Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease.

The effects of respiratory viral infection on the time course of chronic obstructive pulmonary disease (COPD) exacerbation were examined by monitoring changes in systemic inflammatory markers in stable COPD and at exacerbation. Eighty-three patients with COPD (mean [SD] age, 66.6 [7.1] yr, FEV(1), 1.06 [0.61] L) recorded daily peak expiratory flow rate and any increases in respiratory symptoms. Nasal samples and blood were taken for respiratory virus detection by culture, polymerase chain reaction, and serology, and plasma fibrinogen and serum interleukin-6 (IL-6) were determined at stable baseline and exacerbation. Sixty-four percent of exacerbations were associated with a cold occurring up to 18 d before exacerbation. Seventy-seven viruses (39 [58.2%] rhinoviruses) were detected in 66 (39.2%) of 168 COPD exacerbations in 53 (64%) patients. Viral exacerbations were associated with frequent exacerbators, colds with increased dyspnea, a higher total symptom count at presentation, a longer median symptom recovery period of 13 d, and a tendency toward higher plasma fibrinogen and serum IL-6 levels. Non-respiratory syncytial virus (RSV) respiratory viruses were detected in 11 (16%), and RSV in 16 (23.5%), of 68 stable COPD patients, with RSV detection associated with higher inflammatory marker levels. Respiratory virus infections are associated with more severe and frequent exacerbations, and may cause chronic infection in COPD. Prevention and early treatment of viral infections may lead to a decreased exacerbation frequency and morbidity associated with COPD.     

Viruses in asthma exacerbations

PURPOSE OF REVIEW: Respiratory viruses are well recognized as major triggers of acute exacerbations of asthma in children and adults, resulting in frequent outpatients visits and hospitalizations. Clinical and epidemiologic evidence supports this association. The application of molecular diagnostic methods has improved understanding of viral epidemiology and the pathophysiological mechanisms involved in viral induced acute asthma. This article reviews publications since October 2002 for an update of the role of viruses in exacerbations of asthma. RECENT FINDINGS: Respiratory viruses are present in most patients hospitalized for life-threatening asthma and acute non life-threatening asthma. Rhinovirus is the most common, but coinfection with other viruses may be important. Patients with asthma are not more susceptible to upper respiratory tract rhinovirus infections than healthy people but suffer from more severe consequences of the lower respiratory tract infection. Recent epidemiologic studies suggest that viruses provoke asthma attacks by additive or synergistic interactions with allergen exposure or with air pollution. An impaired antiviral immunity to rhinovirus may lead to impaired viral clearance and hence prolonged symptoms. Respiratory viral infections cause asthmatic exacerbations by triggering recruitment of Th2-type cells into the lungs. There is no specific antiviral strategy for prevention of respiratory-triggered asthma exacerbations, although clinical trials of potential antiviral agents are ongoing. Indirect prevention strategies focus on the reduction of overall airway inflammation to reduce the severity of the host response to respiratory viral infections. SUMMARY: Respiratory viral infections are a major cause of morbidity and mortality in asthma. There is a lack of specific antiviral strategies in the prevention or reduction of viral-triggered asthma exacerbations. Recent advances in understanding of the epidemiology and immunopathogenesis of respiratory viral infection in asthma provide opportunities or identification of specific targets for antiviral agents and strategies for management and prevention.     

Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease

There is increasing evidence that chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation in the airways and lung parenchyma; however, little is known about the inflammatory response during acute COPD exacerbation. The objectives of this study were (1) to determine if inflammatory markers associated with neutrophilic inflammation and activation increase at times of acute COPD exacerbation relative to the clinically stable state, and (2) to determine whether the presence of acute bacterial or viral infection at the time of COPD exacerbation could be correlated with increases in sputum markers of inflammation. Induced sputum was collected from patients with COPD when they were clinically stable, during the time of an acute exacerbation, and 1 mo later. Sputum was analyzed at each time point for soluble markers associated with neutrophilic inflammation; myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8). Serologic assays on acute and convalescent sera were performed for respiratory viruses, and induced sputum was also subject to quantitative bacterial cultures, viral cultures, and polymerase chain reaction (PCR) for detection of respiratory viruses. Fourteen of the 50 patients enrolled in the study met predetermined criteria for an acute COPD exacerbation over the 15-mo study period. TNF-alpha and IL-8 were significantly elevated in the sputum of patients during acute COPD exacerbation compared with when they were clinically stable (p = 0.01 and p = 0.05, respectively). Concentrations of these cytokines declined significantly 1 mo after the exacerbation. Three of 14 patients (21%) had confirmed bacterial or viral respiratory tract infections. Patients with documented infection did not demonstrate greater increases in sputum levels of inflammatory cytokines during exacerbations compared with patients without demonstrable infection. We conclude that markers of airway neutrophilic inflammation increase at the time of acute COPD exacerbation and then decline 1 mo later, and that this acute inflammatory response appears to occur independently of a demonstrable viral or bacterial airway infection.     

A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD

Respiratory viruses are associated with severe acute exacerbations of chronic obstructive pulmonary disease (COPD) in hospitalized patients. However, exacerbations are increasingly managed in the community, where the role of viruses is unclear. In community exacerbations, the causal association between viruses and exacerbation maybe confounded by random fluctuations in the prevalence of circulating respiratory viruses. Therefore, to determine whether viral respiratory tract infections are causally associated with community exacerbations, a time-matched case-control study was performed. Ninety-two subjects (mean age 72 yrs), with moderate to severe COPD, (mean FEV(1) 40% predicted), were enrolled. Nasopharyngeal swabs for viral multiplex polymerase chain reaction and atypical pneumonia serology were obtained at exacerbation onset. Control samples were collected in synchrony, from a randomly selected stable patient drawn from the same cohort. In 99 weeks of surveillance, there were 148 exacerbations. Odds of viral isolation were 11 times higher in cases, than their time-matched controls (34 discordant case-control pairs; in 31 pairs only the case had virus and in three pairs only control). Picornavirus (26), influenza A (3), parainfluenza 1,2,3 (2), respiratory syncytial virus (1), and adenovirus (1) were detected in cases while adenovirus (1) and picornavirus (2) were detected in controls. In patients with moderate or severe COPD the presence of a virus in upper airway secretions is strongly associated with the development of COPD exacerbations. These data support the causative role of viruses in triggering COPD exacerbations in the community.     

慢性阻塞性肺疾病急性加重与呼吸道病毒感染的研究进展

慢性阻塞性肺疾病(COPD)是一种呼吸道常见的炎症性疾病,是全世界发病率和病死率较高的疾病之一。慢性阻塞性肺疾病急性加重(AECOPD)是其过程中的重要事件,常导致患者生活质量下降,病死率升高。呼吸道病毒感染与AECOPD密切相关。AECOPD的患者病毒感染具有多样性、季节性及地域性等特点。呼吸道病毒感染可通过活化炎症细胞及介质,参与免疫反应使COPD加重。各种各样的病毒感染对AECOPD的影响及机制可能不同,需要进一步研究。     

Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases.

Respiratory syncytial virus (RSV) is known to cause acute lower respiratory tract infections (ARI) in young children and is involved in exacerbation of chronic obstructive pulmonary disease (COPD) in adults. The role of RSV in stable COPD and the viral load in different respiratory diseases has not been investigated to date. The present authors established and evaluated a quantitative TaqMan real-time polymerase chain reaction assay specific for RSV subgroup A. Absolute quantification for the determination of viral load input was achieved using a control plasmid. The assay allowed for a quantification over a >6-log range and a detection limit of <10 RSV copies per reaction mixture. The assay was 30 times more sensitive than conventional nested polymerase chain reaction assays. Interassay SD was 1.3 and coefficient of variation 4.7% on average. Clinical specimens from infants with ARI (n=62) and elderly adults with COPD (n=125) were compared for viral loads. A total of 47% RSV-positive samples were found in the ARI study group and 28% in the COPD study group. The viral load of both study groups was found to differ significantly. In the ARI study group the viral load was increased almost 2000-fold, suggesting acute infection in this group and former or latent infection in the COPD group. Respiratory syncytial virus-A specific TaqMan real-time polymerase chain reaction assay is a sensitive and rapid method for the determination of viral load in clinical samples. It enables differential statements concerning the involvement of respiratory syncytial virus in acute lower respiratory tract infections and chronic obstructive pulmonary disease to be achieved.     

Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations

RATIONALE: Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial. OBJECTIVES: We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV1, and specific patterns of airway inflammation. METHODS: We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection. RESULTS: Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% when stable, p = 0.08). Patients with infectious exacerbations (29.7% bacterial, 23.4% viral, 25% viral/bacterial coinfection) had longer hospitalizations (p < 0.02) and greater impairment of several measures of lung function (all p < 0.05) than those with noninfectious exacerbations. Patients with exacerbations with coinfection had more marked lung function impairment (p < 0.02) and longer hospitalizations (p = 0.001). Sputum neutrophils were increased in all exacerbations (p < 0.001) and were related to their severity (p < 0.001), independently of the association with viral or bacterial infections; sputum eosinophils were increased during (p < 0.001) virus-associated exacerbations. CONCLUSIONS: Respiratory infections are associated with the majority of COPD exacerbations and their severity, especially those with viral/bacterial coinfection. Airway neutrophilia is related to exacerbation severity regardless of viral and/or bacterial infections. Eosinophilia is a good predictor of viral exacerbations.     

Chronic bronchitis: the role of viruses

Mucus is produced by the epithelial cells in the glands, gland ducts, and the cells lining the airway lumen in the lower airways.The chronic cough and sputum production that defines chronic bronchitis is associated with an inflammatory reaction involving this mucus-secreting apparatus. Respiratory viral infections target the epithelial cells of the lung producing desquamation, microvascular dilatation, edema, and an inflammatory cell infiltrate. These changes predispose the lower airways to bacterial infection by interfering with mucociliary clearance and reducing bacterial killing by macrophages. The exact role of those infections in the pathogenesis of chronic bronchitis has not been clearly determined but they probably play a critical role in inducing bacterial colonization and initiating acute exacerbations of COPD. This article reviews the classification of the viral agents responsible for respiratory tract infection and the nature of the changes they produce in the normal airways and in the airways of patients with chronic bronchitis during acute infections.     

Evaluation of Respiratory Viral Pathogens in Acute Asthma Exacerbations during Childhood

Objective. Common upper respiratory tract viruses are the most frequent and important causes of asthma exacerbations in both children and adults. Prospective epidemiologic studies report that up to 80% of childhood exacerbations are associated with viral upper respiratory tract infections. Materials and methods. The study group consisted of 104 children with asthma aged 3–17 years who received treatment for asthma exacerbations in our clinic between September 2009 and 2010. Nasopharyngeal and nasal swabs were obtained from all patients during an acute attack, and from the control group (31 subjects). These specimens were investigated for the presence of viral respiratory pathogens using a real-time multiplex PCR method. The patients were compared for the presence of respiratory pathogens and factors related to the severity of the asthma exacerbation. Results. A pathogenic respiratory virus was detected in 53.8% of patients in the acute exacerbation group. The most commonly encountered viral agent was Rhinovirus (35.6%). Patients who had an acute exacerbation with or without a detectable viral pathogen were compared according to the severity of the exacerbation, the need for systemic steroids, and hospitalization rates. No statistically significant difference was found. Conclusion. Although viral upper respiratory tract infections are the most common cause of asthma exacerbations, the severity level of the exacerbation seems to be independent of whether a respiratory virus has been detected.     

