Validity and Reliability of a Novel Multimodal Questionnaire for the Assessment of Abdominal Symptoms in People with Cystic Fibrosis (CFAbd-Score).

BACKGROUND AND OBJECTIVE: For people with cystic fibrosis, validated patient-reported outcome measures for the assessment of the complex abdominal involvement are lacking. The objective of this study was to examine whether the CFAbd-Score, a novel questionnaire consisting of 28 items, meets the essential requirements (validity and reliability) for a patient-reported outcome measure according to US Food and Drug Administration recommendations. METHODS: Content validity was assessed by recording the frequencies and severity of symptoms that occurred during the prior 2 weeks in patients with cystic fibrosis (n = 116; aged ≥ 6 years). Comparing the CFAbd-Score results obtained from patients with cystic fibrosis and healthy controls (n = 88), we determined known-groups validity. To explore the structure of the patient-reported outcome measure, a factor analysis was conducted. Internal consistency of the five extracted score domains was assessed using Cronbach's alpha. For test-retest reliability, a subgroup of patients (n = 43) was reevaluated and intra-class correlation coefficients were determined. RESULTS: The CFAbd-Score differentiated patients with cystic fibrosis from healthy controls with a large effect size (17.3 ± 1.1 vs. 8.0 ± 0.7 points; p < 0.001; Cohen's d = 0.85). Items, domains, and scores reflected the relevance to patients with cystic fibrosis and allowed a differentiation between subgroups of patients with cystic fibrosis (e.g., patients with and without abdominal pain, pancreatic sufficiency, and age groups). High item-domain loadings as well as good to excellent internal consistency and reproducibility (Cronbach's α = 0.70-0.92; intra-class correlation coefficient = 0.932, 95% confidence interval 0.874-0.963) indicated construct validity and reliability. CONCLUSIONS: The CFAbd-Score has successfully passed through key steps of the iterative process of patient-reported outcome measure development. Prospectively, the CFAbd-Score is proposed as a patient-centered instrument for monitoring abdominal symptoms and, most interestingly, for evaluating changes in symptoms with novel treatments such as cystic fibrosis transmembrane regulator modulators. TRAIL REGISTRATION: ClinicalTrials.gov: NCT03052283.

Relation of Ultrasound Findings and Abdominal Symptoms obtained with the CFAbd-Score in Cystic Fibrosis Patients.

Abdominal symptoms are a hallmark of Cystic fibrosis (CF). Yet, their association with morphological abnormalities of different abdominal organs is still poorly understood. Aim was therefore to relate these symptoms, assessed with a questionnaire, to findings in abdominal ultrasound (US). In 114 CF patients of all ages, findings in US considering seventeen specific parameters were related to abdominal symptoms compiled with our novel CF-specific 26-modal symptom score (CFAbd-Score). US abnormalities were detected in 95% of the patients. Most frequent findings were pancreatic lipomatosis (88%), liver steatosis (37%), hepatomegaly (31%), and thickened bowel walls (23%). Highest burden of GI-symptoms was clearly associated with pancreatic lipomatosis (p = 0.036). In detail, patients revealing this pathology reported higher rates of abdominal pain (p = 0.018), flatulence (p = 0.006), heartburn (p = 0.04), and reflux of stomach content (p = 0.006). Patients with pancreatic sufficiency had less US-findings (p = 0.033), which in turn was associated with lower rates of abdominal symptoms. The majority of them were carriers of class IV-VI or G551D mutations. Our approach gives new insights regarding the underestimated multi-organ abdominal involvement in CF. The new score can be of high interest e.g. as a complementary tool to assess the gastrointestinal effects of promising novel CF therapeutics.

Abdominal symptoms in cystic fibrosis and their relation to genotype, history, clinical and laboratory findings.

