrobial agents with activity against S. aureus (mean duration, 15 days; range, 6–31 days). Administration of IV antibiotics increased the time to the next sample with growth of S. aureus: the mean interval between two positive samples was 68 days if IV treatment had been administered, in contrast to 49 days if no IV treatment had been administered (p 0.003). When S. aureus recurred in sputum after IV treatment, the isolate belonged to a different clone in 33 of 114 (29%) intervals, in comparison with 68 of 232 (29%) intervals where IV treatment had not been prescribed (OR 0.98, 95% CI 0.60–1.61). In conclusion, we show that 2 weeks of IV antimicrobial treatment can significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.

Objectives In this nationwide retrospective study, we analysed species distribution, antimicrobial susceptibility and time to next occurrence of Achromobacter in Danish cystic fibrosis (CF) patients from 2000 to 2011. Methods Thirty-four primary isolates were identified to species level and subjected to antimicrobial susceptibility testing. Effectiveness of early antimicrobial treatment was assessed by a Kaplan–Meier estimation of time to recurrence. Results Achromobacter xylosoxidans accounted for 13 (38%) of the isolates, and an unnamed species accounted for 11 (32%) of the isolates. Meropenem, piperacillin–tazobactam and trimethoprim–sulfamethoxazole were highly active against chemotherapy-naive Achromobacter, while ceftazidime, colistin and tobramycin were judged adequate for inhalation therapy. Fifty-five percent of 25 patients treated with inhaled ceftazidime, colistin, or tobramycin remained free of Achromobacter three years after acquisition, in contrast to 17% of 22 patients who did not receive inhaled antibiotics (P Conclusions Early treatment with inhaled antibiotics may prevent or postpone chronic infection with Achromobacter in CF patients.

Theme: Patient safety Background: Paediatric Early Warning Score (PEWS) tools can assist healthcare providers in the rapid detection and recognition of changes in patient condition. In the central Denmark region two different PEWS tools tested in large-scale RCT study. However, data from PEWS instruments are only as reliable and accurate as the caregiver who obtains and documents the parameters.AIM: The purpose was to evaluate the inter-rater agreement among nurses using the PEWS systems.DESIGN: The study was conducted in five paediatrics departments. Inter-observer reliability was investigated through simultaneous blinded PEWS assessment on the same patients by two nurses. Fleiss' kappa was utilized to determine the level of agreement among the raters.CONCLUSION: With a paucity of published reliability testing studies, this research attempts to address identified research gaps and will thus inform nursing practice.

Theme: Intensive care Background: There has been an increased number of critically ill patients admitted to paediatric departments. Only a few studies have described the various causes of unplanned admission to paediatric intensive care units (PICU) due to clinical deterioration. However, an understanding of the nature of illness is important to patient safety.PURPOSE: This study described the frequency, clinical characteristics and outcomes of children who experience unplanned admission to a PICU due to clinical deterioration.METHODS: A registry retrospective descriptive study describing and exploring life-threatening situations leading to unexpected transfers to PICU in hospitalised children. The study includes all paediatric departments in the Central Denmark Region.PERSPECTIVE: This study will provide knowledge to assist the research efforts to identify and improve the management of critical ill children in paediatric wards.

Non-influenzae commensal Haemophilus species of low pathogenicity may be difficult to discriminate from Haemophilus influenzae. We investigated the level of misidentifications in respiratory specimens from cystic fibrosis patients and evaluated the colonisation dynamics of genuine H. influenzae isolates. One hundred and ninety-two presumptive H. influenzae isolates were re-examined by assessment of marker genes sodC and fucK, and isolates with aberrant genotypes were subjected to multilocus sequence typing. Misidentifications (3%) were mainly caused by failure to identify porphyrin-synthesising strains, and only a single strain (0.5%) could be classified as ‘non-haemolytic Haemophilus haemolyticus’. Sequential isolates of confirmed H. influenzae isolates from individual patients were typed by pulsed-field gel electrophoresis. Despite the routine prescription of antimicrobial therapy, the majority of H. influenzae isolates were identical with at least one of the strains cultured from the two preceding positive samples from the same patient.

