Tom Fardon

Effects of levocetirizine as add‐on therapy to fluticasone in seasonal allergic rhinitis

Background Addition of H1 antagonists to intranasal corticosteroid treatment of allergic rhinitis (AR) is common in clinical practice and recommended by guidelines, despite some evidence that the additive benefits are negligible.

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts

Introduction Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. Methods We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. Results The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in ‘severe’ patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6u2005min walk distance (6MWD) or lung function decline. Conclusion The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

Proposed changes to management of lower respiratory tract infections in response to the Clostridium difficile epidemic

Clostridium difficile infection (CDI) remains a major healthcare problem associated with antibiotic use in hospitals. Recent years have seen a dramatic increase in the incidence of CDI in the UK and internationally. Lower respiratory tract infections (LRTIs) are the leading indication for antibiotic prescription in hospitals and are therefore a critical battleground in the fight against inappropriate antibiotic use and healthcare-associated infections. This article reviews the evidence for interventions to reduce CDI in hospitalized patients with LRTIs. Reducing prescriptions of cephalosporins and fluoroquinolones in favour of penicillin-based regimens and increased use of tetracyclines have been proposed. Expanding outpatient management of LRTIs and reducing length of hospital stay will limit patient exposure to the healthcare environment in which C. difficile is most easily acquired. Intravenous (iv) broad-spectrum antibiotics are often prescribed when narrower spectrum, oral antimicrobials would be equally effective and, in a proportion of patients, antibiotic therapy is used unnecessarily. Shorter antibiotic regimes may be as effective as prolonged therapy and reduce antibiotic-related complications. Early switch from iv to oral therapy allows simpler antibiotic regimens and facilitates early discharge from hospital. Simple improvements in the management of LRTIs have the potential to reduce the incidence of healthcare-associated infections.

Supervised step-down of inhaled corticosteroids in the community – An observational study

INTRODUCTIONnCurrent asthma guidelines recommend step-down of inhaled corticosteroids (ICS) to the minimum dose required for control of symptoms.nnnAIMnTo determine if supervised step-down of (ICS) in the community has any effect on asthmatic inflammation.nnnMETHODSn119 Community based asthmatics underwent progressive step-down of therapy until they became unstable or reached an (ICS) dose of ≤200 μg beclomethasone dipropionate (BDP) or equivalent. Once unstable, participants stepped back up to the last stable dose of ICS. Exhaled nitric oxide (NO) and mannitol challenge were performed at the start and end of step-down. Asthma Quality of Life Questionnaire (AQLQ) and spirometry were recorded at each step-down visit.nnnRESULTSnThe median (interquartile range) BDP equivalent dose was significantly higher pre vs. post step-down: 400 μg (400-800) and 250 μg (200-400) per day respectively (P < 0.05). Examination of change in PD(10) in individual patients revealed that 34% had an improvement (>+1 dd), 47% had no change (±-1 dd), and 19% had a worsening (<-1 dd). The geometric mean fold ratio in NO for pre vs. post was 0.96 (95% CI 0.87 to 1.06, P = 0.43). Mean (SEM) values for FEV(1) were 86.2% (1.51) vs. 84.5% (1.46) (P = 0.04). There was a significant improvement in AQLQ.nnnCONCLUSIONSnWe have demonstrated that a significant reduction in ICS dose may be achieved in a community setting without any worsening of airways inflammation or lung function, and with an associated improvement quality of life in the majority of patients. This apparent disconnect may reflect enhanced adherence due to supervision of step-down.

An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis

BACKGROUNDnIn cystic fibrosis (CF), cross-sectional studies have reported sputum matrix metalloproteinase (MMP)-9 to be elevated and negatively correlated with FEV1. This longitudinal study examined the association between MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) to prognostic parameters in CF.nnnMETHODnA cross-sectional survey of CF and control subjects; CF patients were followed up for a median of 49 months. MMP-9 and TIMP-1 and TIMP-2 were quantified in sputum and plasma.nnnRESULTSnSeventy-three patients with CF, median age 22 years, and 40 controls were recruited. Fifty-three of these CF patients were followed up. Prospectively, in CF subjects, plasma MMP-9 activity was adversely associated with FEV1 (β -1.15 (95% CI -2.10, -0.20), p = 0.019) and rate of FEV1 decline, and plasma TIMP-1 was adversely associated with mortality: hazard ratio 3.66 (1.91-7.04), p < 0.001.nnnCONCLUSIONSnThese associations further justify investigation of MMP-9 and TIMP-1 as biomarkers for short- to medium-term FEV1 decline and mortality in patients with CF.

