Pulmonary Health Hub

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.

Enacting comprehensive state laws that ban smoking in workplaces and restaurants as well as raising the cigarette tax by $1 per pack across the country could bring in billions in revenue for cash-strapped states, while also saving nearly 2 million lives, according to new estimates from the American Cancer Society Cancer Action Network.

The ACS CAN released two reports on June 15 that examined the public health benefits and economic savings from strengthening state antitobacco policies. In one report, researchers from the University of Illinois at Chicago looked at what would happen if the 27 states without comprehensive smoke-free laws were to enact such laws. In the second report, the same researchers considered the impact if all 50 states and the District of Columbia were to adopt a $1 per pack increase in the cigarette excise tax.

Photo credit: ©bilderbox/fotolia.com

"The bottom line is that strong tobacco control policies are a win-win for state legislators, for the states themselves, and [for] their constituents," said John R. Seffrin, Ph.D., chief executive officer of ACS CAN.

Currently, 23 states and the District of Columbia have enacted comprehensive laws that ban smoking in all bars, restaurants, and workplaces. The remaining 27 states have either less-comprehensive laws or no laws at all in this area. But when the researchers considered the impact if these 27 states were to adopt comprehensive smoking bans, they found that more than 1 million adults would quit smoking, nearly 400,000 children would never start smoking, and smoking-related deaths would fall by 624,000.

On the economic side, those 27 states would see a savings of about $316 million from lung cancer treatment, $875 million from heart attack and stroke treatment, and $128 million from smoking-related pregnancy treatment. And the researchers estimated that Medicaid programs in those 27 states would save a collective $42 million.

The report on tobacco taxes found similar public health and financial gains if a $1 per pack tax increase were enacted around the country. Such a tax would result in 1.4 million adults quitting smoking, 1.69 million children never starting to smoke, and 1.32 million fewer people dying from smoking-related causes. States also could benefit from both decreases in Medicaid spending and increased revenue. The report estimated that the tax would cut Medicaid spending by about $146 million across the states, and would bring in $8.62 billion in new state revenue.

Dr. Seffrin said that the results are attainable. An increasing number of states are adopting smoke-free laws and nearly all the states have increased cigarette excise taxes in recent years.

But he noted the ACS CAN is concerned that the tobacco industry is working to erode current tobacco-control laws at the state level. For example, there have been efforts in several states to add exemptions to the smoke-free laws.

Enacting comprehensive state laws that ban smoking in workplaces and restaurants as well as raising the cigarette tax by $1 per pack across the country could bring in billions in revenue for cash-strapped states, while also saving nearly 2 million lives, according to new estimates from the American Cancer Society Cancer Action Network.

The ACS CAN released two reports on June 15 that examined the public health benefits and economic savings from strengthening state antitobacco policies. In one report, researchers from the University of Illinois at Chicago looked at what would happen if the 27 states without comprehensive smoke-free laws were to enact such laws. In the second report, the same researchers considered the impact if all 50 states and the District of Columbia were to adopt a $1 per pack increase in the cigarette excise tax.

Photo credit: ©bilderbox/fotolia.com

"The bottom line is that strong tobacco control policies are a win-win for state legislators, for the states themselves, and [for] their constituents," said John R. Seffrin, Ph.D., chief executive officer of ACS CAN.

Currently, 23 states and the District of Columbia have enacted comprehensive laws that ban smoking in all bars, restaurants, and workplaces. The remaining 27 states have either less-comprehensive laws or no laws at all in this area. But when the researchers considered the impact if these 27 states were to adopt comprehensive smoking bans, they found that more than 1 million adults would quit smoking, nearly 400,000 children would never start smoking, and smoking-related deaths would fall by 624,000.

On the economic side, those 27 states would see a savings of about $316 million from lung cancer treatment, $875 million from heart attack and stroke treatment, and $128 million from smoking-related pregnancy treatment. And the researchers estimated that Medicaid programs in those 27 states would save a collective $42 million.

The report on tobacco taxes found similar public health and financial gains if a $1 per pack tax increase were enacted around the country. Such a tax would result in 1.4 million adults quitting smoking, 1.69 million children never starting to smoke, and 1.32 million fewer people dying from smoking-related causes. States also could benefit from both decreases in Medicaid spending and increased revenue. The report estimated that the tax would cut Medicaid spending by about $146 million across the states, and would bring in $8.62 billion in new state revenue.