It was hypothesised that increased exercise capacity is related to improved quality of life (QoL) in patients with cystic fibrosis (CF). A 12-week individually tailored unsupervised aerobic exercise programme was offered to 42 patients with CF. At the start and at the end of the exercise programme, data on QoL, current exercise habits and preferences, anthropometric data, exercise test, and lung function test were collected. Adherence was observed by a heart rate (HR) monitor. A total of 24 patients accepted to be enrolled in the exercise programme and 14 completed the programme. Another 14 patients declined to be enrolled in the exercise programme but completed the Cystic Fibrosis Questionnaire for Adolescents and Adults (CFQ-R 14+). Four patients did not want to participate at all. The 14 patients completing the exercise programme had a significantly increased VO(2max), but they showed no significant change in total QoL score. However, the scores in the domain of treatment burden and emotional functioning increased significantly. There was no significant difference in QoL and lung function between patients participating in the exercise programme (n = 24) and non-participants (n = 14). A 12-week individually tailored unsupervised aerobic exercise programme where HR monitors were used significantly affected VO(2max). Improvement in QoL could not be demonstrated in this study. It was hypothesised that increased exercise capacity is related to improved quality of life (QoL) in patients with cystic fibrosis (CF). A 12-week individually tailored unsupervised aerobic exercise programme was offered to 42 patients with CF. At the start and at the end of the exercise programme, data on QoL, current exercise habits and preferences, anthropometric data, exercise test, and lung function test were collected. Adherence was observed by a heart rate (HR) monitor. A total of 24 patients accepted to be enrolled in the exercise programme and 14 completed the programme. Another 14 patients declined to be enrolled in the exercise programme but completed the Cystic Fibrosis Questionnaire for Adolescents and Adults (CFQ-R 14+). Four patients did not want to participate at all. The 14 patients completing the exercise programme had a significantly increased VO(2max), but they showed no significant change in total QoL score. However, the scores in the domain of treatment burden and emotional functioning increased significantly. There was no significant difference in QoL and lung function between patients participating in the exercise programme (n = 24) and non-participants (n = 14). A 12-week individually tailored unsupervised aerobic exercise programme where HR monitors were used significantly affected VO(2max). Improvement in QoL could not be demonstrated in this study.

Aims: To explore whether gender differences in the Scandinavian Cystic Fibrosis (CF) patients exist in the areas of key clinical parameters, complications, and medication. Methods: Cross-sectional data on 890 (416 female) pancreatic insufficient CF patients were evaluated regarding chronic infection, body mass index, lung function, medication, and diabetes, as well as data of Pseudomonas infection status, antibiotic treatment and hospitalization from 1-year follow-up. Results: We found no differences in lung function, body mass index, or frequency of diabetes. The adult group consisted of more males than females (208:168). We found no significant difference in prevalence of chronic Pseudomonas aeruginosa infection, but during the follow-up the incidence of new chronic infection was higher in adult females (10/33 vs. 4/56). Females had higher prevalence of Burkholderia infection (21/416 vs. 11/474). Adult females had more days on intravenous antibiotics (median 39 vs. 26 days/year), and days in hospital (median 2 vs. 0 days/year). More adult females received inhaled and oral steroids. In the pediatric cohort, females were treated more often with macrolides as an anti-inflammatory agent. Conclusion: We found no gender difference in key clinical parameters in our CF population. However, our study showed a higher risk of Pseudomonas and Burkholderia infection among the female patients. Additionally, we found that female patients require more intensified treatment regarding antibiotics, macrolides, steroids and days of hospitalization, indicating a true female disadvantage even with modern aggressive treatment. The finding of more males than females in the adult population suggesting a male advantage, warrants a mortality study. Pediatr Pulmonol. 2010; 45:959-965. (C) 2010 Wiley-Liss, Inc.

Udgivelsesdato: 2010-May-8 BACKGROUND: Cystic fibrosis (CF) affects the lungs causing infections and inflammation. Surfactant protein D (SP-D) is an innate defense lectin primarily secreted in the lungs. We investigated the influence of the SP-D Met11Thr polymorphism on CF lung function; and serum SP-D as a marker for CF lung disease. METHODS: For 107 CF patients (73 children, and 34 adults) serum SP-D and SP-D Met11Thr genotype were available. Leukocyte count was obtained for a subset of patients. Lung function was measured as forced expiratory volume in one second (FEV-1). RESULTS: Serum SP-D was increased in CF patients compared to healthy controls, positively correlated to leukocyte count, and negatively correlated to FEV-1. We found no correlation between SP-D Met11Thr genotype and FEV-1, and we found corresponding genotype frequencies in CF patients and in healthy controls. CONCLUSION: Serum SP-D in CF patients was increased in parallel with leukocyte count and with reduced FEV-1 and may constitute an alternative biomarker for lung disease, in the clinical setting and in research.

