COPD: Bacterial Infection Often Follows on Heels of Viral Infection

DENVER – The majority of patients with chronic obstructive pulmonary disease who acquire a rhinovirus infection develop a secondary bacterial infection shortly thereafter, suggesting that early antiviral therapy might do double duty.

In a study reported at the International Conference of the American Thoracic Society, 60% of patients with COPD who were experimentally infected with rhinovirus and who gave serial sputum samples developed a bacterial infection as well, approximately a week later. This rate was six times higher than the rates seen among smokers with normal lung function and among nonsmokers.

Temporal patterns of pathogen loads and molecular markers suggested that the virus may incite inflammation that, in turn, results in degradation of key defense peptides in the airways, leaving patients vulnerable to bacteria.

The findings raise the possibility that "dual infection is a lot more common than has been reported in [previous] studies," said lead investigator Dr. Patrick Mallia, a U.K. National Institute for Health Research clinical lecturer at the Imperial College London.

"In terms of therapeutics, this may suggest that antiviral drugs may not only be effective against virus-induced exacerbations, but also potentially could prevent or reduce secondary bacterial infection," he commented.

At his institution, COPD patients with an exacerbation are not routinely tested for viruses. But that may change, given the advent of rapid PCR (polymerase chain reaction) assays for detecting viruses and, possibly, expansion of the indications for antiviral agents.

"So although at the moment [testing for viruses] is very much a research exercise, I think the possibility of using antiviral treatment in the future is not that far away," he said.

Interest in the role of viruses and of dual viral-bacterial infection in COPD exacerbations has intensified recently, according to Dr. Mallia. As both types of infections are common in this population, one might expect that dual infection is common as well; yet, on average, studies have found dual infection in only 13% of exacerbations.

"This tends to suggest that actually it’s not so common, but I think there are a number of reasons why these studies may have underestimated the rate of dual infection," he said, such as their cross-sectional or retrospective nature, and one-time testing for pathogens.

"Studies using a single sampling time point during exacerbation will probably underestimate the true prevalence of coinfection, and also can’t tell us what the sequence of infection is," he explained.

To get around these issues, the investigators used their newly developed model of experimental rhinovirus-induced COPD exacerbation. "These patients catch a cold, get lower respiratory symptoms, and get an exacerbation with increased airflow obstruction and airway inflammation," he said.

The study included 30 patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD who were using only short-acting bronchodilators, 28 smokers with normal lung function, and 18 nonsmokers.

They were experimentally inoculated with rhinovirus, the virus most commonly detected in COPD exacerbations. Induced sputum was collected before inoculation and at 5, 9, 12, 15, 21, and 42 days afterward.

None of the participants received treatment for infections because their symptoms did not become severe enough to meet preestablished study criteria for treatment initiation, according to Dr. Mallia.

The load of rhinovirus in sputum was assessed with PCR. The load of bacteria that were classified as potentially pathogenic microorganisms (PPMs) was assessed with semiquantitative bacterial culture.

Study results showed that 20 of the COPD patients, 21 of the smokers, and 11 of the nonsmokers developed rhinovirus infection after inoculation.

Fully 60% of the rhinovirus-infected COPD patients developed secondary bacterial infections (mainly with Haemophilus influenzae and Streptococcus pneumoniae), compared with just 9.5% of the smokers and 10% of the nonsmokers (P less than .001).

Within the COPD group, bacterial infections were significantly more common among the patients who acquired rhinovirus infection than among those who did not. "This suggests that the bacterial infections we were detecting were a consequence of the rhinovirus infections," Dr. Mallia commented.

Both viral and bacterial loads rose and fell over time, but the former infection preceded the latter: The viral load peaked on day 9, whereas the bacterial load peaked almost a week later, on day 15. These are "really the first data that [show] a temporal sequence, that first you get the rhinovirus infection, and then you get the bacterial infection following this," he noted.

Moreover, "you can see immediately that if you take a single sample and you sample early, you may pick up a virus and call it a viral exacerbation, but not pick up the subsequent bacterial infection," he added. "Whereas if the patient happens to present later, you might detect the bacterial infection but not detect ... the virus infection that actually initiated it."

