Does probiotic supplementation affect pulmonary exacerbation and intestinal inflammation in cystic fibrosis: a systematic review of randomized clinical trials

Background:Patients with cystic fibrosis (CF) usually have abnormal intestinal microbiota due to massive exposure to antibiotics.Probiotics could modify the gut microbiota and hence may affect CF management.So the aim of present systematic review was evaluation of the efficacy and safety of probiotic supplementation for the management of cystic fibrosis.Data sources:We searched PubMed,Science Direct,Google Scholar,Springer Cochrane Library Databases until January 2016 for randomized controlled trials (RCTs) performed in pediatric or adult populations related to the study aim.Key words were selected based on Mesh terms.Based on the Critical Appraisal Skills Programme checklist,eligibility of included articles was evaluated.Results:Five studies included in this review represent 188 participants with a follow up period ranging from 1 month to 6 months.The results of the included studies supporting the use of probiotics in management of pulmonary exacerbation and intestinal calprotectin in patients with cystic fibrosis.However the level of evidence was limited.Conclusion:The lack of high quality RCTs makes it impossible to support a general recommendation about the use of probiotics in the treatment of CF pulmonary exacerbation and intestinal inflammation.     

Is there a role for stool metabolomics in cystic fibrosis?

A number of studies utilizing metabolomics have focused on the pathophysiology of cystic fibrosis (CF) lung disease. Here, we performed fecal metabolomics on pancreatic insufficient (PI) and sufficient (PS) children with CF and compared them with healthy controls (HC). Fecal metabolomics can differentiate between PS‐CF and PI‐CF. We identified a potential biomarker of disease severity or cystic fibrosis transmembrane conductance regulator function (m/z, 463.247; retention time, 0.570717 min) that discriminates between HC versus PS‐CF versus PI‐CF. We also identified lipoyl‐GMP as a potential novel inflammatory biomarker, and elevation in fecal glycerol 1,2‐didodecanoate 3‐tetradecanoate may provide clues to the pathogenesis of intestinal inflammation. For the first time, we demonstrate the potential applications of fecal metabolomics in CF.     

Intestinal inflammation in cystic fibrosis

BACKGROUND—There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF.AIMS—To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy.METHODS—Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, α₁ antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1β) were measured.RESULTS—Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1β, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy.CONCLUSIONS—These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.     

Calprotectin as a marker of inflammation in cystic fibrosis.

Calprotectin is an abundant neutrophil cytosolic protein released during neutrophil activation or death. The use of plasma calprotectin concentration as a marker of pulmonary inflammation was tested in 31 children with cystic fibrosis, none of whom was acutely unwell or pyrexic. Twenty three were receiving antibiotics, 21 had positive sputum cultures, but none of the traditional tests clearly diagnosed ongoing infection. Plasma calprotectin was significantly higher in the cystic fibrosis group than in matched controls. Sixteen children with cystic fibrosis had values above the control range (320-1570 micrograms/l). Their chest radiograph Northern score, an index of accumulated pulmonary involvement, and their plasma copper, an index of acute phase response, both correlated with plasma calprotectin. Plasma gamma-glutamyltransferase also correlated weakly with plasma calprotectin: thus, hepatic pathology may be a confounding variable. However, the data still suggested that plasma calprotectin is a better index of inflammation than the traditional indices in general use.     

Calprotectin as a marker of inflammation in cystic fibrosis

Calprotectin is an abundant neutrophil cytosolic protein released during neutrophil activation or death. The use of plasma calprotectin concentration as a marker of pulmonary inflammation was tested in 31 children with cystic fibrosis, none of whom was acutely unwell or pyrexic. Twenty three were receiving antibiotics, 21 had positive sputum cultures, but none of the traditional tests clearly diagnosed ongoing infection. Plasma calprotectin was significantly higher in the cystic fibrosis group than in matched controls. Sixteen children with cystic fibrosis had values above the control range (320-1570 micrograms/l). Their chest radiograph Northern score, an index of accumulated pulmonary involvement, and their plasma copper, an index of acute phase response, both correlated with plasma calprotectin. Plasma gamma-glutamyltransferase also correlated weakly with plasma calprotectin: thus, hepatic pathology may be a confounding variable. However, the data still suggested that plasma calprotectin is a better index of inflammation than the traditional indices in general use.     

