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      Could the Sputum Microbiota Be a Biomarker That Predicts Mortality after Acute Exacerbations of Chronic Obstructive Pulmonary Disease?

      , M.D. 1 , , M.D. 1

      American Journal of Respiratory and Critical Care Medicine

      American Thoracic Society

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          Abstract

          Our understanding of chronic obstructive pulmonary disease (COPD) is shifting to a personalized approach in which we have a better appreciation of the multiple factors involved in its pathogenesis. The technological advances made in the last two decades have revealed a breadth of different biomarkers and mechanisms involved in this disease. In this new “omic” era, the implementation of bioinformatic approaches has allowed us to digest multidimensional datasets to create interpretable results and embrace the existence of multiple noncanonical pathways that contribute to the development and clinical course of complex diseases such as COPD. One of such omic approach is the use of molecular methods that, by measuring microbial genes, allow for a comprehensive characterization of complex microbial communities that we call the microbiome. This advancement from our previous culture-dependent view of the microbial world invites us to reexplore the role of bacteria in COPD. For many years, we have recognized the effects of microbes on the natural history of COPD. In stable COPD, nonpotential pathogenic microorganisms such as many of our oropharyngeal commensals are isolated more frequently than potential pathogenic microorganisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis (1). During acute exacerbations of COPD (AECOPD), culture of respiratory secretions frequently identifies increase in bacterial loads and/or acquisition of a new strain (2–8). AECOPD are associated with increased mobility and mortality, and thus, understanding the complex microbial landscape around AECOPD may reveal novel insights. With the implementation of culture-independent methods, we now know that potential pathogenic microorganisms are frequently found in culture-negative respiratory specimens (3, 9). During AECOPD, the sputum microbiota has decreased diversity and increased proportion of Proteobacteria, whereas other distinct microbiota signatures have been associated with positive bacterial cultures and with elevated eosinophils (10). However, the clinical relevance of these microbiota signatures in airway samples has not been elucidated. In this issue of the Journal, Leitao Filho and colleagues (pp. 1205–1213) used sputum samples obtained at the time of hospital admission for AECOPD in 102 subjects to examine for associations between sputum microbiota and 1-year follow-up mortality (11). In total, there were 19/102 deaths within that period. The nonsurvivor group had a lower alpha diversity (intrasample diversity, or how many different types of bacteria are present in a sample) compared with the survivor group. A decrease in alpha diversity usually identifies microbial communities in which a small number of bacteria bloom and dominate. However, lower alpha diversity may also be the result of microbial pressures, such as antibiotics, that may not have been fully controlled by the investigators (as acknowledged by the authors). Differences in beta diversity (intergroup diversity or a measure of how similar samples from different individuals are) and in taxonomic composition were also noted between survivors and nonsurvivors. At the genus level, the sputum microbiota of survivors was enriched with Rothia, Prevotella, Veillonella, Fusobacterium, and Actinomyces (genera frequently identified as oral commensals), whereas the sputum microbiota of nonsurvivors was enriched with Staphylococcus and Escherichia-Shigella. The presence of Staphylococcus in sputum samples was associated with prolonged hospital stay (an extra 1.5 d) and 7.3 times increased mortality compared with subjects without this genus in their sputum. Even more impressive, the absence of Veillonella genus in a sputum sample was associated with 13.5 times increased mortality during the study period. Importantly, Cox regression models were adjusted for age, sex, smoking status, ethnicity, home oxygen therapy, and use of antibiotics during hospitalization. These provocative results suggest that microbial signatures present in sputum microbiota may be used as a predictor of poor outcome for patients with AECOPD. Although this study generates some provocative results, it has also raised many unanswered questions. First, we must acknowledge that when dealing with high-dimensionality data, statistically significant associations identified need to be cautiously interpreted, even when adjusted for multiple comparisons. As outlined here, the acceptance of microbiota signatures as biomarkers will require extensive validation in separate cohorts. Second, as the authors have acknowledged, many possible confounders were difficult to be fully assessed. An example of this is the use of antibiotics before sampling, a variable that is challenging to control for in the setting of AECOPD and that likely affects the airway microbiota. From a mechanistic point of view, it would be important to determine whether the microbiota signatures identified in this study are representative of changes occurring in the upper or in the lower airway microbiota. There is now increasing evidence that the sputum microbiota is a better reflection of the oral microbiota than of the lower airway microbiota (12, 13), and thus, the signatures identified in sputum in the current study should not be assumed to represent changes of the lower airway microbiota in AECOPD. We are at the very early stages of airway microbiome discovery, and at an even earlier time for its use as a biomarker for diagnosis or prognosis. Most biomarkers in use have required large cohorts for discovery phase, validation phase, and in some, prospective clinical trials. It is well accepted that biomarker development requires certain standards for analytical validity (meaning that the biomarker needs to be accurate, reproducible, and reliable), clinical validity (ability to separate groups with distinct clinical/biological outcomes or differences), and clinical utility (the use of the biomarker should improve measurable clinical outcomes) (14). When studying the airway microbiota, we are still frequently faced with analytical validity challenges, in part related to the low biomass and risk for reagent contamination (most important for lower airway samples), as well as the lack of uniformity of sequencing techniques and analytical approaches. Further, unlike gut microbiome studies, airway microbiome studies have been small and frequently limited to few centers, even when noninvasive samples, such as sputum, are used. Thus, for the most part, the clinical validity is limited by the single discovery cohort design (such as the one described in this study) and the lack of validation. And finally, as promising biomarkers arise, we need effective strategies to test whether the use of microbiome data can affect clinical outcomes. Thus, the current study is an important initial step in biomarker discovery. The road ahead will require larger cohorts and different designs so we can have a personalized approach in which noninvasive microbial signatures may have clinical implications for patients with COPD.