Structural and functional co-conspirators in chronic obstructive pulmonary disease exacerbations

Chronic obstructive pulmonary disease (COPD) exacerbations have a major impact on patients with COPD, yet they are complex events that are associated with a number of triggers and affected by the underlying disease process. A number of conditions can mimic the symptoms of an exacerbation and require evaluation. Airway and systemic inflammatory changes at exacerbation are modulated by infective factors (viruses and bacteria) and lead to the pathophysiologic effects seen at exacerbations with increase in airflow obstruction. Although bacteria or viruses can be isolated at exacerbation, often these organisms act in combination and lead to greater inflammatory changes and more severe exacerbation. Underlying structural changes such as radiologic changes of bronchiectasis that can be found in COPD can also modulate exacerbation severity and contribute to morbidity associated with exacerbations.     

Overview of virus-induced airway disease

Acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are the major cause of morbidity, mortality, and health costs of both diseases. Currently available treatments are poorly effective in both acute treatment of and prevention of acute exacerbations. New treatments for intervention and prophylaxis are therefore required; to facilitate their development, we must understand the causes and mechanisms of exacerbations. Respiratory viral infections (2/3 rhinoviruses) precipitate 80% or more of asthma exacerbations in children, and the majority of exacerbations of asthma and COPD in adults, but mechanisms of virus-induced lower airway inflammation and of host resistance against respiratory viruses are poorly understood. Development of in vitro experimental models of virus infection has identified interferon-beta and nitric oxide as possible therapeutic targets to augment antiviral immunity, and nuclear factor-kappaB as a target for development of anti-inflammatory therapies. In vivo models could also serve to identify and validate targets and as an experimental system to test candidate molecules as they emerge into clinical studies. Studies in asthma have paved the way for development of an asthma model; a similar experimental model in COPD would accelerate development of new therapies for these common diseases with enormous burdens of illness.     

Two cases of asthmatic exacerbation caused by parainfluenza virus 3 infection]

Although viral respiratory tract infections are considered to be the most frequent causes of asthmatic exacerbation, respiratory viruses can rarely be detected in the adult population. We describe 2 cases, in a 43-yr-old man with severe atopic asthma and in a 69-yr-old man with moderate non-atopic asthma. After the onset of nasal discharge, sore throat and fever, the asthma had become exacerbated in both cases during the summer of 2002. In both cases, parainfluenza virus (PIV) 3 viral RNA could be detected from oral gargling by RT-PCR, and the serum viral antibody titer against PIV 3 increased significantly. These cases were therefore diagnosed as undergoing asthmatic exacerbation caused by PIV 3 infection and were successfully treated with systemic steroids. During summer, 2002, in our outpatient clinic, PIV 3 infection was demonstrated in approximately half of the asthmatic exacerbations associated with upper respiratory symptoms, including the present cases. Collectively, PIV 3 seems to represent an important viral cause of asthma exacerbation in summer.     

Diagnosis of pathogens in exacerbations of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is increasing in prevalence. Acute exacerbations of COPD are the major cause worldwide of morbidity, mortality, and health care costs as well as decreased quality of life for the individual. The majority of exacerbations are infectious in etiology. Bacteria are detected in 50% of exacerbations and polymerase chain reaction techniques have established that, in half to two-thirds of exacerbations, viruses are causative pathogens. Combined bacterial and viral infection can be identified in 25% of exacerbations and these dual infections are often more severe. Despite occurring frequently, the mechanisms by which infection with these pathogens causes exacerbations are incompletely understood. This highlights the need for continued research, because a greater understanding of the mechanism of COPD exacerbations may lead to identification of potential targets for the development of therapeutic options for this increasingly common condition.     

Viral infections in patients with chronic obstructive pulmonary disease

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 virus-associated 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.     

The role of viral respiratory infections in the pathogenesis and exacerbation of asthma

Respiratory viral infections are implicated in both the pathogenesis and exacerbation of asthma. Infections with respiratory syncytial virus and parainfluenza virus are the major cause of wheezing-related respiratory infections early in life. Infections in early childhood affect the immune system and modify the risk for subsequent development of allergies and asthma. Later in life, rhinovirus and influenza are implicated frequently in the exacerbation of asthma. The management of respiratory viral infections includes adequate prophylaxis and treatment of acute infections. Insights into the mechanism of viral respiratory tract infections will provide therapeutic targets for treatment and possibly the prevention of virus-induced asthma.     

