Cystic fibrosis patients suffer from chronic lung infection and inflammation due to the secretion of viscous sputum. Sputum viscosity is caused by extracellular DNA, some of which originates from the ...release of neutrophil extracellular traps (NETs). During NET formation neutrophil elastase (NE) partially processes histones to decondense chromatin. NE is abundant in CF sputum and is thought to contribute to tissue damage. Exogenous nucleases are a palliative treatment in CF as they promote sputum solubilization. We show that in a process reminiscent of NET formation, NE enhances sputum solubilization by cleaving histones to enhance the access of exogenous nucleases to DNA. In addition, we find that in Cf sputum NE is predominantly bound to DNA, which is known to downregulate its proteolytic activity and may restrict host tissue damage. The beneficial role of NE in CF sputum solubilization may have important implications for the development of CF therapies targeting NE.
An increasing rate of respiratory colonization and infection in cystic fibrosis (CF) is caused by fungi of the Scedosporium apiospermum species complex or Lomentospora prolificans (Sac-Lp). These ...fungi rank second among the filamentous fungi colonizing the CF airways, after Aspergillus fumigatus. However, the epidemiology, clinical relevance and risk of pulmonary colonization with Sac-Lp are rarely understood in CF. The objective of the present prospective multicenter study was to study pathogen distribution and determine association factors of pulmonary Sac-Lp colonization in patients with CF.
Clinical, microbiological and laboratory data of 161 patients aged 6-59 years with CF in Germany were analyzed for Sac-Lp distribution and association factors. The free statistical software R was utilized to investigate adjusted logistic regression models for association factors.
Of the 161 patients included in the study, 74 (56%) were male. The median age of the study cohort was 23 years (interquartile range 13-32 years). 58 patients of the total cohort (36%) were < 18 years old. Adjusted multivariate regression analysis revealed that Sac-Lp colonization was associated with younger age (OR 0.8684, 95%CI: 0.7955-0.9480, p<0.005) and less colonization with H. influenzae (OR 0.0118, 95%CI: 0.0009-0.1585, p<0.001). In addition, Sac-Lp-colonized patients had more often allergic bronchopulmonary aspergillosis (ABPA) (OR 14.6663, 95%CI: 2.1873-98.3403, p<0.01) and have been colonized more often with the mucoid phenotype of Pseudomonas aeruginosa (OR 9.8941, 95%CI: 1.0518-93.0705, p<0.05).
Newly found association of ABPA and Pseudomonas revealed new probable risk factors for Sac-Lp colonization. Allergy might play a role in inducing immunologic host reactions which lead to a less effective response to species of Sac-Lp.
Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, ...necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported.We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children.Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study.Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus n = 4) including necrotizing pneumonia (n = 4), necrotizing fasciitis (n = 2), pyomyositis (n = 2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (n = 1), preorbital cellulitis (n = 1), and recurrent deep furunculosis in an immunosuppressed patient (n = 1). Specific complications of PVL-SA infections were venous thrombosis (n = 2), sepsis (n = 5), respiratory failure (n = 5), and acute respiratory distress syndrome (n = 3). The median duration of hospital stay was 14 days (range 5-52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified.PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures.
Background
Mepolizumab was originally intended as a therapeutic agent for atopic asthma in adults, and consequently, little is known about its use in children. Up to now, corticosteroids have formed ...the basis of the initial treatment of hypereosinophilic syndromes and are shown to be effective in most patients. To analyze the effect of mepolizumab in children is the aim of this study.
Methods
We are reporting the experience of the effect of mepolizumab in 2 pediatric patients with hypereosinophilic syndrome that was not sufficiently controlled by other drugs. In addition, the literature regarding the treatment with mepolizumab in pediatric and adult patients is reviewed for the most important studies regarding safety and efficacy.
Results
Mepolizumab therapy showed in 2 pediatric patients with severe hypereosinophilic syndrome a safe and efficient therapeutic approach. No significant intolerances appeared. Furthermore, treatment with systemic corticosteroids was terminated, and therefore, severe side effects were avoided in our pediatric cases.
Conclusions
Anti‐IL‐5 antibodies, which can be applied without substantial drug intolerances, are a new, safe, and effective treatment option for pediatric patients with hypereosinophilic syndrome.