Dr. Seffrin said that the results are attainable. An increasing number of states are adopting smoke-free laws and nearly all the states have increased cigarette excise taxes in recent years.

But he noted the ACS CAN is concerned that the tobacco industry is working to erode current tobacco-control laws at the state level. For example, there have been efforts in several states to add exemptions to the smoke-free laws.

Enacting comprehensive state laws that ban smoking in workplaces and restaurants as well as raising the cigarette tax by $1 per pack across the country could bring in billions in revenue for cash-strapped states, while also saving nearly 2 million lives, according to new estimates from the American Cancer Society Cancer Action Network.

The ACS CAN released two reports on June 15 that examined the public health benefits and economic savings from strengthening state antitobacco policies. In one report, researchers from the University of Illinois at Chicago looked at what would happen if the 27 states without comprehensive smoke-free laws were to enact such laws. In the second report, the same researchers considered the impact if all 50 states and the District of Columbia were to adopt a $1 per pack increase in the cigarette excise tax.

Photo credit: ©bilderbox/fotolia.com

"The bottom line is that strong tobacco control policies are a win-win for state legislators, for the states themselves, and [for] their constituents," said John R. Seffrin, Ph.D., chief executive officer of ACS CAN.

Currently, 23 states and the District of Columbia have enacted comprehensive laws that ban smoking in all bars, restaurants, and workplaces. The remaining 27 states have either less-comprehensive laws or no laws at all in this area. But when the researchers considered the impact if these 27 states were to adopt comprehensive smoking bans, they found that more than 1 million adults would quit smoking, nearly 400,000 children would never start smoking, and smoking-related deaths would fall by 624,000.

On the economic side, those 27 states would see a savings of about $316 million from lung cancer treatment, $875 million from heart attack and stroke treatment, and $128 million from smoking-related pregnancy treatment. And the researchers estimated that Medicaid programs in those 27 states would save a collective $42 million.

The report on tobacco taxes found similar public health and financial gains if a $1 per pack tax increase were enacted around the country. Such a tax would result in 1.4 million adults quitting smoking, 1.69 million children never starting to smoke, and 1.32 million fewer people dying from smoking-related causes. States also could benefit from both decreases in Medicaid spending and increased revenue. The report estimated that the tax would cut Medicaid spending by about $146 million across the states, and would bring in $8.62 billion in new state revenue.

Dr. Seffrin said that the results are attainable. An increasing number of states are adopting smoke-free laws and nearly all the states have increased cigarette excise taxes in recent years.

But he noted the ACS CAN is concerned that the tobacco industry is working to erode current tobacco-control laws at the state level. For example, there have been efforts in several states to add exemptions to the smoke-free laws.

Enacting comprehensive state laws that ban smoking in workplaces and restaurants as well as raising the cigarette tax by $1 per pack across the country could bring in billions in revenue for cash-strapped states, while also saving nearly 2 million lives, according to new estimates from the American Cancer Society Cancer Action Network.

The ACS CAN released two reports on June 15 that examined the public health benefits and economic savings from strengthening state antitobacco policies. In one report, researchers from the University of Illinois at Chicago looked at what would happen if the 27 states without comprehensive smoke-free laws were to enact such laws. In the second report, the same researchers considered the impact if all 50 states and the District of Columbia were to adopt a $1 per pack increase in the cigarette excise tax.

Photo credit: ©bilderbox/fotolia.com

"The bottom line is that strong tobacco control policies are a win-win for state legislators, for the states themselves, and [for] their constituents," said John R. Seffrin, Ph.D., chief executive officer of ACS CAN.

Currently, 23 states and the District of Columbia have enacted comprehensive laws that ban smoking in all bars, restaurants, and workplaces. The remaining 27 states have either less-comprehensive laws or no laws at all in this area. But when the researchers considered the impact if these 27 states were to adopt comprehensive smoking bans, they found that more than 1 million adults would quit smoking, nearly 400,000 children would never start smoking, and smoking-related deaths would fall by 624,000.

