Anika Singanayagam

Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies

Objective To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia. Design Analysis of two prospectively collected datasets. Setting Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009. Population 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia. Main outcome measures Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year. Results 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome—hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin. Conclusions The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets.

Severity assessment in community-acquired pneumonia: a review

Severity assessment is an important early step in the management of patients presenting with community-acquired pneumonia. Various pneumonia-specific scores, generic sepsis scores and predictive biomarkers have been proposed as tools to aid clinicians in key management decisions. However, there is no uniform agreement about the optimum severity assessment tool to use. This review provides a summary of current evidence surrounding severity assessment in adult patients presenting with community-acquired pneumonia.

Obesity is associated with improved survival in community-acquired pneumonia

Obesity has been identified as a risk factor for adverse outcomes of 2009 H1N1 influenza. However, the impact of obesity on outcomes of infection remains controversial. There are limited data investigating the effect of obesity on outcomes of community-acquired pneumonia (CAP). This prospective observational study included patients presenting with CAP who had body mass index (BMI) measured on admission. Outcome measures included 30-day mortality and need for mechanical ventilation or inotropic support (MV/IS). 1079 patients were included, with 21% classified as obese (BMI ≥30 kg·m−2). Obesity was independently associated with reduced 30-day mortality from CAP on multivariate analysis (HR 0.53, 95% CI 0.29–0.98). This was not explained by differences in severity of disease on admission or requirement for MV/IS between obese and nonobese groups. Obese patients had higher median C-reactive protein levels and a higher frequency of sepsis using the systemic inflammatory response syndrome criteria (72.4% versus 64.1%; p=0.03), than nonobese patients, suggesting greater systemic inflammation. Obesity was associated with reduced 30-day mortality in patients hospitalised with CAP.

Seven-day antibiotic courses have similar efficacy to prolonged courses in severe community-acquired pneumonia—a propensity-adjusted analysis

There are no studies to guide the optimal duration of therapy in severe community-acquired pneumonia (CAP). The aim of this study was to determine whether 7 days of antibiotic treatment is equivalent to longer-course therapy in severe CAP. In this prospective observational study, we included patients with severe CAP (CURB65 score 3-5) admitted to the hospital with signs and symptoms consistent with pneumonia. A propensity score, derived through multiple logistic regression, was used to match patients into two groups: treated for 7 days vs. treated for >7 days. Patients who died, were admitted to the intensive-care unit, developed complicated pneumonia, failed to reach clinical stability or had positive cultures for microorganisms requiring prolonged treatment within the first 7 days were excluded. Patients outside the mutual range of the propensity score were also excluded. The primary outcome of this study was 30-day mortality. Secondary outcomes were subsequent requirement for mechanical ventilation and/or inotropic support and the development of complicated pneumonia or re-admission within 30 days. Four hundred and twelve patients were suitable for derivation of the propensity score. After matching on propensity score, 164 patients treated for 7 days were compared with 164 treated for >7 days; they were well matched in terms of age, gender, comorbidities, and physiological parameters. The results showed no significant differences in the primary and the secondary outcomes between the two groups. This study therefore suggests that, in the majority of severe CAP patients who have clinically responded, antibiotics can be safely discontinued at 7 days.

An evaluation of clinical stability criteria to predict hospital course in community‐acquired pneumonia

