The effect of azithromycin on sputum inflammatory markers in bronchiectasis.

BACKGROUND: Long term macrolide treatment has been found beneficial in bronchiectasis (BE) -pathogical bronchial dilatation- possibly due to a combined anti-bacterial and immunomodulatory effect. The exact mechanism of inflammatory response is unknown. Here, we investigated the effect of maintenance macrolide treatment on the inflammatory response in BE. In addition, we assessed the inflammatory profile in BE in relation to disease severity. METHODS: During the BAT randomized controlled trial (investigating the effect of 1 year of azithromycin (AZM) in 83 BE patients), data on BE severity, lung function and sputum microbiology was collected. For the current study, a wide range of inflammatory markers were analysed in 3- monthly sputum samples in all participants. RESULTS: At baseline, marked neutrophilic but also eosinophilic inflammation was present in both groups, which remained stable throughout the study and was not affected by AZM treatment. Significant upregulation of pro-inflammatory markers correlated with FEV1 < 50% (TNFα, ECP, IL-21, IL-1, p = 0.01- 0.05), H. influenzae (HI) colonization (MPO, ECP, MIP-1, TNFα, IL-21, Il-8, IL-1, IL-1α, p < 0.001 - 0.04) and number of exacerbations (MPO, ECP, VEGF, MMP-9, p = 0.003 - 0.01). Surprisingly, colonization with P. aeruginosa (PA) was found to correlate with an attenuated inflammatory response compared to non-PA colonized. In placebo-treated patients, presence of an infectious exacerbation was reflected by a significant excessive increase in inflammation as compared to a non-significant upregulation in the AZM-treated patients. CONCLUSION: One year of AZM treatment did not result in attenuation of the inflammatory response in BE. Increasing disease severity and the presence of an exacerbation were reflected by upregulation of pro-inflammatory markers.

The BATTLE study: Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis. Study protocol of a double blind, randomized, placebo-controlled trial: study protocol.

Background: Patients with bronchiectasis typically suffer from chronic symptoms such as a productive cough with or without exacerbations leading to hospitalization, causing reduced quality of life (QoL) and mortality. Long-term inhaled antibiotics to treat chronic bronchial infection is registered for use in cystic fibrosis (CF) bronchiectasis. However, in patients with non-CF bronchiectasis data on long-term antibiotics are limited. Objective: To investigate the effectiveness of maintenance tobramycin inhalation solution (TIS) in bronchiectasis patients without cystic fibrosis. Study design: The BATTLE study is a randomized, double blind placebo controlled, multicenter study in the Netherlands performed in patients aged ≥18-year-old with confirmed bronchiectasis, at least two exacerbations in the preceding year, and minimal one positive sputum culture with gram negative pathogens or Staphylococcus aureus, sensitive to tobramycin in the preceding year and at baseline. Patients will be treated with TIS once daily (OD) or placebo (saline 0.9%) OD for 52 weeks followed by a run-out period of 4 weeks after the last dose. The primary outcome is the yearly rate of pulmonary exacerbations. Among secondary outcome parameters are time to exacerbation, lung function, QoL, microbiological evaluation and safety. Discussion: The BATTLE study is designed to determine the efficacy and safety of maintenance TIS OD in bronchiectasis patients colonized by different pathogens and could lead to important new evidence for TIS therapy in this population.The BATTLE study is registered in Clinical trials.gov with registration number: NCT02657473.

Predicting factors for chronic colonization of Pseudomonas aeruginosa in bronchiectasis.

About 25% of the patients with bronchiectasis are likely to develop a chronic colonization with Pseudomonas aeruginosa. A better understanding of predictors of acquiring Pseudomonas within the patient population may facilitate future focused research. The aim of this retrospective observational study was to investigate predicting factors for P. aeruginosa colonization in patients with bronchiectasis. This was a single-center retrospective cohort study using a bronchiectasis database which consisted of 211 patients with bronchiectasis. Data were collected for demographic details, etiology, spirometry, microbiology data, maintenance medication use, exacerbation frequency, hospital admission rate, and FACED and Bronchiectasis Severity Index (BSI) score. Two hundred eleven patients were identified from our bronchiectasis database. Overall, 25% of the patients (n = 53) had a chronic colonization with P. aeruginosa. Seventeen patients (8%) died in a 5-year follow-up period of whom 7 (41%) had a chronic P. aeruginosa colonization (p > 0.05). After multiple regression analysis, P. aeruginosa-positive patients were significantly associated with an older age (> 55 years) (p = 0.004), the use of hypertonic saline (0.042), and inhalation antibiotics (< 0.001). Furthermore, the presence of PCD (p < 0.001) and post-infectious etiology (p < 0.001) as underlying causes were significantly associated with P. aeruginosa colonization. We observed that independent predictors for P. aeruginosa colonization were age > 55 years, hypertonic saline, and PCD, and post-infectious etiology as underlying causes of bronchiectasis. Since prevention of P. aeruginosa colonization is an important aim in the treatment of bronchiectasis, more attention could be directed to these groups at risk for Pseudomonas colonization.