BACKGROUND & AIMS: Abdominal symptoms (AS) are a hallmark of the multiorgan-disease cystic fibrosis (CF). However, the abdominal involvement in CF is insufficiently understood and, compared to the pulmonary manifestation, still receives little scientific attention. Aims were to assess and quantify AS and to relate them to laboratory parameters, clinical findings, and medical history. METHODS: A total of 131 patients with CF of all ages were assessed with a new CF-specific questionnaire (JenAbdomen-CF score 1.0) on abdominal pain and non-pain symptoms, disorders of appetite, eating, and bowel movements as well as symptom-related quality of life. Results were metrically dimensioned and related to abdominal manifestations, history of surgery, P. aeruginosa and S. aureus colonization, genotype, liver enzymes, antibiotic therapy, lung function, and nutritional status. RESULTS: AS during the preceding 3 months were reported by all of our patients. Most common were lack of appetite (130/131) and loss of taste (119/131) followed by abdominal pain (104/131), flatulence (102/131), and distention (83/131). Significantly increased AS were found in patients with history of rectal prolapse (p = 0.013), distal intestinal obstruction syndrome (p = 0.013), laparotomy (p = 0.022), meconium ileus (p = 0.037), pancreas insufficiency (p = 0.042), or small bowel resection (p = 0.048) as well as in patients who have been intermittently colonized with P. aeruginosa (p = 0.006) compared to patients without history of these events. In contrast, no statistically significant associations were found to CF-associated liver disease, chronic pathogen colonization, lung function, CF-related diabetes, and nutritional status. CONCLUSION: As the complex abdominal involvement in CF is still not fully understood, the assessment of the common AS is of major interest. In this regard, symptom questionnaires like the herein presented are meaningful and practical tools facilitating a wider understanding of the abdominal symptoms in CF. Furthermore, they render to evaluate possible abdominal effects of novel modulators of the underlying cystic fibrosis transmembrane (conductance) regulator (CFTR) defect.

Clinical approach to the diagnosis and treatment of cystic fibrosis and CFTR-related disorders.

INTRODUCTION: Cystic fibrosis (CF) is the most frequent life-shortening autosomal recessive disorder in Caucasians. Defects or absence of the CF-transmembrane conductance regulator impair ion transport in apical membranes of exocrine glands. Leading symptoms of typical CF are exocrine pancreatic insufficiency and progressive pulmonary destruction, causing premature death. Additionally, patients can suffer from chronic rhinosinusitis, hepatic and intestinal involvement, diabetes and predominantly male infertility. Areas covered: CFTR-related disorders affect only one or several different organ systems, often to a milder degree. The definition and usage of the term has seen some variations in the last years, aiming to improve differentiation of the broad clinical spectrum associated with CFTR defects. In this review we present disease characteristics, diagnostic criteria, and treatment options of CFTR-related disorders for a multidisciplinary readership. Expert commentary: CFTR-related disorders are often diagnosed late, leading to lack of specialized attendance and adequate therapy. In clinical care, monitoring of the nutritional status, lung function, airway pathogen colonization and laboratory parameters is necessary to optimize therapy and the course of the disease.

Pseudomonas aeruginosa Acquisition in Cystic Fibrosis Patients in Context of Otorhinolaryngological Surgery or Dentist Attendance: Case Series and Discussion of Preventive Concepts.

Introduction. P. aeruginosa is the primary cause for pulmonary destruction and premature death in cystic fibrosis (CF). Therefore, prevention of airway colonization with the pathogen, ubiquitously present in water, is essential. Infection of CF patients with P. aeruginosa after dentist treatment was proven and dental unit waterlines were identified as source, suggesting prophylactic measures. For their almost regular sinonasal involvement, CF patients often require otorhinolaryngological (ORL) attendance. Despite some fields around ORL-procedures with comparable risk for acquisition of P. aeruginosa, such CF cases have not yet been reported. We present four CF patients, who primarily acquired P. aeruginosa around ORL surgery, and one around dentist treatment. Additionally, we discuss risks and preventive strategies for CF patients undergoing ORL-treatment. Perils include contact to pathogen-carriers in waiting rooms, instrumentation, suction, drilling, and flushing fluid, when droplets containing pathogens can be nebulized. Postsurgery mucosal damage and debridement impair sinonasal mucociliary clearance, facilitating pathogen proliferation and infestation. Therefore, sinonasal surgery and dentist treatment of CF patients without chronic P. aeruginosa colonization must be linked to repeated microbiological assessment. Further studies must elaborate whether all CF patients undergoing ORL-surgery require antipseudomonal prophylaxis, including nasal lavages containing antibiotics. Altogether, this underestimated risk requires structured prevention protocols.

