Reliability of blood eosinophil count in steady-state bronchiectasis.

RATIONALE: The baseline value of eosinophils in peripheral blood (BEC) has been associated with different degrees of severity, prognosis and response to treatment in patients with bronchiectasis. It is not known, however, if this basal value remains constant over time. OBJECTIVES: The aim of this study was to assess whether the BEC remains stable in the long term in patients with bronchiectasis. METHODS AND MEASUREMENTS: Patients from the RIBRON registry of bronchiectasis diagnosed by computed tomography with at least 2 BEC measurements one year apart were included in the study. Patients with asthma and those taking anti-eosinophilic drugs were excluded. Reliability was assessed using the intra-class correlation coefficient (ICC). A patient with a BEC of at least 300 cells/uL or less than 100 cells/uL was considered eosinophilic or eosinopenic, respectively. Group changes over time were also calculated. MAIN RESULTS: Seven hundred and thirteen patients were finally included, with a mean age of 66.5 (13.2) years (65.8 % women). A total of 2701 BEC measurements were performed, with a median number of measurements per patient of 4 (IQR: 2-5) separated by a median of 12.1 (IQR: 10.5-14.3) months between two consecutive measurements. The ICC was good (>0.75) when calculated between two consecutive measurements (approximately one year apart) but had dropped significantly by the time of the next annual measurements. Similarly, the change from an eosinophilic or eosinopenic patient to a non-eosinophilic or non-eosinopenic patient, respectively, was less than 30 % during the first year with respect to the baseline value but was close to 50 % in later measurements. CONCLUSIONS: Given the significant changes observed in the baseline value of the BEC over time, its monitoring is necessary in patients with bronchiectasis in order to more reliably assess its usefulness.

Periodontal Effects of the Reversible Dipeptidyl Peptidase 1 Inhibitor Brensocatib in Bronchiectasis.

AIMS: Brensocatib is a reversible inhibitor of dipeptidyl peptidase 1 (cathepsin C), in development to treat chronic non-cystic fibrosis bronchiectasis. The phase 2, randomized, placebo-controlled WILLOW trial (NCT03218917) was conducted to examine whether brensocatib reduced the incidence of pulmonary exacerbations. Brensocatib prolonged the time to the first exacerbation and led to fewer exacerbations than placebo. Because brensocatib potentially affects oral tissues due to its action on neutrophil-mediated inflammation, we analyzed periodontal outcomes in the trial participants. MATERIALS AND METHODS: Patients with bronchiectasis were randomized 1:1:1 to receive once-daily oral brensocatib 10 or 25 mg or placebo. Periodontal status was monitored throughout the 24-week trial in a prespecified safety analysis. Periodontal pocket depth (PPD) at screening, week 8, and week 24 was evaluated. Gingival inflammation was evaluated by a combination of assessing bleeding upon probing and monitoring the Löe-Silness Gingival Index on 3 facial surfaces and the mid-lingual surface. RESULTS: At week 24, mean ± SE PPD reductions were similar across treatment groups: -0.07 ± 0.007, -0.06 ± 0.007, and -0.15 ± 0.007 mm with brensocatib 10 mg, brensocatib 25 mg, and placebo, respectively. The distribution of changes in PPD and the number of patients with multiple increased PPD sites were similar across treatment groups at weeks 8 and 24. The frequencies of gingival index values were generally similar across treatment groups at each assessment. An increase in index values 0-1 and a decrease in index values 2-3 over time and at the end of the study were observed in all groups, indicating improved oral health. CONCLUSIONS: In patients with non-cystic fibrosis bronchiectasis, brensocatib 10 or 25 mg had an acceptable safety profile after 6 months' treatment, with no changes in periodontal status noted. Improvement in oral health at end of the study may be due to regular dental care during the trial and independent of brensocatib treatment. KNOWLEDGE TRANSFER STATEMENT: The results of this study suggest that 24 weeks of treatment with brensocatib does not affect periodontal disease progression. This information can be used by clinicians when considering treatment approaches for bronchiectasis and suggests that the use of brensocatib will not be limited by periodontal disease risks. Nevertheless, routine dental/periodontal care should be provided to patients irrespective of brensocatib treatment.

Pseudomonas aeruginosa and lung function decline in patients with bronchiectasis.

