Andrew Tuck

Does bacterial density in cystic fibrosis sputum increase prior to pulmonary exacerbation

BACKGROUND Cystic Fibrosis (CF) lung disease is characterised by an inexorable decline in lung function, punctuated by periods of symptomatic worsening known as pulmonary exacerbations (referred to here as CFPE). Despite their clinical significance, the cause of CFPE remains undetermined. It has been suggested that an increase in bacterial density may be a trigger, although this has not been shown empirically. METHODS Here, a previously validated quantitative PCR-based approach was used to assess numbers of Pseudomonas aeruginosa and of total bacteria in respiratory secretions from patients during the period leading up to CFPE. Sputum samples collected from 12 adult CF patients were selected retrospectively to fall approximately 21, 14, 7 and 0 days prior to CFPE diagnosis. In addition, the relationships between clinical parameters (FEV(1), temperature and patient reported outcome measures) and microbiological data were investigated. RESULTS No significant changes either in total bacterial or P. aeruginosa numbers were identified prior to CFPE. Of all the correlations tested, only temperature showed a significant correlation with total bacterial numbers in the period leading to CFPE. CONCLUSIONS These findings strongly suggest that CFPE do not generally result from increased bacterial density within the airways. Instead, data presented here are consistent with alternative models of pulmonary exacerbation.

The rise and fall of pneumococcal serotypes carried in the PCV era

Streptococcus pneumoniae is a major cause of meningitis, sepsis and pneumonia worldwide. Vaccination using pneumococcal conjugate vaccines (PCV) has therefore been part of the UKs childhood immunisation programme since 2006. Here we describe pneumococcal carriage rates in children under five years of age attending the paediatric department of a large UK hospital in response to vaccine implementation over seven winter seasons from 2006 to 2013. S. pneumoniae (n=696) were isolated from nasopharyngeal swabs (n=2267) collected during seven consecutive winters, October to March, 2006/7 to 2012/13. This includes the period immediately following the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2006 in addition to pre- and post-PCV13 introduction in 2010. We show a decrease in PCV13 vaccine serotypes (VT) in the three years following PCV13 vaccine implementation (2010/11 to 2012/13). Serotype 6A represented the only observed VT following PCV13 implementation with all others (including PCV7 serotypes) absent from carriage. Overall pneumococcal carriage, attributable to non-VT (NVT), was consistent across all sampling years with a mean of 31·1%. The ten most frequently isolated NVTs were 6C, 11A, 15B, 23B, 15A, 21, 22F, 35F, 23A and 15C. Fluctuations in the prevalence of each were however noted. Comparing prevalence at 2006/07 with 2012/13 only 15A was shown to have increased significantly (p value of 0·003) during the course of PCV implementation. These data support the increasing evidence that the primary effect of PCVs is due to population immunity by reducing or eliminating the carriage of invasive VT serotypes. With IPD being increasingly attributed to non-vaccine serotypes, surveillance of carriage data continues to act as an early warning system for vaccine design and public health policy that require continual data of both carried pneumococcal serotypes and IPD attributed serotype data.

A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD

Background The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood. Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the incidence and seasonality of these events. Methods In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40–85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses. Results are presented for subjects in the full cohort, followed for 1 year. Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses. Findings The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50). At AECOPD, the most common bacterial species were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, and the most common virus was rhinovirus. Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when M. catarrhalis was detected regardless of season (5.09 (95% CI 2.76 to 9.41)). When NTHi was detected, the increased risk of exacerbation was greater in high season (October–March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)). Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%). A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031). Conclusions AECOPD aetiology varies with season. Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection. Trial registration number Results, NCT01360398.

Citrobacter diversus ventriculitis and brain abscesses in an adult

A case of Citrobacter diversus brain abscesses following urinary infection in an adult is described. The patient was treated with surgical drainage, netilmicin and cefotaxime. Citrobacter species CNS infection is discussed.

