Aim: Denmark has a high standard cystic fibrosis care. However, newborn screening was not impleme... more 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.
Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). How... more Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. Babies with CF were more likely to be born preterm and with low birth weigh...
In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW)... more In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW) measures in children with clinically stable cystic fibrosis. To our knowledge the effect of time-of-day on multiple breath washout measures in patients with cystic fibrosis has not previously been reported. Furthermore, we assessed the influence of chest physiotherapy on N2MBW measures. Ten school children with cystic fibrosis performed N2MBW followed by spirometry and plethysmography in the morning and afternoon at three visits that were one month apart. Chest physiotherapy was performed immediately before the afternoon measurements at visit 2 and immediately before morning and afternoon measurements at visit 3. The influence of time-of-day and chest physiotherapy on the measures was evaluated using linear mixed models. There were adequate quality data from 8 children with median age (range) 9.6 (6.0; 15.1) years. Baseline lung clearance index (LCI) (range) was 9.0 (7.1; 13.0) and base...
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, Jan 27, 2017
With improved prognosis of CF, comorbidities including chronic kidney disease (CKD) are becoming ... more With improved prognosis of CF, comorbidities including chronic kidney disease (CKD) are becoming increasingly important. Identification of those at highest CKD risk is hence a priority. In this cross-sectional study, adults with CF attending the Copenhagen CF Centre at Rigshospitalet with ≥2 measurements of serum creatinine from 2013 to 2015 were included. Data was obtained from an electronic CF database, which contains anonymised clinical and laboratory data on all individuals attending the clinic. CKD was defined as a confirmed (≥3months apart) estimated glomerular filtration rate≤60mL/min/1.73m2. Of 181 individuals, the CKD prevalence was 2.7% and increased to 11% after inclusion of lung transplanted patients. Individuals with CKD were generally older (median 39 (IQR, 36-45) vs. 31 (IQR, 24-39) years; p<0.001), diabetic (86% vs. 41%, p<0.001), with longer median duration of chronic pulmonary infection (28.3 (20.0-35.8) vs. 20.0 (9.9-34.7) years; p=0.008) and with longer int...
Biometrical journal. Biometrische Zeitschrift, Jan 21, 2017
Joint models for longitudinal and time-to-event data have gained a lot of attention in the last f... more Joint models for longitudinal and time-to-event data have gained a lot of attention in the last few years as they are a helpful technique clinical studies where longitudinal outcomes are recorded alongside event times. Those two processes are often linked and the two outcomes should thus be modeled jointly in order to prevent the potential bias introduced by independent modeling. Commonly, joint models are estimated in likelihood-based expectation maximization or Bayesian approaches using frameworks where variable selection is problematic and that do not immediately work for high-dimensional data. In this paper, we propose a boosting algorithm tackling these challenges by being able to simultaneously estimate predictors for joint models and automatically select the most influential variables even in high-dimensional data situations. We analyze the performance of the new algorithm in a simulation study and apply it to the Danish cystic fibrosis registry that collects longitudinal lun...
Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent o... more Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: S...
Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous myc... more Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary cili... more Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary ciliary dyskinesia (PCD). From the sinuses, Pseudomonas aeruginosa can infect the lungs. We studied the effect of endoscopic sinus surgery (ESS) on symptoms of CRS and lower airway infections in PCD patients in a prospective single-arm intervention study of ESS with adjuvant therapy using nasal irrigation with saline, topical nasal steroids, and 2 weeks of systemic antibiotics. Additional treatment with local colistin for 6 months was instigated when P. aeruginosa was cultured at ESS. Twenty-four PCD patients underwent ESS to search for an infectious focus (n = 10), due to severe symptoms of CRS (n = 8), or both (n = 6). Bacteria were cultured from sinus samples in 21 patients (88%), and simultaneous sinus and lung colonization with identical pathogens were observed in 13 patients (62%). Four patients with preoperative P. aeruginosa lung colonization (25%) had no regrowth during follow-up; 2 of these had P. aeruginosa sinusitis. Sinonasal symptoms were improved 12 months after ESS and we observed a trend toward better lung function after ESS. We demonstrated an improvement in CRS-related symptoms after ESS and adjuvant therapy. In selected PCD patients, the suggested regimen may postpone chronic lung infection with P. aeruginosa and stabilize lung function.
