Pediatric Infectious Disease Journal:
Respiratory Syncytial Virus Persistence in Chronic Obstructive Pulmonary Disease
Sikkel, Markus B. MBBS, BSc, MRCS; Quint, Jennifer K. MBBS, BSc, MRCP; Mallia, Patrick MD, MRCP; Wedzicha, Jadwiga A. MA, MD, FRCP; Johnston, Sebastian L. MBBS, PhD, FRCP
From the Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity and MRC, Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK.
Disclosure: The authors report no conflicts of interest.
Address for correspondence: Sebastian L. Johnston, MBBS, PhD, Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity and MRC, Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, Norfolk Place, London W2 1PG, UK. E-mail: firstname.lastname@example.org.
Respiratory syncytial virus (RSV) is predominantly recognized as a pediatric pathogen although sensitive molecular diagnostic techniques have led to its more frequent detection in some adult settings. In some studies RSV has been detected just as frequently in stable chronic obstructive pulmonary disease (COPD) patients as in those suffering disease exacerbations, leading to the suggestion that RSV may persist in COPD. Although some studies have found negligible RSV in stable COPD, others have detected RSV in one-quarter to one-third of stable COPD samples. Possible reasons for this discrepancy are explored within the article. A relationship between RSV detection and increased disease severity, including rate of decline in lung function and systemic/airway inflammation, has been found on both occasions it has been sought. Susceptibility to persistent RSV infection could involve both host and viral factors. Cigarette smoking and COPD are likely to result in impaired antiviral immunity, and RSV is capable of evading immune responses by inducing skewed type 2 T-helper cell responses, antagonizing antiviral cytokines, mimicking chemokines, inhibiting apoptosis, and entering immune-privileged cells such as pulmonary neurons. It can also escape an established immune response through antigenic drift. This article examines current evidence regarding persistence of RSV in COPD and its possible mechanisms. We also discuss various roles for RSV persistence in COPD pathogenesis. Further elucidation of the contribution of persistent RSV to the pathogenesis of COPD requires interventional studies. Persistence of RSV in COPD may have direct relevance to the pathogenesis of childhood diseases such as postbronchiolitic wheeze and asthma.
Chronic obstructive pulmonary disease (COPD) is currently the 4th leading cause of death in adults in the United States and Europe.1 Although smoking is the number one risk factor, the etiology of COPD is multifactorial: genetic factors, air-pollution, and infections also play a role. COPD has a protracted natural history, interspersed with acute symptomatic, physiologic, and functional exacerbations associated with increased airway inflammation.2 These are most often secondary to viral or bacterial infection.3 Exacerbations impact negatively on health-related quality of life,4,5 pulmonary function,6 utilization of health care resources,7,8 and survival.9
Respiratory syncytial virus (RSV), a negative stranded ribonucleic acid virus of the Paramyxoviridae family, is predominantly recognized as a pediatric pathogen.10 It has a wide range of clinical manifestations, from asymptomatic upper respiratory tract infection to acute bronchiolitis in infants. There has been considerable interest in postbronchiolitis sequelae, with clear evidence that postbronchiolitic wheezing is common and longstanding debate regarding whether RSV bronchiolitis can lead to the later development of asthma. RSV is also becoming recognized as an important adult pathogen,11 especially in older patients, those with cardiopulmonary disease and those who are immunocompromised.12,13 Around 10,000 deaths in those over 65 years of age in the United States each year are thought to be attributable to RSV,14 and in certain high-risk populations it has a similar health burden to influenza.