A number of different methods exist to assess clinical stability, a key component of pneumonia management. We compared the prognostic value of different stability criteria through a secondary analysis of the Edinburgh pneumonia study database. We studied four clinical stability criteria (Halms criteria, the ATS criteria, CURB and 50% or more decrease in C-reactive protein from baseline). Outcomes included 30-day mortality, need for mechanical ventilation or vasopressor support (MV/VS), development of a complicated pneumonia, and a combined outcome of the above. A total of 1079 patients (49.8% male), with a median age of 68 years (IQR 53-80), were included. Ninety-three patients (8.6%) died by day 30, 91 patients (8.4%) required MV/VS and 99 patients (9.2%) developed a complicated pneumonia. Patients with increasing severity of pneumonia on admission, assessed by both CURB-65 and PSI, took a progressively longer time to achieve clinical stability assessed by any method (p < 0.001 for all criteria). Halms criteria had the highest area under the curve (AUC) for prediction of 30-day mortality (AUC 0.95 (0.94-0.96)), need for MV/VS (AUC 0.96 (0.95-0.97)) and combined adverse outcome (AUC 0.96 (0.95-0.97)). C-reactive protein had the highest area under the curve for complicated pneumonia (AUC 0.96 (0.95-0.97)). Adding C-reactive protein to Halms criteria increased the area under the curve, but the difference was only statistically significant for complicated pneumonia. All of the criteria performed well in predicting adverse outcomes in patients with pneumonia. Halms criteria performed best when identifying patients at low risk of complications.

Urgent challenges in implementing live attenuated influenza vaccine

Conflicting reports have emerged about the effectiveness of the live attenuated influenza vaccine. The live attenuated influenza vaccine appears to protect particularly poorly against currently circulating H1N1 viruses that are derived from the 2009 pandemic H1N1 viruses. During the 2015-16 influenza season, when pandemic H1N1 was the predominant virus, studies from the USA reported a complete lack of effectiveness of the live vaccine in children. This finding led to a crucial decision in the USA to recommend that the live vaccine not be used in 2016-17 and to switch to the inactivated influenza vaccine. Other countries, including the UK, Canada, and Finland, however, have continued to recommend the use of the live vaccine. This policy divergence and uncertainty has far reaching implications for the entire global community, given the importance of the production capabilities of the live attenuated influenza vaccine for pandemic preparedness. In this Personal View, we discuss possible explanations for the observed reduced effectiveness of the live attenuated influenza vaccine and highlight the underpinning scientific questions. Further research to understand the reasons for these observations is essential to enable informed public health policy and commercial decisions about vaccine production and development in coming years.

T1 Fluticasone propionate alters the resident airway microbiota and impairs anti-viral and anti-bacterial immune responses in the airways

Background Inhaled corticosteroids are the cornerstone of therapy in asthma and COPD but cause only modest reduction in exacerbations and are associated with increased pneumonia frequency. This has raised concern about potential detrimental effects on host-defence against respiratory pathogens. The aim of this study was to evaluate the effects of fluticasone propionate on airway anti-viral and anti-bacterial host-defence. Methods C57BL/6 mice were intranasally treated with fluticasone propionate (1 mg/kg) or vehicle control. 16S Quantitative PCR was used to evaluate total bacterial loads and pyrosequencing was used to evaluate microbiota community composition in lung tissue. Using mouse models of infection with rhinovirus 1B and S. pneumoniae D39, effects of fluticasone administration on anti-viral and anti-bacterial immune responses, airway inflammation and pathogen control were evaluated. Results Mice treated with fluticasone had increased lung bacterial loads compared to vehicle-treated controls at 8 h post administration (p < 0.05). Evaluation of community composition revealed that fluticasone treatment was associated with significant increases in Stenotrophomonas genera (p < 0.05). In a mouse model of S. pneumoniae infection, fluticasone administration suppressed anti-bacterial responses including expression of cytokines IL-6 and TNF-α (4 h post-infection; p < 0.001) and airway neutrophil recruitment (8 h post-infection; p < 0.001) and was also associated with increased lung bacterial loads measured by quantitative culture (8 h post-infection; p < 0.001). In a mouse model of rhinovirus infection, fluticasone suppressed innate anti-viral responses including BAL protein levels of interferon-β and -λ2/3 (day 1 post-infection; p < 0.001). Virus clearance was impaired by fluticasone with increased viral RNA copies observed in lung tissue (day 1&2 post-infection; p < 0.001). The late expression of rhinovirus-induced airway mucins MUC5AC and MUC5B BAL proteins was increased by fluticasone (p < 0.01 and p < 0.05 respectively at day 7). Administration of recombinant interferon-β in combination with fluticasone and rhinovirus led to upregulation of interferon-stimulated genes and improved virus clearance, thereby demonstrating that adverse effects of fluticasone on RV clearance are causally related to interferon suppression. Recombinant IFN-β did not alter the increased mucins observed with fluticasone treatment. Conclusion Fluticasone alters the airway microbiota and impairs airway anti-viral and anti-bacterial host-defence in mice. Human studies are required to confirm the relevance of these effects in the context of inflammatory airway diseases.