Background The co-morbidity of cystic fibrosis (CF) and celiac disease (CD) has been reported sporadically since the 1960s. To our knowledge, this is the first time a systematic screening is performed in a large cohort of CF patients. Methods Transglutaminase-IgA (TGA), endomysium-IgA (EMA) and total IgA in serum were measured in 790 CF patients (48% females, 86% with pancreatic insufficiency). Six patients were diagnosed with CD prior to the study, all receiving a gluten-free diet. Patients with elevated TGA (>50 Units/mL) and a positive EMA test were offered a gastroscopy obtaining mucosal biopsies from the duodenum. Results Four new cases of CD were diagnosed. Two additional patients had positive serological tests, but normal biopsies. In total, 10 cases of CD (1.2%, 1:83) indicate a prevalence rate about three times higher than the general prevalence of CD in Norway and Sweden. No CD patients were detected in the Danish CF cohort. Patients diagnosed with untreated CD reported symptoms typical of both CF and CD (poor weight gain, loose and/or fatty stools, fatigue, irritability, abdominal pain). They improved after introduction of a gluten-free diet. Conclusions Systematic screening for CD in a Scandinavian cohort of CF patients revealed a higher prevalence of CD than in the general population. Clinical signs of CD are difficult to differentiate from CF with malabsorption, and patients may go undiagnosed for a long time. In a population where CD is common we recommend screening for CD in patients with CF.

The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management.Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management.The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme.

Background To better understand the relative effects of infection with nontuberculous mycobacteria and Gram negative bacteria on lung function decline in cystic fibrosis, we assessed the impact of each infection in a Danish setting. Methods Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. We used a mixed effects model with longitudinally structured correlation, while adjusting for clinically important covariates. Results Infections with a significant impact on rate of decline in %FEV1 were Mycobacterium abscessus complex with − 2.22% points per year (95% CI − 3.21 to − 1.23), Burkholderia cepacia complex − 1.95% (95% CI − 2.51 to − 1.39), Achromobacterxylosoxidans − 1.55% (95% CI − 2.21 to − 0.90), and Pseudomonas aeruginosa − 0.95% (95% CI − 1.24 to − 0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope. Conclusions In a national population we have demonstrated the impact on lung function of each chronic CF pathogen. M. abscessus complex was associated with the worst impact on lung function. Eradication of M. abscessus complex may significantly improve lung function., Graphical abstract Effect on lung function of chronic infection from onset to end stage lung disease in Danish cystic fibrosis patients.

Background To determine complications during outpatient parenteral antimicrobial therapy (OPAT) administrated through a peripheral venous line, PICC-line or PORT-A-CATH (PAC). Methods Catheter related complications in patients with cystic fibrosis during OPAT were identified through a retrospective review of patient files supplemented by an interview. Results In 64 treatment episodes with a peripheral venous line, 51 (79.7 %) used bolus injection and 13 (20.3 %) used infusion pump. 27 out of 51 (53.0 %) bolus injection episodes experienced complications, which required removal. None were observed for infusion pump treatments. The infectious complications requiring removal of peripheral venous line were 9 out of 23 (39.1 %) for the PICC line and 11 out of 26 (42.3 %) for the PAC. No anaphylaxis was observed during the OPAT treatments. Conclusions Our data indicate that using an infusion pump to administer the antibiotic treatment minimized peripheral venous line complications. The frequency of complications leading to removal of the catheter is about the same for PICC-lines and PACs, but the average life-time of the latter is much longer. Allergic reactions are not a major problem. Electronic supplementary material The online version of this article (doi:10.1186/s12879-015-1019-4) contains supplementary material, which is available to authorized users.

