American Thoracic Society (ATS): International Conference 2011

DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.

These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.

Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."

COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.

A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.

Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.

"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.

For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).

When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).

And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV₁) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).

"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.

Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).

"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."

Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV₁ and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."

Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.

DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.

These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.

Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."

COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.

A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.

Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.

"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.

For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).

When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).

And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV₁) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).

"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.

Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).

"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."

Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV₁ and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."

Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.

DENVER – Patients with chronic obstructive pulmonary disease have a slower decline in lung function, fewer exacerbations, and a marginally reduced risk of death if treated with anti-inflammatory agents. But the association between COPD and inflammation is hardly straightforward.

These were among the key messages that Dr. Alvar Agusti, director of the Thorax Institute, Hospital Clinic, University of Barcelona, imparted to attendees of the international conference of the American Thoracic Society.

Although "without an appropriate inflammatory response, we would all be dead quickly," inflammation is complex, he said. "There is a part of the inflammatory response that tries to kill or stop the injury, but there is another part that tries to restore the tissue structure and function. So there is both good and bad inflammation."

COPD clearly has a pulmonary inflammatory component. In addition, "it is well known and well established over the past few years that there is also systemic inflammation, and that this systematic inflammation may explain some of the extrapulmonary manifestations of the disease," Dr. Agusti noted.

A study among patients with COPD has shown that the number of inflammatory cells in the small airways increases with disease severity (N. Engl. J. Med. 2004;350:2645-53). But because the study was cross-sectional, "we do not really know if inflammation is driving disease progression, if it is vice versa, or both in a closed loop," he commented.

Also, it is unclear whether this is good or bad inflammation. For example, "all of us are aware that in some patients with COPD, there may be some consequences of interfering with the inflammatory response, such as an increased rate of pneumonia. ... This is clearly something that we need to understand better in relation to the inflammatory response," he observed.

"The evidence we have in vivo supports the effectiveness of anti-inflammatory therapy in COPD when combined with bronchodilator therapy," Dr. Agusti said.

For example, among patients with moderate to severe COPD, bronchial biopsies show that compared with placebo, the combination of fluticasone and salmeterol (a long-acting beta-agonist) has an anti-inflammatory effect at the cellular level, reducing numbers of macrophages, mast cells, and CD4 cells, among others (Am. J. Respir. Crit. Care Med. 2006;173:736-43).

When it comes to clinical outcomes, patients given budesonide plus formoterol with tiotropium have fewer exacerbations than their peers given placebo with tiotropium (Am. J. Respir. Crit. Care Med. 2009;180:741-50).

And in the large TORCH (Towards a Revolution in COPD Health) trial among patients with COPD, the rate of decline of forced expiratory volume in 1 second (FEV₁) was slower in patients given fluticasone and salmeterol than in their peers given a placebo (Am. J. Respir. Crit. Care Med. 2008;178:332-8). Mortality, the trial’s primary outcome, also was marginally lower (hazard ratio, 0.825; P = .052) (N. Engl. J. Med. 2007;356:775-89).

"It’s up to us clinicians to decide whether there is or is not a significant effect on survival," Dr. Agusti said. "However, TORCH also showed us that there are very clear effects ... in the clinic, in patients, when we use anti-inflammatory therapy." For example, health status as measured with the St. George’s Respiratory Questionnaire was better in the group given fluticasone plus salmeterol.

Finally, a newer oral NSAID, roflumilast, has been shown to reduce exacerbations in patients with moderate to severe COPD when added to salmeterol or tiotropium (Lancet 2009;374:695-703).

"We have to consider that inflammation is a vital but extraordinarily complex biological response," Dr. Agusti concluded. "And we need to understand much better the types of inflammation and how they vary between different COPD phenotypes."

Indeed, in the future, inflammatory status may be used to individualize therapy. "Why would you want to use an anti-inflammatory drug in someone who has no inflammation? But this is what we have been doing so far – we are just prescribing based on FEV₁ and symptoms," he said. "If we really want to move toward more personalized medicine, somehow – I do not know how, but somehow – we will have to phenotype our patients better. And inflammation seems like a very good candidate to do this."

Dr. Agusti reported being an adviser to, speaker for, or receiving research funding from Almirall, Astra-Zeneca, Boehringer Ingelheim, Chiessi, GlaxoSmithKline, Esteve, MSD, Nycomed, Novartis, Pfizer, Roche, and Procter & Gamble.

DENVER – Inhaled treprostinil was well tolerated and was associated with improvements in exercise capacity and functional class when added to background therapy in a retrospective study of 18 children with pulmonary arterial hypertension.

