Human rhinovirus infection during naturally occurring COPD exacerbations

George, Siobhan; Garcha, Davinder; Mackay, Alexander; Patel, Anant; Singh, Richa; Sapsford, Raymond J.; Donaldson, Gavin C.; Wedzicha, Jadwiga A.

doi:10.1183/09031936.00223113

Cited by 152 publications

(132 citation statements)

References 28 publications

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“…This observation confirms previous results obtained by other investigators. The increase in the prevalence and load of microorganisms during exacerbations has also been observed in the seminal studies by MONSÓ et al [15] and HILL et al [16], and has more recently been confirmed by GARCHA et al [2] using microbiological culture and the more sensitive quantitative PCR as in the current study by GEORGE et al [14]. Among others, these studies support the ''fall and rise'' hypothesis that suggests that exacerbations originate from an uncontrolled increase in bacterial and/or viral load in the airways that is paralleled by an increase in local (bronchial) and systemic inflammation [17].…”

supporting

confidence: 86%

“…GEORGE et al [14] studied sputum samples from 77 patients with COPD during the stable state and exacerbations, and used real-time quantitative PCR for both human rhinovirus (HRV) and usual respiratory bacteria. They found that HRV prevalence and load during exacerbation were significantly higher than in the stable state and no HRV was found 1 month after the exacerbation.…”

mentioning

confidence: 99%

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Viral, bacterial or both? Regardless, we need to treat infection in COPD

Welte

Miravitlles

2014

European Respiratory Journal

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@ERSpublications Specific prevention of infective exacerbations of COPD is required http://ow.ly/vdIIh Guidelines indicate that pharmacological treatment of chronic obstructive pulmonary disease (COPD) is based on bronchodilators with the addition of inhaled corticosteroids (ICS) in frequent exacerbators [1]. Although this recommendation is in accordance with the best evidence available, it does not take into account that more than half of the exacerbations are infective and infections are not adequately prevented or treated by ICS. In fact, no pharmacological treatment has been able to suppress all exacerbations and, on the contrary, the long-term use of ICS has been associated with higher airway bacterial load in stable COPD [2], and increased risk of pneumonia [3] and tuberculosis [4].Clinicians have always been aware that not all exacerbations of COPD are alike. Some must be treated with anti-infective agents while others respond better to systemic corticosteroids. Markers such as sputum colour and C-reactive protein levels are useful to differentiate exacerbations and guide therapy [5,6]. Recent studies have further characterised these different types of exacerbations, and identified bacterial, viral, inflammatory (eosinophilic) and pauci-inflammatory phenotypes of exacerbations, with the majority (59%) of exacerbations being bacterial or viral. Interestingly, the phenotype of the exacerbation remains constant in a given patient [7]. However, despite these different phenotypes of exacerbations, no studies have attempted to investigate whether different treatments would be more effective in preventing one type of exacerbation or another.Both the high bacterial load in the airways in stable COPD and an increased frequency of exacerbations have been associated with a more rapid decline in lung function and an impairment in quality of life [8][9][10]. More recently, the presence of bronchiectasis in patients with COPD [11] and the persistent colonisation by unusual microorganisms [12] have also been associated with increased mortality. These findings justify the identification of an ''infective phenotype'' that is usually a frequent exacerbator with mucous hypersecretion producing dark sputum during the stable state that is more abundant during exacerbations, and who requires frequent courses of antibiotics and probably demonstrates cylindrical bronchiectasis on computed tomography [13]. Treatment with bronchodilators and ICS never fully prevents infective exacerbations in this phenotype of patients.In order to treat patients with frequent infective exacerbations better, we need to understand the pathogenesis of acute and chronic bronchial infection in COPD. GEORGE et al. [14] studied sputum samples from 77 patients with COPD during the stable state and exacerbations, and used real-time quantitative PCR for both human rhinovirus (HRV) and usual respiratory bacteria. They found that HRV prevalence and load during exacerbation were significantly higher than in the stable state and no HRV was found 1 month after ...

