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.

Recommendations for antibacterial therapy in adults with COVID-19 e an evidence based guideline

The Dutch Working Party on Antibiotic Policy constituted a multidisciplinary expert committee to provide evidence-based recommendation for the use of antibacterial therapy in hospitalized adults with a respiratory infection and suspected or proven 2019 Coronavirus disease (COVID-19). We performed a literature search to answer four key questions. The committee graded the evidence and developed recommendations by using Grading of Recommendations Assessment, Development, and Evaluation methodology. We assessed evidence on the risk of bacterial infections in hospitalized COVID-19 patients, the associated bacterial pathogens, how to diagnose bacterial infections and how to treat bacterial infections. Bacterial co-infection upon admission was reported in 3.5% of COVID-19 patients, while bacterial secondary infections during hospitalization occurred up to 15%. No or very low quality evidence was found to answer the other key clinical questions. Although the evidence base on bacterial infections in COVID-19 is currently limited, available evidence supports restrictive antibiotic use from an antibiotic stewardship perspective, especially upon admission. To support restrictive antibiotic use, maximum efforts should be undertaken to obtain sputum and blood culture samples as well as pneumococcal urinary antigen testing. We suggest to stop antibiotics in patients who started antibiotic treatment upon admission when representative cultures as well as urinary antigen tests show no signs of involvement of bacterial pathogens after 48 hours. For patients with secondary bacterial respiratory infection we recommend to follow other guideline recommendations on antibacterial treatment for patients with hospital-acquired and ventilator-associated pneumonia. An antibiotic treatment duration of five days in patients with COVID-19 and suspected bacterial respiratory infection is recommended upon improvement of signs, symptoms and inflammatory markers. Larger, prospective studies about the epidemiology of bacterial infections in COVID-19 are urgently needed to confirm our conclusions and ultimately prevent unnecessary antibiotic use during the COVID-19 pandemic.

Cost-effectiveness analysis on elderly pneumococcal vaccination in the Netherlands: Challenging the Dutch Health Council's advice.

Recently, the Dutch Health Council advised on elderly pneumococcal vaccination favouring the conventional polysaccharide vaccine over the novel conjugated vaccine. This advice was strongly inspired by a cost-effectiveness analysis considered to show favourable outcomes for the polysaccharide but not for the conjugated vaccine. We argue that using the same data and methods as presented by the Health Council, a different perspective on the results leads to a conclusion that not only the polysaccharide but also the conjugated pneumococcal vaccine is cost-effective. Our alternative perspective concerns the use of realistic vaccine prices, and applying an adequate time horizon for cost-effectiveness modelling. Notably, for one-off vaccination of 65-years old elderly, in all investigated analyses, also the conjugated vaccine seems cost-effective; i.e. well below the threshold of €20,000 per quality-adjusted life year, reflecting the most stringent threshold used for vaccines in the Netherlands.

Feasibility of a quantitative polymerase chain reaction assay for diagnosing pneumococcal pneumonia using oropharyngeal swabs.

Streptococcus pneumoniae is the most important pathogen causing community-acquired pneumonia (CAP). The current diagnostic microbial standard detects S. pneumoniae in less than 30% of CAP cases. A quantitative polymerase chain reaction (PCR) targeting autolysin (lytA) is able to increase the rate of detection. The aim of this study is validation of this quantitative PCR in vitro using different available strains and in vivo using clinical samples (oropharyngeal swabs). The PCR autolysin (lytA) was validated by testing the intra- and inter-run variability. Also, the in vitro specificity and sensitivity, including the lower limit of detection was determined. In addition, a pilot-study was performed using samples from patients (n = 28) with pneumococcal pneumonia and patients (n = 28) with a pneumonia without detection of S. pneumoniae with the current diagnostic microbial standard, but with detection of either a viral and or another bacterial pathogen to validate this test further. The intra- and inter-run variability were relatively low (SD's ranging from 0.08 to 0.96 cycle thresholds). The lower limit of detection turned out to be 1-10 DNA copies/reaction. In-vitro sensitivity and specificity of the tested specimens (8 strains carrying lytA and 6 strains negative for lytA) were both 100%. In patients with pneumococcal and non-pneumococcal pneumonia a cut-off value of 6.000 copies/mL would lead to a sensitivity of 57.1% and a specificity of 85.7%. We were able to develop a quantitative PCR targeting lytA with good in-vitro test characteristics.

Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT).