Inhaled treprostinil (iTRE; brand name, Tyvaso) was approved in 2009 for the treatment of patients with group 1 pulmonary arterial hypertension (PAH) as add-on therapy to improve exercise ability. It was primarily studied in adults with New York Heart Association class III symptoms, and has not been previously studied in children with PAH, said Dr. Erika B. Rosenzweig, director of the pulmonary hypertension center at Columbia University Medical Center in New York.

This study included 6 girls and 12 boys with PAH who were seen at either the Columbia center or the Children’s Hospital in Aurora, Colo., between September 2009 and January 2011. They had a mean age of 11 years, a mean weight of 42 kg, and a mean body mass index of 19.4 kg/m². A total of 11 patients had idiopathic PAH and 7 had associated PAH, including 5 with congenital heart defects. All were on background therapy at the time of iTRE initiation, with the majority (11) on combined endothelin receptor antagonist and phosphodiesterase-5 inhibitor therapy. Prostanoid therapy had been given previously to 10 patients.

All patients received three to nine breaths, with 6 mcg per breath of iTRE, four times daily. The mean treatment duration was 11.5 months (range, 2-20 months). Nine patients received nine breaths four times a day, whereas five patients did not reach that maximal dose because of side effects or per physician discretion. Four patients discontinued iTRE, including three because of bronchospasm, and one because of noncompliance with all medications (who died 3 months later). Side effects requiring down-titration included cough in one patient and nausea/emesis in two. Milder side effects that did not require a dose change occurred in two to six patients each, including cough, sore throat, dyspnea, wheezing, flushing, headache, and diarrhea. No child discontinued because of inability to self-administer the medication, Dr. Rosenzweig noted at an international conference of the American Thoracic Society.

At baseline, two patients were in World Health Organization functional class I, seven were class II, eight in class III, and one in class IV. At follow-up, there were 7 in class I, 10 in class II, 1 in class III, and none in class IV. In all, functional class improvements were seen in 11 of the 18 children.

Of the seven children who were able to complete the 6-minute walk test, the mean improvement was from 446 to 472 meters, which was statistically significant. Of four who completed cardiopulmonary exercise testing, the mean workload improved from 59 to 74 watts and mean peak oxygen consumption from 20 to 22 mL/kg per minute. Neither of those findings was statistically significant. However, in 10 of the patients with measurements of brain natriuretic peptide (which reflects right ventricular dysfunction), levels dropped significantly, from a mean of 88 to 66 pg/mL.

"The authors recognize the limitations of the small sample size, but based on these early data in children, we believe that further study of iTRE appears warranted in larger cohorts of pediatric patients," she concluded.

Dr. Rosenzweig disclosed that she has received research support from and has served as a consultant for United Therapeutics, the manufacturer of Tyvaso.

DENVER – Inhaled treprostinil was well tolerated and was associated with improvements in exercise capacity and functional class when added to background therapy in a retrospective study of 18 children with pulmonary arterial hypertension.

Inhaled treprostinil (iTRE; brand name, Tyvaso) was approved in 2009 for the treatment of patients with group 1 pulmonary arterial hypertension (PAH) as add-on therapy to improve exercise ability. It was primarily studied in adults with New York Heart Association class III symptoms, and has not been previously studied in children with PAH, said Dr. Erika B. Rosenzweig, director of the pulmonary hypertension center at Columbia University Medical Center in New York.

This study included 6 girls and 12 boys with PAH who were seen at either the Columbia center or the Children’s Hospital in Aurora, Colo., between September 2009 and January 2011. They had a mean age of 11 years, a mean weight of 42 kg, and a mean body mass index of 19.4 kg/m². A total of 11 patients had idiopathic PAH and 7 had associated PAH, including 5 with congenital heart defects. All were on background therapy at the time of iTRE initiation, with the majority (11) on combined endothelin receptor antagonist and phosphodiesterase-5 inhibitor therapy. Prostanoid therapy had been given previously to 10 patients.

All patients received three to nine breaths, with 6 mcg per breath of iTRE, four times daily. The mean treatment duration was 11.5 months (range, 2-20 months). Nine patients received nine breaths four times a day, whereas five patients did not reach that maximal dose because of side effects or per physician discretion. Four patients discontinued iTRE, including three because of bronchospasm, and one because of noncompliance with all medications (who died 3 months later). Side effects requiring down-titration included cough in one patient and nausea/emesis in two. Milder side effects that did not require a dose change occurred in two to six patients each, including cough, sore throat, dyspnea, wheezing, flushing, headache, and diarrhea. No child discontinued because of inability to self-administer the medication, Dr. Rosenzweig noted at an international conference of the American Thoracic Society.

