Gut microbiota in adults with cystic fibrosis: Implications for the severity of the CFTR gene mutation and nutritional status.

BACKGROUND: Microbial dysbiosis has been linked to cystic fibrosis (CF); however, the composition of gut microbiota in adult CF patients in relation to severity of CF transmembrane conductance regulator (CFTR) gene mutation and nutritional status have not yet been explored. Study aimed to assess the gut microbiota composition in adults with CF, and its relationship with the severity of CFTR mutations, and BMI. METHODS: Gut microbiota of 41 adults with CF, and 26 non-CF controls were compared using whole 16S rRNA gene sequencing. Differences in the microbial community between groups of patients classified according to the severity of CFTR mutations, and BMI were assessed. The alpha diversity, beta diversity, and taxa abundance were identified to reflect gut microbiota composition. RESULTS: Results showed a significant decrease in alpha diversity of bacterial communities in CF compared to non-CF group, but no significant difference between the CF groups distinguished by the severity of CFTR mutations. However, more severe mutations were associated with the higher relative abundance of Bacteroides and Streptococcus and the lower relative abundance of Faecalibacterium and Blautia. Undernourished CF patients showed significantly lower alpha diversity compared to non-CF group and CF patients with BMI within the norm. Significant differences in the structure of the gut microbiota between CF and non-CF groups, as well as between BMI groups were also found. CONCLUSIONS: Our research indicates that CF is associated with alterations in gut microbiota in adults. Additionally, in adult CF patients, the composition of the gut microbiota is also related to BMI.

Fat-Soluble Vitamins in Standard vs. Liposomal Form Enriched with Vitamin K2 in Cystic Fibrosis: A Randomized Multi-Center Trial.

BACKGROUND: We aimed to assess a liposomal fat-soluble vitamin formulation containing vitamin K2 with standard treatment in cystic fibrosis (CF). METHODS: A multi-center randomized controlled trial was carried out in 100 pancreatic-insufficient patients with CF. The liposomal formulation contained vitamin A as retinyl palmitate (2667 IU daily) and beta-carotene (1333 IU), D3 (4000 IU), E (150 IU), K1 (2 mg), and K2 as menaquinone-7 (400 µg). It was compared with the standard vitamin preparations in the closest possible doses (2500 IU, 1428 IU, 4000 IU, 150 IU, 2.14 mg, respectively; no vitamin K2) over 3 months. RESULTS: Forty-two patients finished the trial in the liposomal and 49 in the control group (overall 91 pts: 22.6 ± 7.6 years, 62.6% female, BMI 19.9 ± 2.8 kg/m2, FEV1% 70% ± 30%). The main outcome was the change of vitamin status in the serum during the study (liposomal vs. standard): all-trans-retinol (+1.48 ± 95.9 vs. -43.1 ± 121.4 ng/mL, p = 0.054), 25-hydroxyvitamin D3 (+9.7 ± 13.4 vs. +2.0 ± 9.8 ng/mL, p = 0.004), α-tocopherol (+1.5 ± 2.5 vs. -0.2 ± 1.6 µg/mL, p < 0.001), %undercarboxylated osteocalcin (-17.2 ± 24.8% vs. -8.3 ± 18.5%, p = 0.061). The secondary outcome was the vitamin status at the trial end: all-trans-retinol (370.0 ± 116.5 vs. 323.1 ± 100.6 ng/mL, p = 0.045), 25-hydroxyvitamin D3 (43.2 ± 16.6 vs. 32.7 ± 11.5 ng/mL, p < 0.001), α-tocopherol (9.0 ± 3.1 vs. 7.7 ± 3.0 µg/mL, p = 0.037), %undercarboxylated osteocalcin (13.0 ± 11.2% vs. 22.7 ± 22.0%, p = 0.008). CONCLUSION: The liposomal fat-soluble vitamin supplement containing vitamin K2 was superior to the standard form in delivering vitamin D3 and E in pancreatic-insufficient patients with CF. The supplement was also more effective in strengthening vitamin K-dependent carboxylation, and could improve vitamin A status.

