Macroenzymes as a reason for aminotransferases flare in cystic fibrosis patients on CFTR modulators therapy - Report of three cases.

It has been shown that macro-ALT/macro-AST cause false increase of ALT/AST activity in standard laboratory testing. This short communication presents a group of cystic fibrosis subjects who developed aminotranferases flare a few months after initiation of CFTR modulators therapy. Patients did not present any clinical signs or symptoms of liver failure and differential examination did not show any underlying liver disease. All patients tested positive for macro-ALT and macro-AST. Despite increased and fluctuating ALT/AST activity in standard tests patients restarted CFTR modulators therapy with good clinical effect and do not present any other than hypertransaminasemia signs or symptoms of progressing liver disease. Our data shows that ALT/AST flare during CFTR modulators therapy may be related to macro-ALT/macro-AST, thus patients with high ALT/AST during CFTR modulators therapy should be tested for macro-ALT/macro-AST.

Pulmonary Function Tests in the Evaluation of Early Lung Disease in Cystic Fibrosis.

BACKGROUND: Properly evaluating respiratory system dysfunction is essential in children with cystic fibrosis (CF). This prospective study aimed to assess the course of early lung disease based on multiple breath nitrogen washout (MBNW), impulse oscillometry (IOS), and conventional techniques, such as spirometry and body plethysmography. METHODS: Over a 2 year recruitment period, subjects with CF aged 7-18 performed pulmonary function tests (PFTs). Moreover, the nutritional and microbiological status, frequency of pulmonary exacerbations (PExs), and patients' health-related quality of life (HRQoL) were assessed. RESULTS: The mean age of the children (n = 69) was 14.09 ± 3.26 years; F/M 37/32. Spirometry-based diagnoses of normal lung function (forced expiratory volume in 1 s, FEV1 ≥ 90%pred), mild (FEV1 70-89%pred) and moderate (FEV1 40-69%pred) lung diseases were established in 34 (49.3%), 25 (36.2%), and 10 (14.5%) patients, respectively. An elevated lung clearance index (LCI > 6.98) was observed in 85% of the subjects with normal FEV1. The presence of Pseudomonas aeruginosa infection (n = 16) and the number of PExs treated with IV antibiotics were associated with significantly worse PFT results. CONCLUSIONS: MBNW and IOS are more helpful tools than conventional techniques in assessing early lung disease in CF. LCI is a more useful parameter for detecting functional abnormalities than FEV1 in school-age children.

Efficacy of the Simeox® Airway Clearance Technology in the Homecare Treatment of Children with Clinically Stable Cystic Fibrosis: A Randomized Controlled Trial.

BACKGROUND: Cystic fibrosis (CF) patients require regular airway clearance therapy (ACT). The aim of this study was to evaluate homecare therapeutic effects of a new ACT (Simeox®) added to the optimal standard of care, including home chest physiotherapy, in the treatment of clinically stable children. METHODS: Forty pediatric CF patients (8-17 years old) with stable disease were randomized 1:1 in a single-center, prospective, open-label, cross-over trial into two groups: with or without Simeox®. Lung function (impulse oscillometry, spirometry, body plethysmography, multi-breath nitrogen washout) results, health-related quality of life, and safety were assessed during the study after 1 month of therapy at home. RESULTS: A significant decrease in proximal airway obstruction (as supported by improvement in airway resistance at 20 Hz (R20Hz) and maximum expiratory flow at 75% of FVC (MEF75)) compared to the control group was observed after 1 month of therapy with the device. Lung-clearance index was stable in the study group, while it worsened in the control group. In addition, the device group demonstrated a significant increase in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) physical score. No side effects were identified during the study. CONCLUSIONS: Simeox® may improve drainage of the airways in children with clinically stable CF and could be an option in chronic treatment of the disease.

Lung Clearance Index in Children with Cystic Fibrosis during Pulmonary Exacerbation.

