Carlos Agustí

Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors

Background: A study was undertaken to investigate the incidence, diagnostic yield of non-invasive and bronchoscopic techniques, and risk factors of airway colonisation in patients with bronchiectasis in a stable clinical situation. Methods: A 2 year prospective study of 77 patients with bronchiectasis in a stable clinical condition was performed in an 800 bed tertiary university hospital. The interventions used were pharyngeal swabs, sputum cultures and quantitative protected specimen brush (PSB) bacterial cultures (cut off point ≥102 cfu/ml) and bronchoalveolar lavage (BAL) (cut off point ≥103 cfu/ml). Results: The incidence of bronchial colonisation with potential pathogenic microorganisms (PPMs) was 64%. The most frequent PPMs isolated were Haemophilus influenzae (55%) and Pseudomonas spp (26%). Resistance to antibiotics was found in 30% of the isolated pathogens. When the sample was appropriate, the operative characteristics of the sputum cultures were similar to those obtained with the PSB taken as a gold standard. Risk factors associated with bronchial colonisation by PPMs in the multivariate analysis were: (1) diagnosis of bronchiectasis before the age of 14 years (odds ratio (OR)=3.92, 95% CI 1.29 to 11.95), (2) forced expiratory volume in 1 second (FEV1) <80% predicted (OR=3.91, 95% CI 1.30 to 11.78), and (3) presence of varicose or cystic bronchiectasis (OR=4.80, 95% CI 1.11 to 21.46). Conclusions: Clinically stable patients with bronchiectasis have a high prevalence of bronchial colonisation by PPMs. Sputum culture is a good alternative to bronchoscopic procedures for evaluation of this colonisation. Early diagnosis of bronchiectasis, presence of varicose-cystic bronchiectasis, and FEV1 <80% predicted appear to be risk factors for bronchial colonisation with PPMs.

MicroRNAs Expressed during Lung Cancer Development Are Expressed in Human Pseudoglandular Lung Embryogenesis

Background/Aims: MicroRNAs (miRNAs) play a role during mouse embryonic development and are also important in carcinogenesis. In order to investigate whether there are similar patterns of miRNA expression levels in pseudoglandular human embryonic lung and in human lung tumors, we have analyzed 18 miRNAs (the let-7 family, the miR-17–92 cluster, miR-221 and miR-222) in human embryonic lung samples and in paired lung tumor and normal lung tissue samples and correlated the results with clinicopathological characteristics. Methods: RNA was obtained from 12 human embryonic lung samples, 33 lung tumor samples and 33 paired normal lung samples. miRNAs were assessed by quantitative real-time PCR. Results: Members of the let-7 family were downregulated and members of the miR-17–92 cluster and miR-221 were overexpressed both in embryonic lung tissue and in lung tumors. Low levels of let-7c were associated with absence of metastases (p = 0.015), early-stage non-small cell lung cancer (NSCLC, p = 0.05), and smokers (p = 0.009). High levels of miR-106a were associated with small-cell lung cancer (p = 0.031), and high levels of miR-19a with advanced NSCLC (p = 0.008). Conclusion: Our study lends support to the model of cancer as an alteration of normal development, as many miRNAs were similarly expressed in early human lung development and stage I-II of lung cancer development.

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 (106 cfu·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.

Pulmonary infiltrates in HIV-infected patients in the highly active antiretroviral therapy era in Spain

