Long-term pulmonary outcomes of young adults born prematurely: a Polish prospective cohort study PREMATURITAS 20.

BACKGROUND: The long-term consequences of prematurity are often not sufficiently recognized. To address this gap, a prospective cohort study, which is a continuation of the multicenter Polish study PREMATURITAS, was conducted, utilizing unique clinical data from 20 years ago. OBJECTIVE: The main goal was to evaluate lung function, detect any structural abnormalities using lung ultrasound, and assess psychological well-being in young adults born between 24 and 34 weeks of gestational age (GA). Additionally, the study aimed to investigate potential associations between perinatal risk factors and abnormalities observed in pulmonary function tests (PFTs) during adulthood. METHODS: The young survivors underwent a comprehensive set of PFTs, a lung ultrasound, along with the quality of life assessment. Information regarding the neonatal period and respiratory complications was obtained from the baseline data collected in the PREMATURITAS study. RESULTS: A total of 52 young adults, with a mean age of 21.6 years, underwent PFTs. They were divided into two groups based on GA: 24-28 weeks (n = 12) and 29-34 weeks (n = 40). The subgroup born more prematurely had significantly higher lung clearance index (LCI), compared to the other subgroup (p = 0.013). LCI ≥ 6.99 was more frequently observed in the more premature group (50% vs. 12.5%, p = 0.005), those who did not receive prenatal steroids (p = 0.020), with a diagnosis of Respiratory Distress Syndrome (p = 0.034), those who received surfactant (p = 0.026), and mechanically ventilated ≥ 7 days (p = 0.005). Additionally, elevated LCI was associated with the diagnosis of asthma (p = 0.010). CONCLUSIONS: The findings suggest pulmonary effects due to prematurity persist into adulthood and their insult on small airway function. Regular follow-up evaluations of young survivors born preterm should include assessments of PFTs. Specifically, the use of LCI can provide valuable insights into long-term pulmonary impairment.

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.

Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward.

BACKGROUND: Newborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out. MATERIALS/PATIENTS AND METHODS: We report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4-13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients. RESULTS: Extensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T). CONCLUSION: This study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening.

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.

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.

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.

[Silent lung zone - application of multi-breath nitrogen washout test (MBNW) in the diagnosis of small airways diseases in children - preliminary report based on literature and own experience].

Small airways are the site of pathological changes often in an early stage in many diseases such as asthma or cystic fibrosis. However this part of the airways is overlooked in conventional respiratory function tests and it is therefore often referred to as "silent lung zone". This paper presents the theoretical background of MBNW multi-breath nitrogen washout in the diagnosis of minor respiratory diseases. The technical issues related to the preparation of pediatric patients for the test. Clinical applications of the MBNW test results are still subject to a number of studies. There is hope for filling the gaps in the small airway function tests. Due to the authors' involvement in the diagnosis and treatment of patients with cystic fibrosis, their own experience in the use of this study was also described. Currently, the method is in the phase of intensive analysis for the early diagnosis of lung disease in cystic fibrosis, when still other functional tests are in normal range or impossible to perform due to patient age. Correlation with medical imaging methods (chest computed tomography) and the severity of structural changes may in future limit the amount of radiology tests. In addition this can reduce the patient's exposure to ionizing radiation. Introduction of lung function tests such a MBW in infants and preschool children with cystic fibrosis and other minor respiratory diseases may modify clinical management and improve prognosis.

Characterization and Optimization of Biosynthesis of Bioactive Secondary Metabolites Produced by Streptomyces sp. 8812.

The nutritional requirements and environmental conditions for a submerged culture of Streptomyces sp. 8812 were determined. Batch and fed-batch Streptomyces sp. 8812 fermentations were conducted to obtain high activity of secondary metabolites. In the study several factors were examined for their influence on the biosynthesis of the active metabolites-7-hydroxy-6-oxo-2,3,4,6-tetrahydroisoquinoline-3-carboxy acid (C10H9NO4) and N-acetyl-3,4-dihydroxy-L-phenylalanine (C11H13NO5): changes in medium composition, pH of production medium, various growth phases of seed culture, amino acid supplementation and addition of anion exchange resin to the submerged culture. Biological activities of secondary metabolites were examined with the use of DD-carboxypeptidase 64-575 and horseradish peroxidase. Streptomyces sp. 8812 mycelium was evaluated under fluorescent microscopy and respiratory activity of the strain was analyzed. Moreover, the enzymatic profiles of the strain with the use of Api ZYM test were analyzed and genetic analysis made. Phylogenetic analysis of Streptomyces sp. 8812 revealed that its closest relative is Streptomyces capoamus JCM 4734 (98%), whereas sequence analysis for 16S rRNA gene using NCBI BLAST algorithm showed 100% homology between these two strains. Biosynthetic processes, mycelium growth and enzyme inhibitory activities of these two strains were also compared.

SYNTHETIC DERIVATIVES OF ISOQUINOLINE, DICARBOXYLIC ACID IMIDES AND THIOIMIDES AS BIOACTIVE COMPOUNDS.

This study is a continuation of a research program aimed at identifying potent drugs against bacterial infections, in which a series of organic compounds: dicarboxylic acid imides and thioimides, isoquinoline derivatives and open chain compounds, were examined for antimicrobial properties against Staphylococcus auneus and Escheiichia coli. In effect of this investigation, the most active compounds (35-40, 47) were selected for in vitiv tests against fourteen clinically important pathogenic isolates, the methicillin resistant Staphylococcus aueus (MRSA) and several reference Gram-negative bacteria: Prteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumonia, Stenonophoinonas inaltophilia, and Acinetobacter baumannii. The obtained data revealed that seven compounds (three dithioimides, 35, 39, 47, and four thioimides, 36-38, 40) exhibit effective antibacterial activity against the tested Staphylococcus auirus MSSA and MRSA strains. Among them, dicarboxylic acid thioimides 37 and 38 were proven to be the most active.

New derivatives of 3,4-dihydroisoquinoline-3-carboxylic acid with free-radical scavenging, D-amino acid oxidase, acetylcholinesterase and butyrylcholinesterase inhibitory activity.

A series of 3,4-dihydroisoquinoline-3-carboxylic acid derivatives were synthesised and tested for their free-radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS·+), superoxide anion radical (O2·-) and nitric oxide radical (·NO) assays. We also studied d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Almost each of newly synthesised compounds exhibited radical scavenging capabilities. Moreover, several compounds showed moderate inhibitory activities against DAAO, AChE and BuChE. Compounds with significant free-radical scavenging activity may be potential candidates for therapeutics used in oxidative-stress-related diseases.