(1) Background: Pulmonary exacerbation (PEx) is one of the main factors affecting the quality of life and life expectancy in patients with cystic fibrosis (CF). Our study aimed to evaluate the change in selected pulmonary function parameters, including lung clearance index (LCI), in patients with CF diagnosed with PEx. (2) Methods: We enrolled 40 children with CF aged 6-17. They performed spirometry and multiple breath nitrogen washout (MBNW) tests during a stable condition period at the beginning and the end of intravenous antibiotic treatment. (3) Results: LCI increased by 65% and FEV1 decreased by ≥10% in 40% of patients with CF during PEx. An absolute change in LCI between a stable condition period and PEx was 1.05 (±1.92) units, which corresponds to a relative change of 11.48% (±18.61) of the baseline. The relative decrease in FEV1 was -9.22% (±12.00) and the z-score was -0.67 (±1.13). After the PEx treatment, FEV1 increased by 11.05% (±9.04) on average, whereas LCI decreased by 1.21 ± 1.59 units on average, which represented 9.42% ± 11.40 compared to the value at the beginning of PEx. (4) Conclusions: The change in LCI captures a higher proportion of events with functional impairment than FEV1 in school-age children with CF.

Metabolomics Comparison of Drug-Resistant and Drug-Susceptible Pseudomonas aeruginosa Strain (Intra- and Extracellular Analysis).

Pseudomonas aeruginosa is a common human pathogen belonging to the ESKAPE group. The multidrug resistance of bacteria is a considerable problem in treating patients and may lead to increased morbidity and mortality rate. The natural resistance in these organisms is caused by the production of specific enzymes and biofilm formation, while acquired resistance is multifactorial. Precise recognition of potential antibiotic resistance on different molecular levels is essential. Metabolomics tools may aid in the observation of the flux of low molecular weight compounds in biochemical pathways yielding additional information about drug-resistant bacteria. In this study, the metabolisms of two P. aeruginosa strains were compared-antibiotic susceptible vs. resistant. Analysis was performed on both intra- and extracellular metabolites. The 1H NMR method was used together with multivariate and univariate data analysis, additionally analysis of the metabolic pathways with the FELLA package was performed. The results revealed the differences in P. aeruginosa metabolism of drug-resistant and drug-susceptible strains and provided direct molecular information about P. aeruginosa response for different types of antibiotics. The most significant differences were found in the turnover of amino acids. This study can be a valuable source of information to complement research on drug resistance in P. aeruginosa.

The effects of the addition of a new airway clearance device to chest physiotherapy in children with cystic fibrosis pulmonary exacerbations.

BACKGROUND: Chest physiotherapy plays a crucial role in managing cystic fibrosis, especially during pulmonary exacerbations. This study evaluated the effects of adding a new airway clearance device to chest physiotherapy in subjects with cystic fibrosis hospitalised due to pulmonary exacerbations. METHODS: This prospective open-label study was carried out at the Pediatric Cystic Fibrosis Centre in Poland between October 2017 and August 2018. Cystic fibrosis patients aged 10 to 18 years who were admitted to the hospital and required intravenous antibiotic therapy due to pulmonary exacerbations were consecutively allocated (1:1) to either chest physiotherapy alone or chest physiotherapy with a new airway clearance device (Simeox; PhysioAssist). Patients performed spirometry and multiple-breath nitrogen washout for lung clearance index assessment upon admission and prior to discharge. RESULTS: Forty-eight cystic fibrosis patients were included (24 in each group). Spirometry parameters in both groups improved significantly after intravenous antibiotic therapy. A significant improvement in the maximum expiratory flow at 25% of forced vital capacity was observed only in the group with a new airway clearance device (p < 0.01 vs. baseline). Trends towards a lower lung clearance index ratio were similar in both groups. No adverse events were observed in either group. CONCLUSIONS: Spirometry parameters increased significantly in cystic fibrosis patients treated for pulmonary exacerbations with intravenous antibiotic therapy and intensive chest physiotherapy. The new airway clearance device was safe and well tolerated when added to chest physiotherapy and may be another option for the treatment of pulmonary exacerbation in cystic fibrosis.

What Is Most Suitable for Children With Cystic Fibrosis-The Relationship Between Spirometry, Oscillometry, and Multiple Breath Nitrogen Washout.