Abstract Background Inhaled antibacterial agents are used to manage chronic pulmonary infections in cystic fibrosis (CF) and non-CF bronchiectasis. However, established nebulized preparations impose ...a substantial time burden on patients. A dry powder formulation of ciprofloxacin for inhalation (ciprofloxacin DPI) has been developed using PulmoSphere™ (Novartis, Pharma AG, Basel, Switzerland) technology (administered using a T-326 inhaler) to maximize antibacterial activity and convenience. Objective This study investigated the tolerability and pharmacokinetic properties of multiple-dose once-daily and twice-daily ciprofloxacin DPI in adults with CF. Methods A Phase I, randomized, single-blind, placebo-controlled, dose-escalation study in patients with CF (median age 29.0 years 19–40), stable pulmonary status, and chronic Pseudomonas aeruginosa colonization. Sequential cohorts received ciprofloxacin DPI 32.5 mg qd (1 capsule for inhalation; n = 6), 65 mg qd (2 capsules for inhalation; n = 6), or 32.5 mg (n = 6) bid for 7 days. Each group was placebo controlled. Results Twenty-five patients were enrolled (12 men; median age, 29.0 years range, 19–40 years; 6, 6, 6, and 7 patients in the ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid and placebo groups, respectively). No serious treatment-emergent adverse events or clinically relevant changes in tolerability parameters, including lung function measurements, were reported. Twenty-one patients (ciprofloxacin, n = 17; placebo, n = 4) experienced 29 mild drug-related treatment-emergent adverse events, including bitter taste (ciprofloxacin, 17 patients; placebo, 2) and bronchospasm (ciprofloxacin, 3; placebo, 2). Ciprofloxacin DPI was absorbed rapidly after inhalation. Systemic exposure to ciprofloxacin was low and comparable between single and multiple dosing in all 3 dose groups, suggesting an absence of substantial drug accumulation. The geometric mean AUCs after the last dose were 0.383, 1.472, and 0.781 mg · h/L with ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. The range of geometric mean t½ in plasma was 3.4 to 9.5 hours. Sputum concentrations of ciprofloxacin were high, with substantial variability. Geometric mean ciprofloxacin concentrations (%CV) in induced sputum were 57.7 (118.2), 177.5 (53.4), and 149.7 (249.7) mg/L 0.75 hours after the last dose of ciprofloxacin DPI 32.5 mg qd, 65 mg qd, and 32.5 mg bid, respectively. Conclusions Ciprofloxacin DPI was well tolerated, especially with respect to lung function, with minimal systemic exposure compared with data from previous studies of oral and intravenous administration, and with no apparent accumulation at steady state. Sputum ciprofloxacin concentrations above 100-times the minimum inhibitory concentration for P aeruginosa were detected. Ciprofloxacin DPI may be effectively delivered to the lungs at microbiologically active concentrations while minimizing the risk for systemic intolerabilities. Eudra clinical trial identifier: 2006-003690-26.
Counselling adolescents with chronic medical conditions (CMCs) can be challenging regarding suitable interviewing skills and clinicians' attitudes toward the patient. Successful communication can be ...a key element of treatment. Motivational Interviewing (MI) is broadly applicable in managing behavioural problems and diseases by increasing patient motivation for lifestyle changes. However, data concerning the applicability, feasibility and implementation of MI sessions in everyday practice are missing from the physicians' point of view.
The present study was conducted as a mixed methods design. Twenty paediatricians were randomized to a 2-day MI course followed by MI consultations. Data were collected through a questionnaire one year after MI training. Factors for effective training and possible barriers to successful use of MI were examined.
Completed questionnaires were returned by 19 of 20 paediatricians. The paediatricians' experiences with MI demonstrate that MI is regarded as a valuable tool when working with adolescents with CMCs. 95% of all respondents reported that they found MI education necessary for their clinical work and were using it also outside the COACH-MI study context. 73.7% percent saw potential to strengthen the connection to their patients by using MI. The doctors were already using more MI conversation techniques after a 2-day MI course. Obstacles were seen in the short training, the lack of time and missing undisturbed environment (interruptions by telephone, staff, etc.) during clinical flow.
MI techniques are not yet a regular part of medical training. However, a 2-day MI course was rated effective and provided a lasting impact by physicians caring for children and adolescents with chronic medical conditions (CMCs), although booster sessions should be offered regularly.
The study was registered in the German Clinical Trials Register (DRKS00014043) on 26/04/2018.
In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate ...within-patient variability of oral glucose tolerance.
In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 11.5; 21.5 years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4.
A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%.
In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.
People with cystic fibrosis experience bronchopulmonary exacerbations, leading to lung damage, lung function decline, increased mortality, and a poor health-related quality of life. To date, there ...are still open questions regarding the rationale for antibiotic use and the optimal duration of antibiotic therapy. This prospective single-center study (DRKS00012924) analyzes exacerbation treatment over 28 days in 96 pediatric and adult people with cystic fibrosis who started oral and/or intravenous antibiotic therapy in an inpatient or outpatient setting after clinician diagnosis of bronchopulmonary exacerbation. Biomarkers of exacerbation were examined in terms of their ability to predict response to treatment and the need for antibiotic therapy. The mean duration of antibiotic therapy was 14 days. Inpatient treatment was associated with a poorer health status, but no significant difference was found in the modified Fuchs exacerbation score between inpatients and outpatients. A significant increase of in-hospital FEV1, home spirometry FEV1, and body-mass index and a significant decrease of the modified Fuchs symptom score, C-reactive protein, and 8 out of the 12 domain scores of the revised cystic fibrosis questionnaire were demonstrated after 28 days. However, a trend towards a FEV1 decline in the inpatient group on day 28 could be demonstrated, while FEV1 was maintained in the outpatient group. Correlation analyses of changes between baseline and day 28 show a strong positive correlation between home spirometry and in-hospital FEV1, strong negative correlations between FEV1 and the modified Fuchs exacerbation score and between FEV1 and C-reactive protein, and a moderately negative correlation between FEV1 and the three domains of the revised cystic fibrosis questionnaire. Responders and non-responders to antibiotic therapy were defined in terms of FEV1 improvement after therapy. A higher baseline C-reactive protein, a greater decrease in C-reactive protein, a higher baseline modified Fuchs exacerbation score, and a greater decrease in the score after 28 days could be found in the responder group, while other baseline and follow-up parameters like FEV1 showed no significant differences. Our data show that the modified Fuchs exacerbation score is applicable in a clinical setting and can detect acute exacerbations regardless of health status. Home spirometry is a useful tool for outpatient exacerbation management. A change in C-reactive protein and a modified Fuchs score change are suitable follow-up markers of exacerbation due to their strong correlation with FEV1. Further studies are needed to assess which patients would benefit from a longer duration of antibiotic therapy. C-reactive protein at exacerbation onset and C-reactive protein decline during and after therapy better predict antibiotic therapy success than FEV1 at therapy onset, while the modified Fuchs score indicates exacerbation regardless of the need for antibiotic therapy, suggesting that antibiotic therapy is only part of exacerbation management.