For many years the majority of research in COPD focused on the role of bacteria16 in both stable COPD and in acute exacerbations. Mirroring advances in our understanding of asthma exacerbations,17–20 recent studies using polymerase chain reaction (PCR)-based methods have led to a re-evaluation of the contribution of viruses. They are now thought to play at least as important a role as bacteria,21–31 with viral infection detected in up to 64% of COPD exacerbations. It is likely that any respiratory virus can cause an exacerbation, but numerically most important in this setting are rhinoviruses, influenza viruses, and coronaviruses.27,31–34
RSV is also implicated as a cause of acute exacerbations. Indirect evidence for this is the temporal association of seasonal acute RSV infections in children to frequencies of COPD hospitalizations.35 More direct evidence comes from recent studies that have used PCR to detect the presence of RSV in COPD exacerbations. This includes a study from Beckham et al27 that detected RSV in 7 of 194 (3.6%) patients with COPD exacerbations treated in both in-patient and out-patient settings. A study by Cameron et al22 investigated the prevalence of RSV in COPD exacerbations requiring intensive care unit treatment and revealed that 7 of 107 (6.5%) episodes were associated with RSV detection, although 2 of these episodes involved coinfection with other organisms. Subsequent studies (outlined below) show that conclusions drawn from these studies are limited with respect to RSV because of the lack of a stable COPD control group, which might also have shown a substantial rate of RSV detection. It is this substantial rate of detection in stable COPD that has led to the suggestion that the virus may persist in this context.
Given the possibility of persistence of RSV in COPD, some authorities have suggested that the virus may contribute to pathogenesis of stable disease in a similar manner to latent adenovirus.36–43 This seems feasible44 given certain common pathologic features of RSV infection and COPD. Inflammation in both contexts is associated with a predominance of CD8+ T-lymphocytes and neutrophil-rich exudates contributing to lung damage.45,46 Further damage in persistent RSV infection could be caused by increased activity of matrix metalloproteinases as evidenced by animal studies.47,48 This article will summarize the current evidence regarding RSV persistence in COPD, and its possible role in disease pathogenesis. Although COPD is clearly not a pediatric disease, evidence indicating that persistence might play a role in COPD pathogenesis would have important implications for a possible role for RSV persistence in acute bronchiolitis, postbronchiolitic wheezing, and the possible relationship with later development of asthma.
Detection of RSV
Changes in our concepts of RSV, and viral infections as a whole, in COPD and asthma would have been impossible without progress in diagnostic techniques. Traditionally, detection has relied on culture of the virus from respiratory secretions. This is difficult with any respiratory virus as samples must contain live virus and susceptible cells lines need to be available, however it is particularly difficult with RSV given its thermolability.49 Immunochemical techniques for detection of virus, such as direct immunofluorescence and antigen-capture enzyme immunoassays are faster than culture, but the sensitivity and the specificity are lower. This may be especially true for adults who have lower viral loads than children.50 Serological techniques are also available but are limited in this setting as they rely on the host's immune response, which may be atypical in latent/persistent infection.
Studies evaluating the use of reverse transcription and amplification of viral nucleic acid by PCR have shown this to have superior sensitivity and specificity as compared with culture or antigen detection methods.50–53 A number of different PCR techniques have been used for detection of RSV RNA. Conventional PCR relies on a qualitative visualization of amplified target product at the end of the reaction using agarose gel electrophoresis. The sensitivity of standard PCR can be increased with a nested PCR, but this may increase the risk of false positives through contamination with previously amplified DNA. Quantitative or real-time PCR is based on detection of a fluorescent signal produced during amplification of a PCR product. By measuring the amplification product in the exponential phase of the reaction, differences in the quantities of starting viral gene copies can be detected, and the initial concentration (viral load) can be calculated. PCR techniques are not uniformly sensitive, however, and many authors have suggested that this explains the disparity in prevalence of RSV found in very similar populations.27,33,34,54
Of course, a sensitive technique is only useful if it follows sound methods of sample collection. In the case of RSV infection it seems that sputum is more sensitive than nasal samples,55 which probably give no additional diagnostic value in COPD exacerbations.34 Also important is prevention of contamination.55,56 Techniques which endeavor to do this include utilization of protected specimen preparation, laboratory areas, and equipment; using the same reaction tube for specimen collection and PCR assay; or in the case of nested PCRs, hanging droplet techniques.
