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Viral infections in patients with chronic obstructive pulmonary disease Jay B. Varkeya and Basil Varkeyb a Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA and bDivision of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Correspondence to Jay B. Varkey, MD, DUMC Box 3824, Duke University Medical Center, Durham, NC 27710, USA Tel: +1 919 970 6672; fax: +1 919 684 8902; e-mail: [email protected] Current Opinion in Pulmonary Medicine 2008, 14:89–94 Purpose of review Chronic obstructive pulmonary disease is a major cause of morbidity and mortality worldwide. There is increasing evidence that implicates viral infections as a major risk factor for exacerbations of chronic obstructive pulmonary disease. Recent studies have attempted to better characterize the epidemiology of viral infections in chronic obstructive pulmonary disease, identify unique clinical manifestations of virusassociated exacerbations, and develop new diagnostic tools and treatments. Recent findings Rhinovirus, the organism most often responsible for causing the common cold, is also the most common infectious cause of chronic obstructive pulmonary disease exacerbations. Coronavirus, influenza, respiratory syncytial virus, parainfluenza, adenovirus, and metapneumovirus are other important viral causes of chronic obstructive pulmonary disease exacerbations. These exacerbations can be severe with prolonged recovery times. Although PCR technology has dramatically increased the detection rate of viruses in patients with chronic obstructive pulmonary disease, it does not differentiate infection from colonization. The use of biomarkers represents an exciting new potential diagnostic tool that may lend new insights into the pathogenesis of viral infections in patients with chronic obstructive pulmonary disease. Summary Despite strong epidemiologic evidence linking respiratory virus infection to exacerbations of chronic obstructive pulmonary disease, many of the cellular and molecular mechanisms by which viruses cause exacerbations remain undetermined. Future research efforts to understand these mechanisms would aid the development of novel therapeutics to reduce the morbidity and mortality of this disease. Keywords chronic obstructive pulmonary disease exacerbations, PCR technology, respiratory viral infections Curr Opin Pulm Med 14:89–94 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1070-5287 Introduction Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide [1]. The Global Burden of Disease Study predicts that by 2020, COPD will have risen to be the third leading cause of mortality [2]. The estimated annual costs of COPD are US$24 billion and 70% of these costs are related to exacerbations that require hospitalization [3]. Historically, bacteria have been considered the main infectious cause of COPD exacerbations [4]. A growing body of evidence, however, implicates viral upper respiratory tract infections (URIs) as the predominant risk factor associated with exacerbations of COPD [5]. Approximately 40–60% of all COPD exacerbations are associated with URIs [6–8,9]. This figure may actually underestimate the true impact that viruses have on individuals with COPD. For instance, it is well recog- nized clinically that upper respiratory tract cold symptoms often precede COPD exacerbations by days to weeks. Therefore, clinical studies that sample for viruses during a COPD exacerbation (days to weeks after the initial onset of symptoms) may fail to detect virus despite using highly sensitive PCR technology. In this article, we will review recent research efforts to better understand the impact of viral infections in patients with COPD. Further research to determine the cellular and molecular mechanism by which viruses cause exacerbations of COPD are needed to develop new therapeutic interventions. Epidemiology Older studies that used cell culture and serology to determine the etiology of COPD exacerbations detected viruses in only 10–20% of cases [10]. More recent studies 1070-5287 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 90 Obstructive, occupational and environmental diseases using PCR technology, however, have consistently detected the presence of one or more viruses in at least 40–60% of all COPD exacerbations. Furthermore, COPD exacerbations occur with much greater frequency during the winter months when respiratory viral infections are prevalent in the community [9,11]. Virus-induced COPD exacerbations that occur during the winter respiratory virus season are associated with worse functional status, worse health-related quality of life and higher health care utilization [12]. The major respiratory viruses associated with exacerbations of COPD are as follows: (1) (2) (3) (4) (5) (6) rhinovirus; coronavirus; influenza; parainfluenza; adenovirus; respiratory syncytial virus (RSV). In more recent studies that have used PCR technology to determine the infectious etiology of COPD exacerbations, rhinovirus has been the most common viral pathogen identified [6]. In a recent prospective cohort of patients with COPD, rhinovirus was detected in 58% of virus-induced COPD exacerbations of COPD and 23% of all COPD exacerbations [6]. Rhinovirus has fastidious growth requirement and more than 100 serotypes, making detection by culture or serology difficult [13]. As a result, early studies that used cell culture and serologic diagnostic methods dramatically underestimated the prevalence of rhinovirus in patients with COPD exacerbations [13]. Other studies have identified several other viruses that cause disease