Adolescents and young adults (AYA) with chronic somatic conditions have an increased risk of comorbid depression and anxiety symptoms. Internet- and mobile-based cognitive behavioural therapy (iCBT) ...might be one possibility to extend the access to evidence-based treatments. Studies suggest that guided iCBT can reduce anxiety and depression symptoms in AYA. However, little is known about the effectiveness of iCBT for AYA with chronic somatic conditions and comorbid symptoms of anxiety and/or depression in routine care. Evidence on the (cost-)effectiveness of iCBT is essential for its implementation in health care.
This multicentre two-armed randomized controlled trial (RCT) aims to evaluate the (cost-) effectiveness of guided iCBT (youthCOACH
) in addition to treatment as usual (TAU) compared to enhanced treatment as usual (TAU+) in AYA aged 12-21 years with one of three chronic somatic conditions (type 1 diabetes, cystic fibrosis, or juvenile idiopathic arthritis). AYA with one of the chronic somatic conditions and elevated symptoms of anxiety or depression (Patient Health Questionnaire PHQ-9 and/or Generalized Anxiety Disorder GAD-7 Screener score ≥ 7) will be eligible for inclusion. We will recruit 212 patients (2 × n = 106) in routine care through three German patient registries. Assessments will take place at baseline and at 6 weeks, 3 months, 6 months, and 12 months post-randomization. The primary outcome will be combined depression and anxiety symptom severity as measured with the PHQ Anxiety and Depression Scale. Secondary outcomes will include health-related quality of life, coping strategies, self-efficacy, stress-related personal growth, social support, behavioural activation, adjustment and trauma-related symptoms, automatic thoughts, intervention satisfaction, working alliance, and Internet usage. The cost-effectiveness will be determined, and potential moderators and mediators of intervention effects will be explored.
iCBT might implicate novel ways to increase the access to evidence-based interventions in this specific population. The distinct focus on effectiveness and cost-effectiveness of youthCOACH
in patients with chronic somatic conditions, as well as intervention safety, will most likely provide important new insights in the field of paediatric e-mental health. A particular strength of the present study is its implementation directly into routine collaborative health care. As such, this study will provide important insights for health care policy and stakeholders and indicate how iCBT can be integrated into existing health care systems.
German Clinical Trials Register (DRKS), DRKS00017161. Registered on 17 September 2019.
Relatively little is known about protective factors and the emergence and maintenance of positive outcomes in the field of adolescents with chronic conditions. Therefore, the primary aim of the study ...is to acquire a deeper understanding of the dynamic process of resilience factors, coping strategies and psychosocial adjustment of adolescents living with chronic conditions.
We plan to consecutively recruit N = 450 adolescents (12-21 years) from three German patient registries for chronic conditions (type 1 diabetes, cystic fibrosis, or juvenile idiopathic arthritis). Based on screening for anxiety and depression, adolescents are assigned to two parallel groups - "inconspicuous" (PHQ-9 and GAD-7 < 7) vs. "conspicuous" (PHQ-9 or GAD-7 ≥ 7) - participating in a prospective online survey at baseline and 12-month follow-up. At two time points (T1, T2), we assess (1) intra- and interpersonal resiliency factors, (2) coping strategies, and (3) health-related quality of life, well-being, satisfaction with life, anxiety and depression. Using a cross-lagged panel design, we will examine the bidirectional longitudinal relations between resiliency factors and coping strategies, psychological adaptation, and psychosocial adjustment. To monitor Covid-19 pandemic effects, participants are also invited to take part in an intermediate online survey.
The study will provide a deeper understanding of adaptive, potentially modifiable processes and will therefore help to develop novel, tailored interventions supporting a positive adaptation in youths with a chronic condition. These strategies should not only support those at risk but also promote the maintenance of a successful adaptation.
German Clinical Trials Register (DRKS), no. DRKS00025125 . Registered on May 17, 2021.
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