The influence of suppressive therapy on the different P. aeruginosa phenotypes harbored in the lu... more The influence of suppressive therapy on the different P. aeruginosa phenotypes harbored in the lungs of cystic fibrosis (CF) patients remains unclear. Our aim was to investigate the phenotypic changes (mucoidy, hypermutability, antibiotic resistance, transcriptomic profiles and biofilm) in P. aeruginosa populations before and after a 2-week course of suppressive antimicrobial therapy in chronically infected CF patients in Denmark. Prospective observational clinical study. Sputum samples were assessed before and after treatment for P. aeruginosa, with regard to: a) colony-forming units (CFU/mL), b) frequency of mucoids and non-mucoids, c) resistance pattern to anti-pseudomonal drugs, d) hypermutability, e) transcriptomic profiles, and f) presence of biofilms. We collected 23 sputum samples (12 before antibiotic treatment and 11 after) and 77 P. aeruginosa from different CF patients. After treatment, the P. aeruginosa burden diminished but antimicrobial resistance to aztreonam, tobramycin and ceftazidime rose; non-mucoid phenotypes presented increased resistance to colistin, tobramycin, meropenem, and ciprofloxacin, and hypermutable phenotypes to ciprofloxacin. In spite of biofilm persistence, a down-regulation of genes involved in denitrification was detected. A 2-week course of suppressive therapy reduces P. aeruginosa lung colonization and influences nitrogen metabolism genes, but also promotes antimicrobial resistance while P. aeruginosa persists in biofilms.
Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts... more Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Aim: Denmark has a high standard cystic fibrosis care. However, newborn screening was not impleme... more 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.
Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). How... more Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. Babies with CF were more likely to be born preterm and with low birth weigh...
In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW)... more In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW) measures in children with clinically stable cystic fibrosis. To our knowledge the effect of time-of-day on multiple breath washout measures in patients with cystic fibrosis has not previously been reported. Furthermore, we assessed the influence of chest physiotherapy on N2MBW measures. Ten school children with cystic fibrosis performed N2MBW followed by spirometry and plethysmography in the morning and afternoon at three visits that were one month apart. Chest physiotherapy was performed immediately before the afternoon measurements at visit 2 and immediately before morning and afternoon measurements at visit 3. The influence of time-of-day and chest physiotherapy on the measures was evaluated using linear mixed models. There were adequate quality data from 8 children with median age (range) 9.6 (6.0; 15.1) years. Baseline lung clearance index (LCI) (range) was 9.0 (7.1; 13.0) and base...
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, Jan 27, 2017
With improved prognosis of CF, comorbidities including chronic kidney disease (CKD) are becoming ... more With improved prognosis of CF, comorbidities including chronic kidney disease (CKD) are becoming increasingly important. Identification of those at highest CKD risk is hence a priority. In this cross-sectional study, adults with CF attending the Copenhagen CF Centre at Rigshospitalet with ≥2 measurements of serum creatinine from 2013 to 2015 were included. Data was obtained from an electronic CF database, which contains anonymised clinical and laboratory data on all individuals attending the clinic. CKD was defined as a confirmed (≥3months apart) estimated glomerular filtration rate≤60mL/min/1.73m2. Of 181 individuals, the CKD prevalence was 2.7% and increased to 11% after inclusion of lung transplanted patients. Individuals with CKD were generally older (median 39 (IQR, 36-45) vs. 31 (IQR, 24-39) years; p<0.001), diabetic (86% vs. 41%, p<0.001), with longer median duration of chronic pulmonary infection (28.3 (20.0-35.8) vs. 20.0 (9.9-34.7) years; p=0.008) and with longer int...