To assess potential mechanisms whereby rhinovirus might induce bacterial infections, the investigators measured sputum levels of two antimicrobial peptides found in the airways that are part of the lung’s innate defenses against infection: secretory leukocyte protease inhibitor (SLPI) and elafin.

Levels of both peptides fell in rhinovirus-infected COPD patients who developed bacterial infection before or at the time when bacterial load peaked. In contrast, levels remained the same or rose slightly in those who did not develop bacterial infection. Furthermore, lower levels of the peptides were correlated with higher bacterial loads.

"This would suggest that bacterial infection is a consequence of low SLPI and elafin levels in the airways," Dr. Mallia commented.

Finally, sputum levels of neutrophil elastase (an enzyme that could degrade the protective peptides) rose in rhinovirus-infected COPD patients who developed bacterial infection but remained essentially at baseline levels in their counterparts who did not.

"We hypothesize that possibly you have a sequence of events – viral infection, high neutrophil elastase levels, and degradation of SLPI and elafin – and that may progress to secondary bacterial infection," he said.

The study gives rise to several potential, related avenues of research, according to Dr. Mallia.

"Certainly, one of the things we are interested in is, Are there markers that can identify those people who are going to go on to develop bacterial infections?" he said. And some evidence suggests that in addition to having antibacterial activity, macrolide antibiotics also have antirhinovirus activity, which the investigators plan to test using their model.

Dr. Mallia reported previously having received research grants from Pfizer and GlaxoSmithKline, and currently receiving a travel grant from Boehringer Ingelheim. The study was funded in part by Pfizer and GlaxoSmithKline.

DENVER – The majority of patients with chronic obstructive pulmonary disease who acquire a rhinovirus infection develop a secondary bacterial infection shortly thereafter, suggesting that early antiviral therapy might do double duty.

In a study reported at the International Conference of the American Thoracic Society, 60% of patients with COPD who were experimentally infected with rhinovirus and who gave serial sputum samples developed a bacterial infection as well, approximately a week later. This rate was six times higher than the rates seen among smokers with normal lung function and among nonsmokers.

Temporal patterns of pathogen loads and molecular markers suggested that the virus may incite inflammation that, in turn, results in degradation of key defense peptides in the airways, leaving patients vulnerable to bacteria.

The findings raise the possibility that "dual infection is a lot more common than has been reported in [previous] studies," said lead investigator Dr. Patrick Mallia, a U.K. National Institute for Health Research clinical lecturer at the Imperial College London.

"In terms of therapeutics, this may suggest that antiviral drugs may not only be effective against virus-induced exacerbations, but also potentially could prevent or reduce secondary bacterial infection," he commented.

At his institution, COPD patients with an exacerbation are not routinely tested for viruses. But that may change, given the advent of rapid PCR (polymerase chain reaction) assays for detecting viruses and, possibly, expansion of the indications for antiviral agents.

"So although at the moment [testing for viruses] is very much a research exercise, I think the possibility of using antiviral treatment in the future is not that far away," he said.

Interest in the role of viruses and of dual viral-bacterial infection in COPD exacerbations has intensified recently, according to Dr. Mallia. As both types of infections are common in this population, one might expect that dual infection is common as well; yet, on average, studies have found dual infection in only 13% of exacerbations.

"This tends to suggest that actually it’s not so common, but I think there are a number of reasons why these studies may have underestimated the rate of dual infection," he said, such as their cross-sectional or retrospective nature, and one-time testing for pathogens.

"Studies using a single sampling time point during exacerbation will probably underestimate the true prevalence of coinfection, and also can’t tell us what the sequence of infection is," he explained.

To get around these issues, the investigators used their newly developed model of experimental rhinovirus-induced COPD exacerbation. "These patients catch a cold, get lower respiratory symptoms, and get an exacerbation with increased airflow obstruction and airway inflammation," he said.

The study included 30 patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD who were using only short-acting bronchodilators, 28 smokers with normal lung function, and 18 nonsmokers.

They were experimentally inoculated with rhinovirus, the virus most commonly detected in COPD exacerbations. Induced sputum was collected before inoculation and at 5, 9, 12, 15, 21, and 42 days afterward.

None of the participants received treatment for infections because their symptoms did not become severe enough to meet preestablished study criteria for treatment initiation, according to Dr. Mallia.