Letter in response to TB during TNF-α inhibitor therapy, despite screening

We read the case-based discussion published in Thorax by Hofland et al 1 with great interest. The case studies reported by the authors raise a very important point about the necessity for continued monitoring of patients on tumour necrosis factor (TNF)-α antagonist therapy, even in the absence of evidence of latent TB infection (LTBI) at the onset of therapy and this is a point that is not discussed in the most recent British Thoracic society (BTS) guidance document on TB and anti-TNF α treatment.2 The two cases described in the article would be classified as ‘low risk’ and thus not offered chemoprophylaxis if managed according to current BTS recommendations. …

S27 Cardiovascular events following Clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies

Background Previous studies have suggested that use of macrolide antibiotics may increase cardiovascular risk. Objective To study the effects of clarithromycin on cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and community acquired pneumonia (CAP). Design Cohort study of two prospectively collected datasets; a multicentre observational study of patients hospitalised with AECOPD and the Edinburgh pneumonia study cohort. Setting COPD dataset includes patients admitted to one of 12 hospitals around the United Kingdom between 2009–2011. The Edinburgh pneumonia study cohort includes patients admitted to NHS Lothian Hospitals between 2005–2009. Main outcome measures Hazard ratios (HR) for cardiovascular events at 1 year (defined as hospitalised with acute coronary syndrome (ACS), decompensated cardiac failure, serious arrhythmia or sudden cardiac death) and hospitalisation for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation MI and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at 1 year. Cox proportional hazard regression was used to calculate hazard ratio’s and 95% confidence intervals after adjusting for significant covariates. Results There were 1323 and 1631 patients in the AECOPD and CAP cohorts with 268 and 171 cardiovascular events respectively over 1 year. Macrolide use in AECOPD was associated with increased risk of cardiovascular events HR 1.60 (1.17–2.20) and ACS HR 1.88 (1.16–3.01). Macrolide use in CAP was associated with increased risk of cardiovascular events HR 1.81 (1.28–2.55) and ACS HR 1.90 (1.07–3.33). There was a significant association between macrolide use and cardiovascular but not all cause mortality in AECOPD HR 1.67 (1.11–2.51) and 1.24 (0.96–1.61). Macrolide use in CAP was associated with a trend towards increased risk of all cause and cardiovascular mortality HR 1.13 (0.85–1.51) and 1.57 (0.84–2.82). These relationships persisted after propensity matching. Statins and other cardiac drugs attenuated this increased risk. Longer durations of macrolide use were associated with more cardiovascular events. The effect of macrolides was most evident in patients with pre-existing cardiovascular disease or at high risk of cardiovascular disease according to the QRISK2 score. Conclusions The use of clarithromycin in the setting of AECOPD or CAP is associated with increased cardiovascular events. Abstract S27 Figure 1

Systemic cytokine storm in severe eosinophilic dermatitis

### Learning point for clinicians Severe eosinophilic dermatitis with systemic symptoms is rare. We report, for the first time, that the systemic clinical symptoms and high CRP (123 mg/l) were due to an IL-6 and IL-8 cytokine storm. Systemic disease control was only achieved with high dose oral prednisolone, topical triamcinolone to affected skin and dapsone. A 27-year-old woman presented with a 12-day history of worsening fever and rash. Erythematous, indurated and pruritic lesions had been developing on her inner thighs. They went on to spread to her arms and back. She was previously fit and well with no relevant past medical or family history. During her first week in hospital, she became intermittently confused and disorientated and was also intermittently febrile between 38.3°C and 40°C. Her skin lesions became ‘woody hard’ subcutaneous swelling and were associated with dark mottling of the overlying skin. During her second week in …