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          Most cited references 13

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          New strains of bacteria and exacerbations of chronic obstructive pulmonary disease.

          The role of bacterial pathogens in acute exacerbations of chronic obstructive pulmonary disease is controversial. In older studies, the rates of isolation of bacterial pathogens from sputum were the same during acute exacerbations and during stable disease. However, these studies did not differentiate among strains within a bacterial species and therefore could not detect changes in strains over time. We hypothesized that the acquisition of a new strain of a pathogenic bacterial species is associated with exacerbation of chronic obstructive pulmonary disease. We conducted a prospective study in which clinical information and sputum samples for culture were collected monthly and during exacerbations from 81 outpatients with chronic obstructive pulmonary disease. Molecular typing of sputum isolates of nonencapsulated Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa was performed. Over a period of 56 months, the 81 patients made a total of 1975 clinic visits, 374 of which were made during exacerbations (mean, 2.1 per patient per year). On the basis of molecular typing, an exacerbation was diagnosed at 33.0 percent of the clinic visits that involved isolation of a new strain of a bacterial pathogen, as compared with 15.4 percent of visits at which no new strain was isolated (P<0.001; relative risk of an exacerbation, 2.15; 95 percent confidence interval, 1.83 to 2.53). Isolation of a new strain of H. influenzae, M. catarrhalis, or S. pneumoniae was associated with a significantly increased risk of an exacerbation. The association between an exacerbation and the isolation of a new strain of a bacterial pathogen supports the causative role of bacteria in exacerbations of chronic obstructive pulmonary disease. Copyright 2002 Massachusetts Medical Society
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            Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush.