Preclinical atherosclerosis in cystic fibrosis: Two distinct presentations are related to pancreatic status.

BACKGROUND: Patients with cystic fibrosis (CF) are exposed to overlapping cardiovascular risk factors. We hypothesized that CF is characterized by increased arterial stiffness and greater intima-media thickness (IMT). METHODS: This cross-sectional study assessed the digital volume pulse arterial stiffness index (SIDVP) using photopletysmography, measured intima-media complex thickness (IMT) at the common carotid artery, and obtained an extended set of clinical and atherosclerosis-related laboratory parameters. RESULTS: Fifty-five patients with moderate-to-severe CF (mean age 26.3±8.6 years, BMI 20.3±3.1 kg/m2, FEV1 62±26%) and 51 healthy controls (25.1±4.4 years, BMI 21.7±3.0 kg/m2) entered the study. SIDVP was greater in pancreatic insufficient (PI), but not pancreatic sufficient (PS) CF patients compared with control (7.3±1.8 m/s vs 6.0±1.2 m/s; p=7.1 × 10-5). IMT was increased in PS (but not PI) participants relative to control (552±69 µm vs 456±95 µm, p=0.0011). SIDVP was also greater in PI than in PS patients (7.3±1.8 m/s vs 6.3±1.7 m/s, p=0.0232) and IMT was higher in PS compared with PI (552±69 µm vs 453±82 µm, p=0.0002). SIDVP independently associated with age, PI, the lack of liver cirrhosis, and with Pseudomonas aeruginosa colonization. PS was the only independent correlate of IMT in CF. CONCLUSIONS: PI patients are at risk of developing general arterial stiffness. PS may relate to carotid IMT thickening, which underscores the need for further study that could lead to reconsideration of dietary guidance in PS CF.

The determinants of survival among adults with cystic fibrosis-a cohort study.

BACKGROUND: Cystic fibrosis (CF) is one of the most common autosomal recessive diseases. Factors contributing to disease exacerbations and survival rate of CF patients are type of mutation in the CFTR gene, poor nutritional status, lung failure, and infection development by Pseudomonas aeruginosa. The study aimed to evaluate the relationship between the severity of mutation, nutritional status, lung function, and Pseudomonas aeruginosa prevalence and survival rate in adult patients with cystic fibrosis. METHODS: A study of 124 (68 ♀ and 56 ♂) adults with CF aged 18-51 years were evaluated for (a) type of mutation in the CFTR gene, (b) nutritional status (BMI), (c) lung function (FEV1%), and (d) Pseudomonas aeruginosa prevalence. For statistical calculations, Kaplan-Meier analysis of survival, chi-squared test for multiple samples, and logistic regression were used. RESULTS: The type of mutation (χ2 = 12.73, df = 3, p = 0.005), FEV1% (χ2 = 15.20, df = 2, p = 0.0005), Pseudomonas aeruginosa prevalence (χ2 = 11.48, df = 3, p = 0.009), and BMI (χ2 = 31.08, df = 4, p < 0.000) significantly differentiated the probability of survival of patients with CF. The shortest life expectancy was observed in patients with a severe type of mutation on both alleles, FEV1% < 40, subjects in whom Pseudomonas culture was extensively drug-resistant or pandrug-resistant, and patients whose BMI was lower than 18.5 kg/m2. The period from 30 to 40 years of age was the most critical in CF adults' lifespan. The risk of adults with CF death doubled with Pseudomonas aeruginosa prevalence (OR = 2.06, 95% CI 1.29; 2.28) and eightfold when the bacteria acquired antibiotic resistance (OR = 8.11, 95% CI 1.67; 38.15). CONCLUSIONS: All factors included in the study were significantly related to the survival rate of patients with cystic fibrosis.

Pseudomonas aeruginosa, the type of mutation, lung function, and nutritional status in adults with cystic fibrosis.