At baseline, two patients were in World Health Organization functional class I, seven were class II, eight in class III, and one in class IV. At follow-up, there were 7 in class I, 10 in class II, 1 in class III, and none in class IV. In all, functional class improvements were seen in 11 of the 18 children.

Of the seven children who were able to complete the 6-minute walk test, the mean improvement was from 446 to 472 meters, which was statistically significant. Of four who completed cardiopulmonary exercise testing, the mean workload improved from 59 to 74 watts and mean peak oxygen consumption from 20 to 22 mL/kg per minute. Neither of those findings was statistically significant. However, in 10 of the patients with measurements of brain natriuretic peptide (which reflects right ventricular dysfunction), levels dropped significantly, from a mean of 88 to 66 pg/mL.

"The authors recognize the limitations of the small sample size, but based on these early data in children, we believe that further study of iTRE appears warranted in larger cohorts of pediatric patients," she concluded.

Dr. Rosenzweig disclosed that she has received research support from and has served as a consultant for United Therapeutics, the manufacturer of Tyvaso.

DENVER – Inhaled treprostinil was well tolerated and was associated with improvements in exercise capacity and functional class when added to background therapy in a retrospective study of 18 children with pulmonary arterial hypertension.

Inhaled treprostinil (iTRE; brand name, Tyvaso) was approved in 2009 for the treatment of patients with group 1 pulmonary arterial hypertension (PAH) as add-on therapy to improve exercise ability. It was primarily studied in adults with New York Heart Association class III symptoms, and has not been previously studied in children with PAH, said Dr. Erika B. Rosenzweig, director of the pulmonary hypertension center at Columbia University Medical Center in New York.

This study included 6 girls and 12 boys with PAH who were seen at either the Columbia center or the Children’s Hospital in Aurora, Colo., between September 2009 and January 2011. They had a mean age of 11 years, a mean weight of 42 kg, and a mean body mass index of 19.4 kg/m². A total of 11 patients had idiopathic PAH and 7 had associated PAH, including 5 with congenital heart defects. All were on background therapy at the time of iTRE initiation, with the majority (11) on combined endothelin receptor antagonist and phosphodiesterase-5 inhibitor therapy. Prostanoid therapy had been given previously to 10 patients.

All patients received three to nine breaths, with 6 mcg per breath of iTRE, four times daily. The mean treatment duration was 11.5 months (range, 2-20 months). Nine patients received nine breaths four times a day, whereas five patients did not reach that maximal dose because of side effects or per physician discretion. Four patients discontinued iTRE, including three because of bronchospasm, and one because of noncompliance with all medications (who died 3 months later). Side effects requiring down-titration included cough in one patient and nausea/emesis in two. Milder side effects that did not require a dose change occurred in two to six patients each, including cough, sore throat, dyspnea, wheezing, flushing, headache, and diarrhea. No child discontinued because of inability to self-administer the medication, Dr. Rosenzweig noted at an international conference of the American Thoracic Society.

At baseline, two patients were in World Health Organization functional class I, seven were class II, eight in class III, and one in class IV. At follow-up, there were 7 in class I, 10 in class II, 1 in class III, and none in class IV. In all, functional class improvements were seen in 11 of the 18 children.

Of the seven children who were able to complete the 6-minute walk test, the mean improvement was from 446 to 472 meters, which was statistically significant. Of four who completed cardiopulmonary exercise testing, the mean workload improved from 59 to 74 watts and mean peak oxygen consumption from 20 to 22 mL/kg per minute. Neither of those findings was statistically significant. However, in 10 of the patients with measurements of brain natriuretic peptide (which reflects right ventricular dysfunction), levels dropped significantly, from a mean of 88 to 66 pg/mL.

"The authors recognize the limitations of the small sample size, but based on these early data in children, we believe that further study of iTRE appears warranted in larger cohorts of pediatric patients," she concluded.

Dr. Rosenzweig disclosed that she has received research support from and has served as a consultant for United Therapeutics, the manufacturer of Tyvaso.

DENVER – Inhaled treprostinil was well tolerated and was associated with improvements in exercise capacity and functional class when added to background therapy in a retrospective study of 18 children with pulmonary arterial hypertension.

Inhaled treprostinil (iTRE; brand name, Tyvaso) was approved in 2009 for the treatment of patients with group 1 pulmonary arterial hypertension (PAH) as add-on therapy to improve exercise ability. It was primarily studied in adults with New York Heart Association class III symptoms, and has not been previously studied in children with PAH, said Dr. Erika B. Rosenzweig, director of the pulmonary hypertension center at Columbia University Medical Center in New York.