Impact and associations of eosinophilic inflammation in COPD: analysis of the AERIS cohort

Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) predicts response to treatment, especially corticosteroids. We studied the nature of eosinophilic inflammation in COPD prospectively to examine the stability of this phenotype and its dynamics across exacerbations, and its associations with clinical phenotype, exacerbations and infection. 127 patients aged 40–85 years with moderate to very severe COPD underwent repeated blood and sputum sampling at stable visits and within 72 h of exacerbation for 1 year. Blood eosinophils ≥2% was prevalent at baseline, and predicted both predominantly raised stable-state eosinophils across the year (area under the curve 0.841, 95% CI 0.755–0.928) and increased risk of eosinophilic inflammation at exacerbation (OR 9.16; p<0.001). Eosinophils ≥2% at exacerbation and eosinophil predominance at stable visits were associated with a lower risk of bacterial presence at exacerbation (OR 0.49; p=0.049 and OR 0.25; p=0.065, respectively). Bacterial infection at exacerbation was highly seasonal (winter versus summer OR 4.74; p=0.011) in predominantly eosinophilic patients. Eosinophilic inflammation is a common and stable phenotype in COPD. Blood eosinophil counts in the stable state can predict the nature of inflammation at future exacerbations, which when combined with an understanding of seasonal variation provides the basis for the development of new treatment paradigms for this important condition. Blood eosinophil levels in COPD predict the nature of inflammation at future exacerbations and may guide therapy http://ow.ly/W10o30dNQiq

Evaluation of swabbing methods for estimating the prevalence of bacterial carriage in the upper respiratory tract: a cross sectional study

Objectives Bacterial carriage in the upper respiratory tract is usually asymptomatic but can lead to respiratory tract infection (RTI), meningitis and septicaemia. We aimed to provide a baseline measure of Streptococcus pneumoniae, Moraxella catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae and Neisseria meningitidis carriage within the community. Self-swabbing and healthcare professional (HCP) swabbing were compared. Design Cross-sectional study. Setting Individuals registered at 20 general practitioner practices within the Wessex Primary Care Research Network South West, UK. Participants 10 448 individuals were invited to participate; 5394 within a self-swabbing group and 5054 within a HCP swabbing group. Self-swabbing invitees included 2405 individuals aged 0–4 years and 3349 individuals aged ≥5 years. HCP swabbing invitees included 1908 individuals aged 0–4 years and 3146 individuals aged ≥5 years. Results 1574 (15.1%) individuals participated, 1260 (23.4%, 95% CI 22.3% to 24.5%) undertaking self-swabbing and 314 (6.2%, 95% CI 5.5% to 6.9%) undertaking HCP-led swabbing. Participation was lower in young children and more deprived practice locations. Swab positivity rates were 34.8% (95% CI 32.2% to 37.4%) for self-taken nose swabs (NS), 19% (95% CI 16.8% to 21.2%) for self-taken whole mouth swabs (WMS), 25.2% (95% CI 20.4% to 30%) for nasopharyngeal swabs (NPS) and 33.4% (95% CI 28.2% to 38.6%) for HCP-taken WMS. Carriage rates of S. aureus were highest in NS (21.3%). S. pneumoniae carriage was highest in NS (11%) and NPS (7.4%). M. catarrhalis carriage was highest in HCP-taken WMS (28.8%). H. influenzae and P. aeruginosa carriage were similar between swab types. N. meningitidis was not detected in any swab. Age and recent RTI affected carriage of S. pneumoniae and H. influenzae. Participant costs were lower for self-swabbing (£41.21) versus HCP swabbing (£69.66). Conclusions Higher participation and lower costs of self-swabbing as well as sensitivity of self-swabbing favour this method for use in large population-based respiratory carriage studies.

Relationships between mucosal antibodies, non-typeable haemophilus influenzae (NTHi) infection and airway inflammation in COPD