On the economic side, those 27 states would see a savings of about $316 million from lung cancer treatment, $875 million from heart attack and stroke treatment, and $128 million from smoking-related pregnancy treatment. And the researchers estimated that Medicaid programs in those 27 states would save a collective $42 million.

The report on tobacco taxes found similar public health and financial gains if a $1 per pack tax increase were enacted around the country. Such a tax would result in 1.4 million adults quitting smoking, 1.69 million children never starting to smoke, and 1.32 million fewer people dying from smoking-related causes. States also could benefit from both decreases in Medicaid spending and increased revenue. The report estimated that the tax would cut Medicaid spending by about $146 million across the states, and would bring in $8.62 billion in new state revenue.

Dr. Seffrin said that the results are attainable. An increasing number of states are adopting smoke-free laws and nearly all the states have increased cigarette excise taxes in recent years.

But he noted the ACS CAN is concerned that the tobacco industry is working to erode current tobacco-control laws at the state level. For example, there have been efforts in several states to add exemptions to the smoke-free laws.

Enacting comprehensive state laws that ban smoking in workplaces and restaurants as well as raising the cigarette tax by $1 per pack across the country could bring in billions in revenue for cash-strapped states, while also saving nearly 2 million lives, according to new estimates from the American Cancer Society Cancer Action Network.

The ACS CAN released two reports on June 15 that examined the public health benefits and economic savings from strengthening state antitobacco policies. In one report, researchers from the University of Illinois at Chicago looked at what would happen if the 27 states without comprehensive smoke-free laws were to enact such laws. In the second report, the same researchers considered the impact if all 50 states and the District of Columbia were to adopt a $1 per pack increase in the cigarette excise tax.

Photo credit: ©bilderbox/fotolia.com

"The bottom line is that strong tobacco control policies are a win-win for state legislators, for the states themselves, and [for] their constituents," said John R. Seffrin, Ph.D., chief executive officer of ACS CAN.

Currently, 23 states and the District of Columbia have enacted comprehensive laws that ban smoking in all bars, restaurants, and workplaces. The remaining 27 states have either less-comprehensive laws or no laws at all in this area. But when the researchers considered the impact if these 27 states were to adopt comprehensive smoking bans, they found that more than 1 million adults would quit smoking, nearly 400,000 children would never start smoking, and smoking-related deaths would fall by 624,000.

On the economic side, those 27 states would see a savings of about $316 million from lung cancer treatment, $875 million from heart attack and stroke treatment, and $128 million from smoking-related pregnancy treatment. And the researchers estimated that Medicaid programs in those 27 states would save a collective $42 million.

The report on tobacco taxes found similar public health and financial gains if a $1 per pack tax increase were enacted around the country. Such a tax would result in 1.4 million adults quitting smoking, 1.69 million children never starting to smoke, and 1.32 million fewer people dying from smoking-related causes. States also could benefit from both decreases in Medicaid spending and increased revenue. The report estimated that the tax would cut Medicaid spending by about $146 million across the states, and would bring in $8.62 billion in new state revenue.

Dr. Seffrin said that the results are attainable. An increasing number of states are adopting smoke-free laws and nearly all the states have increased cigarette excise taxes in recent years.

But he noted the ACS CAN is concerned that the tobacco industry is working to erode current tobacco-control laws at the state level. For example, there have been efforts in several states to add exemptions to the smoke-free laws.

Enacting comprehensive state laws that ban smoking in workplaces and restaurants as well as raising the cigarette tax by $1 per pack across the country could bring in billions in revenue for cash-strapped states, while also saving nearly 2 million lives, according to new estimates from the American Cancer Society Cancer Action Network.

The ACS CAN released two reports on June 15 that examined the public health benefits and economic savings from strengthening state antitobacco policies. In one report, researchers from the University of Illinois at Chicago looked at what would happen if the 27 states without comprehensive smoke-free laws were to enact such laws. In the second report, the same researchers considered the impact if all 50 states and the District of Columbia were to adopt a $1 per pack increase in the cigarette excise tax.

Photo credit: ©bilderbox/fotolia.com

"The bottom line is that strong tobacco control policies are a win-win for state legislators, for the states themselves, and [for] their constituents," said John R. Seffrin, Ph.D., chief executive officer of ACS CAN.