The load of rhinovirus in sputum was assessed with PCR. The load of bacteria that were classified as potentially pathogenic microorganisms (PPMs) was assessed with semiquantitative bacterial culture.

Study results showed that 20 of the COPD patients, 21 of the smokers, and 11 of the nonsmokers developed rhinovirus infection after inoculation.

Fully 60% of the rhinovirus-infected COPD patients developed secondary bacterial infections (mainly with Haemophilus influenzae and Streptococcus pneumoniae), compared with just 9.5% of the smokers and 10% of the nonsmokers (P less than .001).

Within the COPD group, bacterial infections were significantly more common among the patients who acquired rhinovirus infection than among those who did not. "This suggests that the bacterial infections we were detecting were a consequence of the rhinovirus infections," Dr. Mallia commented.

Both viral and bacterial loads rose and fell over time, but the former infection preceded the latter: The viral load peaked on day 9, whereas the bacterial load peaked almost a week later, on day 15. These are "really the first data that [show] a temporal sequence, that first you get the rhinovirus infection, and then you get the bacterial infection following this," he noted.

Moreover, "you can see immediately that if you take a single sample and you sample early, you may pick up a virus and call it a viral exacerbation, but not pick up the subsequent bacterial infection," he added. "Whereas if the patient happens to present later, you might detect the bacterial infection but not detect ... the virus infection that actually initiated it."

To assess potential mechanisms whereby rhinovirus might induce bacterial infections, the investigators measured sputum levels of two antimicrobial peptides found in the airways that are part of the lung’s innate defenses against infection: secretory leukocyte protease inhibitor (SLPI) and elafin.

Levels of both peptides fell in rhinovirus-infected COPD patients who developed bacterial infection before or at the time when bacterial load peaked. In contrast, levels remained the same or rose slightly in those who did not develop bacterial infection. Furthermore, lower levels of the peptides were correlated with higher bacterial loads.

"This would suggest that bacterial infection is a consequence of low SLPI and elafin levels in the airways," Dr. Mallia commented.

Finally, sputum levels of neutrophil elastase (an enzyme that could degrade the protective peptides) rose in rhinovirus-infected COPD patients who developed bacterial infection but remained essentially at baseline levels in their counterparts who did not.

"We hypothesize that possibly you have a sequence of events – viral infection, high neutrophil elastase levels, and degradation of SLPI and elafin – and that may progress to secondary bacterial infection," he said.

The study gives rise to several potential, related avenues of research, according to Dr. Mallia.

"Certainly, one of the things we are interested in is, Are there markers that can identify those people who are going to go on to develop bacterial infections?" he said. And some evidence suggests that in addition to having antibacterial activity, macrolide antibiotics also have antirhinovirus activity, which the investigators plan to test using their model.

Dr. Mallia reported previously having received research grants from Pfizer and GlaxoSmithKline, and currently receiving a travel grant from Boehringer Ingelheim. The study was funded in part by Pfizer and GlaxoSmithKline.

DENVER – The majority of patients with chronic obstructive pulmonary disease who acquire a rhinovirus infection develop a secondary bacterial infection shortly thereafter, suggesting that early antiviral therapy might do double duty.

In a study reported at the International Conference of the American Thoracic Society, 60% of patients with COPD who were experimentally infected with rhinovirus and who gave serial sputum samples developed a bacterial infection as well, approximately a week later. This rate was six times higher than the rates seen among smokers with normal lung function and among nonsmokers.

Temporal patterns of pathogen loads and molecular markers suggested that the virus may incite inflammation that, in turn, results in degradation of key defense peptides in the airways, leaving patients vulnerable to bacteria.

The findings raise the possibility that "dual infection is a lot more common than has been reported in [previous] studies," said lead investigator Dr. Patrick Mallia, a U.K. National Institute for Health Research clinical lecturer at the Imperial College London.

"In terms of therapeutics, this may suggest that antiviral drugs may not only be effective against virus-induced exacerbations, but also potentially could prevent or reduce secondary bacterial infection," he commented.

At his institution, COPD patients with an exacerbation are not routinely tested for viruses. But that may change, given the advent of rapid PCR (polymerase chain reaction) assays for detecting viruses and, possibly, expansion of the indications for antiviral agents.

"So although at the moment [testing for viruses] is very much a research exercise, I think the possibility of using antiviral treatment in the future is not that far away," he said.

