Reply to the Comment: Research Design Concerns in a TriNetX Analysis of Venous Thromboembolism in Pediatric Cystic Fibrosis Patients.

BACKGROUND : Recent data on the yield of bronchoscopy in pediatric cystic fibrosis (CF) patients are lacking. Therapeutic bronchoscopic lavage with the mucolytic recombinant human deoxyribonuclease (rhDNase) has been used during CF bronchoscopies, but efficacy data are scarce. METHODS: A retrospective review of all bronchoscopies performed in pediatric CF patients in our hospital in the past 15 years. AIMS OF THE STUDY: To evaluate indications for and safety of bronchoscopy in pediatric CF patients, to describe the findings of bronchoscopy and the contribution of these findings to clinical management, and to evaluate the application of bronchoscopic lavage with rhDNase. RESULTS: Between 1992 and 2007, 66 bronchoscopies were performed in 48 CF patients (25 males) at a median (range) age of 8.3 (0.1 to 20.4) years. Indications for bronchoscopy were persistent atelectasis (42%), refractory symptoms (29%), need for microbiologic culture (11%), suspected anatomic abnormality (11%), and bronchial toilet (7%). Relevant new information with therapeutic consequences was obtained in 28 (42%) bronchoscopies, including a first Pseudomonas aeruginosa infection (n≤3), infection with atypical mycobacteria (n≤3), or Aspergillus fumigatus (n≤5), and severe tracheo(broncho)malacia (n≤4). In patients with atelectasis, rhDNase lavage was associated with improved chest radiograph scores and a transient decline in forced vital capacity. In 7 of 11 patients with refractory symptoms, lung function tended to improve after rhDNase lavage. No serious complications were observed after bronchoscopy and rhDNase lavage. CONCLUSIONS: Bronchoscopy provides clinically relevant information in about 40% of these pediatric CF patients. Lavage with rhDNase seemed safe, and was associated with improved chest radiographs in patients with therapy resistant atelectasis. Copyright

Dissociation of systemic and mucosal autoimmunity in cystic fibrosis

* Two recent papers have been published which have attempted to build a full population pharmacokinetic model for tobramycin in children with cystic fibrosis. * However, neither study was able to provide any information about between-subject variability (BSV) and between-occasion variability (BOV), which is necessary to justify and draw conclusions about the use of target concentration intervention (TCI). * In the publications no simulations were provided to show any new directions or evaluate current therapy. * This study provides sound evidence that TCI must be undertaken in this patient group, as the BOV is significantly less than the BSV. * The simulations from this model clearly show that current dosing and monitoring methods will not achieve the necessary targets to maximize the pharmacokinetic-pharmacodynamic relationships of aminoglycosides in this patient group. * The model presented is able to be easily incorporated into Bayesian dose individualization software, e.g. Abbottbase or TCIworks, to achieve dosing targets more accurately. The primary aim was to estimate the population pharmacokinetic parameters of once-daily intravenous (i.v.) tobramycin in paediatric cystic fibrosis (CF) patients and to investigate the influence of covariates. The second aim was to assess the need for target concentration intervention (TCI) for tobramycin in this patient group. Retrospective demographic, dosing and concentration data were collected from 35 CF patients (21 female, 14 male) aged 0.5-17.8 years, from whom 318 tobramycin plasma concentrations were available. NONMEM was used to estimate the population pharmacokinetics of tobramycin. Simulations were performed using weight-based dosing with a weight from a covariate distribution model to evaluated current dosing schedules and monitoring practices. A two-compartment model best described the data with population parameter estimates for clearance of central compartment (CL) of 6.37 l h(-1) per 70 kg; volume of central compartment (V(c)) of 18.7 l per 70 kg; intercompartmental clearance (Q) of 0.393 l h(-1); and volume of peripheral compartment (V(per)) of 1.32 l. The inclusion of total body weight as covariate reduced the random component of between-subject variability in CL from 50.1% to 11.7% and in V(c) from 62.2% to 11.6%. The between-occasion variability on CL was estimated in the final model as 6.5%. Simulations show that one dose does not fit all and TCI and dose adjustment are required. This study provides the first pharmacokinetic model of once-daily i.v. tobramycin for the use of target concentration intervention in paediatric CF patients.

