Risk of piperacillin‐induced hemolytic anemia in patients with cystic fibrosis and antipseudomonal treatment: a prospective observational study

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is a rare but severe side effect caused by numerous drugs. Case reports and case series suggest that piperacillin-related DIIHA may be more common among patients with cystic fibrosis (CF). However, the prevalence is speculative. The aim of this prospective, observational study was determine the prevalence of DIIHA in such affected patients. METHODS AND MATERIALS: Patients with CF hospitalized for parenteral antibiotic therapy at Charité Universitätsmedizin Berlin, who had previously been exposed to IV antibiotics, were enrolled. Blood samples were collected on Days 3 and 12 of antibiotic treatment courses. Serological studies were performed using standard techniques with gel cards. Screening for drug-dependent antibodies (ddab) was performed in the presence of the drugs and their urinary metabolites. RESULTS A total of 52 parenteral antibiotic cycles in 43 patients were investigated. Ddab against piperacillin were detected in two patients (4.7%). The direct AHG was positive with anti-IgG only in both patients. However only one of these patients developed mild immune hemolytic anemia. Both patients had been repeatedly treated with piperacillin without any evident hemolysis. There was no correlation between the exposure to piperacillin and the prevalence of ddab. CONCLUSION: Our prospective study indicates that piperacillin-induced ddab occur more frequently in patients with CF than previously suggested. The question related to the significance of piperacillin-dependent antibodies may reflect new aspects in this field

Contrast agent-free functional magnetic resonance imaging with matrix pencil decomposition to quantify abnormalities in lung perfusion and ventilation in patients with cystic fibrosis

BackgroundPrevious studies showed that contrast-enhanced (CE) morpho-functional magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion in patients with cystic fibrosis (CF). Novel matrix pencil decomposition MRI (MP-MRI) enables quantification of lung perfusion and ventilation without intravenous contrast agent administration.ObjectivesTo compare MP-MRI with established morpho-functional MRI and spirometry in patients with CF.MethodsThirty-nine clinically stable patients with CF (mean age 21.6 ± 10.7 years, range 8–45 years) prospectively underwent morpho-functional MRI including CE perfusion MRI, MP-MRI and spirometry. Two blinded chest radiologists assessed morpho-functional MRI and MP-MRI employing the validated chest MRI score. In addition, MP-MRI data were processed by automated software calculating perfusion defect percentage (QDP) and ventilation defect percentage (VDP).ResultsMP perfusion score and QDP correlated strongly with the CE perfusion score (both r = 0.81; p < 0.01). MP ventilation score and VDP showed strong inverse correlations with percent predicted FEV1 (r = −0.75 and r = −0.83; p < 0.01). The comparison of visual and automated parameters showed that both MP perfusion score and QDP, and MP ventilation score and VDP were strongly correlated (r = 0.74 and r = 0.78; both p < 0.01). Further, the MP perfusion score and MP ventilation score, as well as QDP and VDP were strongly correlated (r = 0.88 and r = 0.86; both p < 0.01).ConclusionMP-MRI detects abnormalities in lung perfusion and ventilation in patients with CF without intravenous or inhaled contrast agent application, and correlates strongly with the well-established CE perfusion MRI score and spirometry. Automated analysis of MP-MRI may serve as quantitative noninvasive outcome measure for diagnostic monitoring and clinical trials

Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial.

RATIONALE Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. OBJECTIVE To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). METHODS This phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). We report results from Part 1. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the MRI global chest score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. RESULTS Fifty-one children were enrolled and received LUM/IVA (n=35) or placebo (n=16). For the change in MRI global chest score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference <0; higher score indicating greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. CONCLUSIONS This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years. Clinical trial registered with ClinicalTrials.gov (NCT03625466)

Lack of Correlation of Sinonasal and Otologic Reported Symptoms With Objective Measurements Among Patients With Primary Ciliary Dyskinesia: An International Study.

peer reviewedSinonasal and otologic symptoms are common among patients with primary ciliary dyskinesia (PCD) of all ages. We used baseline data from the ENT Prospective International Cohort of PCD patients (EPIC-PCD), the first PCD cohort focused on ENT disease manifestations. We assessed agreement between patient- or parent-reported symptoms and relevant examination findings, and calculated unweighted Cohen’s kappa to adjust for agreement by chance. We included 404 participants, from 12 centres. We found no correlation between patient-reported sinonasal symptoms and relevant clinical examination findings. Otologic symptoms correlated poorly or weakly with otoscopy and audiometry findings, with age and centre identified as determinants of agreement

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients

Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF.The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF.Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy

Impact of Long-Term Tiotropium Bromide Therapy on Annual Lung Function Decline in Adult Patients with Cystic Fibrosis.

Chronic lung disease is the leading cause of death in patients with Cystic Fibrosis (CF) and is often treated with bronchodilators. It is not known whether long-term tiotropium bromide treatment may have a positive impact on lung function.This retrospective cohort study estimated annual lung function decline utilizing longitudinal data for forced expiratory volume in 1 s (FEV1).A total of 160 adult patients with CF were analyzed. The subjects treated for 24 months with tiotropium bromide had a significantly slower decline of mean annual change of FEV1 (treated: -0.3±4.0%; control: -2.3±5.0%; p = 0.0130). In patients with FEV1 ≥70% predicted, long-term tiotropium bromide treatment was associated with greater improvements in annual lung function decline (FEV1 ≥70% predicted: treated: +0.5±4.7%; control: -4.0±6.3%; p = 0.0132; FEV1 50-69% predicted: treated: -0.5±4.4%; control: -0.8±3.8%; p = 0.7142; FEV1 ≤49% predicted: treated: -0.6±3.4%; control: -2.4±4.8%; p = 0.0898).This study suggests that long-term tiotropium bromide treatment may be associated with reduced annual decline of FEV1 in patients with CF, particularly in adults with a mild degree of severity

Outcomes by allocation.

<p>Outcomes by allocation.</p