Comparative cutoff points for adenosine monophosphate and methacholine challenge testing

BACKGROUNDnCurrent use of the PC20 (provocation concentration that causes a decrease in forced expiratory volume in 1 second of 20%) cutoff point for bronchial challenge precludes its use in patients with more severe airflow obstruction.nnnOBJECTIVEnTo evaluate the efficacy and safety of lower cutoff points for adenosine monophosphate (AMP) and methacholine (MCH) bronchial challenge tools to monitor response to treatment in chronic asthma.nnnMETHODSnWe retrospectively examined data from 5 previously published studies (2 using AMP, 2 using MCH, and 1 with MCH and AMP arms) and recalculated 10% and 15% cutoff points for AMP and MCH. Data were analyzed for correlation of single results and doubling dose shifts after anti-inflammatory treatment intervention.nnnRESULTSnA total of 175 individual MCH challenges and 152 AMP challenges were evaluated. Evaluating the doubling dose shift produced by the addition of anti-inflammatory treatment (inhaled corticosteroids or montelukast) produced the following Pearson correlation coefficients: MCH PD20 (provocation dose that causes a decrease in forced expiratory volume in 1 second of 20%) vs PD15, 0.80; MCH PD20 vs PD10, 0.65; AMP PC20 vs PC15, 0.96; and AMP PC20 vs PC10, 0.84 (P < .001 for all). Subgroup analysis of AMP for before and after inhaled corticosteroids only (n = 41) shows AMP PC20 vs PC15 of 0.92 and AMP PC20 vs PC10 of 0.84 (P < .001 for both).nnnCONCLUSIONSnThe 10% and 15% cutoff points strongly predict the 20% cutoff value for AMP and MCH, as do the doubling dose shifts after anti-inflammatory treatment. The lower thresholds are suitable for monitoring response to therapy, and they expose patients to significantly less provocation agent.

S124 Derivation and validation of the bronchiectasis severity index: an international multicentre observational study

Introduction There are no risk stratification tools for morbidity and mortality in bronchiectasis. As more treatments become available, it is important to identify patients at risk of exacerbations, hospital admissions and mortality to target novel therapies. Methods A prospective observational study at a specialist bronchiectasis clinic in Edinburgh, UK was used to derive a bronchiectasis severity index using cox-proportional hazards regression to identify independent predictors of mortality and hospital admission over 4 years follow-up. Averaged ß-coefficients were used to award points for each independent variable and the discrimination of a derived score was tested using the area under the receiver operator characteristic curve (AUC). The score was validated in independent cohorts from Dundee, UK (N = 218), Leuven, Belgium (N = 253), Monza, Italy (N = 105) and Newcastle, UK (N = 126). Results 608 patients were included in the derivation cohort. Independent predictors of future hospital admissions were prior hospital admissions hazard ratio (HR) 13.5 (9.40–19.46), MRC dyspnoea score > 4, HR 2.42 (1.66–3.52), FEV1 <30% predicted HR 1.52 (1.03–2.25), Pseudomonas aeruginosa colonisation HR 2.16 (1.36–3.43), colonisation with other organisms HR 1.66 (1.12–2.44) and > 3 lobes involved on HRCT HR 1.48 (1.02–2.15). In the model for mortality, independent predictors were Age >70 years 8.57 (1.15–63.63), FEV1 <30% predicted HR 4.47 (1.60–12.53), prior hospital admissions HR 2.43 (1.30–4.53) and 3 or more exacerbations per year prior to the study HR 2.03 (1.02–4.03). The bronchiectasis severity index derived from these models was composed of prior hospitalisation (5 points), MRC dyspnoea score (0–3 points), FEV1 (0–3 points), bacterial colonisation (0- 3 points) Age (0–6 points) BMI <18.5 (2 points) Exacerbation frequency (0–2 points) and radiological extent (1 point). The AUC for mortality was 0.80 (0.74–0.86) and the AUC for hospitalisation was 0.88 (0.84–0.91). There was a clear difference in exacerbation frequency and quality of life using the St. Georges Respiratory Questionnaire between patients classified as low, intermediate and high risk by the score (p < 0.0001 for all comparisons). In the validation cohorts, the AUC for mortality ranged from 0.81–0.84 and for hospitalisation was AUC 0.80–0.88. Conclusions The bronchiectasis severity index identifies patients at risk of future mortality, hospital admissions and exacerbations.