OBJECTIVES: The objective of this study was to analyse lung function decline over time in bronchiectasis, along with the factors associated with it. METHODS: Spirometry was measured every year in this observational, prospective study in 849 patients from the Spanish Bronchiectasis Registry (RIBRON). The main outcome was the decline in the rate of forced expiratory volume during the first second (FEV1). To be included in this study, patients needed a baseline assessment and at least one subsequent assessment. FEV1 decline was analysed using a mixed-effects linear regression model adjusted for clinically significant variables. RESULTS: We recruited 849 bronchiectasis patients with at least two annual lung function measurements (follow-up range 1-4 years). A total of 2262 lung function tests were performed (mean 2.66 per patient, range 2-5). Mean baseline FEV1 was 1.78 L (standard deviation (SD) 0.76; 71.3% predicted). Mean age was 69.1 (SD 15.4) years; 543 (64% women. The adjusted rates of FEV1 decline were -0.98% predicted/year (95% confidence interval (CI) -2.41 to -0.69) and -31.6 (95% CI -44.4 to -18.8) mL. The annual FEV1 decline was faster in those patients with chronic bronchial infection by Pseudomonas aeruginosa (-1.37% (52.1 mL) vs -0.37% (-24.6 mL); p < 0.001), greater age, increased number of severe exacerbations in the previous year and higher baseline FEV1 value. DISCUSSION: In patients with bronchiectasis, the annual rate of FEV1 decline was -31.6 mL/year and it was faster in older patients and those with chronic bronchial infection by P. aeruginosa, increased number of previous severe exacerbations and higher baseline FEV1 value.

Inflammatory Asthma Phenotype Discrimination Using an Electronic Nose Breath Analyzer.

BACKGROUND AND OBJECTIVE: Patients with persistent asthma have different inflammatory phenotypes. The electronic nose is a new technology capable of distinguishing volatile organic compound (VOC) breath-prints in exhaled breath. The aim of the study was to investigate the capacity of electronic nose breath-print analysis to discriminate between different inflammatory asthma phenotypes (eosinophilic, neutrophilic, paucigranulocytic) determined by induced sputum in patients with persistent asthma. METHODS: Fifty-two patients with persistent asthma were consecutively included in a cross-sectional proof-of-concept study. Inflammatory asthma phenotypes (eosinophilic, neutrophilic and paucigranulocytic) were recognized by inflammatory cell counts in induced sputum. VOC breath-prints were analyzed using the electronic nose Cyranose 320 and assessed by discriminant analysis on principal component reduction, resulting in cross-validated accuracy values. Receiver operating characteristic (ROC) curves were calculated. RESULTS: VOC breath-prints were different in eosinophilic asthmatics compared with both neutrophilic asthmatics (accuracy 73%; P=.008; area under ROC, 0.92) and paucigranulocytic asthmatics (accuracy 74%; P=.004; area under ROC, 0.79). Likewise, neutrophilic and paucigranulocytic breath-prints were also different (accuracy 89%; P=.001; area under ROC, 0.88). CONCLUSION: An electronic nose can discriminate inflammatory phenotypes in patients with persistent asthma in a regular clinical setting. ClinicalTrials.gov identifier: NCT02026336.

Inflammatory asthma phenotype discrimination using an electronic nose breath analyzer

Background and Objective: Patients with persistent asthma have different inflammatory phenotypes. The electronic nose is a new technology capable of distinguishing volatile organic compound (VOC) breath-prints in exhaled breath. The aim of the study was to investigate the capacity of electronic nose breath-print analysis to discriminate between different inflammatory asthma phenotypes eosinophilic, neutrophilic, paucigranulocytic) determined by induced sputum in patients with persistent asthma. Methods: Fifty-two patients with persistent asthma were consecutively included in a cross-sectional proof-of-concept study. Inflammatory asthma phenotypes (eosinophilic, neutrophilic and paucigranulocytic) were recognized by inflammatory cell counts in induced sputum. VOC breath-prints were analyzed using the electronic nose Cyranose 320 and assessed by discriminant analysis on principal component reduction, resulting in cross-validated accuracy values. Receiver operating characteristic (ROC) curves were calculated. Results: VOC breath-prints were different in eosinophilic asthmatics compared with both neutrophilic asthmatics (accuracy 73%; P=.008; area under ROC, 0.92) and paucigranulocytic asthmatics (accuracy 74%; P=.004; area under ROC, 0.79). Likewise, neutrophilic and paucigranulocytic breath-prints were also different (accuracy 89%; P=.001; area under ROC, 0.88). Conclusion: An electronic nose can discriminate inflammatory phenotypes in patients with persistent asthma in a regular clinical setting. ClinicalTrials.gov identifier: NCT02026336 (AU)