Interest in the role of viruses and of dual viral-bacterial infection in COPD exacerbations has intensified recently, according to Dr. Mallia. As both types of infections are common in this population, one might expect that dual infection is common as well; yet, on average, studies have found dual infection in only 13% of exacerbations.

"This tends to suggest that actually it’s not so common, but I think there are a number of reasons why these studies may have underestimated the rate of dual infection," he said, such as their cross-sectional or retrospective nature, and one-time testing for pathogens.

"Studies using a single sampling time point during exacerbation will probably underestimate the true prevalence of coinfection, and also can’t tell us what the sequence of infection is," he explained.

To get around these issues, the investigators used their newly developed model of experimental rhinovirus-induced COPD exacerbation. "These patients catch a cold, get lower respiratory symptoms, and get an exacerbation with increased airflow obstruction and airway inflammation," he said.

The study included 30 patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II COPD who were using only short-acting bronchodilators, 28 smokers with normal lung function, and 18 nonsmokers.

They were experimentally inoculated with rhinovirus, the virus most commonly detected in COPD exacerbations. Induced sputum was collected before inoculation and at 5, 9, 12, 15, 21, and 42 days afterward.

None of the participants received treatment for infections because their symptoms did not become severe enough to meet preestablished study criteria for treatment initiation, according to Dr. Mallia.

The load of rhinovirus in sputum was assessed with PCR. The load of bacteria that were classified as potentially pathogenic microorganisms (PPMs) was assessed with semiquantitative bacterial culture.

Study results showed that 20 of the COPD patients, 21 of the smokers, and 11 of the nonsmokers developed rhinovirus infection after inoculation.

Fully 60% of the rhinovirus-infected COPD patients developed secondary bacterial infections (mainly with Haemophilus influenzae and Streptococcus pneumoniae), compared with just 9.5% of the smokers and 10% of the nonsmokers (P less than .001).

Within the COPD group, bacterial infections were significantly more common among the patients who acquired rhinovirus infection than among those who did not. "This suggests that the bacterial infections we were detecting were a consequence of the rhinovirus infections," Dr. Mallia commented.

Both viral and bacterial loads rose and fell over time, but the former infection preceded the latter: The viral load peaked on day 9, whereas the bacterial load peaked almost a week later, on day 15. These are "really the first data that [show] a temporal sequence, that first you get the rhinovirus infection, and then you get the bacterial infection following this," he noted.

Moreover, "you can see immediately that if you take a single sample and you sample early, you may pick up a virus and call it a viral exacerbation, but not pick up the subsequent bacterial infection," he added. "Whereas if the patient happens to present later, you might detect the bacterial infection but not detect ... the virus infection that actually initiated it."

To assess potential mechanisms whereby rhinovirus might induce bacterial infections, the investigators measured sputum levels of two antimicrobial peptides found in the airways that are part of the lung’s innate defenses against infection: secretory leukocyte protease inhibitor (SLPI) and elafin.

Levels of both peptides fell in rhinovirus-infected COPD patients who developed bacterial infection before or at the time when bacterial load peaked. In contrast, levels remained the same or rose slightly in those who did not develop bacterial infection. Furthermore, lower levels of the peptides were correlated with higher bacterial loads.

"This would suggest that bacterial infection is a consequence of low SLPI and elafin levels in the airways," Dr. Mallia commented.

Finally, sputum levels of neutrophil elastase (an enzyme that could degrade the protective peptides) rose in rhinovirus-infected COPD patients who developed bacterial infection but remained essentially at baseline levels in their counterparts who did not.

"We hypothesize that possibly you have a sequence of events – viral infection, high neutrophil elastase levels, and degradation of SLPI and elafin – and that may progress to secondary bacterial infection," he said.

The study gives rise to several potential, related avenues of research, according to Dr. Mallia.

"Certainly, one of the things we are interested in is, Are there markers that can identify those people who are going to go on to develop bacterial infections?" he said. And some evidence suggests that in addition to having antibacterial activity, macrolide antibiotics also have antirhinovirus activity, which the investigators plan to test using their model.

Dr. Mallia reported previously having received research grants from Pfizer and GlaxoSmithKline, and currently receiving a travel grant from Boehringer Ingelheim. The study was funded in part by Pfizer and GlaxoSmithKline.