The Use of Doripenem in Pediatric Cystic Fibrosis Patients in Case of Meropenem Shortages

High dose intermittent ticarcillin–clavulanate administration in pediatric cystic fibrosis patients

Evaluation of the safety of cefepime prolonged infusions in pediatric patients with cystic fibrosis.

Airway clearance therapy in the school environment: Retrospective analysis of a cohort of pediatric patients with cystic fibrosis

BPI-ANCA of pediatric cystic fibrosis patients can impair BPI-mediated killing of E. coli DH5alpha in vitro.

This study was performed to examine the prevalence and clinical correlates of bactericidal/permeability-increasing protein anti-neutrophil cytoplasmic antibodies (BPI-ANCA) in pediatric cystic fibrosis (CF) patients and to elucidate their possible role in CF pulmonary pathology. Sera of 27 CF patients were tested for ANCA by indirect immunofluorescence (IFT) and by enzyme-linked immunosorbent assay (ELISA) for ANCA sub-specificities. BPI-ANCA were examined by using standard ELISA for BPI, lipopolysaccharide-binding protein (LBP), and BPI/LBP fusion proteins to epitope map the main binding sites and look for cross-reactivity with LBP. Pulmonary function and serum concentrations of total immunoglobulin G (IgG) were measured and infections were diagnosed. In addition, release of reactive oxygen species (ROS) by neutrophil granulocytes was measured after stimulation with monoclonal BPI-ANCA. Using IFT, two patients showed atypical ANCA staining, six patients exhibited perinuclear ANCA staining, and no cytoplasmic ANCA staining was detected. Of 27 patients, 13 (48%) were BPI-ANCA (IgG) positive, and three were also immunoglobulin A (IgA) BPI-ANCA positive; one patient had ANCA against lactoferrin; and no proteinase 3 ANCA was detected in any of the patients. All BPI-ANCA bound to the C-terminal region of the molecule; none bound to the N-terminus or to LBP. There was no significant correlation between clinical data and the occurrence of BPI-ANCA in this cross-sectional study. Release of ROS from granulocytes was induced by monoclonal BPI-ANCA. Activation of neutrophils and possible modulation of BPI-mediated opsonophagocytosis and disposal of Gram-negative bacteria and lipopolysaccharides by BPI-ANCA raise the possibility that they contribute to pulmonary pathology in pediatric CF patients but intervention longitudinal studies in large groups of patients are needed to establish a causative association.

Background: “CFTR modulators” (also named “caftor”) have been developed and introduced into clinical practice to improve the functionality of defective CFTR protein. Therapeutic drug monitoring (TDM) is not currently used for CFTR modulators in routine clinical practice and there is still much to learn about the pharmacokinetic/pharmacodynamic (PK/PD) and the safety profiles of these drugs in a real-world setting. Moreover, therapeutic ranges are not yet available for both pediatric and adult cystic fibrosis (CF) patients. Methods: A new and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for contemporary quantification of ivacaftor (IVA), tezacaftor (TEZ) and elexacaftor (ELX) in plasma samples has been developed and validated. The clinical performance of our method has been tested on samples collected during the routine clinical practice from n = 25 pediatric patients (aged between 7 and 17 years) affected by cystic fibrosis. This LC-MS/MS method has been validated according to ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines for the validation of bioanalytical methods. Results: Our method fulfilled ICH guidelines in terms of accuracy, precision, selectivity, specificity and carry-over. Intra- and inter-day accuracy and precision were ≤15%. The 9-day autosampler stability was 90–100% for TEZ and ELX; meanwhile, it fell to 76% for IVA. An injection volume of 1 µL and a wider quantification range (0.1–20 µg/mL) represent a novelty of our method in terms of sensitivity and fields of application. Finally, the evaluation of PK exposure parameters for IVA revealed strong agreement with previously published reports and with results from the summary of product characteristics (SmPCs). Conclusions: This method could be adopted to contemporarily measure ELX/TEZ/IVA plasma levels for both PK studies and monitor therapy compliance, especially in case of poor or partial responses to treatment, or to evaluate drug–drug interactions when multiple concomitant medications are required. Considering also the high cost burden of these medications to the health system, a TDM-based approach could facilitate more cost-effective patient management.