Effects of intranasal corticosteroid on nasal adenosine monophosphate challenge in persistent allergic rhinitis

Background:u2002 Response to a single dose nasal adenosine monophosphate challenge has been used as a surrogate inflammatory marker for allergic rhinitis. Attenuation of response following intranasal corticosteroid would further validate the challenge.

Addition of fexofenadine to inhaled corticosteroid therapy to reduce inflammatory biomarkers in atopic asthma

BACKGROUNDnWe previously showed that H1-antihistamines may shift the PC20 (provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%) threshold to adenosine monophosphate (AMP) challenge but may paradoxically prolong recovery.nnnOBJECTIVESnTo measure AMP recovery using a constant predetermined AMP PC20 and to evaluate whether fexofenadine use confers add-on effects to treatment with either fluticasone propionate alone or combined fluticasone propionate-salmeterol.nnnMETHODSnFourteen atopic patients with mild-to-moderate asthma (forced expiratory volume in 1 second of 76%) completed a double-blind, randomized, crossover study consisting of 3-week treatment blocks of either fluticasone propionate-salmeterol, 250 microg twice daily, or fluticasone propionate alone, 250 microg twice daily, in conjunction with either fexofenadine, 180 mg once daily, or matched placebo. Recovery after a predetermined AMP PC20 challenge was measured (primary outcome), along with exhaled nitric oxide levels, plasma eosinophil cationic protein levels, peripheral eosinophil counts, pulmonary function, diary card outcomes, and quality of life (all secondary outcomes).nnnRESULTSnThere were no differences in any of the primary or secondary outcomes when fexofenadine was added to treatment with either fluticasone propionate-salmeterol or fluticasone propionate alone. The mean AMP recovery time was 25.0 vs 23.4 minutes for fexofenadine and placebo, respectively, as add-on to fluticasone-salmeterol and 22.5 vs 23.9 minutes, respectively, as add-on to fluticasone alone.nnnCONCLUSIONnFexofenadine did not affect recovery to a fixed dose of AMP challenge or any other surrogate inflammatory markers when given as add-on therapy to corticosteroid-treatedatopic asthmatic patients.

Aggregatibacter aphrophilus in a patient with recurrent empyema: a case report.

IntroductionAggregatibacter aphrophilus (formerly Haemophilus aphrophilus and H. paraphrophilus) is classically associated with infective endocarditis. Other infections reported in the literature include brain abscess, bone and joint infections and endophthalmitis. There are only two cases of empyema ever reported due to this organism. We report the isolation of A. aphrophilus from pleural fluid on three separate hospital admissions in a patient with recurrent empyema.Case presentationA 65-year-old female patient of Caucasian origin presented with a three-week history of fever, shortness of breath and dry cough. She was found to have a pleural empyema so a chest drain was inserted and a sample of pus was sent to the microbiology laboratory. After overnight incubation, a chocolate blood agar plate incubated in 5% carbon dioxide showed a profuse growth of small, round, glistening colonies which were identified as Gram-negative coccobacilli. They were oxidase- and catalase-negative. Biochemical testing using RapID NH confirmed the identity of the organism as A. aphrophilus. It was susceptible to amoxicillin, levofloxacin and doxycycline. Our patient was treated with intravenous amoxicillin with clavulanic acid and clarithromycin followed by oral doxycycline, but was re-admitted twice over the next three months with recurrent empyema and the same organism was isolated. Each episode was managed with chest drainage and a six-week course of antibiotic--doxycycline for the second episode and amoxicillin for the third episode, after which she has remained well.ConclusionThis is the first case report of recurrent empyema due to A. aphrophilus. Our patient had no underlying condition to explain the recurrence. Although our isolate was doxycycline susceptible, our patient had recurrent infection after treatment with this antibiotic, suggesting that this antibiotic is ineffective in treatment of deep-seated A. aphrophilus infection. This organism can be difficult to identify in the laboratory because, unlike closely related Haemophilus spp., it is oxidase-negative, catalase-negative and X and V independent.