INTRODUCTION: In cystic fibrosis (CF), pathological lung changes begin early in life. The technological progress currently gives many diagnostic possibilities. However, pulmonary function testing in children remains problematic. OBJECTIVES: Our study aimed to correlate the results of impulse oscillometry (IOS) with those of multiple breath nitrogen washout (MBNW) in our pediatric CF population. We also compared those parameters between the groups with and without spirometric features of obturation. METHODS: We collected 150 pulmonary function test sets, including spirometry, IOS, and MBNW in patients with CF aged 12.08 ± 3.85 years [6-18]. The study group was divided into two subgroups: IA (without obturation) and IB (with obturation). We also compared Sacin, Scond, and oscillometry parameters of 20 patients aged 14-18 years who reached the appropriate tidal volume (VT) during MBNW. RESULTS: Statistical analysis showed a negative correlation between lung clearance index (LCI) and spimoetric parameters. Comparison of subgroups IA (n = 102) and IB (n = 48) indicated a statistically significant difference in LCI (p < 0.001) and FEV1z-score (p < 0.001), FEV1% pred (p < 0.001), MEF25z-score (p < 0.001), MEF50 z-score (p < 0.001), MEF75 z-score (p < 0.001), R5% pred (p < 0.05), and R20% pred (p < 0.01). LCI higher than 7.91 was found in 75.33% of the study group, in subgroup IB-91.67%, and IA-67.6%. CONCLUSIONS: LCI derived from MBNW may be a better tool than IOS for assessing pulmonary function in patients with CF, particularly those who cannot perform spirometry.

Lung function deterioration in school children with cystic fibrosis.

INTRODUCTION: Lung disease in cystic fibrosis (CF) begins early in life but the capabilities for detecting abnormalities of pulmonary dysfunction in children remain limited. OBJECTIVE: The study aimed to evaluate the early progression of lung function by the analysis of pulmonary hyperinflation, ventilation inhomogeneity (VI), trapped gas and airway obstruction with age. METHODS: One hundred CF children aged 7 to 18, divided into two groups aged 7 to 12 (n = 40) and 13 to 18 (n = 60), were enrolled. Patients performed multiple-breath nitrogen washout (MBNW) tests and plethysmography for measurements of lung clearance index (LCI), functional residual capacity (FRCpleth , FRCMBNW ), volume of trapped gas (VT ), total resistance, and effective and specific effective airway resistance (Reff , sReff ). RESULTS: We obtained a positive correlation of FRCpleth , FRCMBNW , and LCI with age. A linear correlation between FRCMBNW and FRCpleth (P < .0001) was observed. VI was higher in the group of older patients (9.79 in the group aged 7-12 and 11.67 in the group aged 13-18). An increased effective specific airway resistance >2 (z-score) was present in 58% of all subjects (50% and 63.3%, respectively). Pulmonary hyperinflation (FRCpleth >2 z-score) was observed in 33% of all patients: 25% and 36.6%, respectively. Trapped gas (VT > 2 z-score) was present in 18% of all children: 30% and 10%, respectively. CONCLUSION: A gradual decline in lung function is associated with an increase in VI, airway obstruction, pulmonary hyperinflation and development of trapped gas. In children who cannot perform either spirometry or plethysmography, MBNW can deliver a measurement of LCI connecting with VI as well as FRCMBNW to indicate indirectly the increase of hyperinflation.

Possible metabolic switch between environmental and pathogenic Pseudomonas aeruginosa strains: 1H NMR based metabolomics study.

The study aimed to assess whether Pseudomonas aeruginosa strains from different sources can be distinguished by the metabolomic fingerprint and to check whether antibiotic susceptibility distinctions are available through metabolomic analysis. 1H NMR spectroscopy analysis of the bacteria metabolites was performed. Twenty-nine strains were tested (18 isolated form cystic fibrosis patients and 11 environmental). Thirty-one metabolites were identified, 12 were up-regulated in strains from CF patients, while 2 were higher level in strains from the environment. Changed carbohydrate catabolic metabolism and the metabolic shift toward the utilization of amino acids is suggested in strains from CF patients.

Clinical outcomes for cystic fibrosis patients with Pseudomonas aeruginosa cross-infections.