Evidence Regarding Persistence of RSV in COPD
In contrast to the studies in patients undergoing acute exacerbations in whom rhinoviruses, coronaviruses, and influenza viruses predominate, in stable COPD the most common virus reported has been RSV. This may represent persistent infection. In a study by Seemungal et al33 on a London cohort of COPD patients, 68 paired stable and exacerbation nasal aspirate samples in patients with spirometrically-proven COPD were tested for RSV by nested PCR. RSV was detected in 16 (23.5%) stable COPD patients and in 19 of 168 (14.2%) exacerbations in these 68 patients (Table 1). It was the only virus detected at greater frequency when stable compared with exacerbation. Repeat PCRs with fewer cycles resulted in the majority of positives becoming negative suggesting the virus was present at low viral loads. Significant relationships with severity of disease were observed, with those with RSV detection during stable disease having more severely impaired gas exchange (higher Paco2) and markers of systemic inflammation [higher serum interleukin (IL)-6 and fibrinogen]. These relationships with disease severity suggested viral detection represented true positives rather than contamination, as contamination would be expected to have no relationship with disease severity.
In a later study on the same cohort, Wilkinson et al44 investigated RSV in stable COPD only, in 241 sputum samples from 74 patients collected quarterly over a 2-year time period. All patients had COPD defined by spirometry and were at least 6 weeks away from their last exacerbation symptom and/or treatment. Fifty-nine of 74 (79.7%) patients had RSV detected by nested PCR in at least 1 sputum sample in the stable state during the study. Overall RSV was detected in the stable state in 32.8% of the 241 stable sputum samples collected (Table 1). The authors confirmed the identity of the PCR product by sequencing. They also went on to show clustering of RSV detections in individuals rather than a random distribution of positives, again suggesting contamination was unlikely. Investigation of relationship with disease severity indicated that those with more frequent RSV detections when stable had more rapid decline in lung function (Fig. 1), providing further evidence of RSV persistence and its relationship with severity of disease.
In a study by Borg et al,54 quantitative PCR for RSV was performed on nasopharyngeal aspirates from children with acute respiratory infections, and nasal lavage and induced sputum from elderly patients with spirometry-proven COPD, both at exacerbation and in the stable state. In this study, RSV was found at similar rates in adults in the stable and exacerbation groups (27.9% and 28.3%, respectively) (Table 1). Quantitative PCR performed on these samples and on samples taken from children with acute respiratory tract infections found that the viral load in the children with acute infection was almost 2000-fold higher than both stable and exacerbation COPD patients. This suggests low-grade RSV infection, potentially indicative of latency and persistence, in the COPD patients. Relationships with severity of COPD were not assessed in this study.
A longitudinal study investigating persistent RSV infection in COPD was designed by Falsey et al.55 Sputum and nasal swabs from 112 subjects, who had been diagnosed with COPD by a physician, were collected in the stable state, at 2 monthly intervals, and at exacerbation over a 1-year period. Both nested and quantitative PCR techniques, along with serological methods were used to detect RSV. In contrast with the studies above, RSV was detected in only 3 of 315 (0.95%) stable sputum samples and 0 of 685 stable nasal samples but in 5 of 69 (7.2%) exacerbation sputum samples and 6 of 92 (6.5%) exacerbation nasal samples (Table 1). The authors suggest that failure to identify RSV in stable patients means persistence is unlikely. As detections were so rare in this study, no relationships with COPD severity could be investigated.
Falsey et al's55 results are corroborated by 2 previous studies in which PCR techniques were used to identify a number of respiratory viruses, of which RSV was one, from respiratory samples of COPD patients. In a 2:1 case-control study, Rohde et al34 collected samples from 85 patients with an exacerbation of COPD and 42 stable COPD patients. Nested PCR detected RSV in 22% of the exacerbation group but in none of the stable group (Table 1). The 2 groups were shown to be comparable in terms of basic clinical status by assessment of forced expiratory volume at 1 second (FEV1) immediately before discharge. A study by Papi et al24 investigated patients with exacerbations from a cohort of COPD patients in Italy. A PCR assay was used to detect RSV in induced sputum specimens at exacerbation and then at a subsequent visit during convalescence in 64 patients. Prevalence of RSV was found to be 6.3% at exacerbation and only 3.1% during convalescence (Table 1), hence providing little support for persistent RSV in COPD.
Evaluating the Evidence
Clearly there is disparity between the conclusions of the above studies. The most likely reasons for this disparity may be variable sensitivity of PCR techniques used, PCR contamination, or differences in the populations studied.