Non-typeable Haemophilus influenzae (NTHi) is a key pathogen in COPD, being associated with airway inflammation and risk of exacerbation. Why some patients are susceptible to colonisation is not understood. We hypothesised that this susceptibility may be due to a deficiency in mucosal humoral immunity. The aim of our study (NCT01701869) was to quantify the amount and specificity of antibodies against NTHi in the lungs and the associated risk of infection and inflammation in health and COPD. Phlebotomy, sputum induction and bronchoscopy were performed on 24 mild-to-moderate COPD patients and 8 age and smoking-matched controls. BAL (Bronchoalveolar lavage) total IgG1, IgG2, IgG3, IgM and IgA concentrations were significantly increased in COPD patients compared to controls. NTHi was detected in the lungs of 7 of the COPD patients (NTHi+ve—29%) and these patients had a higher median number of previous exacerbations than NTHi-ve patients as well as evidence of increased systemic inflammation. When comparing NTHi+ve versus NTHi-ve patients we observed a decrease in the amount of both total IgG1 (p = 0.0068) and NTHi-specific IgG1 (p = 0.0433) in the BAL of NTHi+ve patients, but no differences in total IgA or IgM. We observed no evidence of decreased IgG1 in the serum of NTHi+ve patients, suggesting this phenomenon is restricted to the airway. Furthermore, the NTHi+ve patients had significantly greater levels of IL-1β (p = 0.0003), in BAL than NTHi-ve COPD patients.This study indicates that the presence of NTHi is associated with reduced levels and function of IgG1 in the airway of NTHi-colonised COPD patients. This decrease in total and NTHI-specific IgG1 was associated with greater systemic and airway inflammation and a history of more frequent exacerbations and may explain the susceptibility of some COPD patients to the impacts of NTHi.

Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations

Background Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD. Objective To characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes. Methods We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes. Results The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including Haemophilus and Moraxella, with disease severity, exacerbation events and bronchiectasis. Conclusions Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient. Trial registration number Results, NCT01360398.

Clostridium difficile in Children: A Review of Existing and Recently Uncovered Evidence

The clinical significance of the presence of Clostridium difficile in childrens faeces remains uncertain using current diagnostic procedures. Clostridium difficile is a relatively common finding in infants with no symptoms of gastrointestinal disease, suggesting it may be an incidental finding and form part of the normal gut micro-flora in this age group. On the other hand, particularly in older children or those with significant co-morbidity, there are examples where C. difficile causes disease and exerts considerable morbidity and even mortality (C. difficile infection, CDI). Between these extremes lie a substantial group of children who have both diarrhoea and C. difficile in their stools but where the nature of the association is not clear: Clostridium difficile associated disease (CDAD). We review the significance of C. difficile in children presenting recently uncovered paediatric data from a large UK epidemiological study that informs some key unanswered questions.

Relationship of CT-quantified emphysema, small airways disease and bronchial wall dimensions with physiological, inflammatory and infective measures in COPD

BackgroundCOPD is a complex, heterogeneous disease characterised by progressive development of airflow limitation. Spirometry provides little information about key aspects of pathology and is poorly related to clinical outcome, so other tools are required to investigate the disease. We sought to explore the relationships between quantitative CT analysis with functional, inflammatory and infective assessments of disease to identify the utility of imaging to stratify disease to better predict outcomes and disease response.MethodsPatients from the AERIS study with moderate-very severe COPD underwent HRCT, with image analysis determining the quantity of emphysema (%LAA<− 950), small airways disease (E/I MLD) and bronchial wall thickening (Pi10). At enrolment subjects underwent lung function testing, six-minute walk testing (6MWT), blood sampling for inflammatory markers and sputum sampling for white cell differential and microbiological culture and PCR.Results122 subjects were included in this analysis. Emphysema and small airways disease had independent associations with airflow obstruction (β = − 0.34, p < 0.001 and β = − 0.56, p < 0.001). %LAA<− 950 had independent associations with gas transfer (β = − 0.37, p < 0.001) and E/I MLD with RV/TLC (β = 0.30, p =0.003). The distance walked during the 6MWT was not associated with CT parameters, but exertional desaturation was independently associated with emphysema (β = 0.73, p < 0.001). Pi10 did not show any independent associations with lung function or functional parameters.No CT parameters had any associations with sputum inflammatory cells. Greater emphysema was associated with lower levels of systemic inflammation (CRP β = − 0.34, p < 0.001 and fibrinogen β = − 0.28, p =0.003). There was no significant difference in any of the CT parameters between subjects where potentially pathogenic bacteria were detected in sputum and those where it was not.ConclusionsThis study provides further validation for the use of quantitative CT measures of emphysema and small airways disease in COPD as they showed strong associations with pulmonary physiology and functional status. In contrast to this quantitative CT measures showed few convincing associations with biological measures of disease, suggesting it is not an effective tool at measuring disease activity.