Currently, 23 states and the District of Columbia have enacted comprehensive laws that ban smoking in all bars, restaurants, and workplaces. The remaining 27 states have either less-comprehensive laws or no laws at all in this area. But when the researchers considered the impact if these 27 states were to adopt comprehensive smoking bans, they found that more than 1 million adults would quit smoking, nearly 400,000 children would never start smoking, and smoking-related deaths would fall by 624,000.

On the economic side, those 27 states would see a savings of about $316 million from lung cancer treatment, $875 million from heart attack and stroke treatment, and $128 million from smoking-related pregnancy treatment. And the researchers estimated that Medicaid programs in those 27 states would save a collective $42 million.

The report on tobacco taxes found similar public health and financial gains if a $1 per pack tax increase were enacted around the country. Such a tax would result in 1.4 million adults quitting smoking, 1.69 million children never starting to smoke, and 1.32 million fewer people dying from smoking-related causes. States also could benefit from both decreases in Medicaid spending and increased revenue. The report estimated that the tax would cut Medicaid spending by about $146 million across the states, and would bring in $8.62 billion in new state revenue.

Dr. Seffrin said that the results are attainable. An increasing number of states are adopting smoke-free laws and nearly all the states have increased cigarette excise taxes in recent years.

But he noted the ACS CAN is concerned that the tobacco industry is working to erode current tobacco-control laws at the state level. For example, there have been efforts in several states to add exemptions to the smoke-free laws.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

DENVER – When you prescribe a long-acting beta-agonist for a child with asthma, you may want to consider adding an inhaled corticosteroid as well, according to a meta-analysis conducted by Food and Drug Administration investigators.

"Overall, there was an increased risk of asthma-related hospitalizations, intubation, or death to asthmatics of all ages using long-acting beta-agonists [LABAs]," Dr. Ann W. McMahon said at the annual meeting of the Pediatric Academic Societies.

Dr. McMahon and her colleagues also found an age effect as well, with asthmatics aged 4-11 years at greater risk, compared with older patients. "Children are at increased risk, primarily of hospitalization, from asthma with LABA use compared to the overall population."

The elevated overall and age-related risks are no longer statistically significant, however, when patients are prescribed an inhaled corticosteroid (ICS) along with a LABA as part of a study protocol, Dr. McMahon said.

"Although further study is indicated, simultaneous use of inhaled corticosteroids and LABAs may mitigate this risk in children," said Dr. McMahon, deputy director of the division of pharmacovigilance, office of surveillance and epidemiology, FDA.

In a previous meta-analysis, LABA use was associated with a higher overall risk for adverse outcomes, a risk difference estimate of 2.80 for an asthma composite index of asthma-related hospitalizations, intubations, and deaths. In a 2008 meta-analysis that included 60,954 patients of all ages from 110 trials, Mark Levenson, Ph.D., one of Dr. McMahon’s FDA colleagues, found the highest risk associated with LABA therapy was among those aged 4-11 years, who had a risk difference estimate of 14.83/1,000 participants.

Dr. McMahon presented a secondary analysis of the 2008 meta-analysis in which she and her associates assessed a subset of patients assigned an ICS as part of their study regimen. Using a forest plot analysis, they compared 7,862 patients also treated with a LABA versus 7,330 who did not receive a LABA.

"What we see here is no overall risk for this subset of patients and no particular age trend either," Dr. McMahon said. The overall risk difference was 0.2/1,000 patients.

"I just want to caution that this is a smaller group of patients. So whether we can conclude this is definitive, I would say probably not," Dr. McMahon said. "But it is very intriguing that this subgroup that took assigned inhaled corticosteroids really did not have an age effect or an overall increased risk."

In contrast, when all users and nonusers of inhaled corticosteroids were combined, overall risk associated with LABA use was 6.3 additional adverse events per 1,000 patients.

Another analysis of the data looked at all patients who took some concomitant ICS therapy (those intentionally prescribed an ICS and those noted to be taking an ICS at baseline). This analysis "looks very similar, with a slight increased risk overall" of 6.1 events per 1,000 patients, Dr. McMahon said.