Studies should use the Diderichsen approach to unpick the causal chains that link social inequalities and health http://ow.ly/H406C

Respiratory infection is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Chronic Pseudomonas aeruginosa (PA) infections ultimately occur in virtually all patients. It is impossible to eradicate PA when a patient has been chronically colonized. Immunotherapy with specific egg-yolk antibodies (IgY) may be an alternative to antibiotics for the prevention of PA infections. We wanted to determine if treatment with specific IgY can prolong the period between the first and the second PA colonization? And long-term, can the treatment diminish the number of positive PA cultures and postpone the onset of chronic colonization? CF patients gargled daily with an IgY-antibody preparation, purified from eggs of hens immunized with PA bacteria. They were compared to a group of patients who did not gargle with the preparation. Both groups had their first colonization with PA eradicated by antibiotics. The basic treatment was essentially the same in both groups. In the initial study, the period between the first and second colonization with PA was significantly prolonged for the treated vs. the control group (Kaplan-Meier P = 0.015, Breslow test). In the prolonged study, the treated group had only 2.5 sputum cultures positive for PA per 100 months of observation, and none of these patients became chronically colonized with PA. No adverse events were reported. In the control group, 13.7 cultures per 100 months of observation were positive for PA, and 5 (24%) patients became chronically colonized with PA. This feasibility study shows that antipseudomonal IgY has the potential to effectively prevent PA colonization without any severe adverse effects. A phase III study should be initiated.

More than 1900 different mutations in the CFTR gene have been reported. These are grouped into classes according to their effect on the synthesis and/or function of the CFTR protein. CFTR repair therapies that are mutation or mutation class specific are under development. To progress efficiently in the clinical phase of drug development, knowledge of the relative frequency of CFTR mutation classes in different populations is useful. Therefore, we describe the mutation class spectrum in 25,394 subjects with CF from 23 European countries.In 18/23 countries, 80% or more of the patients had at least one class II mutation, explained by F508del being by far the most frequent mutation. Overall 16.4% of European patients had at least one class I mutation but this varied from 3 countries with more than 30% to 4 countries with less than 10% of subjects. Overall only respectively 3.9, 3.3 and 3.0% of European subjects had at least one mutation of classes III, IV and V with again great variability: 14% of Irish patients had at least one class III mutation, 7% of Portuguese patients had at least one class IV mutation, and in 6 countries more than 5% of patients had at least one class V mutation.

Forty-four of 48 Burkholderia cepacia complex strains cultured from Danish cystic fibrosis patients were Burkholderia multivorans , a distribution of species that has not been reported before. Although cases of cross infections were demonstrated, no major epidemic clone was found. The species distribution may represent the sporadic acquisition of bacteria from the environment.

Pulmonary insufficiency is the main cause of death in cystic fibrosis (CF). We analysed forced expiratory volume in 1 s (FEV1) data of 14,732 patients registered in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database in 2007. We used linear and logistic regressions to investigate associations between FEV1 % predicted and clinical outcomes. Body mass index (BMI), chronic infection by Pseudomonas aeruginosa, pancreatic status and CF-related diabetes (CFRD) showed a statistically significant (all p

Patients with cystic fibrosis (CF) often suffer from gastrointestinal (GI) dysfunction including obstructive symptoms, malabsorption and pain, but the underlying pathophysiology remains obscure.To compare GI motility and transit times in CF patients and healthy controls.Ten CF patients (five women, median age 23) with pancreatic insufficiency were studied. Total gastrointestinal transit time (GITT) and segmental colonic transit times (SCTT) were assessed by radiopaque markers. Gastric emptying and small intestinal transit were evaluated using the magnet-based motility tracking system (MTS-1). With each method patients were compared with 16 healthy controls.Basic contraction frequencies of the stomach and small intestine were normal, but the pill reached the cecum after 7 h in only 20% of CF patients while in 88% of controls (p = 0.001). Paradoxically, velocity of the magnetic pill through the upper small intestine tended to be faster in CF patients (median 1.1 cm/min, range 0.7-1.7) compared with controls (median 1.0 cm/min, range 0.6-1.7) (p = 0.09). No statistically significant differences were found in median gastric emptying time (CF: 58 min, range 6-107 vs. healthy: 41 min, range 4-125 (p = 0.24)), GITT (CF: 2 days, range 0.5-3.3 vs. healthy: 1.5 days, range 0.7-2.5 (p = 0.10)), right SCTT (CF: 0.5 day, range 0-1.1 vs. healthy: 0.4 day, range 0-1.0 (p = 0.85)), or left SCTT (CF: 1.0 day, range 0-2.2 vs. healthy 0.6 day, range 0.2-1.2 (p = 0.10)).In spite of normal contraction patterns, overall passage through the small intestine is significantly delayed in CF patients while upper small intestinal transit may be abnormally fast.