Dynamics of soluble and cellular inflammatory markers in nasal lavage obtained from cystic fibrosis patients during intravenous antibiotic treatment.

BACKGROUND: In cystic fibrosis (CF) patients, the upper airways display the same ion channel defect as evident in the lungs, resulting in chronic inflammation and infection. Recognition of the sinonasal area as a site of first and persistent infection with pathogens, such as Pseudomonas aeruginosa, reinforces the "one-airway" hypothesis. Therefore, we assessed the effect of systemic antibiotics against pulmonary pathogens on sinonasal inflammation. METHODS: Nasal lavage fluid (NLF) from 17 CF patients was longitudinally collected prior to and during elective intravenous (i.v.) antibiotic treatment to reduce pathogen burden and resulting inflammation (median treatment time at time of analysis: 6 days). Samples were assessed microbiologically and cytologically. Cytokine and chemokine expression was measured by Cytometric Bead Array and ELISA (interleukin (IL)-1ß, IL-6, IL-8, MPO, MMP9, RANTES and NE). Findings were compared with inflammatory markers from NLF obtained from 52 healthy controls. RESULTS: Initially, the total cell count of the NLF was significantly higher in CF patients than in controls. However after i.v. antibiotic treatment it decreased to a normal level. Compared with controls, detection frequencies and absolute concentrations of MPO, IL-8, IL-6 and IL-1ß were also significantly higher in CF patients. The detection frequency of TNF was also higher. Furthermore, during i.v. therapy sinonasal concentrations of IL-6 decreased significantly (P = 0.0059), while RANTES and MMP9 levels decreased 10-fold and two-fold, respectively. PMN-Elastase, assessed for the first time in NFL, did not change during therapy. CONCLUSIONS: Analysis of NLF inflammatory markers revealed considerable differences between controls and CF patients, with significant changes during systemic i.v. AB treatment within just 6 days. Thus, our data support further investigation into the collection of samples from the epithelial surface of the upper airways by nasal lavage as a potential diagnostic and research tool.

Sinonasal inhalation of tobramycin vibrating aerosol in cystic fibrosis patients with upper airway Pseudomonas aeruginosa colonization: results of a randomized, double-blind, placebo-controlled pilot study.

RATIONALE: In cystic fibrosis (CF), the paranasal sinuses are sites of first and persistent colonization by pathogens such as Pseudomonas aeruginosa. Pathogens subsequently descend to the lower airways, with P. aeruginosa remaining the primary cause of premature death in patients with the inherited disease. Unlike conventional aerosols, vibrating aerosols applied with the PARI Sinus™ nebulizer deposit drugs into the paranasal sinuses. This trial assessed the effects of vibrating sinonasal inhalation of the antibiotic tobramycin in CF patients positive for P. aeruginosa in nasal lavage. OBJECTIVES: To evaluate the effects of sinonasal inhalation of tobramycin on P. aeruginosa quantification in nasal lavage; and on patient quality of life, measured with the Sino-Nasal Outcome Test (SNOT-20), and otologic and renal safety and tolerability. METHODS: Patients were randomized to inhalation of tobramycin (80 mg/2 mL) or placebo (2 mL isotonic saline) once daily (4 minutes/nostril) with the PARI Sinus™ nebulizer over 28 days, with all patients eligible for a subsequent course of open-label inhalation of tobramycin for 28 days. Nasal lavage was obtained before starting and 2 days after the end of each treatment period by rinsing each nostril with 10 mL of isotonic saline. RESULTS: Nine patients participated, six initially receiving tobramycin and three placebo. Sinonasal inhalation was well tolerated, with serum tobramycin <0.5 mg/L and stable creatinine. P. aeruginosa quantity decreased in four of six (67%) patients given tobramycin, compared with zero of three given placebo (non-significant). SNOT-20 scores were significantly lower in the tobramycin than in the placebo group (P=0.033). CONCLUSION: Sinonasal inhalation of vibrating antibiotic aerosols appears promising for reducing pathogen colonization of paranasal sinuses and for control of symptoms in patients with CF.