Non-cystic fibrosis bronchiectasis: clinical presentation, diagnosis and treatment, illustrated by data from a Dutch Teaching Hospital.

This review article describes the epidemiology, clinical presentation, diagnostic workup and treatment options in adult non-cystic fibrosis (non-CF) bronchiectasis (widening of mainly small and medium-sized bronchi as seen on chest computed tomography (CT) scan). We illustrate evidence from the literature with our own data retrieved from chart review, involving 236 adult patients with recurrent lower respiratory tract infections and high-resolution CT-proven non-CF bronchiectasis, who visited the outpatient clinic for respiratory diseases of a large Dutch teaching hospital between 2000 and 2010. Non-CF bronchiectasis can be described as a final common pathway of a vicious cycle of excessive bronchial inflammation, bacterial colonisation and infection. Non-CF bronchiectasis may arise from several causes, headed by infection and immunodeficiency, and is clinically characterised by a chronic, productive cough and infectious exacerbations. Once non-CF bronchiectasis is diagnosed using high-resolution CT scanning, a protocol-driven work-up to identify the underlying cause is recommended. Non-medicinal treatment options are primarily directed at clearance of bronchial secretions, which can further be improved by inhalation of hyperosmolar agents. Antibiotic treatment of exacerbations is a cornerstone medicinal treatment in bronchiectasis management. Patients with frequent exacerbations can be considered for long-term low-dose macrolide treatment, supported by robust evidence. Inhaled antibiotics might be beneficial in selected patients colonised with Pseudomonas aeruginosa. Important developments in the last decade include the introduction of international guidelines and the proposal for a validated scoring system for disease severity. Bronchiectasis patients are encountered by physicians in diverse medical professions and the disease itself is still underdiagnosed. The authors aim to increase awareness of the condition and provide practical tools for diagnosis and treatment.

Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms.

Macrolide antibiotics are well known for their antibacterial and anti-inflammatory properties. This article provides an overview of the biological mechanisms through which macrolides exert this 'double effect'. Their antibacterial effect consists of the inhibition of bacterial protein synthesis, impaired bacterial biofilm synthesis, and the attenuation of other bacterial virulence factors. Apart from these direct antimicrobial effects, macrolides are known for their modulating effect on many components of the human immune system. By influencing the production of cytokines, they have a dampening effect on the proinflammatory response. Furthermore, the majority of cells involved in the immune response are, in one way or another, influenced when macrolide antibiotics are administered. Having such an obvious effect on the various aspects of the immune system, macrolides seem to be exceptionally suited for the treatment of chronic inflammatory diseases.

Immunomodulatory effects of macrolide antibiotics - part 2: advantages and disadvantages of long-term, low-dose macrolide therapy.

The available evidence for long-term, low-dose treatment with 14- and 15-membered ring macrolides in non-cystic fibrosis (CF) bronchiectasis, COPD, chronic sinusitis, and asthma is reviewed with special attention to possible adverse effects and the emergence of resistance during long-term macrolide treatment. Macrolide maintenance therapy has been proven to be of benefit in diffuse panbronchiolitis and CF, presumably due to an anti-inflammatory mechanism of action in addition to its direct antimicrobial effect. Solid evidence to justify this treatment regimen for non-CF bronchiectasis, asthma, or sinusitis is still lacking, although a beneficial effect of long-term macrolide therapy has been found in small clinical trials on these subjects. Data from randomized trials of long-term macrolide treatment in COPD are conflicting. A sufficiently long duration of treatment and the careful selection of patients appears to be crucial. Aside from its beneficial effects, possible side effects of macrolide treatment should be taken into account, the most important of these being gastrointestinal upset and cardiac arrhythmias. Development of macrolide resistance among respiratory pathogens is very common during long-term macrolide treatment. Whether this finding is clinically significant is a matter of debate.

Rituximab in life threatening antisynthetase syndrome.

This case study reports a patient with severe interstitial pneumonitis, mild polyarthritis and polymyositis, accompanied by the presence of anti-Jo-1 antibodies diagnosed as antisynthetase syndrome. The concurrence of anti-Jo-1 with anti-Ro/SSA antibodies leads to a more severe form of interstitial lung disease. This patient was referred to our hospital because of life threatening respiratory failure. He was refractory to glucocorticoids and cyclophosphamide, but was successfully treated with two sequential infusions of rituximab. Clinical condition improved very rapidly. Response to treatment was well correlated with a fall of levels of serum soluble IL2-receptor. A decrease in pulmonary disease activity was visualized on PET-scans before and after two sequential rituximab infusions.