This study included 6 girls and 12 boys with PAH who were seen at either the Columbia center or the Children’s Hospital in Aurora, Colo., between September 2009 and January 2011. They had a mean age of 11 years, a mean weight of 42 kg, and a mean body mass index of 19.4 kg/m². A total of 11 patients had idiopathic PAH and 7 had associated PAH, including 5 with congenital heart defects. All were on background therapy at the time of iTRE initiation, with the majority (11) on combined endothelin receptor antagonist and phosphodiesterase-5 inhibitor therapy. Prostanoid therapy had been given previously to 10 patients.

All patients received three to nine breaths, with 6 mcg per breath of iTRE, four times daily. The mean treatment duration was 11.5 months (range, 2-20 months). Nine patients received nine breaths four times a day, whereas five patients did not reach that maximal dose because of side effects or per physician discretion. Four patients discontinued iTRE, including three because of bronchospasm, and one because of noncompliance with all medications (who died 3 months later). Side effects requiring down-titration included cough in one patient and nausea/emesis in two. Milder side effects that did not require a dose change occurred in two to six patients each, including cough, sore throat, dyspnea, wheezing, flushing, headache, and diarrhea. No child discontinued because of inability to self-administer the medication, Dr. Rosenzweig noted at an international conference of the American Thoracic Society.

At baseline, two patients were in World Health Organization functional class I, seven were class II, eight in class III, and one in class IV. At follow-up, there were 7 in class I, 10 in class II, 1 in class III, and none in class IV. In all, functional class improvements were seen in 11 of the 18 children.

Of the seven children who were able to complete the 6-minute walk test, the mean improvement was from 446 to 472 meters, which was statistically significant. Of four who completed cardiopulmonary exercise testing, the mean workload improved from 59 to 74 watts and mean peak oxygen consumption from 20 to 22 mL/kg per minute. Neither of those findings was statistically significant. However, in 10 of the patients with measurements of brain natriuretic peptide (which reflects right ventricular dysfunction), levels dropped significantly, from a mean of 88 to 66 pg/mL.

"The authors recognize the limitations of the small sample size, but based on these early data in children, we believe that further study of iTRE appears warranted in larger cohorts of pediatric patients," she concluded.

Dr. Rosenzweig disclosed that she has received research support from and has served as a consultant for United Therapeutics, the manufacturer of Tyvaso.

DENVER – Inhaled treprostinil was well tolerated and was associated with improvements in exercise capacity and functional class when added to background therapy in a retrospective study of 18 children with pulmonary arterial hypertension.

Inhaled treprostinil (iTRE; brand name, Tyvaso) was approved in 2009 for the treatment of patients with group 1 pulmonary arterial hypertension (PAH) as add-on therapy to improve exercise ability. It was primarily studied in adults with New York Heart Association class III symptoms, and has not been previously studied in children with PAH, said Dr. Erika B. Rosenzweig, director of the pulmonary hypertension center at Columbia University Medical Center in New York.

This study included 6 girls and 12 boys with PAH who were seen at either the Columbia center or the Children’s Hospital in Aurora, Colo., between September 2009 and January 2011. They had a mean age of 11 years, a mean weight of 42 kg, and a mean body mass index of 19.4 kg/m². A total of 11 patients had idiopathic PAH and 7 had associated PAH, including 5 with congenital heart defects. All were on background therapy at the time of iTRE initiation, with the majority (11) on combined endothelin receptor antagonist and phosphodiesterase-5 inhibitor therapy. Prostanoid therapy had been given previously to 10 patients.

All patients received three to nine breaths, with 6 mcg per breath of iTRE, four times daily. The mean treatment duration was 11.5 months (range, 2-20 months). Nine patients received nine breaths four times a day, whereas five patients did not reach that maximal dose because of side effects or per physician discretion. Four patients discontinued iTRE, including three because of bronchospasm, and one because of noncompliance with all medications (who died 3 months later). Side effects requiring down-titration included cough in one patient and nausea/emesis in two. Milder side effects that did not require a dose change occurred in two to six patients each, including cough, sore throat, dyspnea, wheezing, flushing, headache, and diarrhea. No child discontinued because of inability to self-administer the medication, Dr. Rosenzweig noted at an international conference of the American Thoracic Society.

At baseline, two patients were in World Health Organization functional class I, seven were class II, eight in class III, and one in class IV. At follow-up, there were 7 in class I, 10 in class II, 1 in class III, and none in class IV. In all, functional class improvements were seen in 11 of the 18 children.

