Menno M. van der Eerden

Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial

BACKGROUND Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care. METHODS We did a randomised, double-blind, placebo-controlled, single-centre trial in The Netherlands between May 19, 2010, and June 18, 2013. Patients (≥18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone (≤10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00985244. FINDINGS We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1·94 (95% CI 1·50-2·52) for the azithromycin group and 3·22 (2·62-3·97) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0·58, 95% CI 0·42-0·79; p=0·001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0·015). INTERPRETATION Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care. FUNDING SoLong Trust.

Highly Pathogenic Avian Influenza Virus H5N1 Infects Alveolar Macrophages without Virus Production or Excessive TNF-Alpha Induction

Highly pathogenic avian influenza virus (HPAIV) of the subtype H5N1 causes severe, often fatal pneumonia in humans. The pathogenesis of HPAIV H5N1 infection is not completely understood, although the alveolar macrophage (AM) is thought to play an important role. HPAIV H5N1 infection of macrophages cultured from monocytes leads to high percentages of infection accompanied by virus production and an excessive pro-inflammatory immune response. However, macrophages cultured from monocytes are different from AM, both in phenotype and in response to seasonal influenza virus infection. Consequently, it remains unclear whether the results of studies with macrophages cultured from monocytes are valid for AM. Therefore we infected AM and for comparison macrophages cultured from monocytes with seasonal H3N2 virus, HPAIV H5N1 or pandemic H1N1 virus, and determined the percentage of cells infected, virus production and induction of TNF-alpha, a pro-inflammatory cytokine. In vitro HPAIV H5N1 infection of AM compared to that of macrophages cultured from monocytes resulted in a lower percentage of infected cells (up to 25% vs up to 84%), lower virus production and lower TNF-alpha induction. In vitro infection of AM with H3N2 or H1N1 virus resulted in even lower percentages of infected cells (up to 7%) than with HPAIV H5N1, while virus production and TNF-alpha induction were comparable. In conclusion, this study reveals that macrophages cultured from monocytes are not a good model to study the interaction between AM and these influenza virus strains. Furthermore, the interaction between HPAIV H5N1 and AM could contribute to the pathogenicity of this virus in humans, due to the relative high percentage of infected cells rather than virus production or an excessive TNF-alpha induction.

The EMBARC European bronchiectasis registry: Protocol for an international observational study

Bronchiectasis is one of the most neglected diseases in respiratory medicine. There are no approved therapies and few large-scale, representative epidemiological studies. The EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) registry is a prospective, pan-European observational study of patients with bronchiectasis. The inclusion criterion is a primary clinical diagnosis of bronchiectasis consisting of: 1) a clinical history consistent with bronchiectasis; and 2) computed tomography demonstrating bronchiectasis. Core exclusion criteria are: 1) bronchiectasis due to known cystic fibrosis; 2) age <18 years; and 3) patients who are unable or unwilling to provide informed consent. The study aims to enrol 1000 patients by April 2016 across at least 20 European countries, and 10 000 patients by March 2020. Patients will undergo a comprehensive baseline assessment and will be followed up annually for up to 5 years with the goal of providing high-quality longitudinal data on outcomes, treatment patterns and quality of life. Data from the registry will be available in the form of annual reports. and will be disseminated in conference presentations and peer-reviewed publications. The European Bronchiectasis Registry aims to make a major contribution to understanding the natural history of the disease, as well as guiding evidence-based decision making and facilitating large randomised controlled trials. The European Bronchiectasis Registry will recruit 10 000 patients over 5 years http://ow.ly/Ul7Pd

Detection of respiratory viruses and Legionella spp. by real-time polymerase chain reaction in patients with community acquired pneumonia

We conducted a study on throat swabs obtained from a group of hospitalized patients with community acquired pneumonia (CAP). Throat swab specimens from 242 adults admitted to hospital with CAP were tested. In total, 1 or more aetiological agents were identified by real-time PCR in 55 (23%) patients. The most frequently detected pathogens were coronavirus (17%), parainfluenza virus (6%) and influenza virus (4%). Overall, viral pathogens were identified by conventional techniques in 7 (2%) patients, and real-time PCR in 50 (21%) patients (p<0.0001). The diagnostic yield increased from 137 cases (57% of patients using conventional microbiological assays) to 158 cases (65% of patients using real-time PCR assays and conventional microbiological assays; p=0.06). A significantly higher percentage of mortality was present in patients with a mixed bacterial and viral infection. L. pneumophila PCR was positive in only 3 out of 11 cases (27%) of Legionnaires’ disease (LD). This study demonstrates that real-time PCR can increase the number of microbiological detections of respiratory pathogens, mainly as a result of detection of respiratory viruses.