in patients with COPD including coronavirus, influenza, parainfluenza, RSV, adenovirus and human metapneumovirus [6,9,14–16,17]. The prevalence of each of these viruses can vary widely depending on geography and local epidemiologic trends. For example, a recent Hong Kong study [18] found that influenza was the most common virus identified in patients hospitalized with COPD exacerbations. The high prevalence of influenza in that study, however, may have been due to the relatively low influenza vaccination rate (40.3%) among study participants. By contrast, the relatively low prevalence of influenza seen in a prospective cohort from a London outpatient clinic [13] was most likely attributable to the 74% influenza vaccination rate among that population. A prospective study conducted at the University of Ferrara in Italy [19] recently demonstrated that many patients hospitalized with COPD exacerbations have concomitant viral and bacterial infections. Approximately 25% of the patients hospitalized for COPD exacerbations in this study were determined to be coinfected. Patients that were coinfected were found to have more severe functional impairment and longer lengths of hospitalization. In the London cohort, systemic inflammation (measured by cytokine levels), exacerbations symptoms, and lung function changes were all more severe when evidence for both bacterial and viral infection was present. Specifically, exacerbations associated with both Haemophilus influenza and rhinovirus exhibited a larger decrease in forced expiratory volume in 1 s (FEV1), larger bacterial load and higher serum interleukin (IL)-6 levels than those without both pathogens [20]. These studies suggest that patients coinfected with virus and bacteria may have more severe exacerbations. Clinical manifestations COPD exacerbations are typically characterized by increased dyspnea, increased cough, increased sputum volume and increased sputum purulence from baseline. In addition, nonspecific symptoms such as fever, fatigue and malaise may also be present. There are few clinical indicators that help differentiate COPD exacerbations caused by viral infections from exacerbations caused by nonviral etiologies. In the London cohort, cold symptoms (increased nasal congestion or rhinorrhea), cold symptoms accompanied with increased dyspnea and sore throat were all associated with having virus detected from nasal aspirates [6]. In a case control study of hospitalized patients with COPD conducted in Germany, fever was found to be more frequent among patients with detectable virus (12 of 48, 25%) than in patients in whom viruses were not detected (two of 37, 5%, P ¼ 0.03) [7]. Changes in sputum characteristics (increased volume or purulence) were not found to be related to virus detection in patients with COPD exacerbation [6]. Purulent sputum is not specific to COPD exacerbations of bacterial etiology. Almost all COPD exacerbations are marked by sputum neutrophilia and this often results in a change in sputum color [21]. A recent study [19], however, demonstrated that sputum eosinophilia occurred only in patients with viral-induced COPD exacerbations. The reasons for this finding are not entirely clear. Prior studies [22,23] have demonstrated that experimental rhinovirus infections induce lower airway eosinophilia and rhinovirus infection of respiratory epithelial cells induce several proinflammatory mediators that promote eosinophil recruitment [24]. If confirmed in future studies, the presence of sputum eosinophilia may represent an easy way to discriminate viral exacerbations from bacterial exacerbations. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Chronic obstructive pulmonary disease Varkey and Varkey 91 Viral exacerbations are also associated with patients who have frequent exacerbations, severe exacerbations and require a prolonged time to recover from symptoms. In the London cohort, respiratory viruses were associated with a median symptom recovery time of 13 days compared with a median symptom recovery time of 6 days for non-viral exacerbations [6]. Respiratory viruses can also be detected in patients with COPD during periods of stability. In the London cohort, RSV was detected in more patients during periods of stability (24%) than during exacerbations (14%) [6]. In the same cohort, viruses apart from RSV were detected in 16.2% of patients with stable COPD. The most common viruses detected in patients with stable disease were rhinovirus (7.3% of patients with stable disease) and coronavirus (5.9% of patients with stable disease) [6]. Detection of viruses in stable COPD patients probably represents asymptomatic colonization. Patients with stable COPD who were found to have detectable RSV, however, were also found to be more likely to have higher plasma fibrinogen levels, higher serum IL-6 levels, and more likely to be hypercarbic [6]. This raises the possibility that certain respiratory viruses, particularly RSV, may cause chronic low-grade infection and play a role in the pathogenesis of airway inflammation and subsequent deterioration in lung function in patients with COPD. A follow-up study of 74 patients with stable COPD [25] demonstrated that patients in whom RSV was frequently detected had higher airway inflammation and faster FEV1 decline compared with those with less frequent detection of RSV. It is unclear, however, if RSV and pulmonary function decline are causally linked. It is possible that inflammation predisposes the airways to viral persistence. Alternatively, patients with more aggressive COPD and faster disease progression may have impaired