The Dutch Working Party on Antibiotic Policy in collaboration with the Dutch Association of Chest Physicians, the Dutch Society for Intensive Care and the Dutch College of General Practitioners have updated their evidence-based guidelines on the diagnosis and treatment of community-acquired pneumonia (CAP) in adults who present to the hospital. This 2016 update focuses on new data on the aetiological and radiological diagnosis of CAP, severity classification methods, initial antibiotic treatment in patients with severe CAP and the role of adjunctive corticosteroids. Other parts overlap with the 2011 guideline. Apart from the Q fever outbreak in the Netherlands (2007-2010) no other shifts in the most common causative agents of CAP or in their resistance patterns were observed in the last five years. Low-dose CT scanning may ultimately replace the conventional chest X-ray; however, at present, there is insufficient evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. A pneumococcal urine antigen test is now recommended for all patients presenting with severe CAP; a positive test result can help streamline therapy once clinical stability has been reached and no other pathogens have been detected. Coverage for atypical microorganisms is no longer recommended in empirical treatment of severe CAP in the non-intensive care setting. For these patients (with CURB-65 score >2 or Pneumonia Severity Index score of 5) empirical therapy with a 2nd/3rd generation cephalosporin is recommended, because of the relatively high incidence of Gram-negative bacteria, and to a lesser extent S. aureus. Corticosteroids are not recommended as adjunctive therapy for CAP.

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.

Predicting pneumococcal community-acquired pneumonia in the emergency department: evaluation of clinical parameters.

The aim of this study was to quantify the value of clinical predictors available in the emergency department (ED) in predicting Streptococcus pneumoniae as the cause of community-acquired pneumonia (CAP). A prospective, observational, cohort study of patients with CAP presenting in the ED was performed. Pneumococcal aetiology of CAP was based on either bacteraemia, or S. pneumoniae being cultured from sputum, or urinary immunochromatographic assay positivity, or positivity of a novel serotype-specific urinary antigen detection test. Multivariate logistic regression was used to identify independent predictors and various cut-off values of probability scores were used to evaluate the usefulness of the model. Three hundred and twenty-eight (31.0%) of 1057 patients with CAP had pneumococcal CAP. Nine independent predictors for pneumococcal pneumonia were identified, but the clinical utility of this prediction model was disappointing, because of low positive predictive values or a small yield. Clinical criteria have insufficient diagnostic capacity to predict pneumococcal CAP. Rapid antigen detection tests are needed to diagnose S. pneumoniae at the time of hospital admission.

Guideline adherence for empirical treatment of pneumonia and patient outcome. Treating pneumonia in the Netherlands.

INTRODUCTION: According to the Dutch guidelines, severity of community acquired pneumonia (CAP) (mild, moderate-severe, severe) should be based on either PSI, CURB65 or a 'pragmatic' classification. In the last mentioned, the type of ward of admission, as decided by the treating physician, is used as classifier: no hospital admission is mild, admission to a general ward is moderate-severe and admission to an intensive care unit (ICU) is severe CAP. Empiric antibiotic recommendations for each severity class are uniform. We investigated, in 23 hospitals, which of the three classification systems empirical treatment of CAP best adhered to, and whether a too narrow spectrum coverage (according to each of the systems) was associated with a poor patient outcome (in-hospital mortality or need for ICU admission). PATIENTS AND METHODS: Prospective observational study in 23 hospitals. RESULTS: 271 (26%) of 1047 patients with CAP confirmed by X-ray were categorised in the same severity class with all three classification methods. Proportions of patients receiving guideline-adherent antibiotics were 62.9% (95% CI 60.0-65.8%) for the pragmatic, 43.1% (95% CI 40.1-46.1%) for PSI and 30.5% (95% CI 27.8-33.3%) for CURB65 classification. 'Under-treatment' based on the pragmatic classification was associated with a trend towards poor clinical outcome, but no such trend was apparent for the other two scoring systems. CONCLUSIONS: Concordance between three CAP severity classification systems was low, implying large heterogeneity in antibiotic treatment for CAP patients. Empirical treatment appeared most adherent to the pragmatic classification. Non-adherence to treatment recommendations based on the PSI and CURB65 was not associated with a poor clinical outcome.

SWAB/NVALT (Dutch Working Party on Antibiotic Policy and Dutch Association of Chest Physicians) guidelines on the management of community-acquired pneumonia in adults.

The Dutch Working Party on Antibiotic Policy (SWAB) and the Dutch Association of Chest Physicians (NVALT) convened a joint committee to develop evidence-based guidelines on the diagnosis and treatment of community acquired pneumonia (CAP). The guidelines are intended for adult patients with CAP who present at the hospital and are treated as outpatients as well as for hospitalised patients up to 72 hours after admission. Areas covered include current patterns of epidemiology and antibiotic resistance of causative agents of CAP in the Netherlands, the possibility to predict the causative agent of CAP on the basis of clinical data at first presentation, risk factors associated with specific pathogens, the importance of the severity of disease upon presentation for choice of initial treatment, the role of rapid diagnostic tests in treatment decisions, the optimal initial empiric treatment and treatment when a specific pathogen has been identified, the timeframe in which the first dose of antibiotics should be given, optimal duration of antibiotic treatment and antibiotic switch from the intravenous to the oral route. Additional recommendations are made on the role of radiological investigations in the diagnostic work-up of patients with a clinical suspicion of CAP, on the potential benefit of adjunctive immunotherapy, and on the policy for patients with parapneumonic effusions.