Incidence of viral respiratory pathogens causing exacerbations in adult cystic fibrosis patients.

Abstract Respiratory infections caused by respiratory viruses are common in paediatric cystic fibrosis (CF) patients and are associated with increased morbidity. There is only little data on the incidence of viral respiratory pathogens causing exacerbations in the adult CF patient population. In this observational pilot study we show, by using molecular as well as conventional techniques for viral isolation, that during 1 y a viral pathogen could be isolated in 8/24 (33%) adult CF patients who presented with a pulmonary exacerbation. This result shows that there is a considerable incidence of viral pathogens in pulmonary exacerbations in adult CF patients. Newly identified viruses such as pandemic influenza A/H1N1, human metapneumovirus, human bocavirus, and human coronavirus NL63 were not detected in our population, except for 1 human coronavirus NL63.

Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia.

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters. Levels of interleukin (IL)-6, IL-8, IL-10, IL-1&bgr;, tumour necrosis factor-&agr;, interferon (IFN)-&ggr;, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals. Systemic cytokine levels were also measured on days 7 and 30. In bronchoalveolar lavage fluid of CAP patients, levels of IL-6, IL-8 and IFN-&ggr; were significantly increased compared with healthy individuals, but no correlations with disease severity were found. Systemic levels of IL-6, IL-10 and IFN-&ggr; were significantly higher in severe CAP patients than in nonsevere CAP patients and healthy individuals. Moreover, these cytokines showed a significant correlation with the pneumonia severity index. In the total group of CAP patients, systemic IL-8 and IL-22 levels were also increased compared with healthy individuals. We therefore conclude that IL-6, IL-10 and IFN-&ggr; are important cytokines in CAP, although differences in disease severity upon admission are only reflected by systemic levels of these cytokines.

Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD.

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised. Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-&ggr;, interleukin (IL)-4, tumour necrosis factor (TNF)-&agr; and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry. We found significantly increased proportions of IFN-&ggr;+ and TNF-&agr;+ CD8+ T-cells in COPD patients, when compared with healthy controls. This was most evident in patients with less severe disease. In contrast, expression profiles in circulating CD4+ T-cells were similar in COPD patients and healthy controls for all cytokines tested, except for IL-17F. COPD patients with more severely reduced diffusing capacity had lower proportions of IL-17A+ CD4+ T-cells. Proportions of IL-22+ cells in the CD4+ memory T-cell population were significantly increased in active smokers, when compared with past smokers. Collectively, this comprehensive cytokine analysis of circulating T-cells in COPD patients revealed a correlation for CD8+ T-cells between Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and IFN-&ggr; or TNF-&agr; expression, but not for CD4+ T-cells.

CURB-65 Pneumonia Severity Assessment Adapted for Electronic Decision Support

BACKGROUND Accurate severity assessment is crucial to the initial management of community-acquired pneumonia (CAP). The CURB-65 (confusion, uremia, respiratory rate, BP, age ≥ 65 years) score contains data that are entered routinely in electronic medical records and are, thus, electronically calculable. The aim of this study was to determine whether an electronically generated severity estimate using CURB-65 elements as continuous and weighted variables better predicts 30-day mortality than the traditional CURB-65. METHODS In a retrospective cohort study at a US university-affiliated community teaching hospital, we identified 2,069 patients aged 18 years or older with CAP confirmed by radiographic findings in the ED. CURB-65 elements were extracted from the electronic medical record, and 30-day mortality was identified with the Utah Population Database. Performance of a severity prediction model using continuous and weighted CURB-65 variables was compared with the traditional CURB-65 in the US derivation population and validated in the original 1,048 patients from the CURB-65 international derivation study. RESULTS The traditional, binary CURB-65 score predicted mortality in the US cohort with an area under the curve (AUC) of 0.82. Our severity prediction model generated from continuous, weighted CURB-65 elements was superior to the traditional CURB-65, with an out-of-bag AUC of 0.86 (P < .001). This finding was validated in the international database, with an AUC of 0.85 for the electronic model compared with 0.80 for the traditional CURB-65 (P = .01). CONCLUSIONS Using CURB-65 elements as continuous and weighted data improved prediction of 30-day mortality and could be used as a real-time, electronic decision support tool or to adjust outcomes by severity when comparing processes of care.