Antecedentes: Pacientes con asma persistente tienen diferentes fenotipos inflamatorios bronquiales. La nariz electrónica es una nueva tecnología capaz de distinguir compuestos orgánicos volátiles (VOCs), huellas olfatorias del aire exhalado. El objetivo de este estudio fue investigar la capacidad que tiene la nariz electrónica de discriminar las huellas olfatorias en los diferentes fenotipos bronquiales de asma determinados por el esputo inducido (eosinofílicos, neutrofílicos, paucigranulocíticos) en pacientes con asma persistente. Método: Cincuenta y dos pacientes con asma persistente fueron incluidos en un estudio transversal. Los fenotipos inflamatorios asmáticos fueron determinados a través de recuento de células inflamatorias del esputo inducido. Los VOCs fueron analizados a través de una nariz electrónica Cyranose 320TM y evaluados por un análisis de discriminación de componentes principales, resultando en valores de precisión con validación cruzada. Se calcularon las características operativas del receptor (ROC). Resultados: Los VOCs de los asmáticos eosinofílicos fueron diferentes a los neutrofílicos (precisión 73%; p= 0.008; área bajo ROC 0.92) y de los pacientes paucigranulocíticos (precisión 74%; p= 0.004; área bajo ROC 0.79). Del mismo modo, las huellas olfatorias entre los neutrofílicos y paucigranulocíticos eran diferentes (precisión 89%; p= 0.001; área bajo ROC 0.88). Conclusión: La nariz electrónica puede discriminar los fenotipos inflamatorios bronquiales en los pacientes con asma persistente en un entorno clínico regular. ClinicalTrials.gov: NCT02026336 (AU)

Corticosteroids as adjunctive treatment in community-acquired pneumonia.

Community-acquired Pneumonia (CAP) is the first leading infectious cause of death in developed countries. The mortality rate in severe CAP is very high and has not changed in recent years, despite advances in antimicrobial therapy and supportive measures. Several studies have identified an excessive host inflammatory response as a marker of poor prognosis in CAP. Corticosteroids are anti-inflammatory and immunosupressive agents widely used in modern medicine. Chronic use of corticosteroids has been related to immunosuppression and higher incidence of pneumonia due to opportunistic and high resistant bacteria. However, the use of corticosteroids as adjunctive therapy in CAP may be beneficial due to their anti-inflammatory effect. Experimental pneumonia studies showed that corticosteroid administration was associated with a reduction in circulating and pulmonary cytokine levels, an improvement in histopathological severity scores and a decreased bacterial burden. Several randomized controlled trials (RCT) testing the usefulness of corticosteroids in CAP have been performed in the recent years with conflicting results. However, two recent meta-analyses found improved mortality in the subgroup with severe CAP and/or receiving >5 days of glucocorticoid treatment. Dosage, duration of treatment and side effects are two important aspects not well determined yet. This review discusses the association of corticosteroids as adjunctive therapy and its association with clinical outcomes and side effects in patients with CAP.

An experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated piglets.

The objectives of the study were to validate a model of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in ventilated piglets and to study the time-course of biological markers and histopathological changes. 12 piglets were intubated and inoculated with 15 mL of a suspension of 10(6) colony forming units of MRSA in every lobe through the bronchoscope channel. The piglets were ventilated for 12 h (n = 6) and 24 h (n = 6). Clinical parameters were assessed every 6 h and pro-inflammatory cytokines were measured in serum and in bronchoalveolar lavage (BAL) at baseline and sacrifice. Histopathology of each lobe and cultures from blood, lungs and BAL were performed. Animals developed histopathological evidence of pneumonia at necropsy. At 12 h, pneumonia was present in all animals and was severe pneumonia at 24 h. Microbiological studies confirmed the presence of MRSA. A significant increase in interleukin (IL)-6, IL-8 and tumour necrosis factor-α values was seen in BAL at 24 h and IL-6 at 12 h. In serum, only IL-6 levels had increased significantly at 24 h. In ventilated piglets, bronchoscopic inoculation of MRSA induces pneumonia at 12 h and severe pneumonia at 24 h. This severity was associated with a corresponding increase in systemic and local inflammatory response.

Animal models of ventilator-associated pneumonia.