Of the seven children who were able to complete the 6-minute walk test, the mean improvement was from 446 to 472 meters, which was statistically significant. Of four who completed cardiopulmonary exercise testing, the mean workload improved from 59 to 74 watts and mean peak oxygen consumption from 20 to 22 mL/kg per minute. Neither of those findings was statistically significant. However, in 10 of the patients with measurements of brain natriuretic peptide (which reflects right ventricular dysfunction), levels dropped significantly, from a mean of 88 to 66 pg/mL.

"The authors recognize the limitations of the small sample size, but based on these early data in children, we believe that further study of iTRE appears warranted in larger cohorts of pediatric patients," she concluded.

Dr. Rosenzweig disclosed that she has received research support from and has served as a consultant for United Therapeutics, the manufacturer of Tyvaso.

DENVER – Inhaled treprostinil was well tolerated and was associated with improvements in exercise capacity and functional class when added to background therapy in a retrospective study of 18 children with pulmonary arterial hypertension.

Inhaled treprostinil (iTRE; brand name, Tyvaso) was approved in 2009 for the treatment of patients with group 1 pulmonary arterial hypertension (PAH) as add-on therapy to improve exercise ability. It was primarily studied in adults with New York Heart Association class III symptoms, and has not been previously studied in children with PAH, said Dr. Erika B. Rosenzweig, director of the pulmonary hypertension center at Columbia University Medical Center in New York.

This study included 6 girls and 12 boys with PAH who were seen at either the Columbia center or the Children’s Hospital in Aurora, Colo., between September 2009 and January 2011. They had a mean age of 11 years, a mean weight of 42 kg, and a mean body mass index of 19.4 kg/m². A total of 11 patients had idiopathic PAH and 7 had associated PAH, including 5 with congenital heart defects. All were on background therapy at the time of iTRE initiation, with the majority (11) on combined endothelin receptor antagonist and phosphodiesterase-5 inhibitor therapy. Prostanoid therapy had been given previously to 10 patients.

All patients received three to nine breaths, with 6 mcg per breath of iTRE, four times daily. The mean treatment duration was 11.5 months (range, 2-20 months). Nine patients received nine breaths four times a day, whereas five patients did not reach that maximal dose because of side effects or per physician discretion. Four patients discontinued iTRE, including three because of bronchospasm, and one because of noncompliance with all medications (who died 3 months later). Side effects requiring down-titration included cough in one patient and nausea/emesis in two. Milder side effects that did not require a dose change occurred in two to six patients each, including cough, sore throat, dyspnea, wheezing, flushing, headache, and diarrhea. No child discontinued because of inability to self-administer the medication, Dr. Rosenzweig noted at an international conference of the American Thoracic Society.

At baseline, two patients were in World Health Organization functional class I, seven were class II, eight in class III, and one in class IV. At follow-up, there were 7 in class I, 10 in class II, 1 in class III, and none in class IV. In all, functional class improvements were seen in 11 of the 18 children.

Of the seven children who were able to complete the 6-minute walk test, the mean improvement was from 446 to 472 meters, which was statistically significant. Of four who completed cardiopulmonary exercise testing, the mean workload improved from 59 to 74 watts and mean peak oxygen consumption from 20 to 22 mL/kg per minute. Neither of those findings was statistically significant. However, in 10 of the patients with measurements of brain natriuretic peptide (which reflects right ventricular dysfunction), levels dropped significantly, from a mean of 88 to 66 pg/mL.

"The authors recognize the limitations of the small sample size, but based on these early data in children, we believe that further study of iTRE appears warranted in larger cohorts of pediatric patients," she concluded.

Dr. Rosenzweig disclosed that she has received research support from and has served as a consultant for United Therapeutics, the manufacturer of Tyvaso.

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.

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.

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.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – The addition of daily azithromycin to standard treatment reduced the frequency of chronic obstructive pulmonary disease exacerbations and improved quality of life at 1 year in a large, prospective, randomized, placebo-controlled clinical trial involving more than 1,100 high-risk COPD patients.

Use of the macrolide antibiotic was associated with a significantly greater incidence of hearing decrement, although the overall rate was low and tended to reverse when the drug was stopped, Dr. Richard K. Albert reported at an international conference of the American Thoracic Society.

Macrolide antibiotics have antimicrobial and immunomodulary effects, and chronic administration has been associated with improvements in other inflammatory lung conditions, such as cystic fibrosis. However, previous studies that examined the use of macrolides in COPD have produced conflicting results, with five showing improvements and two failing to demonstrate a benefit. These studies have all been small – the largest included only 109 patients – and all had study-design problems, according Dr. Albert, professor of medicine at the University of Colorado at Denver, and chief of medicine at Denver Health.