Objective: To study the incidence, etiology, and outcome of pulmonary infiltrates (PIs) in HIV‐infected patients and to evaluate the yield of diagnostic procedures. Design: Prospective observational study of consecutive hospital admissions. Setting: Tertiary hospital. Patients: HIV‐infected patients with new‐onset radiologic PIs from April 1998 to March 1999. Methods: The study protocol included chest radiography, blood and sputum cultures, serologic testing for “atypical” causes of pneumonia, testing for Legionella urinary antigen, testing for cytomegalovirus antigenemia, and bronchoscopy in case of diffuse or progressive PIs. Results: One hundred two episodes in 92 patients were recorded. The incidence of PIs was 18 episodes per 100 hospital admission‐years (95% confidence interval [CI]: 15‐21). An etiologic diagnosis was achieved in 62 cases (61%). Bacterial pneumonia (BP), Pneumocystis carinii pneumonia (PCP), and mycobacteriosis were the main diagnoses. The incidences of BP and mycobacteriosis were not statistically different in highly active antiretroviral therapy (HAART) versus non‐HAART patients. The incidence of PCP was lower in those receiving HAART (p = .011), however. Nine patients died (10%). Independent factors associated with higher mortality were mechanical ventilation (odds ratio [OR] = 83; CI: 4.2‐1,682), age >50 years (OR = 23; CI: 2‐283), and not having an etiologic diagnosis (OR = 22; CI: 1.6‐293). Conclusions: Pulmonary infiltrates are still a frequent cause of hospital admission in the HAART era, and BP is the main etiology. There was no difference in the rate of BP and mycobacteriosis in HAART and non‐HAART patients. Not having an etiologic diagnosis is an independent factor associated with mortality.

Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs.

Objective:To assess the efficacy of linezolid compared with vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus (MRSA) in ventilated pigs. Methods:Forty pigs (30 kg) were intubated and challenged via bronchoscopy with a suspension of 106 colony forming units of MRSA into every lobe. Afterwards, pigs were ventilated up to 96 hours. Twelve hours after bacterial inoculation, the animals were randomized into 4 groups of treatment: group 1, control; group 2, vancomycin twice daily; group 3, continuous infusion of vancomycin; and group 4, linezolid. Clinical and laboratory parameters were monitored throughout the study. Bacterial cultures of bronchoalveolar lavage fluid and lung tissue samples were performed at the end of the study. Measurements of histopathology derangements of lung samples and studies of intrapulmonary drug penetration were performed. Results:A total of 34 animals completed the study. No differences in clinical and laboratory parameters were observed. The percentage of bronchoalveolar lavage fluid and lung tissue samples with positive cultures for MRSA in controls and groups 2, 3, and 4 was respectively 75%, 11%, 11%, and 0% (p < .01); 52%, 9%, 24%, and 2.5% (p < .01). Histopathology studies demonstrated signs of pneumonia in 95%, 69%, 58%, and 57% and signs of severe pneumonia in 48%, 29%, 22%, and 0% of controls and groups 2, 3, and 4, respectively (p < .01). In addition, pharmacokinetics/pharmacodynamics profile in serum and lung tissue showed better results for linezolid compared with both vancomycin treatments. Conclusions:In this animal model of MRSA pneumonia, linezolid showed a better efficacy than vancomycin showed because of a better pharmacokinetics/pharmacodynamics index.

Utilidad de la criobiopsia en el diagnóstico de la enfermedad pulmonar intersticial difusa : análisis de rentabilidad y coste

BACKGROUND Assessment of patients with suspected interstitial lung disease (ILD) includes surgical lung biopsy (SLB) when clinical and radiological data are inconclusive. However, cryobiopsy is acquiring an important role in the ILD diagnostic process. The objective of this study was to evaluate the diagnostic yield, safety and economic costs of the systematic use of cryobiopsy in the assessment of patients with suspected ILD. METHODS This was a retrospective observational study of patients who had undergone transbronchial cryobiopsy for evaluation of ILD from January 2011 to January 2014. The procedures were performed with a video bronchoscope using a cryoprobe for the collection of lung parenchyma specimens, which were analyzed by pathologists. Diagnostic yield, complications and economic costs of this technique were analyzed. RESULTS Criobiopsy specimens from a total of 33 patients were included. A specific diagnosis was obtained in 26, producing a diagnostic yield of 79%. In 5 patients, SLB was required for a histopathological confirmation of disease, but the procedure could not be performed in 4, due to severe comorbidities. The most frequent complications were pneumothorax (12%) and gradei (9%) or gradeii (21%) bleeding. There were no life-threatening complications. The systematic use of cryobiopsy saved up to €59,846. CONCLUSION Cryobiopsy is a safe and potentially useful technique in the diagnostic assessment of patients with ILD. Furthermore, the systematic use of cryobiopsy has an important economic impact.

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 (106 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.

