The association between gut microbiome and growth in infants with cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), pathophysiologic changes in the gastrointestinal tract lead to malnutrition and altered gut microbiome. Microbiome alterations have been linked to linear growth, gut inflammation and respiratory manifestations. Elucidating these gut microbiome alterations may provide insight into future nutritional management in CF. METHODS: Infants were followed for 12-months at four sites in the United States (US-CF) and Australia (AUS-CF). 16S rRNA gene sequencing was performed on longitudinal stool samples. Associations between microbial abundance and age, antibiotic prophylaxis, malnutrition, and breast feeding were evaluated using generalized linear mixed models. Taxonomic and predictive functional features were compared between groups. RESULTS: Infants with CF (N = 78) were enrolled as part of a larger study. AUS-CF infants had higher mean weight-for-age z-scores than US-CF infants (p = 0.02). A subset of participants (CF N = 40, non-CF disease controls N = 10) provided stool samples for microbiome analysis. AUS-CF infants had lower stool alpha diversity compared to US-CF infants (p < 0.001). AUS-CF infants had higher relative abundance of stool Proteobacteria compared to US-CF infants which was associated with antibiotic prophylaxis (p < 0.001). Malnutrition (weight-for-age <10th percentile) was associated with depleted Lactococcus (p < 0.001). Antibiotic prophylaxis (p = 0.002) and malnutrition (p = 0.012) were linked with predicted decreased activity of metabolic pathways responsible for short chain fatty acid processing. CONCLUSIONS: In infants with CF, gut microbiome composition and diversity differed between the two continents. Gut microbial diversity was not linked to growth. The relationship between malnutrition and antibiotic prophylaxis with reduced SCFA fermentation could have implications for gut health and function and warrants additional investigation.

Feasibility of parental collected nasal swabs for virus detection in young children with cystic fibrosis.

BACKGROUND: The detrimental role of viruses has been well described in CF, although the pattern of virus infections has not been investigated in a longitudinal study. The primary aim was to determine the feasibility of fortnightly parent collected swabs in young children with CF. METHODS: Children under three years with CF were recruited. Nasal swabs were collected by parents every fortnight and during periods of symptoms over 12 months. Nasal swabs were posted and virus detected using real-time PCR. RESULTS: Only 27% of the patients completed the study to 10 months, although 98% of the swabs returned were adequate for analysis. Mould was observed growing on 23% of the returned swabs. There was no evidence to demonstrate relationships with symptoms and viruses, prolonged symptoms, prolonged shedding or patterns of virus infections. CONCLUSIONS: This study highlights the need to further investigate the role of viruses in children with CF using a robust method of frequent collection in children for a longitudinal study, with appropriate storage and shipping techniques to avoid mould growth or other potential contaminants.

Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children.

BACKGROUND: The diagnosis of latent Mycobacterium tuberculosis (MTB) infection with a tuberculin skin test (TST) in children is complicated by the potential influence of prior exposure to Bacille Calmette Geurin (BCG) vaccination or environmental mycobacteria. A whole blood assay has recently been developed to quantitatively measure interferon gamma (IFN-gamma) production by lymphocytes specific to the MTB antigens ESAT-6 and CFP-10, but its use and assessment in children has been limited. A study was undertaken to compare the performance of the whole blood IFN-gamma assay with the TST in diagnosing latent tuberculosis (TB) infection or TB disease in children in routine clinical practice. METHODS: One hundred and six children with a high risk of latent TB infection or TB disease were enrolled in the study. High risk was defined as contact with TB disease, clinical suspicion of TB disease, or recent arrival from an area of high TB prevalence. The whole blood IFN-gamma assay was undertaken in 101 children. RESULTS: Seventeen (17%) of the 101 assays yielded inconclusive results due to failure of positive or negative control assays. There was poor correlation between the whole blood IFN-gamma assay and the TST (kappa statistic 0.3) with 26 (70%) of the 37 children defined as latent TB infection by TST having a negative whole blood IFN-gamma assay. There were no instances of a positive whole blood IFN-gamma assay with a negative TST. Mitogen (positive) control IFN-gamma responses were significantly correlated with age (Spearman's coefficient = 0.53, p<0.001) and, in children with latent TB infection identified by TST, those with a positive IFN-gamma assay were older (median 12.9 v 6.92 years, respectively, p = 0.007). The whole blood IFN-gamma assay was positive in all nine children with TB disease. CONCLUSION: There was poor agreement between the whole blood IFN-gamma assay and TST for the diagnosis of latent TB. The whole blood IFN-gamma assay may have lower sensitivity than the TST in diagnosing TB infection in children. A significant proportion of whole blood IFN-gamma assays fail when used as a screening assay in routine practice.