            The lower airways of asymptomatic chronic obstructive pulmonary disease (COPD) patients can be colonized by bacteria, mainly Haemophilus influenza, Streptococcus pneumoniae, and Moraxella catarrhalis. However, the role of lower airway bacteria in stable and exacerbated COPD has not been well defined. To determine the importance of lower airway bacterial infection in COPD we studied 40 outpatients with stable COPD (Group A: age 61.1 +/- 9.9 yr; [mean +/- SD]; FEV1/FVC 51.7 +/- 12.5) and 29 outpatients with exacerbated COPD (Group B: age 63.4, SD 9.0 yr; FEV1/FVC 52.0, SD 9.6), using the protected specimen brush (PSB) for microbiology sampling. Group A consisted of outpatients with stable COPD having normal or near-normal chest X-rays, with clinical indications for performing fiber-bronchoscopy (pulmonary nodule, remote hemoptysis); Group B consisted of patients with exacerbated COPD who voluntarily accepted lower airway microbiology sampling. To avoid contamination by upper airway flora the PSB was used for bacterial sampling in all the cases and concentrations > or = 1,000 colony-forming units/milliliter (CFU/ml) were considered positive. Results were as follows: Group A: Lung function data in outpatients with stable COPD were lower than the reference values for this population (FVC 2.97 +/- 1.02 L, FVC% 71.4 +/- 22.4, FEV1 1.59 +/- 0.79 L, FEV1% 51.2 +/- 23.0). Positive PSB cultures were obtained in 10 of 40 cases (25%), mainly of H. influenzae and S. pneumoniae. Two of 40 cases had positive cultures at concentrations > or = 10,000 CFU/ml (5.0%).(ABSTRACT TRUNCATED AT 250 WORDS)
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              Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation.

               N. Soler,  A. Torres,  S Ewig (1998)
              We carried out a comprehensive microbiological study of the upper and lower airways in patients with severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation in order to describe microbial patterns and analyze their clinical significance. Quantitative cultures of tracheobronchial aspirates (TBAs), bronchoscopically retrieved protected specimen brush (PSB) and bronchoalveolar lavage fluid (BALF) at admission to the ICU and after 72 h, as well as serology for bacteria and respiratory viruses were performed. Fifty patients (mean age 68 +/- 8, 46 males) were studied prospectively. Potentially pathogenic microorganisms (PPMs) and/or a positive serology were present in 36 of 50 (72%) patients, including 12 (33%) polymicrobial cases. Only six (12%) had no pathogen in any sample in the absence of antimicrobial pretreatment. Microbial patterns corresponded to community-acquired pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) in 19 of 34 (56%) and to gram-negative enteric bacilli (GNEB), Pseudomonas, and Stenotrophomonas spp. in 15 of 34 (44%) of isolates. Chlamydia pneumoniae and respiratory viruses were found in 18% and 16% of investigations, respectively. Repeated investigation after 72 h in 19 patients with PPMs in the initial investigation revealed eradication of virtually all isolates of community-acquired pathogens and GNEB but persistence of three of five Pseudomonas spp. and both Stenotrophomonas spp. as well as the emergence of new GNEB, Pseudomonas and Stenotrophomonas spp. Clinical parameters neither predicted the presence of PPMs nor of GNEB and Pseudomonas/Stenotrophomonas spp. Nevertheless, severe pneumonia attributable to initially isolated pathogens occurred in two patients with severe COPD exacerbation. We conclude that pathogens were more frequently present than previously reported. The rate of GNEB and Pseudomonas/Stenotrophomonas spp. isolates was high. The presence of pathogens was clinically unpredictable. Thus, in this population of patients with severe exacerbations of COPD, it may be advisable to obtain respiratory samples and to treat according to diagnostic results. Further studies are warranted to clarify this issue.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                15 May 2019
                15 May 2019
                15 May 2019
                15 May 2019
                : 199
                : 10
                : 1175-1176
                Affiliations
                [ 1 ]Division of Pulmonary and Critical Care Medicine

                New York University School of Medicine

                New York, New York
                Article
                201811-2138ED
                10.1164/rccm.201811-2138ED
                6519852
                30485116
                Copyright © 2019 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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                Figures: 0, Tables: 0, Pages: 2
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