acquired or innate immune responses that allow RSV to persist [25]. A similar study [26] that tested respiratory secretions from patients with COPD both during illness and at regular intervals over a 1-year period showed no definitive evidence that low-grade chronic RSV infection even occurs. Clearly, further research to clarify the nature and consequences of viral persistence in patients with COPD is required. Diagnosis Prior to the widespread use of PCR techniques for viral detection, traditional methods for detecting virus, usually involving cell culture often paired with serology, severely underestimated the impact of viruses in patients with COPD. A comparison of different diagnostic methods for the detection of respiratory viruses including virus culture, antigen detection tests, serology, and PCR demonstrated that PCR is far more sensitive and at least equally specific to the older traditional diagnostic methods [27,28]. A recent 1-year prospective study of patients hospitalized with COPD exacerbations that used traditional viral cell culture and serology detected virus in approximately 10% of patients [29]. A PCR of nasopharyngeal aspiration specimens was performed on the same cohort and detected nearly three times higher the number of viruses detected by conventional viral culture [18]. Research is ongoing to determine the best ways to utilize PCR and other molecular diagnostic tests in the clinical setting. In a case–control study of 85 patients hospitalized with COPD exacerbation and 42 patients with stable COPD, sputum and nasal lavage specimens were analyzed to determine the preferred site for virus detection. In this study, respiratory viruses were detected in 47% of induced sputum samples obtained from patients with COPD exacerbation. Nasal lavage samples, however, only yielded virus in 31% of samples [7]. The reason for this discrepancy is not entirely clear; however, it is well recognized that URI symptoms often precede COPD exacerbation by several days. It would seem intuitive then that nasal lavage samples would be more likely to yield virus when URI symptoms are present and that induced sputum would be more likely to yield virus when lower respiratory tract symptoms are present. In addition, there is an increasing body of evidence that rhinovirus may directly infect the lower airway in patients with COPD [30–32]; therefore, it makes sense that sampling lower airway secretions in addition to the upper airways may lead to a higher diagnostic yield of viruses [18]. Although molecular diagnostics perform with much greater sensitivity than traditional tests to detect viruses, they do not discriminate between organisms causing disease and those causing asymptomatic colonization. This is a critically important issue since studies have demonstrated that several viruses are occasionally detectable in stable asymptomatic patients with COPD [6]. In the absence of symptoms, there are few indications for a clinician to initiate therapeutic interventions solely on the basis of a detected virus. The potential use of biomarkers in the blood or breath to predict the etiology and clinical course of a COPD exacerbation may soon allow clinicians to initiate early, targeted therapeutic interventions. A recent study [33] demonstrated the potential of gene expression profile technology to discriminate patients with influenza A from patients with bacterial infections. Biomarkers that reliably distinguish between viral and bacterial infection could dramatically reduce the overuse of antibiotics to treat COPD exacerbations. Pathogenesis Despite the epidemiologic evidence linking respiratory virus infection to exacerbations of COPD, the exact Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 92 Obstructive, occupational and environmental diseases cellular and molecular mechanisms by which viruses cause exacerbations remain largely undetermined [4]. Nevertheless, recent research has produced considerable insight into interactions which may eventually facilitate the development of new therapeutics. COPD. A better understanding of the pathogenesis may facilitate the development of new treatments for viralinduced exacerbations of COPD. Treatment A key issue regarding virus-induced exacerbations of airway diseases is whether upper respiratory tract viruses, such as rhinovirus, can also infect the lower airway. The optimal temperature for the growth of rhinovirus is 338C; as a result, it has long been assumed that rhinovirus cannot infect the lower respiratory tract. There is now an increasing body of evidence from experimental rhinovirus infections that respiratory viruses that typically cause URIs can in fact infect the lower airway [30–32]. In clinical trials, the increased diagnostic yield for detecting virus from sputum samples compared with nasal lavage also supports the theory that viruses that cause URIs can also infect the lower airways [7,34]. Recent research suggests that many respiratory viruses, including the major group of rhinovirus, attach to airway epithelial cells through intercellular adhesion molecule (ICAM-1). Induction of ICAM-1 expression promotes the recruitment and activation of inflammatory cells [35]. Viral infection of epithelial cells can lead to destruction of epithelial lining of the airways and the extent of destruction varies according to virus type. For example, influenza typically causes extensive epithelial necrosis, whereas rhinovirus causes only patchy damage [36]. Viral infection of epithelial cells also initiates and regulates the release of proinflammatory cytokines and chemokines such as tumor necrosis