Animal models are an essential step between "in vitro" testing and clinical studies. Different animal models have been useful for the study of pathophysiology, diagnosis and therapy in ventilator-associated pneumonia (VAP). Aspiration has been studied in dog and cat models and bacteriological diagnosis has been evaluated in baboons. Pigs have been used for studying either spontaneous or induced VAP. Intubated piglets in prone position were administered analgesia and muscle paralysis was induced, and the intubated piglets underwent mechanical ventilation for several days. In this model, spontaneous VAP due to common bacterial pig colonisation develops within a few days. Pneumonia can also be induced by inoculating high concentrations of microorganisms (Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus). Different clinical, physiological, microbiological and pathological parameters of infection have been studied in this model. In addition, administration of antibiotics and inflammatory modulators and their consequences in microbiological eradication and local and systemic inflammation have been evaluated with interesting translational results. Although bronchial inoculation of healthy subjects does not resemble the common pathophysiological mechanisms, the experimental model of ventilator-associated pneumonia induced by the inoculation of high concentrations of microorganisms in mechanically ventilated piglets is useful for the study of the local and systemic responses of lung infection and for the determination of potential measures of prevention or therapeutic modulation.

Corticosteroids in severe pneumonia.

The mortality rate in severe community- or hospital-acquired pneumonia is very high, ranging 20-50%. Despite advances in antimicrobial therapy and supportive measures, this rate has not changed in recent years, suggesting that other factors are also responsible for the poor outcome. An abnormal increase in the local and systemic inflammatory response is associated with poor outcome, and this occurs despite adequate antibiotic therapy. There is evidence that acute administration of corticosteroids decreases the inflammatory response and might decrease mortality in severe pneumonia. This has been shown in one small randomised controlled study, terminated prematurely due to 0% mortality in the intervention arm. In addition, an experimental study showed that glucocorticosteroids decrease lung inflammatory response and lung bacterial burden, confirming the results obtained through in vitro investigations. Although these results are promising and suggest a novel role of glucocorticosteroids in pneumonia, the inherent risks and potential side-effects of these drugs require further controlled clinical trials in order to better define the target population before their general use in clinical practice. Specifically, dosage, period of administration, titration, tapering and side-effects are some of the key questions that need to be investigated.

Effects of glucocorticoids in ventilated piglets with severe pneumonia.

There is clinical evidence suggesting that glucocorticoids may be useful in severe pneumonia, but the pathogenic mechanisms explaining these beneficial effects are unknown. The aim of the present study was to determine the effects of adding glucocorticoids to antibiotic treatment in an experimental model of severe pneumonia. In total, 15 Lagerwhite-Landrace piglets were ventilated for 96 h. After intubation, a 75 mL solution containing Pseudomonas aeruginosa (10(6) cfu x mL(-1)) was bronchoscopically inoculated. The animals were randomised into three groups 12 h after inoculation: 1) untreated; 2) treated with ciprofloxacin; and 3) treated with ciprofloxacin plus methylprednisolone. Physiological and laboratory parameters were monitored throughout the study. Pro-inflammatory cytokines were measured in serum and bronchoalveolar lavage (BAL). Histopathology of the lungs and cultures from blood, BAL and lungs were performed. At the end of the study, piglets receiving the antibiotic plus glucocorticoids showed: 1) a decrease in the concentration of interleukin-6 in BAL; and 2) a decrease in the global bacterial burden both in BAL and lung tissue. In conclusion, in this experimental model of pneumonia, the association of glucocorticoids with antibiotics attenuates local inflammatory response and decreases bacterial burden in the lung.

Experimental Pseudomonas aeruginosa pneumonia: evaluation of the associated inflammatory response.

An abnormal inflammatory response (IR) in pneumonia is associated with poor outcomes and high mortality. Animal models could help to better understand the relationship between the pulmonary infection and the associated IR. The aims of the present study were to validate an experimental model of pneumonia induced by the inoculation of Pseudomonas aeruginosa in ventilated piglets and to study the associated IR over a long period of time (96 h). Five Lagerwhite-Landrace piglets were ventilated for 4 days. After intubation, a solution containing 75 mL of P. aeruginosa (10(6) colony-forming units.mL(-1)) was bronchoscopically inoculated. Physiological and laboratory parameters were monitored throughout the study. Pro-inflammatory cytokines were measured in serum and in bronchoalveolar lavage (BAL). Histopathology of the lungs and cultures from blood, BAL and lungs were performed. All the animals developed histopathological evidence of pneumonia. Microbiological studies of both BAL and lung confirmed the presence of P. aeruginosa in all the samples. Throughout the study, an increase in interleukin-6 was observed in serum and in BAL. In conclusion, the experimental model of pneumonia induced by the inoculation of high concentrations of Pseudomonas aeruginosa in ventilated piglets is feasible and could be appropriate for the evaluation of different aspects of the associated inflammatory response.