BACKGROUND: Forced expiratory volume in 1 s as a percentage of predicted (%FEV1) is a key outcome in cystic fibrosis (CF) and other lung diseases. As people with CF survive for longer periods, new methods are required to understand the way %FEV1 changes over time. An up to date approach for longitudinal modelling of %FEV1 is presented and applied to a unique CF dataset to demonstrate its utility at the clinical and population level.METHODS AND FINDINGS: The Danish CF register contains 70,448 %FEV1 measures on 479 patients seen monthly between 1969 and 2010. The variability in the data is partitioned into three components (between patient, within patient and measurement error) using the empirical variogram. Then a linear mixed effects model is developed to explore factors influencing %FEV1 in this population. Lung function measures are correlated for over 15 years. A baseline %FEV1 value explains 63% of the variability in %FEV1 at 1 year, 40% at 3 years, and about 30% at 5 years. The model output smooths out the short-term variability in %FEV1 (SD 6.3%), aiding clinical interpretation of changes in %FEV1. At the population level significant effects of birth cohort, pancreatic status and Pseudomonas aeruginosa infection status on %FEV1 are shown over time.CONCLUSIONS: This approach provides a more realistic estimate of the %FEV1 trajectory of people with chronic lung disease by acknowledging the imprecision in individual measurements and the correlation structure of repeated measurements on the same individual over time. This method has applications for clinicians in assessing prognosis and the need for treatment intensification, and for use in clinical trials.

Background An increased incidence of Achromobacter xylosoxidans infections has been observed at the Cystic Fibrosis Centre at Aarhus University Hospital, as the proportion of patients colonised with A. xylosoxidans increased from 6 to 10% from 2005 to 2009. Methods Pulsed field gel electrophoresis (PFGE) was used to type isolates of A. xylosoxidans . Results Four patients infected for 2–7years were part of a larger epidemic spread involving both Danish CF centres, while 11 patients carried strains with unique genotypes. Longitudinal analysis of isolates from ten patients with multiple preserved isolates showed that each patient persistently carried isolates of a single genotype. Following lung transplantation, two patients showed re-colonisation of the lung grafts with the pre-transplant A. xylosoxidans strain. Conclusions A. xylosoxidans has been transmitted between patients from our clinic, but the recent increase in incidence is not caused by cross infections.

To explore whether gender differences in the Scandinavian Cystic Fibrosis (CF) patients exist in the areas of key clinical parameters, complications, and medication.Cross-sectional data on 890 (416 female) pancreatic insufficient CF patients were evaluated regarding chronic infection, body mass index, lung function, medication, and diabetes, as well as data of Pseudomonas infection status, antibiotic treatment and hospitalization from 1-year follow-up.We found no differences in lung function, body mass index, or frequency of diabetes. The adult group consisted of more males than females (208:168). We found no significant difference in prevalence of chronic Pseudomonas aeruginosa infection, but during the follow-up the incidence of new chronic infection was higher in adult females (10/33 vs. 4/56). Females had higher prevalence of Burkholderia infection (21/416 vs. 11/474). Adult females had more days on intravenous antibiotics (median 39 vs. 26 days/year), and days in hospital (median 2 vs. 0 days/year). More adult females received inhaled and oral steroids. In the pediatric cohort, females were treated more often with macrolides as an anti-inflammatory agent.We found no gender difference in key clinical parameters in our CF population. However, our study showed a higher risk of Pseudomonas and Burkholderia infection among the female patients. Additionally, we found that female patients require more intensified treatment regarding antibiotics, macrolides, steroids and days of hospitalization, indicating a true female disadvantage even with modern aggressive treatment. The finding of more males than females in the adult population suggesting a male advantage, warrants a mortality study.