factor (TNF)-a [37,38], IL-8 [37,39], epithelial-derived neutrophil attractant (ENA78) [39], leukotriene B4 (LTB4) [40], CCL5 (RANTES) [4,41] and endothelin-1 [42]. IL-8, ENA-78, and LTB4 attract neutrophils which stimulate mucus production and results in increased production of purulent sputum. CCL5 (RANTES) attracts eosinophils, lymphocytes, macrophages and activated T cells, resulting in apoptosis of virus-infected cells [43]. This results in airway inflammation, airway remodeling, tissue destruction, and loss of lung function [43]. Endothelin-1 causes bronchoconstriction and vasoconstriction, resulting in airflow obstruction and impaired gas exchange [4]. In addition, IL-6 is also released from epithelial cells and can be found in the sputum, breath and plasma of COPD patients during exacerbations [6,44,45]. Increased levels of IL-6 produces systemic inflammation which can result in the cachexia, muscle wasting, depression, and vascular events that can characterize severe, complicated exacerbations of COPD [4]. More research is needed to better understand the mechanisms by which respiratory viruses affect patients with Regardless of the etiology, bronchodilators, corticosteroids and, when necessary, mechanical ventilation should continue to be the mainstay of treatment for almost all COPD exacerbations. For virus-induced COPD exacerbations, however, specific, clinically proven treatments are currently limited. Viruses, as noted in the preceding discussion, play a significant role in COPD exacerbations. Viral infection, however, can often coexist with bacterial pathogens in patients with COPD exacerbations. Therefore, for severe exacerbations marked by increased dyspnea, increased sputum production and increased purulence the use of antibacterial agents is still indicated. Further research is needed to better identify individuals who get the greatest benefit from antibacterial therapy during a COPD exacerbation. This research would lead to a more discriminate use of antibacterial agents to treat COPD exacerbations. In specific circumstances, antiviral agents may be useful for the treatment of COPD exacerbations; however, the number of drugs available at this time is limited. When clinical signs and symptoms of influenza are present during a known influenza epidemic, the use of oseltamivir in COPD exacerbations appears appropriate [46]. The novel capsid-binding inhibitor, pleconaril, and the 3C protease inhibitor, ruprintrivir, modestly reduce symptoms during human rhinovirus-induced colds [47,48]. The efficacy of these compounds in patients with virusinduced COPD exacerbations, however, has not yet been examined. Anti-inflammatory therapy may have a therapeutic role in COPD exacerbations [37]. Several potential antiinflammatory treatments are now in clinical development [49]. Future therapies could range from selective inhibitors of key virus-induced signaling pathways in epithelial cells, to antagonists of specific chemokines that may play a key role in pathogenesis [5]. ICAM-1 has been specifically described as a potential target to block as a means to preventing rhinovirus infection [13]. Nitric oxide appears to be an important component of the host antiviral response because it exerts direct antiviral activity against several viruses associated with exacerbations of COPD and also inhibits virus-induced generation of several cytokines/chemokines from epithelial cells [50]. Therefore, the potential of nitric oxide to Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Chronic obstructive pulmonary disease Varkey and Varkey 93 reduce virus-induced inflammation in COPD would be an avenue for further research. In the absence of a plethora of specific options to treat virus-induced exacerbations of COPD, traditional methods of preventing the transmission and acquisition of respiratory viruses cannot be overemphasized. Immunization with standard influenza virus vaccine is associated with reduced hospitalization rates, fewer outpatient visits, less severe illness, and lower mortality related to pneumonia and influenza in older persons [51–53] and a reduced risk of influenza-related illness in persons with COPD [54]. Unfortunately, vaccination approaches have not been successful for RSV and, given the large number of viral serotypes, are not feasible for human rhinovirus [5]. Every patient with COPD and close contacts of patients with COPD should be reminded at every clinic visit to practice good hand hygiene, especially during the winter season when respiratory viruses are prevalent in the community. Conclusion Measures to prevent viral infection in patients with COPD may lead to a reduction in the frequency of exacerbations, a reduction in the severity of exacerbations, and a reduction in hospital admissions [13]. The prevention and early treatment of viral infections in patients with COPD will have an important impact on the considerable morbidity and mortality of this disease. Novel strategies focused on prevention and treatment strategies require further exploration. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 162). 1 Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001; 163:1256–1276. 2 Lopez AD, Murray CC. The global burden of disease. Nat Med 1998; 4:1241–1243. 3 Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000; 117:5S–9S. 4 Mallia P, Johnston SL. How viral infections cause exacerbations of airway diseases. Chest 2006; 130:1203–1210. This is an excellent comprehensive review of the evidence for viruses as a cause of exacerbations of COPD and asthma. 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