INTRODUCTION: Pseudomonas aeruginosa cross-infections are related to increased morbidity and mortality in cystic fibrosis (CF). OBJECTIVES: The aim of the study was to evaluate the incidence of cross-infections with P. aeruginosa in children with CF. METHODOLOGY: CF patients from whom at least one P. aeruginosa strain had been isolated were included in the study. The strain genotyping was performed using pulse-field gel electrophoresis. The history of contacts between patients was established based on questionnaires. RESULTS: The study group consisted of 75 patients (aged 1.0-19.2 years) and the material included 170 P. aeruginosa strains. Cross-infections occurred in a group of 26 patients. In this group, the risk of the predicted occurrence of forced expiratory volume in 1 second ≤ 70% was five times greater and the risk of longer cumulative hospitalization time for intravenous antibiotic therapy (>14 days/year) was almost five times greater. In the clonal groups of strains, the multidrug-resistance rate was significantly higher than in other groups. In 2011, all tested strains were susceptible to colistin, whereas in 2012, three strains from the largest clonal group showed high levels of resistance to colistin. CONCLUSION: Cross-infections with P. aeruginosa occurred in our group of patients and were associated with poor clinical outcomes. Antimicrobial resistance rate in the strains isolated from such infections was significantly higher, and this included three strains resistant to colistin.

Metabolomic studies of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a common, Gram-negative environmental organism. It can be a significant pathogenic factor of severe infections in humans, especially in cystic fibrosis patients. Due to its natural resistance to antibiotics and the ability to form biofilms, infection with this pathogen can cause severe therapeutic problems. In recent years, metabolomic studies of P. aeruginosa have been performed. Therefore, in this review, we discussed recent achievements in the use of metabolomics methods in bacterial identification, differentiation, the interconnection between genome and metabolome, the influence of external factors on the bacterial metabolome and identification of new metabolites produced by P. aeruginosa. All of these studies may provide valuable information about metabolic pathways leading to an understanding of the adaptations of bacterial strains to a host environment, which can lead to new drug development and/or elaboration of new treatment and diagnostics strategies for Pseudomonas.

Change in lung clearance index with microbiological status in children with cystic fibrosis.

The impact of infections caused by bacteria, especially Gram-negative, on the progression of lung disease in cystic fibrosis is well established. Decline in pulmonary function commence already at early age. In this group of patients, the lung clearance index seems to be a better marker than FEV1 allowing non-invasive monitoring of changes in small airways. The aim of this study was to investigate the association between the microbiological status and LCI derived from multiple breath washout (MBW) technique as well as FEV1 and FVC in children suffering from cystic fibrosis. Over the 1-year recruitment period, 136 CF patients aged 5-18 with: Staphylococcus aureus (n-27), Pseudomonas aeruginosa (first time (n-27), intermittent (n-9), and chronic (34) infection), Aspergillus fumigatus (n-6) and without pathogenic flora (n-33) were included in the study. Patients had performed a spirometry and MBW test during the visit at outpatient clinic. The study showed that the lung clearance index in patients infected with Aspergillus fumigatus was significantly higher (P < 0.05) than in those with normal throat flora. There was also statistically significant differences in the lung clearance index obtained in subjects with chronic Pseudomonas aeruginosa infection and those with first Pseudomonas aeruginosa infection (P < 0.05). Furthermore, significant statistical differences (P < 0.05) were observed between the groups of patients with chronic Pseudomonas aeruginosa infection FEV1 > 70% and FEV1 < 70%. In conclusion, LCI was associated with microbiological status of CF patients. Chronic lung infections, especially Aspergillus fumigatus and Pseudomonas aeruginosa, were associated with increased LCI. Early eradication of pathological flora positively affects the maintenance of lower LCI.

Cross-infections with Pseudomonas aeruginosa in patients with cystic fibrosis attending the Warsaw Centre.