Dr. Albert and his colleagues enrolled 1,142 patients with moderate to severe COPD who were at increased risk for acute exacerbations based on having received supplemental oxygen within the previous year, a history of receiving systemic corticosteroids, and/or a history of hospitalization or an emergency department visit for a COPD exacerbation within the past year. Patients with asthma, bronchiectasis, hepatic or renal insufficiency, resting tachycardia, prolonged QTc intervals, or predefined audiometric abnormalities were excluded. The high-risk patient population enrolled in the study represents about a third of all patients with COPD, Dr. Albert noted.

The patients were randomized to receive azithromycin (250 mg/day) or placebo along with usual treatment for 1 year. At baseline, they had a mean age of 65 years, 41% were women, and 82% were white. They had postbudesonide FEV₁ (forced expiratory volume in 1 second) of 1.1 mL, FEV₁ about 40% of predicted, and an FEV₁/FVC (forced vital capacity) ratio of 42%. All had a history of smoking, with an average of about 55 pack-years, and about one-fifth were current smokers. The majority (85%) had received systemic corticosteroids for an acute exacerbation of COPD (AECOPD) in the past year, three-quarters were taking long-acting beta-agonists (LABAs) and/or inhaled corticosteroids, and about two-thirds were on long-acting muscarinic antagonists (LAMAs).

In all, 1,117 patients (558 azithromycin and 559 placebo) were included in the intent-to-treat analysis, and 996 (494 azithromycin and 502 placebo) were actually evaluated at 1 year. The primary end point (the median time to first AECOPD) was 266 days for the azithromycin group, compared with 174 days for those taking placebo, a statistically significant difference (hazard ratio, 0.73). A secondary end point (rate of AECOPD) was 1.48 per patient-year for azithromycin vs. 1.83 per patient-year for placebo, again highly statistically significant, Dr. Albert said.

Improvements seen with azithromycin over placebo were significant, despite the fact that the majority of patients was taking inhaled corticosteroids, LAMAs, and/or LABAs, he noted.

There were trends for reductions in all-cause and COPD-related hospitalizations, as well as emergency department and urgent care visits with azithromycin, but these were not statistically significant. There was a slightly significant difference in frequency of unscheduled office visits favoring the azithromycin group. A reduction in intubation was also seen with azithromycin, but the numbers weren’t large enough to reach significance.

On the St. George’s Respiratory Questionnaire, a standardized self-completed questionnaire for measuring impaired health and perceived well-being in patients with airway diseases (Respir. Med. 1991;85[suppl. B]:25-31; discussion 33-7), the azithromycin group had a drop in its score by 2.8 units at 1 year, compared with just 0.6 units for placebo, also highly statistically significant.

The frequency of serious, nonfatal adverse events including pneumonia, neoplasm, gastrointestinal tract problems, QT prolongation, or other cardiovascular problems did not differ significantly between the two groups. Fatal serious adverse events also did not differ, although there were slightly more neoplasms in the placebo group. Adverse events leading to drug discontinuation did not differ, he said.

However, the measured hearing decrement was significantly more common in the azithromycin group, occurring in 142 (25%) vs. 110 (20%) of the placebo group. The mean change in hearing in decibels was small (0.7 dB), compared with no change in the placebo group at 3 months, with no significant difference seen at 12 months.

Data suggested that the audiometry that was used to assess hearing may have overestimated the degree of hearing decrement. Of 80 azithromycin patients who had hearing decrements detected prior to the 12-month study evaluation, investigators stopped the drug in 61. Of those, hearing returned to normal in 21 patients. Of the 19 patients for whom the azithromycin wasn’t stopped, hearing returned to normal in 6 patients. Similarly, of 45 placebo patients with hearing decrements that was detected prior to 12 months, placebo was stopped in 37 and returned to normal in 14. Of eight patients who continued taking the placebo, hearing returned in two.

"While we believe there are differences in the frequency with which azithromycin causes hearing disorders, we think we have overestimated that frequency in both groups," Dr. Albert said.

At enrollment, 14% of the azithromycin and 15% of the placebo group were colonized with selected respiratory pathogens. Excluding those patients, 12% of the azithromycin group became colonized with respiratory flora during the study, compared with 28% of the placebo group at the 12-month assessment, a highly significant difference. Colonization with macrolide-resistant pathogens did not differ between the groups at baseline. However, during the study, 47 (81% of those who had culture obtained) in the azithromycin group had become colonized with resistant pathogens, compared with 108 (47% of those cultured) in the placebo group. No association was found between colonization and pneumonia, he said.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Albert stated that he had no relevant disclosures.

DENVER – At least 30% of asthmatic children do not get vaccinated against influenza, according to the results of a nationwide survey of parents.