Intestinal inflammation in cystic fibrosis.

BACKGROUND: There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS: To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS: Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha(1) antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1beta) were measured. RESULTS: Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS: These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.     

Faecal calprotectin concentrations in apparently healthy children aged 0-12 years in urban Kampala, Uganda: a community-based survey

Background  

Calprotectin is a calcium and zinc binding protein, abundant in neutrophils and is extremely stable in faeces. Faecal calprotectin is used as a non-specific marker for gastrointestinal inflammation. It has a good diagnostic precision to distinguish between irritable bowel syndrome and inflammatory bowel disease. Studies have established normal concentrations in healthy children; all these studies have been performed in high-income countries. The objective of this study was to determine the concentration of faecal calprotectin in apparently healthy children aged 0-12 years in urban Kampala, Uganda.     

Fecal calprotectin: validation as a noninvasive measure of bowel inflammation in childhood inflammatory bowel disease

BACKGROUND: Calprotectin is an abundant neutrophil protein, which is extremely stable in feces. This study aimed to validate fecal calprotectin as a marker of bowel inflammation against invasive measures in children with inflammatory bowel disease (IBD), including colitis and small bowel Crohn disease. METHODS: Fecal calprotectin was measured using a simple enzyme-linked immunosorbent assay in 36 spot stool samples from 22 children before colonoscopy and from 14 children before technetium-99 (99Tc) scanning. Using standard scoring systems, the severity of inflammation was assessed macroscopically and histologically at six standard sites in those who underwent colonoscopy and also at six standard sites in those who underwent 99Tc scanning. The subscores from each site were summated to give combined severity and extent scores for macroscopic and for histologic inflammation in the group undergoing colonoscopy and total inflammation in the group undergoing 99Tc scanning. RESULTS: In the 22 children who underwent colonoscopy, median fecal calprotectin was 4.9 mg/L (0.1-272.5 mg/L) (range). Disease groups included six normal cases, nine ulcerative colitis cases, two isolated Crohn colitis cases, two indeterminate colitis cases, and three allergic colitis cases. Fecal calprotectin correlated closely with colonic macroscopic inflammation (r = 0.75, P < 0.001) and histologic inflammation (r = 0.85, P < 0.001). Of the 14 children undergoing 99Tc scanning, 10 had Crohn disease, 3 had ulcerative colitis, and 1 had allergic colitis. Median fecal calprotectin was 9.1 mg/L (0.3-141.7 mg/L), and this correlated closely with the 99Tc scanning score (r = 0.80, P = 0.001). CONCLUSION: Fecal calprotectin correlates closely with the best invasive measures of colonic and small bowel inflammation in childhood inflammatory bowel disease. As a sensitive objective measure of bowel inflammation that is risk-free and noninvasive, fecal calprotectin lends itself particularly to the monitoring of and assessment of therapeutic interventions in children with inflammatory bowel disease.     

Predictive factors for premature birth and respiratory exacerbation in pregnancies of women with cystic fibrosis

ObjectiveIn this present study, the authors evaluated the predictive factors for adverse maternal-fetal outcomes in pregnancies of women with cystic fibrosis (CF). Patients were followed up by a referral center for adults in southern Brazil.MethodsThis is a retrospective cohort study that used data from electronic medical records regarding pregnancies of women diagnosed with CF.ResultsThe study included 39 pregnancies related to 20 different women. The main adverse outcomes were high prevalence rates of premature birth (38.5%) and maternal respiratory exacerbation (84.6%). Lower body mass index (BMI) values (< 20.8) and younger ages of CF diagnosis increased the risk of premature birth. The presence of methicillin-resistant and absence of methicillin-sensitive Staphylococcus aureus, as well as a younger age of diagnosis, increased the risk of maternal respiratory exacerbation during pregnancy.ConclusionsConception in women with CF is often associated with maternal and fetal complications. Continuous monitoring by a multidisciplinary team should emphasize appropriate nutritional status, investigation of bacterial colonization, and immediate attention to respiratory exacerbations.     