AIM: 1. To assess the prevalence of cross-infections with P. aeruginosa in order to evaluate the epidemiological situation of this infection in patients with cystic fibrosis attending our centre; 2. To correlate the clinical features of the patients carrying a potentially transmissible strain with the entire study group in order to determine the risk factors and possible effects of its acquisition. MATERIAL AND METHODS: 170 Pseudomonas aeruginosa strains obtained from the respiratory tract of 75 cystic fibrosis patients attending the Warsaw Centre in 2011 and 2012 were typed using restriction enzyme analysis-pulsed field gel electrophoresis (Spe I restriction enzyme was used). Simultaneously, the information concerning contacts between patients, as well as several clinical data regarding the course of the disease were collected. RESULTS: Twenty four clusters of strains were detected. The main cluster included 49 isolates derived from 21 patients. The other detected clusters included 2 to 12 isolates derived from 1 to 7 patients. Three clusters comprised the isolates derived from three pairs of siblings. There were 15 clusters containing 2 to 7 strains belonging to the same patient. The remaining 24 patients were infected with their own strains, not fitting any clonal group. Several clinical parameters showed that the 21 patients whose strains constituted the main cluster, were in worse clinical condition than the other patients in the study group. Moreover, the total duration of their hospitalizations in order to perform intravenous antibiotic treatment was longer. CONCLUSIONS: 1. Frequent hospitalizations of CF patients with a more severe course of the disease seem to be a risk factor of cross-infections with P. aeruginosa. 2. Intensification of measures to prevent cross-infection, such as hygienic precautions, patient segregation, introduction of home intravenous antibiotic therapy programme, as well as further education of patients and their parents should lead to the improvement of the epidemiological situation in our centre. .

Surgeon's viewpoint on lung transplantation in cystic fibrosis patients - preliminary report.

INTRODUCTION: The surgeon's viewpoint on a patient with cystic fibrosis differs from that of a pediatrician or internist. The problems a cystic fibrosis specialist encounters are different from those faced by the surgeon who takes over the patient in a very advanced, often terminal stage of the disease. Hence, the main problem for the surgeon is the decision concerning the surgery (lung transplantation, pneumonectomy, lobectomy). It is, therefore, important to lay down fundamental and appropriate rules concerning the indications and contraindications for lung transplantation, especially in patients with cystic fibrosis. AIM: The aim of this study was to analyze the methods of qualifying and preparing patients for surgery, as well as carrying out the procedure of transplantation and postoperative short and long-term care. MATERIAL AND METHODS: The investigation was carried out on 16 patients with cystic fibrosis. Three were operated on and 10 were on the waiting list for transplantation. Two patients on the waiting list died, one patient was disqualified from transplantation. During qualification for lung transplantation, strict indications, contraindications and other factors (such as blood type, patient's height, coexisting complications) were taken under consideration. RESULTS: All the 3 patients after lung transplantation are alive and under our constant surveillance. Ten patients await transplantation, though four of them are suspended due to hepatitis C infection. Two patients on the waiting list died: one from respiratory insufficiency and the other in the course of bridge to-transplant veno-venous extracorporeal membrane oxygenation due to hepatic failure. One patient has been disqualified because of cachexia. CONCLUSIONS: Since lung transplantation is the final treatment of the end-stage pulmonary insufficiency in cystic fibrosis patients, the number of such procedures in cystic fibrosis is still too low in Poland. The fast development of these procedures is highly needed. It is necessary to develop better cooperation between different disciplines and specialists, especially between pediatricians and surgeons. The correct choice of the suitable moment for lung transplantation is crucial for the success of the procedure.

[Immunological response (IgM) to Legionella pneumophila infection in children]. / Odpowiedz odpornosciowa w klasie IgM na zakazenie Legionella pneumophila u dzieci.

Most of the publications report cases of Legionella infection among adults. In our studies the level of IgM to Legionella pneumophila sg 1 was determined by ELISA method in serum samples of 144 children with symptoms of respiratory tract infections. Children were from 5 months to 18 years old. The significant level of IgM was found in 41 sera collected from 34 children aged 2 years and above. There were samples collected from 21 girls and 13 boys. The highest percentage of significant level of IgM was found in the age group 4-10 years (31.8%) and 10-14 years (31.7%). Among the youngest children (below 2 years) the equivocal results were found in 6 samples. The significant difference in IgM level was found between the children age groups. There was not found the significant differences in IgM level depending on gender. Obtained results indicated the importance of such kind of studies and necessity of adjusting cut-off values to age groups of children.