Additionally, parents who choose not to have their children immunized against influenza are significantly less likely to perceive colds and flu as important triggers of their child’s asthma than are parents who do have their children vaccinated, suggesting an educational opportunity for health care providers. "Changing vaccination behavior will require educational messages that help shift parental concerns from the impact of the vaccine to the impact of influenza itself," Dr. Toby C. Lewis said at an international conference of the American Thoracic Society.

The survey was part of the C.S. Mott Children’s Hospital National Poll on Children’s Health (NPCH), a Web-based survey of national public opinion and perceptions regarding major health care issues for U.S. children. It is administered to approximately 2,000 households, with data weighted to reflect U.S. census demographic distribution. Among 1,621 parents who responded to the survey during Aug. 13-Sept. 7, 2010, 237 (15%) parents of children aged 2-17 years with diagnosed asthma were identified. The parents were 50% white, 24% black, 20% Hispanic, and 6% other, from a broad spectrum of economic backgrounds.

A total of 70% reported that their children had been vaccinated against seasonal or pandemic H1N1 influenza during the 2009-2010 winter season, and 65% indicated that they planned to have their child vaccinated against influenza in the upcoming (2010-2011) season. There were no significant differences between the asthmatic children who were and were not vaccinated in 2009-2010 with respect to household income, race/ethnicity, parental education, child’s age, child’s sex, or proportion with public insurance, reported Dr. Lewis, a pediatric pulmonologist at C.S. Mott Children’s Hospital, Ann Arbor, Mich.

However, parents who did not vaccinate their children against influenza were significantly less likely than those who did vaccinate to indicate that getting a viral infection was "a very important" trigger of their child’s asthma (47% vs. 72%). There were no significant differences in their views about other asthma triggers such as outdoor or indoor allergies, tobacco smoke, or exercise. On the flip side, nonvaccinating parents were significantly more likely to be concerned about vaccine side effects (60% vs. 30%) and about getting the flu from the vaccine (44% vs. 13%). The survey did not ask parents specifically what "side effects" they were concerned about, Dr. Lewis noted.

Also significantly different was who influenced their decision to vaccinate, with the child’s health care provider indicated by 84% of vaccinating parents, compared with just 22% of nonvaccinating parents. "Child’s school" was endorsed by 45% vs. 11%, respectively.

Dr. Lewis sees that 22% as a somewhat positive sign, suggesting that even some parents who are hesitant to vaccinate still trust their child’s health care provider. "If we can help parents understand the risks of influenza better, we may be able to help drive behavior. I think it’s also important to tailor educational messages to the parents’ specific concern," she said in an interview.

She advised physicians not to berate parents who have expressed hesitancy about vaccination, but rather to try to create an alliance and communicate the health message about the benefits of vaccination. And, she added, even if the parent doesn’t seem receptive at first, "Don’t give up!"

The NPCH is funded by the University of Michigan’s department of pediatrics and communicable diseases. Dr. Lewis said she has previously received funding from the National Institutes of Health for unrelated research.

DENVER – At least 30% of asthmatic children do not get vaccinated against influenza, according to the results of a nationwide survey of parents.

Additionally, parents who choose not to have their children immunized against influenza are significantly less likely to perceive colds and flu as important triggers of their child’s asthma than are parents who do have their children vaccinated, suggesting an educational opportunity for health care providers. "Changing vaccination behavior will require educational messages that help shift parental concerns from the impact of the vaccine to the impact of influenza itself," Dr. Toby C. Lewis said at an international conference of the American Thoracic Society.

The survey was part of the C.S. Mott Children’s Hospital National Poll on Children’s Health (NPCH), a Web-based survey of national public opinion and perceptions regarding major health care issues for U.S. children. It is administered to approximately 2,000 households, with data weighted to reflect U.S. census demographic distribution. Among 1,621 parents who responded to the survey during Aug. 13-Sept. 7, 2010, 237 (15%) parents of children aged 2-17 years with diagnosed asthma were identified. The parents were 50% white, 24% black, 20% Hispanic, and 6% other, from a broad spectrum of economic backgrounds.

A total of 70% reported that their children had been vaccinated against seasonal or pandemic H1N1 influenza during the 2009-2010 winter season, and 65% indicated that they planned to have their child vaccinated against influenza in the upcoming (2010-2011) season. There were no significant differences between the asthmatic children who were and were not vaccinated in 2009-2010 with respect to household income, race/ethnicity, parental education, child’s age, child’s sex, or proportion with public insurance, reported Dr. Lewis, a pediatric pulmonologist at C.S. Mott Children’s Hospital, Ann Arbor, Mich.