Contamination has been suggested55 as a possibility in studies showing persistence. We believe this is unlikely given the relationships between infection in the stable state and disease severity33,44 found on both occasions it has been sought. Such an effect could not be explained by contamination.
Recurrent reinfection is another possibility given the ubiquity of the pathogen and its poor induction of specific immunity. This type of recurrence might give the impression of persistence if infection was aborted at an early stage before it produced an exacerbation.55 The sensitivity of PCR could mean that RSV was detected in the absence of significant active infection caused by amplification of dead virus particles. This explanation also seems unlikely given the frequent detections within the same individuals over a short time interval, especially in the study by Wilkinson et al.44
Alternatively results may have reflected true differences in study populations in terms of demographics or disease severity. All 6 studies studied patients of a similar age, suggesting that this was not a contributing factor (Table 1). Lung function was slightly different between the articles, however, with FEV1 of 39% and 41% of predicted where it was measured in the articles supporting persistence33,44 and 44%, 44%, and 50% in the 3 articles that do not support persistence.24,34,55 This may suggest that the differences in RSV detection between studies might be explained by differences in severity of COPD in the different study populations in a similar manner as a positive correlation was found between disease severity and rate of RSV detection within some of the studies.33,44
Geographical differences may also account for some of the variation given that the dynamics of RSV epidemics seem to be local rather than national or global.56 Additionally, Falsey et al's study was unusual in that all RSV found was group B (RSV-B).55 RSV-B shows differing characteristics to group A RSV (RSV-A) both in terms of viral load58 and clinical manifestations.59 Of note the main structural difference in the virion between the groups is in the G glycoprotein—the very component that is proposed to be most important in the induction of persistence.60 The disparity in findings may reflect a discrepancy between RSV-A and RSV-B in the likelihood of persistence.
Despite these possibilities, given the historical context of improved methods of detection allowing viral detection in new patient groups, it seems most likely that the discrepancies between groups are because of variable assay sensitivity. Of the studies published investigating RSV infection in stable COPD, 3 have detected RSV at high frequencies33,44,54 and 3 have not.24,34,55 Some assays used in the latter studies may have been suitably sensitive for detecting relatively higher viral loads associated with acute respiratory illnesses, but not sensitive enough to detect very low viral loads likely to be relevant to persistence. Although all methods used were nested and report good sensitivities, differences in extraction could have accounted for subtle differences in sensitivity sufficient to account for the different detection frequencies reported.
Effects of Persistence of RSV in COPD Patients
With the increasing evidence suggestive of RSV persistence in COPD it is important to examine the clinical relevance of this phenomenon. As discussed above, Wilkinson et al44 showed strong relationships between respiratory physiology and RSV detection. Patients with RSV found in >50% of sputum samples had a mean decline in FEV1 of 101.4 mL per year as compared with 51.2 mL per year in patients with RSV in 50% of samples or less (Fig. 1). This statistically significant difference was independent of possible confounders such as exacerbation frequency, bacterial load, and smoking status. In addition, Seemungal et al33 revealed significant relationships among RSV detection in the stable state, raised Paco2,and systemic inflammatory markers.
Wilkinson et al also investigated relationships with airway inflammation and showed increases in the inflammatory mediators IL-6 and IL-8, and the marker of neutrophil activity, myeloperoxidase in the sputum of patients with frequent RV detections, compared with those without.44 These relationships were not statistically independent of lung function decline suggesting an association between RSV detections in the lower airway, increasing airway inflammation and the reduction in FEV1. These relationships strongly suggest detection of RSV is associated with disease severity, though whether causally, or as an epiphenomenon cannot as yet be determined.
Mechanisms of Persistence of RSV in COPD Patients
Immune Evasion/Escape by the Virus.