The use of corticosteroids in syntomathic asthma in childhood.

Corticosteroids (CS) have been used in the management of wheezing illnesses for several decades and have become the cornerstone of the management of childhood asthma. Inhaled corticosteroids are considered first-line treatment for frequent, persistent asthma in every guideline. Whilst undoubtedly they have provided enormous benefit to those asthmatics who would otherwise have been prescribed oral corticosteroids and so been at a high risk of side-effects, there is good evidence that inhaled corticosteroids are prescribed not only to too many asthmatic children but also to children who do not have asthma or who have other wheezing disorders. This review will assess the evidence for the benefit of corticosteroids, their use, and current prescribing practices in the common wheezing disorders of childhood.

Assessment of tidal breathing parameters in infants with cystic fibrosis.

Simple methods are needed to assess lung function in infants with cystic fibrosis (CF). This study determined the relationship between simple measurements obtained from tidal breathing with those from more complicated forced expiratory manoeuvres. Healthy infants and infants with CF were recruited from two maternity units and five specialist CF hospitals, respectively. Respiratory rate, tidal volume, minute ventilation and the tidal breathing ratio (TPTEF:TE) were measured in sedated infants and compared with forced expiratory volume in 0.4 seconds (FEV0.4) measured by the raised volume technique. Altogether, 95 healthy infants and 47 infants with CF of similar age, sex, ethnicity and proportion exposed to maternal smoking were recruited. There was no difference in TPTEF:TE and tidal volume between healthy infants and those with CF. Minute ventilation was significantly greater in infants with CF due to a mean (95% confidence interval) increase in respiratory rate of 5.8 (3.2-8.4) min(-1). Thirteen (28%) infants with CF had a respiratory rate elevated by >2 SD. However, no association between respiratory rate and FEV0.4 could be identified. Tidal breathing ratio was not useful in identifying diminished airway function in infants with cystic fibrosis. An elevated respiratory rate may be due in part to ventilation heterogeneity but is poorly predictive of diminished airway function measured by forced expiration.

Exploring the relationship between forced maximal flow at functional residual capacity and parameters of forced expiration from raised lung volume in healthy infants.

The raised volume rapid thoraco-abdominal compression technique (RVRTC) is being increasingly used to assess airway function in infants, but as yet no consensus exists regarding the equipment, methods, or analysis of recorded data. The aim of this study was to explore the relationship between maximal flow at functional residual capacity (V'(maxFRC)) and parameters derived from raised lung volumes, and to address analytical aspects of the latter technique in an attempt to assist with future standardization initiatives. Forced vital capacity (FVC) from lung volume raised to 3 kPa, timed forced expiratory volumes (FEV(t)), and forced expiratory flow parameters at different percentages of expired FVC (FEF(%)) were measured in 98 healthy infants (1-69 weeks of age). V'(maxFRC) using the tidal rapid thoraco-abdominal compression (RTC) technique was also measured. The within-subject relationships and within-subject variability of the various parameters were assessed. Duration of forced expiration was < 0.5 sec in 5 infants, meaning that FEV(0.3) and FEV(0.4) were the only timed volume parameters that could be calculated in all infants during the first months of life, and even when it could be calculated, FEV(0.5) approached FVC in many of these infants. It is recommended that FEV(0.4) be routinely reported in infants less than 3 months of age. Contrary to previous reports, within subject variability of V'(maxFRC) was less than that of FEF(75) (mean CV = 6.3% and 8.9%, respectively).A more standardized protocol when analyzing data from the RVRTC would facilitate comparisons of results between centers in the future.