However, parents who did not vaccinate their children against influenza were significantly less likely than those who did vaccinate to indicate that getting a viral infection was "a very important" trigger of their child’s asthma (47% vs. 72%). There were no significant differences in their views about other asthma triggers such as outdoor or indoor allergies, tobacco smoke, or exercise. On the flip side, nonvaccinating parents were significantly more likely to be concerned about vaccine side effects (60% vs. 30%) and about getting the flu from the vaccine (44% vs. 13%). The survey did not ask parents specifically what "side effects" they were concerned about, Dr. Lewis noted.

Also significantly different was who influenced their decision to vaccinate, with the child’s health care provider indicated by 84% of vaccinating parents, compared with just 22% of nonvaccinating parents. "Child’s school" was endorsed by 45% vs. 11%, respectively.

Dr. Lewis sees that 22% as a somewhat positive sign, suggesting that even some parents who are hesitant to vaccinate still trust their child’s health care provider. "If we can help parents understand the risks of influenza better, we may be able to help drive behavior. I think it’s also important to tailor educational messages to the parents’ specific concern," she said in an interview.

She advised physicians not to berate parents who have expressed hesitancy about vaccination, but rather to try to create an alliance and communicate the health message about the benefits of vaccination. And, she added, even if the parent doesn’t seem receptive at first, "Don’t give up!"

The NPCH is funded by the University of Michigan’s department of pediatrics and communicable diseases. Dr. Lewis said she has previously received funding from the National Institutes of Health for unrelated research.

DENVER – At least 30% of asthmatic children do not get vaccinated against influenza, according to the results of a nationwide survey of parents.

Additionally, parents who choose not to have their children immunized against influenza are significantly less likely to perceive colds and flu as important triggers of their child’s asthma than are parents who do have their children vaccinated, suggesting an educational opportunity for health care providers. "Changing vaccination behavior will require educational messages that help shift parental concerns from the impact of the vaccine to the impact of influenza itself," Dr. Toby C. Lewis said at an international conference of the American Thoracic Society.

The survey was part of the C.S. Mott Children’s Hospital National Poll on Children’s Health (NPCH), a Web-based survey of national public opinion and perceptions regarding major health care issues for U.S. children. It is administered to approximately 2,000 households, with data weighted to reflect U.S. census demographic distribution. Among 1,621 parents who responded to the survey during Aug. 13-Sept. 7, 2010, 237 (15%) parents of children aged 2-17 years with diagnosed asthma were identified. The parents were 50% white, 24% black, 20% Hispanic, and 6% other, from a broad spectrum of economic backgrounds.

A total of 70% reported that their children had been vaccinated against seasonal or pandemic H1N1 influenza during the 2009-2010 winter season, and 65% indicated that they planned to have their child vaccinated against influenza in the upcoming (2010-2011) season. There were no significant differences between the asthmatic children who were and were not vaccinated in 2009-2010 with respect to household income, race/ethnicity, parental education, child’s age, child’s sex, or proportion with public insurance, reported Dr. Lewis, a pediatric pulmonologist at C.S. Mott Children’s Hospital, Ann Arbor, Mich.

However, parents who did not vaccinate their children against influenza were significantly less likely than those who did vaccinate to indicate that getting a viral infection was "a very important" trigger of their child’s asthma (47% vs. 72%). There were no significant differences in their views about other asthma triggers such as outdoor or indoor allergies, tobacco smoke, or exercise. On the flip side, nonvaccinating parents were significantly more likely to be concerned about vaccine side effects (60% vs. 30%) and about getting the flu from the vaccine (44% vs. 13%). The survey did not ask parents specifically what "side effects" they were concerned about, Dr. Lewis noted.

Also significantly different was who influenced their decision to vaccinate, with the child’s health care provider indicated by 84% of vaccinating parents, compared with just 22% of nonvaccinating parents. "Child’s school" was endorsed by 45% vs. 11%, respectively.

Dr. Lewis sees that 22% as a somewhat positive sign, suggesting that even some parents who are hesitant to vaccinate still trust their child’s health care provider. "If we can help parents understand the risks of influenza better, we may be able to help drive behavior. I think it’s also important to tailor educational messages to the parents’ specific concern," she said in an interview.

She advised physicians not to berate parents who have expressed hesitancy about vaccination, but rather to try to create an alliance and communicate the health message about the benefits of vaccination. And, she added, even if the parent doesn’t seem receptive at first, "Don’t give up!"

The NPCH is funded by the University of Michigan’s department of pediatrics and communicable diseases. Dr. Lewis said she has previously received funding from the National Institutes of Health for unrelated research.