RSV enters its host's respiratory epithelium by cell surface fusion and subsequent replication begins an inflammatory response,48,61 which may be modulated by the virus itself. CD4+ T-cell cytokine profiles can be broadly split into a T-helper 1 (TH1) or T-helper 2 (TH2) response depending on which subset of CD4+ cell predominates.62 TH1 responses are generally directed at cytotoxicity and specific viral destruction via cytokines such as interferon (IFN)-γ and tumor necrosis factor-α, whereas TH2 cells produce different cytokines such as IL-4, IL-5, and IL13. TH2 cytokines cause preferential isotype switching by plasma cells toward the immunoglobulin (Ig)E and IgA subclasses63 as may occur in children who wheeze post-RSV bronchiolitis where high levels of RSV-specific IgE have been reported.64 Preferential induction of TH2 versus TH1 responses could in theory favor persistence rather than clearance of virus.
RSV has been shown to initiate a TH2-type response in certain circumstances. It has been reported to do this in 2 ways. First, the RSV G glycoprotein65 has the ability to induce TH2 responses directly,62,66,67 and second, RSV induction of thymus-and-activation-regulated-chemokine (TARC) production in respiratory epithelial cells has been reported.68 TARC is involved in the recruitment of TH2 cells and could skew the immune response toward TH2 and away from TH1. Another transcription factor involved in TARC production (STAT6) is then activated by TH2 cytokines inducing a positive feedback loop and further production of TH2 cytokines.
The importance of TH1/TH2 responses in RSV clearance has been directly shown in studies in RSV bronchiolitis, where it was shown that elevated ratios of TH2:TH1 cytokines (eg, IL-10:IL-12 and IL-4:IFN–γ) were associated with impaired virus clearance.67 Thus induction of a TH2 response, could plausibly contribute to viral evasion and possible persistence. This has also been shown in a guinea pig model of RSV persistence where, although persistence was observed whether there was a TH1 or TH2 skew in immune response, there were lower viral loads in the TH1 skewed animals.69
There are other mechanisms that RSV may use to evade the host's immune response. The nonstructural proteins (NS1 and NS2) have been shown to antagonize IFN-α, IFN-β, and IFN-λ responses70,71—this would result in impaired antiviral immunity and possible persistence of virus. The RSV G glycoprotein, important in the TH2 skew, also has structural homology with the chemoattractant chemokine fractalkine and competes with it in the chemotaxis of leukocytes to further modify the immune response.60 The same protein also allows RSV access to immune-privileged cells such as pulmonary neurons in the murine model,72 and hence opportunity for latent infection of a similar type to the herpes simplex viruses.
RSV can also escape an established immune response. Antigenic drift is capable of producing neutralizing-antibody escape variants that are less susceptible to the anti-F antibody response.71 In addition, during replication RSV exhibits a conformationally altered envelope which shows decreased affinity to anti-F antibody.73 Finally, the virus can avoid early abortion of infection via inhibition of apoptosis in host cells.74 These immune evasion and escape mechanisms could help explain persistence and subsequent lung damage contributing to COPD pathogenesis (Fig. 2).
Many patients with COPD are iatrogenically immunosuppressed with frequent courses or prolonged use of oral or inhaled corticosteroids. Indeed an increased incidence of pneumonia has recently been reported with prolonged inhaled steroid use.75 Additionally, abnormalities in lung structure and mucocilliary clearance make persistent infection of the lower respiratory tract more likely.
The toxic effects of some of the causative agents of COPD are also immunosuppressive. Carcinogens in cigarette smoke cause a significant reduction in release of the antiviral immune mediators IFN-α, IFN-β,76,77 and nitric oxide.78 Environmental pollutants may also make viral persistence more likely. For example, carbon black, a component of particulate pollution, helps tip the immune response to RSV from TH1 to TH2 phenotype in the murine model.79
There is also evidence that certain nucleotide polymorphisms in the cytokines IL-4 and IL-10, and in components of the innate immune system such as surfactant protein A-1 are found more frequently in children hospitalized with RSV than noninfected controls.79a There is no similar data in COPD, but it is possible that nucleotide polymorphisms will play a role in host susceptibility to RSV persistence as well.
Little data exist investigating susceptibility to viral infection in COPD patients, but it seems likely that impaired antiviral immunity will be relevant to RSV persistence and its relationships with disease severity. These aspects clearly need urgent investigation.
