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      Detection of Cell-Dissociated Non-Typeable Haemophilus influenzae in the Airways of Patients with Chronic Obstructive Pulmonary Disease

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          Non-typeable Haemophilus influenzae (NTHi) is the most commonly found pathogen in the lower respiratory airways of patients with COPD. NTHi is predominantly regarded as an intracellular pathogen; however, like most pathogens, it can exist and co-exist in two broad forms: cell-associated (intracellularly or adhered to cells) or cell-dissociated (biofilm dispersed or planktonic). We sought to investigate if cell-dissociated NTHi can be detected from the sputum of COPD patients and assess this relationship to disease severity and airway inflammation.


          DNA was extracted from the sputum plug and cell-free supernatant to quantify absolute (cell-associated and cell-dissociated NTHi) and cell-dissociated NTHi, respectively, from 87 COPD subjects attending an observational longitudinal COPD exacerbation study. NTHi was quantified using TaqMan hydrolysis probes, targeting the OMP P6 gene using qPCR.


          At stable state cell-dissociated NTHi was detected 56% of subjects with a median (IQR) of 9.95x10 2 gene copies (1.26x10 2 to 1.90x10 4). Cell-dissociated NTHi correlated with absolute NTHi levels (r=0.34, p<0.01) but not airway inflammation or spirometry at stable state. At exacerbation, cell-dissociated NTHi correlated with lung function (FEV 1 r=0.629, p=0.005; FEV 1%predicted r=0.564, p=0.015; FVC r=0.476 p=0.046) and sputum neutrophilic inflammation (% neutrophils r=0.688, p=0.002; total neutrophils r=0.518, p=0.028).


          In patients with COPD, NTHi can exist in both cell-associated and cell-dissociated forms. Cell-dissociated NTHi is associated with neutrophilic airway inflammation during exacerbations of COPD and may be a driving factor in worsening lung function during these episodes.

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          Most cited references 22

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          How bacterial pathogens colonize their hosts and invade deeper tissues.

          Bacterial pathogens have evolved a wide range of strategies to colonize and invade human organs, despite the presence of multiple host defense mechanisms. In this review, we will describe how pathogenic bacteria can adhere and multiply at the surface of host cells, how some bacteria can enter and proliferate inside these cells, and finally how pathogens may cross epithelial or endothelial host barriers and get access to internal tissues, leading to severe diseases in humans.
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            The role of the bacterial microbiome in lung disease.

            Novel culture-independent techniques have recently demonstrated that the lower respiratory tract, historically considered sterile in health, contains diverse communities of microbes: the lung microbiome. Increasing evidence supports the concept that a distinct microbiota of the lower respiratory tract is present both in health and in various respiratory diseases, although the biological and clinical significance of these findings remains undetermined. In this article, the authors review and synthesize published reports of the lung microbiota of healthy and diseased subjects, discuss trends of microbial diversity and constitution across disease states, and look to the extrapulmonary microbiome for hypotheses and future directions for study.
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              Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease

              Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                12 June 2020
                : 15
                : 1357-1365
                [1 ]Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford , Oxford, UK
                [2 ]Oxford NIHR Biomedical Research Centre, University of Oxford , Oxford, UK
                [3 ]Target Discovery Institute, Nuffield Department of Medicine, University of Oxford , Oxford, UK
                [4 ]Department of Immunity, Infection and Inflammation, University of Leicester , Leicester, UK
                [5 ]Institute for Lung Health, University of Leicester , Leicester, UK
                Author notes
                Correspondence: Mona Bafadhel Respiratory Medicine Unit, NDM Research Building, Old Campus Road, University of Oxford , OxfordOX3 7FZ, UKTel +44 1865 612898 Email
                © 2020 Thulborn et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 3, Tables: 4, References: 36, Pages: 9
                This work was funded by the Medical Research Council, the Wellcome Trust & Academy of Medical Sciences and 330 the Oxfordshire Health Services Research Committee. This paper presents independent research funded by the National Institute for Health Research and the views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
                Original Research

                Respiratory medicine

                nthi, infection, neutrophils, copd


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