The Impact of Cystic Fibrosis on the Immunologic Profile of Pediatric Patients

ObjectiveTo compare the immunologic state of 44 pediatric patients with cystic fibrosis (CF) with a control group consisting of 16 healthy individuals.MethodsCF patients aged 3 to 12 years with moderate to good clinical score were selected for the study. Erythrocytic glutathione, production of reactive oxygen species, cytokines (TNF-a, IFN-g, IL-8, IL-6, IL-10) in peripheral blood mononuclear cells cultures under spontaneous and BCG- or PHA-stimulated conditions, serum concentrations of TGF-b2, IgA, IgG, IgM, IgE, and salivary IgA were evaluated.ResultsThe spontaneous production of TNF-a, IL-6, and IL-10, the PHA-stimulated production of IL-6, and the serum TGF-b2, IgA, and IgG were increased in samples from CF patients. Healthy subjects had a higher production of TNF-a in response to BCG.ConclusionAlthough CF patients appeared clinically stable, the results of their peripheral blood examinations demonstrated an impact on the immune system.     

Gastrointestinale Manifestationen bei zystischer Fibrose

The gene product of cystic fibrosis – the CFTR – is expressed within the gastrointestinal tract in epithelial cells of the small and large bowel, the pancreatic acini and the biliary tree, but not in the liver. For some of the manifestations of CF in the GI-tract there is a genotype-phenotype-correlation. Patients with the ΔF508 mutation present with pancreatic insufficiency (PI). PI correlates with the appearance of meconium ileus and distal intestinal obstruction syndrome (DIOS). The gold standard for the diagnosis of PI is the quantitative determination of fat in a 3–5 stool collection. The treatment consists in the administration of microcapsulated pancreatic extracts in a dose of 5.000 to 10.0000 units of liapse/kg/day. Higher doses up to 50.000 units of lipase/kg/day have been implicated with the occurence of fibrosing colonopathy in the early 90ties. As for the hepato-biliary manifestations of CF, cholelithiasis, atresia of the cystic duct and a biliary cirrhosis are the main pathologies. The focal nodular cirrhosis turns into a multilobular cirrhosis in 24% of all adults with CF combined with portal hypertension and esophageal varices. In newborn a prolonged neonatal cholestasis can occur with symptoms similar to those in extrahepatic biliary atresia. The treatment of the hepatopathy in CF is difficult. The oral administration of ursodeoxcholic acid (15–20 mg/kg/day) was shown to be effective in some studies. Up to 25% of CF patients are suffering from gastro-esophageal reflux disease (GER). An esophagoscopy is assessing the degree of esophagitis, which is treated with omeprazol. The meconium ileus of the newborn is pathognomonic for the presence of cystic fibrosis. DIOS is present in 35% of 1000 patient years particularly in adolescents and adults with CF. Together with DIOS an acute appendicitis or an intusseption can be present. Since the daily dose of oral panceratic extracts has been limited, the occurence of fibrosing colonopathy has decreased. More often in the last few years a severe pancolitis was noticed in adult patients with CF due to Clostridium difficile infection. Diarrhea, abdominal pain together with signs of inflammation lead to that severe, sometime life threatening disease. The ultrasonographic visualization of the colon shows enormous enlargement of the inflamed colon easely. Rare manifestation of CF in the GI-tract comprise malignant disease like adenocarcinoma, the infection with Giardia lamblia, the development of inflammatory bowel disease, e. g. Crohn's disease and the occurence of celiac disease.     