Age again made a difference, with a point estimate risk of 19.8/1,000 participants for those aged 4-11 years, a statistically significant higher risk compared with that of patients aged 12-17 years, 18-64 years, and 65 years and older.

"Children are at increased risk primarily of [asthma-related] hospitalization," Dr. McMahon said. Data on intubations and deaths were insufficient to calculate these outcomes among children, she added.

Dr. McMahon’s findings concur with those of other published studies. For example the Salmeterol Multicenter Asthma Research Trial (SMART) and the Serevent Nationwide Surveillance (SNS) study in the United Kingdom "both gave similar results to the extent that there was a three- to fourfold increase in risk of serious asthma outcomes such as asthma-related death and intubation" associated with LABA use (Chest 2006;129:15-26; BMJ 1993;306:1034-7). However, these trials did not include children younger than 12 years and did not include enough adolescents for investigators to be able to analyze those data separately, she added.

Three of the LABAs approved for asthma treatment in the United States are combined LABA/ICS inhalers: Advair (salmeterol, fluticasone); Dulera (formoterol, mometasone); and Symbicort (formoterol, budesonide). Other approved LABA products that do not contain an ICS are Brovana (arformoterol), Foradil (formoterol), and Serevent (salmeterol).

Dr. McMahon said she had no relevant financial disclosures.

DENVER – When you prescribe a long-acting beta-agonist for a child with asthma, you may want to consider adding an inhaled corticosteroid as well, according to a meta-analysis conducted by Food and Drug Administration investigators.

"Overall, there was an increased risk of asthma-related hospitalizations, intubation, or death to asthmatics of all ages using long-acting beta-agonists [LABAs]," Dr. Ann W. McMahon said at the annual meeting of the Pediatric Academic Societies.

Dr. McMahon and her colleagues also found an age effect as well, with asthmatics aged 4-11 years at greater risk, compared with older patients. "Children are at increased risk, primarily of hospitalization, from asthma with LABA use compared to the overall population."

The elevated overall and age-related risks are no longer statistically significant, however, when patients are prescribed an inhaled corticosteroid (ICS) along with a LABA as part of a study protocol, Dr. McMahon said.

"Although further study is indicated, simultaneous use of inhaled corticosteroids and LABAs may mitigate this risk in children," said Dr. McMahon, deputy director of the division of pharmacovigilance, office of surveillance and epidemiology, FDA.

In a previous meta-analysis, LABA use was associated with a higher overall risk for adverse outcomes, a risk difference estimate of 2.80 for an asthma composite index of asthma-related hospitalizations, intubations, and deaths. In a 2008 meta-analysis that included 60,954 patients of all ages from 110 trials, Mark Levenson, Ph.D., one of Dr. McMahon’s FDA colleagues, found the highest risk associated with LABA therapy was among those aged 4-11 years, who had a risk difference estimate of 14.83/1,000 participants.

Dr. McMahon presented a secondary analysis of the 2008 meta-analysis in which she and her associates assessed a subset of patients assigned an ICS as part of their study regimen. Using a forest plot analysis, they compared 7,862 patients also treated with a LABA versus 7,330 who did not receive a LABA.

"What we see here is no overall risk for this subset of patients and no particular age trend either," Dr. McMahon said. The overall risk difference was 0.2/1,000 patients.

"I just want to caution that this is a smaller group of patients. So whether we can conclude this is definitive, I would say probably not," Dr. McMahon said. "But it is very intriguing that this subgroup that took assigned inhaled corticosteroids really did not have an age effect or an overall increased risk."

In contrast, when all users and nonusers of inhaled corticosteroids were combined, overall risk associated with LABA use was 6.3 additional adverse events per 1,000 patients.

Another analysis of the data looked at all patients who took some concomitant ICS therapy (those intentionally prescribed an ICS and those noted to be taking an ICS at baseline). This analysis "looks very similar, with a slight increased risk overall" of 6.1 events per 1,000 patients, Dr. McMahon said.

Age again made a difference, with a point estimate risk of 19.8/1,000 participants for those aged 4-11 years, a statistically significant higher risk compared with that of patients aged 12-17 years, 18-64 years, and 65 years and older.

"Children are at increased risk primarily of [asthma-related] hospitalization," Dr. McMahon said. Data on intubations and deaths were insufficient to calculate these outcomes among children, she added.