Temporary impairment of reticulocyte haemoglobin content in subjects with community-acquired pneumonia.

INTRODUCTION: In the case of inflammation, imbalance of iron homoeostasis is caused by increased retention of iron within cells of the reticuloendothelial system. Iron-restricted erythropoiesis occurs because of decreased availability of iron for haemoglobin (Hb) synthesis in erythroid progenitor cells. Deviations in reticulocyte haemoglobin (Ret-He) content are investigated together with inflammation markers in subjects with community-acquired pneumonia (CAP). Short-term alterations with regard to Ret-He during and after completing antibiotic treatment are investigated. METHODS: A total of 75 patients, classified into three subgroups with CURB-65 scores of ≤1, 2 and ≥3, participated in the study. RESULTS: Within the three subgroups, Hb results demonstrate a decline from the day of admission until day 4. From day 4, an increase towards higher values is observed at day 14. Within 24 h after admission, Ret-He results are situated within the lower quartile region of the reference range interval. Until day 4 of hospital admission, a steady trend towards a decline of 3-8% is established. During antibiotic treatment, an increase in reticulocyte count occurs from 0.039 ± 0.014 × 10(12) /L at day 4 to 0.057 ± 0.020 × 10(12) /L at day 14 (mean ± SD). Recovery of Hb and Ret-He occurs towards values within the reference range. CONCLUSION: In subjects with CAP, acute inflammation results in impairment of Ret-He at an early stage. After onset of pneumonia, decreased results of Ret-He and Ret-He/RBC-He ratio are demonstrated, reflecting acute erythropoietic dysfunction, which are amongst others caused by functional iron depletion.

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.

Sputum colour reported by patients is not a reliable marker of the presence of bacteria in acute exacerbations of chronic obstructive pulmonary disease.

Sputum colour is regarded as a good marker of bacterial involvement in acute exacerbations of chronic obstructive pulmonary disease (COPD) and guides many physicians in deciding on antibiotic treatment. Although most doctors rely on the sputum colour that is reported by patients, it can also be assessed using a validated colour chart. In this study, reported sputum colour and assessed sputum colour were compared as markers of the presence of bacteria, bacterial load, and systemic inflammation. Data on 257 exacerbations in 216 patients hospitalized with an acute exacerbation were analysed (mean age, 72 years; mean forced expiratory volume in 1 s, 44.8% + or - 17.8% (+ or - standard deviation)). Sputum colour was reported by the patients and assessed at the laboratory with a colour chart. Subsequently, quantitative sputum cultures were performed. C-reactive protein was measured as a marker of systemic inflammation. A sputum sample was obtained in 216 exacerbations (84%), of which 177 (82%) were representative. A pathogen was identified in 155 patients (60%). Assessed sputum colour was a better marker of the presence of bacteria (OR 9.8; 95% CI 4.7-20.4; p <0.001) than reported sputum colour (OR 1.7; 95% CI 1.0-3.0; p 0.041). The sensitivity and specificity were 73% and 39% for reported sputum colour, and 90% and 52% for assessed sputum colour. Assessed sputum colour was clearly related to sputum bacterial load and C-reactive protein levels, whereas reported sputum colour was not. It is concluded that sputum colour reported by patients is an unreliable marker of the presence of bacteria in acute exacerbations of COPD. Assessed sputum colour is clearly superior and is also related to bacterial load and systemic inflammation.

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.

Incidence and completeness of notification of Legionnaires' disease in The Netherlands: covariate capture-recapture analysis acknowledging regional differences.

To estimate incidence and completeness of notification of Legionnaires' disease (LD) in The Netherlands in 2000 and 2001, we performed a capture-recapture analysis using three registers: Notifications, Laboratory results and Hospital admissions. After record-linkage, 373 of the 780 LD patients identified were notified. Ascertained under-notification was 52.2%. Because of expected and observed regional differences in the incidence rate of LD, alternatively to conventional log-linear capture-recapture models, a covariate (region) capture-recapture model, not previously used for estimating infectious disease incidence, was specified and estimated 886 LD patients (95% confidence interval 827-1022). Estimated under-notification was 57.9%. Notified, ascertained and estimated average annual incidence rates of LD were 1.15, 2.42 and 2.77/100 000 inhabitants respectively, with the highest incidence in the southern region of The Netherlands. Covariate capture-recapture analysis acknowledging regional differences of LD incidence appears to reduce bias in the estimated national incidence rate.