OBJECTIVE: The aim of this study was to describe the relationship between the prevalence of Pseudomonas aeruginosa (PA) and lung function, as well as the nutritional status and type of gene mutation in adult patients with cystic fibrosis (CF). METHODS: This cross-sectional study evaluated 103 Polish adults with CF the following: • The occurrence of PA and the level of bacterial susceptibility to antibiotics; • Type of mutation in the CFTR gene; • Nutritional status assessed by body mass index (BMI), and • Lung function measured by forced expiratory volume in 1 s (FEV1%). RESULTS: The absence or presence of PA and the level of bacterial resistance were significantly related to the type of gene mutation (P < 0.001). In patients with a severe mutation, PA more often was extensively drug resistant or pandrug resistant compared with Pseudomonas culture-negative patients or patients with mild or unclassified mutations on both alleles. Associations were found between the presence of PA and lower values of BMI (P < 0.001), and FEV1% (P < 0.001). The risk for PA occurrence and the development of bacterial resistance increased twice in the case of severe mutation (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.62-3.89), four times when BMI decreased <18.5 (OR, 4.15; 95% CI, 1.43-10.08). and six times when FEV1% fell <40 (OR, 6.75; 95% CI, 3.11-14.64). CONCLUSIONS: The presence of PA is associated with lower FEV1% and BMI values. Deterioration of lung function, undernutrition, and severe type of gene mutation are linked to a higher probability of PA acquisition and resistance to antibiotic treatment.

Severe Genotype, Pancreatic Insufficiency and Low Dose of Pancreatic Enzymes Associate with Abnormal Serum Sterol Profile in Cystic Fibrosis.

BACKGROUND: Several factors could lead to lipid disturbances observed in cystic fibrosis (CF). This study aimed to assess sterol homeostasis in CF and define potential exogenous and endogenous determinants of lipid dysregulation. METHODS: The study involved 55 CF patients and 45 healthy subjects (HS). Sterol concentrations (µg/dL) were measured by gas chromatography/mass spectrometry. CF was characterised by lung function, pancreatic status, liver disease and diabetes coexistence, Pseudomonas aeruginosa colonisation and BMI. CFTR genotypes were classified as severe or other. RESULTS: Campesterol and ß-sitosterol concentrations were lower (p = 0.0028 and p < 0.0001, respectively) and lathosterol levels (reflecting endogenous cholesterol biosynthesis) were higher (p = 0.0016) in CF patients than in HS. Campesterol and ß-sitosterol concentrations were lower in patients with a severe CFTR genotype, pancreatic insufficiency and lower pancreatic enzyme dose (lipase units/gram of fat). In multiple regression analyses, ß-sitosterol and campesterol concentrations were predicted by genotype and pancreatic insufficiency, whereas cholesterol and its fractions were predicted by phytosterol concentrations, age, dose of pancreatic enzymes, nutritional status and genotype. CONCLUSIONS: Independent determinants of lipid status suggest that malabsorption and pancreatic enzyme supplementation play a significant role in sterol abnormalities. The measurement of campesterol and ß-sitosterol concentrations in CF patients may serve for the assessment of the effectiveness of pancreatic enzyme replacement therapy and/or compliance, but further research is required.

Leukocyte Telomere Length Is Not Reduced in Children and Adults with Cystic Fibrosis but Associates with Clinical Characteristics-A Cross-Sectional Study.

We hypothezied that telomere length is considerably altered in cystic fibrosis (CF) patients compared to healthy subjects (HS), and that leukocyte telomere length variation reflects the severity of CF. Relative telomere length (RTL) was assessed by qPCR in 70 children aged 5-10 (34 CF; 36 HS) and 114 adults aged 18-45 (53 CF; 61 HS). Telomere length was similar in CF and HS (median (interquartile range): 0.799 (0.686-0.950) vs. 0.831 (0.707-0.986); p = 0.5283) both in children and adults. In adults, women had longer telomeres than men (0.805 (0.715-0.931) vs. 0.703 (0.574-0.790); p = 0.0002). Patients treated with inhaled corticosteroids had a shorter RTL compared to those without steroid therapy (0.765 (0.664-0.910) vs. 0.943 (0.813-1.191); p = 0.0007) and this finding remained significant after adjusting for gender, age, BMI, and child/adult status (p = 0.0003). Shorter telomeres were independently associated with the presence of comorbidities (0.763 (0.643-0.905) vs. 0.950 (0.783-1.130); p = 0.0006) and antibiotic treatment at the moment of blood sampling (0.762 (0.648-0.908) vs. 0.832 (0.748-1.129); p = 0.0172). RTL correlated with number of multiple-day hospitalizations (rho = -0.251; p = 0.0239), as well as number of hospitalization days (rho = -0.279; p = 0.0113). Leukocyte RTL in children and adults with CF was not shorter than in healthy controls, and did not seem to have any potential as a predictor of CF survival. However, it inversely associated with the investigated clinical characteristics.