Variability of markers of inflammation and infection in induced sputum in children with cystic fibrosis

To determine reproducibility of inflammatory marker concentrations in induced sputum from subjects with cystic fibrosis (CF), 15 nonexpectorating children, 6 to 13 years of age with mild CF lung disease, underwent 3 weekly sputum inductions with 3% saline. Neutrophil elastase concentration and bacterial cultures were reproducible. This study provides useful information for investigators designing trials of anti-inflammatory therapies in CF involving sputum induction.     

Structural lung changes,lung function,and non‐invasive inflammatory markers in cystic fibrosis

Robroeks CMHHT, Roozeboom MH, de Jong PA, Tiddens HAWM, Jöbsis Q, Hendriks HJ, Yntema J‐BL, Brackel HL, van Gent R, Robben S, Dompeling E. Structural lung changes, lung function, and non‐invasive inflammatory markers in cystic fibrosis.
Pediatr Allergy Immunol 2010: 21: 493–500.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non‐invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non‐invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8‐isoprostane, hydrogen peroxide, interferon‐gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non‐invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas‐negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8‐isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non‐invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non‐invasive monitoring of airway inflammation in CF adds to better follow‐up of patients.     

Effects of therapy with lansoprazole on intestinal permeability and inflammation in young cystic fibrosis patients

BACKGROUND: Defective pancreatic bicarbonate secretion with low intestinal pH or intestinal inflammation of any origin increase intestinal permeability in cystic fibrosis (CF). METHODS: In this open study, the authors evaluated the effect of a proton-pump inhibitor on intestinal permeability and inflammation in 14 young, pancreatic-insufficient CF patients. Permeability was measured by a three-sugar permeability test before and after 1 year of lansoprazole use, and urinary nitric oxide (NO) oxidation products were assessed before and during that year as a marker of inflammation. RESULTS: After 1 year of lansoprazole use, median urinary recovery percentages changed from 2.5% to 1.7% (P = 0.064), from 24.9% to 24.5% (no significance), and from 10.5% to 11.1% (no significance) for lactulose, mannitol, and L-rhamnose, respectively. Despite the fact that the median urinary excretion ratios decreased from 0.108 to 0.083 (P = 0.03) and from 0.246 to 0.176 (P = 0.016) for lactulose and mannitol and for lactulose and rhamnose, respectively, they both remained increased. Median urinary NO products-to-creatinine ratios were 0.287 for CF patients before lansoprazole and 0.130 for healthy control participants (P = 0.002). Although there was a tendency toward a decrease in the NO products-to-creatinine ratio during treatment, this was not significant at the end point. CONCLUSIONS: Intestinal permeability is considerably increased in CF patients and is partly corrected after the use of a proton-pump inhibitor for 1 year, which may point to a harmful effect of the acid luminal contents on the tight junctional related paracellular permeability pathway. The start and end values for the NO products-to-creatinine ratio in CF patients were not significantly different, but were considerably increased when compared with control participants (P = 0.002).     

No evidence for a clear link between active intestinal inflammation and autism based on analyses of faecal calprotectin and rectal nitric oxide

AIM: Due to parental concern regarding the child's bowel habits and the ongoing discussion whether there might be an association between autism and intestinal inflammation, two inflammatory markers were analysed in a group of children with autism. METHODS: Twenty-four consecutive children with autism (3-13 years) of unknown aetiology were investigated with respect to faecal calprotectin and rectal nitric oxide (NO). RESULTS: One child who previously had a severe Clostridium difficile infection displayed raised levels of both these inflammatory markers and one child with extreme constipation for whom only calprotectin was possible to measure had raised levels. The remaining children displayed results that did not indicate an active inflammatory status in the intestine when the two inflammatory markers were combined. CONCLUSION: By the use of two independent markers of inflammatory reactions in the gut, i.e. rectal NO and faecal calprotectin we were not able to disclose evidence of a link between the autistic disorder and active intestinal inflammation.     