Airway function in infants newly diagnosed with cystic fibrosis.

The lung function of infants with cystic fibrosis is often reduced shortly after diagnosis. We measured the airway function of newly diagnosed infants to test whether this reduction is independent of clinically recognised lower respiratory illness. We compared the airway function of 33 infants with cystic fibrosis and 87 healthy controls after adjustment for sex, age, bodyweight and length, and exposure to maternal smoking. Airway function was significantly reduced in children with cystic fibrosis, even in those without clinically recognised previous lower respiratory illness. Our findings raise important questions about the onset and natural history of impaired airway function in infants with cystic fibrosis.

Lung function testing in infants with cystic fibrosis: lessons from the past and future directions.

Despite the increasing awareness of the need to identify early pulmonary changes in cystic fibrosis (CF) noninvasively, the role of lung function testing in infancy and early childhood remains less clear than in older children with CF. The aim of this review is to summarize available data, discuss the information gained from these publications, and put this information into perspective with more recent developments of lung function testing in both infants and older children with CF. While some of the available data have been the foundation of the current level of understanding of respiratory physiology in CF, interpretation of other data has been hampered by differences between centers with regard to the methods and equipment used, patient selection, small number of subjects, and lack of appropriate reference data. A structured multicenter approach based on recently published recommendations for the measurement of lung function in infancy, together with pursuit of recent developments such as assessment of raised lung volume flow volume curves and ventilation inhomogeneity may help to more effectively utilize lung function tests in infants in the future.

Difficult asthma: defining the problems.

A retrospective survey was undertaken of children with difficult asthma, attending a respiratory clinic. The clinical and laboratory profiles of asthmatic children who were poorly controlled on > or = 800 microg of inhaled corticosteroids (ICS) were studied and compared to children well-controlled on > or = 800 microg ICS. Assessments were made of atopy, growth, lung function, treatment adherence, home environment, and responsiveness to corticosteroids (CS). Fiftyseven "difficult" and 23 well-controlled children were studied. Significant differences in the home environment were identified. Smoking was significantly more common in the difficult-to-control group. Nine children had alternative diagnoses. Poor CS responsiveness was present in 10 children. Adverse home environments, poor treatment supervision, alternative diagnoses, and unresponsiveness to CS were the most important factors in difficult asthma. A full assessment, including bronchoscopy, is indicated to avoid unnecessary increases in CS to doses that could cause side-effects.

What do parents of wheezy children understand by "wheeze"?

BACKGROUND: Reported wheeze is the cornerstone of asthma diagnosis. AIMS: To determine what parents understand by wheeze. METHODS: Two studies were undertaken: (1) Parents of clinic attendees with reported wheeze (n=160) were asked by questionnaire what they understood by "wheeze" and how they knew their child was wheezy. Responses were compared to definitions of wheeze in 12 epidemiology studies and their response options. (2) The extent of agreement of parents' reports (n=139) of acute wheezing in their children and clinicians' findings of "wheeze" and "asthma" was examined. RESULTS: (1) "Sound" and "difficulty in breathing" were perceived central to "wheeze". "What you hear" was not selected by 23% (95% confidence interval (CI) 16-30%). "Whistling" was mentioned by 11% (CI 6-15%) but featured in 11 of 12 epidemiology questionnaires. (2) There was les than 50% agreement between parents' and clinicians' reports of wheeze and asthma. CONCLUSIONS: Conceptual understandings of "wheeze" for parents of children with reported wheeze are different from epidemiology definitions. Parents' reports of acute wheeze and clinicians' findings also differ.