The Plausibility and Role of RSV Persistence in COPD
RSV persistence is a relatively new concept in COPD research but not in pediatrics, animal models, or cell culture systems. These are discussed elsewhere in this issue of the journal, but briefly RSV exhibits prolonged infection and induction of airway hyperreactivity in the guinea pig model,80,81 infection for up to 2 months in bovine B lymphocytes,82 and infection of the respiratory epithelia of mice for >100 days after infection and 150 days if they are T cell depleted.83 In humans prolonged shedding has been described in immunosuppressive states such as prolonged corticosteroid use, human immunodeficiency virus infection and in children with T-cell immunodeficiency.84 The concept of persistence in RSV also fits in with other members of the antisense RNA virus family Paramyxoviridae—measles is known to exhibit persistence, resulting in subacute sclerosing panencephalitis.
In immunocompetent adults recurrent reinfection with RSV is common throughout adult life and is generally limited to the upper respiratory tract.85 Persistence is not thought to occur in such cases. The reasons that persistence is feasible in COPD are likely to be related to immunosuppression in this population.
The relevance of persistent RSV in COPD pathogenesis is impossible to precisely define given the current evidence. A number of possibilities require further investigation (Fig. 2). The first possibility is a direct contribution to the structural damage in COPD via increasing inflammation or matrix metalloproteinases activation. This is certainly possible but perhaps an oversimplification.
A second possibility, which may overlap with the first, is that persistent RSV could contribute to lung damage caused by other entities. This might occur through enhancement of inflammatory responses to cigarette smoke or infectious agents.63,86 Physical desquamation of epithelial cells could also result in interactions between RSV and bacteria similar to that found between influenza and pneumococcus,87 and subsequent lung damage.
The third possibility is that persistent RSV does not have a causal role in the pathogenesis of COPD but instead is an epiphenomenon secondary to an impaired immune response. Viruses are commonly found in stable COPD. In 1 study,33 16.2% of patients with stable COPD had non-RSV virus detected, most commonly rhinovirus (7.3%) and coronavirus (5.9%). RSV might simply be part of this viral flora and be more a symptom than a cause of advanced disease. Perhaps the drop in FEV1 and increase in inflammatory markers in chronic RSV33,44 are merely indicative of more severe COPD in which RSV is more likely to persist.
Elucidation of Role of RSV Persistence and Treatment Strategies
To further elucidate the role of persistent RSV in COPD it would be desirable to perform longitudinal, placebo-controlled interventional studies to assess the effects of anti-RSV therapies on the progress of COPD. This is not easy at present given the paucity of current preventative and therapeutic options available against RSV. Vaccine development has been problematic both in terms of efficacy and safety. Because RSV causes repeated infections throughout life it is difficult to induce lasting immunity. Also, the immune response against RSV may, in certain circumstances, be more damaging than the direct effects of the virus and hence there are risks in inducing defective active immunity. This was shown by the disastrous formalin-inactivated vaccine in the 1960s, which led to more severe disease upon subsequent exposure to RSV and the deaths of 2 children.
Passive immunization has met with more success. Palivizumab is a humanized monoclonal antibody that is the standard for preventing RSV infection in premature infants and those with cardiorespiratory problems. Although used successfully in adult transplant recipients, it is untested in the elderly88 and its efficacy against low-grade persistent infection is unknown.
Other treatment options include specific small molecule antivirals, such as aerosolized ribavirin which has been used with some success in children49 and bone-marrow transplant recipients.89 Again its efficacy in the context of low-grade persistent infection is unknown. Strategies to augment antiviral immunity may be most successful in the long term. Generic strategies may include use of IFN-inducers and TLR ligands.
In summary, persistence of RSV in COPD, although controversial and clearly not fully understood, is feasible through evasion of and escape from the host's immune system in combination with the impaired immunity found in patients with COPD. There is a possibility that RSV persistence has a role in the pathogenesis of COPD, either directly or by facilitating inflammatory or infective damage. Future research should focus on providing further definitive evidence of persistence in longitudinal studies and the role of persistence in COPD pathogenesis by prevention or treatment of latent/persistent infection. Elucidation of the role of persistent RSV in COPD may also have an impact on our understanding of childhood conditions that can occur after RSV infection such as postbronchiolitic wheezing and asthma.
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