Dr. McMahon’s findings concur with those of other published studies. For example the Salmeterol Multicenter Asthma Research Trial (SMART) and the Serevent Nationwide Surveillance (SNS) study in the United Kingdom "both gave similar results to the extent that there was a three- to fourfold increase in risk of serious asthma outcomes such as asthma-related death and intubation" associated with LABA use (Chest 2006;129:15-26; BMJ 1993;306:1034-7). However, these trials did not include children younger than 12 years and did not include enough adolescents for investigators to be able to analyze those data separately, she added.

Three of the LABAs approved for asthma treatment in the United States are combined LABA/ICS inhalers: Advair (salmeterol, fluticasone); Dulera (formoterol, mometasone); and Symbicort (formoterol, budesonide). Other approved LABA products that do not contain an ICS are Brovana (arformoterol), Foradil (formoterol), and Serevent (salmeterol).

Dr. McMahon said she had no relevant financial disclosures.

DENVER – When you prescribe a long-acting beta-agonist for a child with asthma, you may want to consider adding an inhaled corticosteroid as well, according to a meta-analysis conducted by Food and Drug Administration investigators.

"Overall, there was an increased risk of asthma-related hospitalizations, intubation, or death to asthmatics of all ages using long-acting beta-agonists [LABAs]," Dr. Ann W. McMahon said at the annual meeting of the Pediatric Academic Societies.

Dr. McMahon and her colleagues also found an age effect as well, with asthmatics aged 4-11 years at greater risk, compared with older patients. "Children are at increased risk, primarily of hospitalization, from asthma with LABA use compared to the overall population."

The elevated overall and age-related risks are no longer statistically significant, however, when patients are prescribed an inhaled corticosteroid (ICS) along with a LABA as part of a study protocol, Dr. McMahon said.

"Although further study is indicated, simultaneous use of inhaled corticosteroids and LABAs may mitigate this risk in children," said Dr. McMahon, deputy director of the division of pharmacovigilance, office of surveillance and epidemiology, FDA.

In a previous meta-analysis, LABA use was associated with a higher overall risk for adverse outcomes, a risk difference estimate of 2.80 for an asthma composite index of asthma-related hospitalizations, intubations, and deaths. In a 2008 meta-analysis that included 60,954 patients of all ages from 110 trials, Mark Levenson, Ph.D., one of Dr. McMahon’s FDA colleagues, found the highest risk associated with LABA therapy was among those aged 4-11 years, who had a risk difference estimate of 14.83/1,000 participants.

Dr. McMahon presented a secondary analysis of the 2008 meta-analysis in which she and her associates assessed a subset of patients assigned an ICS as part of their study regimen. Using a forest plot analysis, they compared 7,862 patients also treated with a LABA versus 7,330 who did not receive a LABA.

"What we see here is no overall risk for this subset of patients and no particular age trend either," Dr. McMahon said. The overall risk difference was 0.2/1,000 patients.

"I just want to caution that this is a smaller group of patients. So whether we can conclude this is definitive, I would say probably not," Dr. McMahon said. "But it is very intriguing that this subgroup that took assigned inhaled corticosteroids really did not have an age effect or an overall increased risk."

In contrast, when all users and nonusers of inhaled corticosteroids were combined, overall risk associated with LABA use was 6.3 additional adverse events per 1,000 patients.

Another analysis of the data looked at all patients who took some concomitant ICS therapy (those intentionally prescribed an ICS and those noted to be taking an ICS at baseline). This analysis "looks very similar, with a slight increased risk overall" of 6.1 events per 1,000 patients, Dr. McMahon said.

Age again made a difference, with a point estimate risk of 19.8/1,000 participants for those aged 4-11 years, a statistically significant higher risk compared with that of patients aged 12-17 years, 18-64 years, and 65 years and older.

"Children are at increased risk primarily of [asthma-related] hospitalization," Dr. McMahon said. Data on intubations and deaths were insufficient to calculate these outcomes among children, she added.