Detection and follow up of exocrine pancreatic insufficiency in cystic fibrosis: a review

Pancreatic function testing is particularly difficult when the degree of remaining function has to be quantified. Detection of pancreatic insufficiency can suggest the diagnosis of cystic fibrosis (CF). It is, however; also important to follow the degree of pancreatic insufficiency in CF since its function can decline with age. Adaptation of pancreatic enzyme replacement therapy on residual function is necessary. Different tests with their advantages and disadvantages are critically reviewed in this article with respect to specificity, sensitivity, performance and cost-effectiveness. Conclusion Elastase-1 detection in faeces is probably the easiest test for the detection of pancreatic insufficiency in cystic fibrosis. For clinical follow-up tests, measuring the fat assimilation such as steatocrit and breath tests are more suited. Received: 25 November 1999 / Accepted: 8 March 2000     

Therapeutic strategies to correct malfunction of CFTR

Cystic fibrosis (CF) is a systemic autosomal recessive inherited disorder that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although the gene was cloned 11 years ago, there still is no definitive treatment to correct the functional deficit. Current treatment strategies focus on pancreatic enzyme replacement and control of pulmonary inflammation and infection. This review examines novel strategies still in preclinical development or phase 1 clinical trials. Gene therapy is an evolving area of study that offers the potential for a cure for cystic fibrosis. CF lung disease is a significant barrier to effective gene delivery and transfer, but new vectors show promise in overcoming these limitations. There are also new pharmacological therapies aimed at correcting defects in CFTR processing and function. These are tailored to the specific class of mutation but may offer therapeutic benefit to many patients. They include phenylbutyrate, flavonoids, aminoglycosides and xanthines.     

Serum interleukin-1 alpha and soluble interleukin-2 receptor concentrations in cystic fibrosis

Interleukin (IL)-1 and IL-2 may participate in the systemic inflammatory response and hypergammaglobulinaemia observed in patients with cystic fibrosis. Thirty seven patients with cystic fibrosis were compared with 25 normal controls. High IgG and IgM concentrations were associated with more severe pulmonary disease. IL-1 alpha and soluble IL-2 receptor concentrations were higher in the cystic fibrosis group than in the controls and also correlated with concentrations of IgG and IgM. These results suggest that these cytokines may contribute to enhanced immunoglobulin synthesis and silent inflammatory activity in clinically stable patients with cystic fibrosis.     

Serum interleukin-1 alpha and soluble interleukin-2 receptor concentrations in cystic fibrosis.

Interleukin (IL)-1 and IL-2 may participate in the systemic inflammatory response and hypergammaglobulinaemia observed in patients with cystic fibrosis. Thirty seven patients with cystic fibrosis were compared with 25 normal controls. High IgG and IgM concentrations were associated with more severe pulmonary disease. IL-1 alpha and soluble IL-2 receptor concentrations were higher in the cystic fibrosis group than in the controls and also correlated with concentrations of IgG and IgM. These results suggest that these cytokines may contribute to enhanced immunoglobulin synthesis and silent inflammatory activity in clinically stable patients with cystic fibrosis.     

粪便钙卫蛋白在新生儿期的临床研究进展

新生儿胃肠功能异常与生后生长发育落后密切相关,寻找能反映胃肠功能的早期特异性指标有助于指导合理的肠道喂养,预测评价胃肠道疾病的发生.钙卫蛋白是一种主要来源于中性粒细胞的钙-锌结合蛋白质,是急性炎性细胞活化的标志物.有研究表明新生儿期粪便钙卫蛋白呈高水平表达,肠道损伤时粪便钙卫蛋白含量明显升高,并可作为检测胃肠道疾病（如喂养不耐受、新生儿腹泻、坏死性小肠结肠炎等）的发生,评价肠道疾病严重程度的无创性指标.该文就新生儿期粪便钙卫蛋白水平的变化及临床意义作一综述.