The effectiveness of bronchial artery embolisation in patients with haemoptysis.

INTRODUCTION: Bronchial artery embolisation (BAE) is one of the methods used in massive and recurring haemoptysis. The aim of the study is to determine the effectiveness and complications of bronchial artery embolisation in recurring haemoptysis. MATERIAL AND METHODS: The analysis included 47 embolisation procedures performed on 30 patients treated between 2011 and 2017 in the Department of Respiratory Medicine, Allergology and Pulmonary Oncology due to haemoptysis. The patient's age ranged between 18 and 71 years, while mean age at the time of BAE was 33.5 years. Patients with tuberculosis constituted 73.33% (n = 22) of the sample and underwent 31 embolisation procedures in total. The remaining part of the sample (n = 8) collectively underwent 16 BAEs. The analysis was conducted by verifying the medical documentation, as well as carrying face-to-face and phone conversations. RESULTS: Immediate control due to the inhibition of bleeding was obtained in 95.75% of cases. Recurrence within 3 days of BAE was reported in 5 patients (10.63%), and 4 re-embolisation procedures were conducted. In 10 patients (33.33%), recurrence was observed during the first year post-BAE, while it was reported in 17 cases during the whole observation period (56.66% of patients). The subjects who underwent re-embolisation demonstrated recurrence-free periods lasting from 2 days to 63 months. In patients with recurrence but no re-embolisation, the shortest and longest haemoptysis-free time was 2 and 35 months, respectively. 11 patients (36.66%) required several embolisation procedures during the whole observation period. CONCLUSIONS: BAE is a highly successful procedure in treating haemoptysis. The risk of complications is low.

Enhanced Suppressive Activity of Regulatory T Cells in the Microenvironment of Malignant Pleural Effusions.

Cancer metastatic spread to serous cavity causes malignant pleural effusions (MPEs), indicating dismal prognosis. Tumor microenvironment can implement suppressive activity on host immune responses. Thus, we investigated the prevalence of Tregs and the relationship between them and TGF-ß and IL-10 concentrations and measured expression of FOXP3, CTLA-4, CD28, and GITR genes, as well as protein expression of selected genes in benign effusions and MPEs. The percentage of Tregs was determined by means of multicolor flow cytometry system. TGF-ß and IL-10 concentrations were measured using human TGF-ß1 and IL-10 ELISA kit. Relative mRNA expression of studied genes was analyzed by real-time PCR. The frequency of Tregs was significantly higher in MPEs compared to benign effusions; however, the level of TGF-ß and IL-10 in analyzed groups was comparable, and no correlation between concentrations of TGF-ß and IL-10 and percentage of Tregs was observed. Relative mRNA expression of all the genes was higher in CD4+CD25+ compared to CD4+CD25- cells. In CD4+CD25+ cells from MPEs, relative mRNA expression of FOXP3, CTLA-4, and CD28 genes was significantly higher than in benign effusions; however, the level of CD4+CD25+CTLA-4+ cells in analyzed groups showed no significant differences. We found numerous genes correlations in an entire CD4+CD25+ cell subset and CD4+CD25+ cells from MPEs. Enhanced suppressive activity of Tregs is observed in the microenvironment of MPEs. Understanding of relations between cellular and cytokine immunosuppressive factors in tumor microenvironment may determine success of anticancer response.