Copeptin was found to be a stable biomarker of inflammation and stress response in cardiac, renal, metabolic, and respiratory conditions such as pneumonia. The aim of this study was to investigate the copeptin levels in biological fluids (serum and sputum supernatant) of cystic fibrosis pediatric patients during pulmonary exacerbation and remission and to investigate the possible influence of copeptin levels on disease severity and quality of life. Copeptin serum concentrations were measured in 28 pediatric cystic fibrosis (CF) patients: 13 in stable condition and 15 during pulmonary exacerbation. In 10 CF patients, copeptin was also measured in the sputum. In all the patients, we assessed complete blood count, BMI, sputum culture, lung function, and chest imaging (with Brasfield score). The severity of symptoms was assessed using the Shwachman-Kulczycki (SK) score, and the quality of life was assessed with the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). Copeptin concentrations in serum and sputum supernatant was measured using an ELISA kit. Statistical analysis was done in Statistica v.12. Serum and sputum copeptin levels were higher in CF patients during pulmonary exacerbation than in a stable period, but the differences were not significant (p = 0.58 and p = 0.13, respectively). Copeptin did not correlate significantly with any clinical, laboratory, or spirometry markers of exacerbation. There was, however, a significant inverse correlation between the serum copeptin level and symptoms severity (r = ‐0.77, p = 0.008) and radiological changes (r = ‐0.5626, p = 0.036) during pulmonary exacerbation in pediatric CF patients. Copeptin also inversely correlated with the quality of life domains in CF patients: vitality and eating habits, mostly loss of appetite (p = 0.031 and p = 0.016, respectively). Copeptin may be useful to identify patients with a higher risk of deterioration to improve their outcomes.

Microbiology of the Upper and Lower Airways in Pediatric Cystic Fibrosis Patients.

To determine the utility of Second-look endoscopy with debridement (SLED) after functional endoscopic sinus surgery (ESS) in pediatric cystic fibrosis (CF) patients. To compare outcomes in pediatric CF patients undergoing sinus surgery for chronic sinusitis with or without SLED. To describe findings present at the time of SLED. Retrospective chart review of 61 ESS procedures performed at a tertiary care pediatric center from 2013 to 2016. Data collected included demographics, SLED findings, and 6-month pre-/postoperative disease specific outcomes including incidence of sinonasal and pulmonary exacerbations and revisions. Sixty-one cases were reviewed. SLED was performed in 38 cases on average 22.4 days postoperatively. Average preoperative Lund-Mackay score was 14.9 and 14.8 among patients undergoing ESS with and without SLED, respectively. Pre-/postoperative intranasal steroid use and extent of surgery performed was similar among all patients. At the time of SLED, rates of synechiae, polyps and maxillary antrostomy obstruction were 26.3%, 23.7%, and 7.9%, respectively. The incidence and number of days to onset of postoperative sinonasal exacerbations requiring antibiotic therapy within 6 months of ESS were 1.0 (SD 1.0) and 85 days (SD 45.7); and 1.3 (SD 1.0) and 80.4 days (SD 40.5) for patients undergoing ESS with and without SLED, respectively (P value .33). The number of days to first pulmonary exacerbation was 113.9 (SD 45.5) and 47.4 (SD 34.1) among SLED and non-SLED patients, respectively (P value .01). No significant difference was observed in revision rates and time to revision ESS (30% and overall average 1.4 years, respectively). The utility of SLED among pediatric CF patients remains unclear. While debridement did not have a significant impact on sinonasal exacerbations or revision rates, pulmonary exacerbations for patients undergoing SLED were delayed. Further studies are needed to clarify the impact of SLED.

Medication adherence is poor among pediatric cystic fibrosis (CF) patients, with adolescents having one of the lowest adherence rates. We wanted to identify an adherence intervention that would be acceptable to CF adolescents and assess its feasibility. We surveyed 40 adolescents with CF and asked about barriers to and motivators for their own adherence and to generate ideas for potential adherence interventions. Since most of the respondents chose frequent spirometry at home and medication reminders for interventions, we selected 5 subjects, 10 to 14 years of age, with CF to test the feasibility of home spirometry and medication reminders in pediatric CF patients. This article summarizes the results of both the survey and the feasibility pilot study.

Continuous vancomycin in a pediatric cystic fibrosis patient.