Biometrical journal. Biometrische Zeitschrift, Jan 21, 2017
Joint models for longitudinal and time-to-event data have gained a lot of attention in the last f... more Joint models for longitudinal and time-to-event data have gained a lot of attention in the last few years as they are a helpful technique clinical studies where longitudinal outcomes are recorded alongside event times. Those two processes are often linked and the two outcomes should thus be modeled jointly in order to prevent the potential bias introduced by independent modeling. Commonly, joint models are estimated in likelihood-based expectation maximization or Bayesian approaches using frameworks where variable selection is problematic and that do not immediately work for high-dimensional data. In this paper, we propose a boosting algorithm tackling these challenges by being able to simultaneously estimate predictors for joint models and automatically select the most influential variables even in high-dimensional data situations. We analyze the performance of the new algorithm in a simulation study and apply it to the Danish cystic fibrosis registry that collects longitudinal lun...
Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent o... more Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: S...
Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous myc... more Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary cili... more Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary ciliary dyskinesia (PCD). From the sinuses, Pseudomonas aeruginosa can infect the lungs. We studied the effect of endoscopic sinus surgery (ESS) on symptoms of CRS and lower airway infections in PCD patients in a prospective single-arm intervention study of ESS with adjuvant therapy using nasal irrigation with saline, topical nasal steroids, and 2 weeks of systemic antibiotics. Additional treatment with local colistin for 6 months was instigated when P. aeruginosa was cultured at ESS. Twenty-four PCD patients underwent ESS to search for an infectious focus (n = 10), due to severe symptoms of CRS (n = 8), or both (n = 6). Bacteria were cultured from sinus samples in 21 patients (88%), and simultaneous sinus and lung colonization with identical pathogens were observed in 13 patients (62%). Four patients with preoperative P. aeruginosa lung colonization (25%) had no regrowth during follow-up; 2 of these had P. aeruginosa sinusitis. Sinonasal symptoms were improved 12 months after ESS and we observed a trend toward better lung function after ESS. We demonstrated an improvement in CRS-related symptoms after ESS and adjuvant therapy. In selected PCD patients, the suggested regimen may postpone chronic lung infection with P. aeruginosa and stabilize lung function.
The influence of suppressive therapy on the different P. aeruginosa phenotypes harbored in the lu... more The influence of suppressive therapy on the different P. aeruginosa phenotypes harbored in the lungs of cystic fibrosis (CF) patients remains unclear. Our aim was to investigate the phenotypic changes (mucoidy, hypermutability, antibiotic resistance, transcriptomic profiles and biofilm) in P. aeruginosa populations before and after a 2-week course of suppressive antimicrobial therapy in chronically infected CF patients in Denmark. Prospective observational clinical study. Sputum samples were assessed before and after treatment for P. aeruginosa, with regard to: a) colony-forming units (CFU/mL), b) frequency of mucoids and non-mucoids, c) resistance pattern to anti-pseudomonal drugs, d) hypermutability, e) transcriptomic profiles, and f) presence of biofilms. We collected 23 sputum samples (12 before antibiotic treatment and 11 after) and 77 P. aeruginosa from different CF patients. After treatment, the P. aeruginosa burden diminished but antimicrobial resistance to aztreonam, tobramycin and ceftazidime rose; non-mucoid phenotypes presented increased resistance to colistin, tobramycin, meropenem, and ciprofloxacin, and hypermutable phenotypes to ciprofloxacin. In spite of biofilm persistence, a down-regulation of genes involved in denitrification was detected. A 2-week course of suppressive therapy reduces P. aeruginosa lung colonization and influences nitrogen metabolism genes, but also promotes antimicrobial resistance while P. aeruginosa persists in biofilms.
Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts... more Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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