Congruence Between Pulmonary Function and Computed Tomography Imaging Assessment of Cystic Fibrosis Severity.

In cystic fibrosis, pulmonary function tests (PFTs) and computed tomography are used to assess lung function and structure, respectively. Although both techniques of assessment are congruent there are lingering doubts about which PFTs variables show the best congruence with computed tomography scoring. In this study we addressed the issue by reinvestigating the association between PFTs variables and the score of changes seen in computed tomography scans in patients with cystic fibrosis with and without pulmonary exacerbation. This retrospective study comprised 40 patients in whom PFTs and computed tomography were performed no longer than 3 weeks apart. Images (inspiratory: 0.625 mm slice thickness, 0.625 mm interval; expiratory: 1.250 mm slice thickness, 10 mm interval) were evaluated with the Bhalla scoring system. The most frequent structural abnormality found in scans were bronchiectases and peribronchial thickening. The strongest relationship was found between the Bhalla sore and forced expiratory volume in 1 s (FEV1). The Bhalla sore also was related to forced vital capacity (FVC), FEV1/FVC ratio, residual volume (RV), and RV/total lung capacity (TLC) ratio. We conclude that lung structural data obtained from the computed tomography examination are highly congruent to lung function data. Thus, computed tomography imaging may supersede functional assessment in cases of poor compliance with spirometry procedures in the lederly or children. Computed tomography also seems more sensitive than PFTs in the assessment of cystic fibrosis progression. Moreover, in early phases of cystic fibrosis, computed tomography, due to its excellent resolution, may be irreplaceable in monitoring pulmonary damage.

Interstitial pneumonia with autoimmune features (IPAF) and radiological findings suggestive of lymphocytic interstitial pneumonia (LIP) - case report.

Interstitial pneumonia with autoimmune features (IPAF) is a term to describe individuals with both interstitial lung disease (ILD) and combinations of other clinical, serologic, and/or pulmonary morphologic features, which presumably originate from an underlying systemic autoimmune condition, but do not meet current rheumatologic criteria for a defined connective tissue disease (CTD). Predominantly, interstitial pneumonia arises in the course of an established CTD, but it is not so rare for the ILD to be the first, and possibly the one and only manifestation of a latent CTD. Lymphocytic Interstitial Pneumonia (LIP) is an uncommon disease, characterized by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes, plasma cells and other lymphoreticular elements. The cause of LIP is still unknown but it could be also a manifestation of CTD. Clinically, it is highly variable, from spontaneous resolution to progressive respiratory failure and death despite glucocorticoid treatment. Since there are no recent standards for the management of LIP, the disease is treated empirically. We report a case of a HIV-negative 54-year-old woman, who was suspected of LIP according to clinical features and radiological findings. Positive laboratory results were highly suggestive of underlying autoimmune process, but did not fulfil the criteria of any particular CTD. Because of severe general condition of the patient, immunosuppressive treatment was started immediately, without further invasive diagnostics including lung biopsy, which is required for a definitive diagnosis. We present two-year observation of the patient with all our doubts concerning clinical proceedings.

Small Airway Obstruction in Chronic Obstructive Pulmonary Disease: Potential Parameters for Early Detection.

The impulse oscillometry (IOS) is recognized as a complementary method to spirometry in the diagnostics of obstructive pulmonary disorders. The IOS enables to measure total respiratory resistance (R5) and proximal respiratory resistance (R20), with the R5-R20 difference reflecting small airway resistance. This study seeks to evaluate the usefulness of R5-R20, maximal mid-expiratory flow (MMEF), and forced expiratory volume in 3 s/forced vital capacity ratio (FEV3/FVC), in the assessment of small airway obstruction in chronic obstructive pulmonary disease (COPD). One hundred and six COPD patients and 43 control subjects, aged over 55, were investigated. Spirometry and IOS were used to assess pulmonary function. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were evaluated. The findings demonstrate significant reductions in FEV3/FVC and MMEF, and an increase in R5-R20 difference in COPD patients; the changes that depended on the severity of airway obstruction. The sensitivity of R5-R20 in reflecting the MMEF was 84%, specificity 44.2%, PPV 72.4%, and NPV 61.3%. We conclude that the R5-R20 difference is superior to spirometry in the assessment of small bronchi obstruction. A high sensitivity of R5-R20 in reflecting the MMEF makes the IOS method particularly useful for detection of mild lung injury, while a high specificity of the spirometric FEV3/FVC ratio makes it useful to exclude obstruction of small airways. Both methods are thus complimentary.