Linezolid limits burden of methicillin-resistant Staphylococcus aureus in biofilm of tracheal tubes.

Objective: To evaluate the effects of systemic treatment with linezolid compared with vancomycin on biofilm formation in mechanically ventilated pigs with severe methicillin-resistant Staphylococcus aureus–induced pneumonia. Design: Prospective randomized animal study. Setting: Departments of Pneumology, Microbiology, and Pharmacy of the Hospital Clínic, Barcelona, and Scientific and Technological Services of the University of Barcelona. Subjects: We prospectively analyzed 70 endotracheal tube samples. Endotracheal tubes were obtained from pigs either untreated (controls, n = 20), or treated with vancomycin (n = 32) or linezolid (n = 18). Interventions: The endotracheal tubes were obtained from a previous randomized study in tracheally intubated pigs with methicillin-resistant Staphylococcus aureus severe pneumonia, and mechanically ventilated for 69 ± 16 hrs. Measurements and Main Results: Distal and medial hemisections of the endotracheal tube were assessed to quantify methicillin-resistant Staphylococcus aureus burden, antibiotic biofilm concentration by high-performance liquid chromatography or bioassay, and biofilm thickness through scanning electron microscopy. We found a trend toward a significant variation in biofilm methicillin-resistant Staphylococcus aureus burden (log colony-forming unit/mL) among groups (p = .057), and the lowest bacterial burden was found in endotracheal tubes treated with linezolid (1.98 ± 1.68) in comparison with untreated endotracheal tubes (3.72 ± 2.20, p = .045) or those treated with vancomycin (2.97 ± 2.43, p = .286). Biofilm linezolid concentration was 19-fold above the linezolid minimum inhibitory concentration, whereas biofilm vancomycin concentration (1.60 ± 0.91 µg/mL) was consistently below or close to the vancomycin minimum inhibitory concentration. Biofilm was thicker in the vancomycin group (p = .077). Conclusions: Systemic treatment with linezolid limits endotracheal tube biofilm development and methicillin-resistant Staphylococcus aureus burden. The potential clinical usefulness of linezolid in decreasing the risk of biofilm-related respiratory infections during prolonged tracheal intubation requires further investigation.

Pulmonary infections in non-HIV-immunocompromised patients

Purpose of review Pulmonary infections are the most frequent complications in non-HIV-immunocompromised patients and portend a high mortality. This scenario represents a challenging task for clinicians and an important subject of clinical research from different perspectives. This review comments on the results of relevant original articles in this area published from 2003 to the present. Recent findings The present review addresses the etiology of the pulmonary infiltrates in immunocompromised patients, the use of new emerging diagnostic tools and medical devices in the clinical management of these infiltrates, and the greater understanding of the inflammatory immune response associated with infection in this setting. Summary Advances in diagnostic tests and therapeutic devices are facilitating the clinical management of pulmonary infections. New challenges are emerging, however, such as the growing evidence regarding the important role of respiratory viruses as a common cause of lower respiratory tract infections. Finally, new insights into the mechanisms of the inflammatory response associated with pulmonary complications can help understanding their pathogenesis, improve prevention and diagnosis, and anticipate future therapeutic modalities.

Associated inflammatory response in pneumonia: role of adjunctive therapy with glucocorticoids

Purpose of review This article reviews the potential use of glucocorticoids as adjunctive therapy in the management of patients with severe bacterial pneumonia or pulmonary infections of other etiologies. Recent findings The importance of an adequate assessment of the inflammatory process and the appearance of inflammatory markers that correlate with the severity of pneumonia is underlined. A recent randomized clinical trial indicates that adjunctive treatment of severe community-acquired pneumonia with glucocorticoids reduces complications and improves survival. The role of glucocorticoids in other lung infections is also reviewed. The design of new compounds with similar anti-inflammatory properties to classical glucocorticoids but with significantly fewer side effects constitutes a specific challenge for the near future. Summary Although adjunctive treatment with glucocorticoids in severe pneumonia is probably indicated, further randomized clinical trials are urgently needed to confirm the preliminary positive results. In this regard, a proper evaluation of the inflammatory response is likely to be essential for the accurate selection of the target population.