Download Viral infections in patients with chronic obstructive pulmonary disease

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
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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.
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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
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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).
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