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supporting

confidence: 86%

mentioning

confidence: 99%

Viral, bacterial or both? Regardless, we need to treat infection in COPD

Welte

Miravitlles

2014

European Respiratory Journal

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“…In addition, the production of inflammatory mediators and increased neutrophil influx during respiratory viral infection in asthma and COPD patients has been reported and likely contributes to the pulmonary damage patients experience during viral infections (25,26). Recent studies have also demonstrated an association between respiratory viral infections and bacterial infections in asthma and COPD patients, but the mechanism underlying this relationship remains unclear (30,31).…”

Section: Fig 1 Epithelial Responses To Respiratory Virus Infection Inmentioning

confidence: 99%

Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis

Hendricks

Bomberger

2016

J Virol

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Respiratory virus infections are common but generally self-limiting infections in healthy individuals. Although early clinical studies reported low detection rates, the development of molecular diagnostic techniques by PCR has led to an increased recognition that respiratory virus infections are associated with morbidity and acute exacerbations of chronic lung diseases, such as cystic fibrosis (CF). The airway epithelium is the first barrier encountered by respiratory viruses following inhalation and the primary site of respiratory viral replication. Here, we describe how the airway epithelial response to respiratory viral infections contributes to disease progression in patients with CF and other chronic lung diseases, including the role respiratory viral infections play in bacterial acquisition in the CF patient lung.

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“…In contrast, in patients with chronic airway diseases including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis, RV may cause prolonged and severe lower respiratory symptoms and, in the cases of COPD and cystic fibrosis, may lead to progression of lung disease (6)(7)(8). In those with COPD but not in healthy subjects, RV also promotes acquisition of secondary bacterial infections (8,9). These observations indicate that RV, which infects and replicates primarily in airway epithelial cells (10), may impair innate immune functions of airway epithelium in subjects with chronic airway diseases, but the mechanisms are not well understood.…”

Section: Clinical Relevancementioning

confidence: 99%

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Faris¹,

Ganesan²,

Chattoraj³

et al. 2016

Am J Respir Cell Mol Biol

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Rhinovirus (RV), which causes exacerbation in patients with chronic airway diseases, readily infects injured airway epithelium and has been reported to delay wound closure. In this study, we examined the effects of RV on cell repolarization and differentiation in a model of injured/regenerating airway epithelium (polarized, undifferentiated cells). RV causes only a transient barrier disruption in a model of normal (mucociliary-differentiated) airway epithelium. However, in the injury/regeneration model, RV prolongs barrier dysfunction and alters the differentiation of cells. The prolonged barrier dysfunction caused by RV was not a result of excessive cell death but was instead associated with epithelial-to-mesenchymal transition (EMT)-like features, such as reduced expression of the apicolateral junction and polarity complex proteins, E-cadherin, occludin, ZO-1, claudins 1 and 4, and Crumbs3 and increased expression of vimentin, a mesenchymal cell marker. The expression of Snail, a transcriptional repressor of tight and adherence junctions, was also up-regulated in RV-infected injured/regenerating airway epithelium, and inhibition of Snail reversed RV-induced EMT-like features. In addition, compared with sham-infected cells, the RV-infected injured/regenerating airway epithelium showed more goblet cells and fewer ciliated cells. Inhibition of epithelial growth factor receptor promoted repolarization of cells by inhibiting Snail and enhancing expression of E-cadherin, occludin, and Crumbs3 proteins, reduced the number of goblet cells, and increased the number of ciliated cells. Together, these results suggest that RV not only disrupts barrier function, but also interferes with normal renewal of injured/regenerating airway epithelium by inducing EMT-like features and subsequent goblet cell hyperplasia.Keywords: barrier function; epithelial-to-mesenchymal transition; Crumbs polarity complex; epithelial growth factor receptor; goblet cell hyperplasia Clinical RelevanceTo the best of our knowledge, this is the first study to demonstrate that rhinovirus delays cell repolarization in a model of injured/regenerating, but not normal, airway epithelium by inducing epithelial-to-mesenchymal transition-like features. Furthermore, rhinovirus reduces ciliated cell differentiation and promotes goblet-cell differentiation and mucin gene expression. These changes depended partially on persistent EGFR activation induced by rhinovirus. Such changes during regeneration can lead to airway epithelium with impaired barrier and mucociliary clearance functions.Airway epithelium that lines the respiratory tract acts as a physical barrier between the external environment and the lung and plays an important role in maintaining tissue homeostasis. Paracellular permeability of airway epithelium is maintained through the co-operation of two functionally distinct structural components: tight and adherence junctions located in the apicolateral membranes. Tight junctions regulate the transport of solutes and ions across airway epithelium...

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Human rhinovirus infection during naturally occurring COPD exacerbations

Cited by 152 publications

References 28 publications

Viral, bacterial or both? Regardless, we need to treat infection in COPD

Viral, bacterial or both? Regardless, we need to treat infection in COPD

Digging through the Obstruction: Insight into the Epithelial Cell Response to Respiratory Virus Infection in Patients with Cystic Fibrosis

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

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