T helper 17 cells are involved in the local and systemic inflammatory response in community-acquired pneumonia

Background Recent findings in mouse models suggest that T helper (Th)17 cells, characterised by production of interleukin (IL)-17A and IL-22, are involved in the immunopathogenesis of pneumonia. Objective In this study, we aimed to identify the involvement of Th17 cells in human community-acquired pneumonia (CAP). Design Within 24 h of admission, T cells from peripheral blood (n=39) and bronchoalveolar lavage (BAL, n=20) of CAP patients and of 10 healthy individuals were analysed by intracellular flow cytometry for the production of various cytokines, including IL-17A and IL-22. Peripheral blood T cells were also analysed 7 and 30 days after admission. Th17 cytokine profiles were correlated with pneumonia severity index and microbial aetiology. Results In the BAL of CAP patients, proportions of IL-17A and IL-22 single positive, as well as IL-17A/IL-22 double positive CD4 T cells were significantly increased compared with healthy individuals. Significantly increased proportions of IL-17A/IL-22 double positive CD4 T cells in BAL were found in non-severe and severe CAP patients, as well as in pneumococcal and non-pneumococcal CAP. In the peripheral blood of CAP patients upon admission, we found significantly increased proportions of IL-17A/IL-22 double positive CD4 T cells. One week after admission, the proportions of these double positive cells were still significantly increased in CAP patients compared with healthy individuals. Conclusions These data indicate that Th17 cells are engaged in the local and systemic immune response in human pneumonia. Especially, IL-17A/IL-22 double positive Th17 cells may be involved in the immunopathogenesis of CAP.

Evaluation of an algorithm for switching from IV to PO therapy in clinical practice in patients with community-acquired pneumonia.

BACKGROUND In patients with community-acquired pneumonia (CAP), switching from IV to PO antibiotics offers advantages over IV therapy alone, including improved cost-effectiveness through reductions in the length of hospital stay and treatment costs. OBJECTIVE The aim of this study was to determine whether a method for switching therapy in clinical practice could be used in patients with CAP and whether differences were found in the duration of IV treatment and length of hospital stay between the 5 risk classes of the Pneumonia Severity Index (PSI) after the therapy switch. METHODS This was a prospective, observational study of patients aged >/=18 years presenting with CAP at our teaching hospital between December 1998 and November 2000. Microbiological and serological tests were performed, and signs and symptoms of CAP, C-reactive protein levels, and white blood cell counts were assessed throughout treatment and at the 1-month follow-up. Patients were stratified by PSI risk class. When the patients temperature had been normalized for 72 hours and respiratory symptoms (dyspnea, coughing, and thoracal pain) had improved, patients were switched from IV to PO therapy (same drug). RESULTS The study included 180 patients with CAP Clinical cure was seen in 174 (97%) patients. No significant difference between the 5 risk classes was found in duration of therapy. Patients in risk class V remained hospitalized for a significantly longer period than patients in risk classes I through IV (P < 0.001). Furthermore, after patients were switched to PO antibiotics, the level of C-reactive protein decreased in patients in all risk classes and was normalized by follow-up. CONCLUSIONS In the population studied, use of specific criteria (ie, absence of fever for 72 hours and reduction in respiratory symptoms) allowed successful switch from IV to PO antibiotic therapy for the treatment of CAP Duration of therapy was not affected by PSI risk class, but those in risk class V were hospitalized longer than other risk classes.