C-MET inhibitors in the treatment of lung cancer.

OPINION STATEMENT: Lung cancer is the most common malignant neoplasm and constitutes the most common neoplastic cause of death globally. The results of therapies employing standard chemotherapy are unsatisfactory. Currently, efforts are being made to personalize the therapy; numerous clinical studies are being conducted around the world to assess the efficacy and safety of agents directed at molecular targets. One of these molecular targets is the c-MET proto-oncogene, whose primary ligand is hepatocyte growth factor (HGF). C-MET hyperactivity has been observed in numerous neoplasms, including non-small-cell lung carcinoma. Prolonged or continuous activity of the receptor leads to excessive cell proliferation and is related to the development or progression of neoplastic disease. C-MET inhibitors can be classified into three groups: small-molecule tyrosine kinase inhibitors of the c-MET receptor (crizotinib, tivantinib, cabozantinib, foretinib), as well as monoclonal antibodies against c-MET (onartuzumab) and against the HGF ligand (ficlatuzumab, rilotumumab). The efficacy and safety of these agents is assessed both in monotherapy and in combination with other molecularly targeted agents. Furthermore, the toxicity profile of c-MET inhibitors is completely different from that of standard chemotherapy. The best understood c-MET inhibitor used in the treatment of non-small-cell lung carcinoma patients is crizotinib. It is registered for patients with the presence of ALK gene rearrangements after the failure of the first line of treatment based on platinum derivatives. The purpose of this present paper is to present clinical studies that assessed the efficacy and safety of c-MET inhibitors for the treatment of non-small-cell lung carcinoma, as well as current indications for the use of these molecules.

Actual status of therapeutic vaccination in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related death worldwide. Although treatment methods such as surgery, radiotherapy and/or chemotherapy have improved, prognosis remains unsatisfactory, and developing new therapeutic strategies is still an urgent matter. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumour cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumour antigens have shown this method to work only in a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumour cells because they evade host immune control.

The PK/PD index (CMAX/MIC) for ciprofloxacin in patients with cystic fibrosis.

In order to evaluate the efficacy of an antibacterial therapy, three basic PK/PD indexes were defined: the ratio between the maximum drug concentration obtained after a single dose and minimum inhibitory concentration MIC (CMAX/MIC), the ratio between the area under the curve of dependence between the drug concentration in blood and time within 24 hours to MIC (AUC24/MIC), and the time when the concentration of the drug in blood is higher than MIC (T > MIC). The aim of the study was an analysis of the pharmacokinetics of ciprofloxacin and the PK/PD: CMAX/MIC index in patients with cystic fibrosis. Six patients with cystic fibrosis, with the identified microbiological factor were subjected to the examination. The patients received ciprofloxacin in the dose of 400 mg/12 h (i.v.). Plasma drug concentration was measured by HPLC-UV method after the first dose (Cmax1) and at steady state (Cssmax, Cssmin). The following mean values of ciprofloxacin blood concentrations were obtained from the analyzed patients: Cmax1 = 2.34 (+/- 1.15) microg/mL, Cssmax = 2.49 (+/- 1.44) pg/mL, Cssmin = 0.42 (+/- 0.22) pg/mL. The mean values of the Cmax1/MIC and Cssmax/MIC indexes were 3.66 +/- 2.34) and 3.38 (+/-1.73), respectively. Low values of the Cmax/MIC index for ciprofloxacin in the analyzed patients may indicate too low concentrations of the drug in the blood in relation to the MIC value of pathogens and the need to verify the assumed administration scheme.