Reduced nasal nitric oxide production in cystic fibrosis patients with elevated systemic inflammation markers.

BACKGROUND: Nitric oxide (NO) is produced within the respiratory tract and can be detected in exhaled bronchial and nasal air. The concentration varies in specific diseases, being elevated in patients with asthma and bronchiectasis, but decreased in primary ciliary dyskinesia. In cystic fibrosis (CF), conflicting data exist on NO levels, which are reported unexplained as either decreased or normal. Functionally, NO production in the paranasal sinuses is considered as a location-specific first-line defence mechanism. The aim of this study was to investigate the correlation between upper and lower airway NO levels and blood inflammatory parameters, CF-pathogen colonisation, and clinical data. METHODS AND FINDINGS: Nasal and bronchial NO concentrations from 57 CF patients were determined using an electrochemical analyser and correlated to pathogen colonisation of the upper and lower airways which were microbiologically assessed from nasal lavage and sputum samples. Statistical analyses were performed with respect to clinical parameters (lung function, BMI), laboratory findings (CRP, leucocytes, total-IgG, fibrinogen), and anti-inflammatory and antibiotic therapy. There were significant correlations between nasal and bronchial NO levels (rho = 0.48, p<0.001), but no correlation between NO levels and specific pathogen colonisation. In patients receiving azithromycin, significantly reduced bronchial NO and a tendency to reduced nasal NO could be found. Interestingly, a significant inverse correlation of nasal NO to CRP (rho = -0.28, p = 0.04) and to leucocytes (rho = -0.41, p = 0.003) was observed. In contrast, bronchial NO levels showed no correlation to clinical or inflammatory parameters. CONCLUSION: Given that NO in the paranasal sinuses is part of the first-line defence mechanism against pathogens, our finding of reduced nasal NO in CF patients with elevated systemic inflammatory markers indicates impaired upper airway defence. This may facilitate further pathogen acquisition in the sinonasal area, with consequences for lung colonisation and the overall outcome in CF.

Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38.

BACKGROUND: Tissue factor (TF), the surface receptor for the serine protease factor VIIa (FVIIa) and the initiator of the extrinsic coagulation cascade, supports vessel development and tumor metastasis by activation of extracellular, protease-dependent signaling pathways. The molecular mechanisms that do not require proteolytic activity of FVIIa are not yet known. The aim of the study, therefore, was to investigate the effects of active-site-inhibited FVIIa (FFR-FVIIa) on TF-mediated signaling. METHODS AND RESULTS: After stimulation with FVIIa and FFR-FVIIa, migration and activation of the GTPase Rac (Rac1) or the mitogen-activated protein kinase p38 (p38) were analyzed in J82 cells. FVIIa and FFR-FVIIa stimulated migration and activation of Rac1 and p38 in a TF-specific, dose- and time-dependent manner. Enhancement of migration required activation of Rac1 and p38, because it was abolished after inhibition with SB203580 or overexpression of dominant negative p38 and Rac1. The cytoplasmic domain of TF was necessary because no effects of FFR-FVIIa could be detected after transfection of a TF deletion mutant lacking the cytoplasmic domain. CONCLUSIONS: We identified a novel signaling pathway through which TF stimulates migration by activation of p38 and Rac1 independent of the proteolytic activity of FVIIa but dependent on the cytoplasmic domain of TF. Binding of FFR-VIIa to TF may stimulate vessel wall remodeling by enhancement of migration through activation of Rac1 and p38. This novel link may provide an insight into the understanding of the nonhemostatic functions of TF.