Immune Responses in Rhinovirus-Induced Asthma Exacerbations

Acute asthma exacerbations are responsible for urgent care visits and hospitalizations; they interfere with school and work productivity, thereby driving much of the morbidity and mortality associated with asthma. Approximately 80 to 85 % of asthma exacerbations in children, adolescents, and less frequently adults are associated with viral upper respiratory tract viral infections, and rhinovirus (RV) accounts for ～60–70 % of these virus-associated exacerbations. Evidence suggests that it is not the virus itself but the nature of the immune response to RV that drives this untoward response. In particular, evidence supports the concept that RV acts to exacerbate an ongoing allergic inflammatory response to environmental allergens present at the time of the infection. The interaction of the ongoing IgE- and T cell-mediated response to allergen superimposed on the innate and adaptive immune responses to the virus and how this leads to triggering of an asthma exacerbation is discussed.     

Prevention of exacerbations: how are we doing and can we do better?

Prevention of exacerbations of chronic obstructive pulmonary disease (COPD) can involve removing the cause or reducing the patient's vulnerability to the cause. This article addresses the following issues: What is the problem during an exacerbation, what are the causes of an exacerbation, what can prevent exacerbations, and who are we? The difference between a patient with COPD during an exacerbation and after recovery is small. It is unlikely that patients with early COPD experience less exposure to exacerbation causes than those with severe disease; it is just that the consequences are more severe for those with severe disease. Interventions that produce small absolute benefits can therefore have a disproportionately large effect on exacerbation reduction. Recognized causes include season, cold weather, pollution events, bacterial infection, viral infection, and treatment withdrawal. Countries with warmer climates have much larger mortality in cold weather than those with colder climates. Reducing exacerbations in more temperate climates may be altered as much by changes in clothing and bedroom heating as by changes in treatment. Taking more exercise in cold weather may be the underlying reason for the reduction of exacerbations after pulmonary rehabilitation. Influenza vaccination reduces influenza severity and reduces transmission from health care workers to patients. There are a number of pharmacologic interventions shown to reduce (the effect of) exacerbations, including inhaled corticosteroids, long-acting beta-agonists, long-acting anticholinergics, mucolytics, and perhaps antibiotics that reduce Haemophilus carriage. The effect of the bronchodilators is additive to inhaled corticosteroids; how far the other interventions are complementary is unclear. So far, we have had a very medical response to COPD exacerbations. Altering social and behavioral aspects is likely to be complementary.     

How viral infections cause exacerbation of airway diseases

Exacerbations of asthma and COPD are major causes of morbidity, mortality, and health-care costs. Over the last decade, studies using new molecular diagnostic techniques have established that respiratory viruses are a major cause of exacerbations of both asthma and COPD. The most prevalent viruses detected during exacerbations are the rhinoviruses. Despite the burden of disease associated with exacerbations, little is known about the mechanisms of virus-induced exacerbations of airway diseases. Exacerbations are associated with increased airway inflammation in patients with both asthma and COPD, but many questions remain unanswered regarding the key inflammatory cells and mediators involved. Identifying the key inflammatory mediators involved in exacerbations holds the promise of developing diagnostic and prognostic markers of exacerbation. In addition, such studies can identify new therapeutic targets for the development of novel drugs for the prevention and treatment of exacerbations.     

Viral infections in obstructive airway diseases

The most common syndromes associated with obstructive lung disease are asthma and chronic obstructive pulmonary disease (COPD). Evidence for a viral etiology of asthmatic exacerbations is well known, but evidence for a role for viruses in COPD exacerbation is just emerging. Viruses may cause chronic infection in both diseases. This paper reviews some studies on the effects of respiratory viruses on asthma and COPD published in 2002 and discusses their relevance to current thinking in pulmonary medicine.