Dr. McMahon’s findings concur with those of other published studies. For example the Salmeterol Multicenter Asthma Research Trial (SMART) and the Serevent Nationwide Surveillance (SNS) study in the United Kingdom "both gave similar results to the extent that there was a three- to fourfold increase in risk of serious asthma outcomes such as asthma-related death and intubation" associated with LABA use (Chest 2006;129:15-26; BMJ 1993;306:1034-7). However, these trials did not include children younger than 12 years and did not include enough adolescents for investigators to be able to analyze those data separately, she added.

Three of the LABAs approved for asthma treatment in the United States are combined LABA/ICS inhalers: Advair (salmeterol, fluticasone); Dulera (formoterol, mometasone); and Symbicort (formoterol, budesonide). Other approved LABA products that do not contain an ICS are Brovana (arformoterol), Foradil (formoterol), and Serevent (salmeterol).

Dr. McMahon said she had no relevant financial disclosures.

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 ratio of controller to total asthma medication fills predicts the risk of exacerbations in pediatric patients with persistent asthma, results from a large study demonstrated.

"The occurrence of asthma exacerbations requiring medical attention is a key health outcome, and may be an indicator of the quality of asthma care," Dr. Louis Vernacchio reported at the annual meeting of the Pediatric Academic Societies. "Exacerbations that are cared for in the office setting may be more common than hospital admissions or ED visits, but there is currently no standard methodology for defining exacerbations cared for in the office setting. It would be nice to develop process measures that relate to asthma outcomes, particularly to exacerbations," he said.

Dr. Vernacchio, of the Pediatric Physicians’ Organization at Children’s (PPOC) and the general pediatrics division at Children’s Hospital Boston, and his associate, Jennifer M. Muto, set out to assess the accuracy of claims-based definitions of asthma exacerbations cared for in the office setting and to evaluate potential risk factors for asthma exacerbations that could serve as process measures for quality improvement. They analyzed medical claims from a large not-for-profit insurer for patients of the PPOC, a large independent practice association affiliated with Children’s Hospital Boston. The study population included 19,469 patients aged 5-17 years who were continuously enrolled in 2008 and 19,779 patients aged 5-17 years who were continuously enrolled in 2009. Of these, 530 (2.7%) met Healthcare Effectiveness Data and Information Set (HEDIS) criteria for persistent asthma in 2008 and 507 (2.6%) did so in 2009.

Proposed definitions of asthma exacerbations cared for in an office setting included office visits for asthma with oral steroid prescription filled the day of or the day after a visit (definition 1); office visits for asthma with oral steroid prescription filled the day of or the day after a visit or with nebulizer treatment given in the office (definition 2); office visits for asthma with oral steroid prescription filled the day of or the day after a visit or with oral steroid prescription filled the day of or the day after a visit or with nebulizer treatment given in the office, or coded as "with status asthmaticus" or "with acute exacerbation" (definition 3).

The researchers compared each of those three definitions to a chart review, which was considered the gold standard. Two clinicians independently reviewed 144 asthma visits and evaluated three elements in each chart: history of present illness, physical examination, and assessment. "If they found evidence of exacerbation in two of those three areas, we counted the visit as an exacerbation visit," Dr. Vernacchio said.

Receiver operating characteristic curve analysis revealed that definition 1 had a sensitivity of 24.7% and a specificity of 90.5%, definition 2 had a sensitivity of 56.8% and a specificity of 76.2%, and definition 3 had a sensitivity of 95.1% and a specificity of 68.3%. "The overall area under the curve is best with the third definition, but there’s a tradeoff in sensitivity and specificity," he said.

Logistic regression analysis of associations with exacerbations revealed that the ratio of controller to total asthma prescription fills was the process measure that correlated most closely to the risk of asthma exacerbations, with risk ratios near 2.0 for those in the third and fourth quartiles of controller to total asthma prescription fills ratio (corresponding to ratios of 0.5-0.8 and less than 0.5, respectively).

"This ratio can serve as the basis for quality improvement projects in pediatric asthma," Dr. Vernacchio said. He noted that the proposed 2012 HEDIS measure uses a cutoff value of 0.5, "which is well below what appears optimal in our data."

Dr. Vernacchio said that he had no relevant financial conflicts to disclose.

DENVER – The ratio of controller to total asthma medication fills predicts the risk of exacerbations in pediatric patients with persistent asthma, results from a large study demonstrated.

"The occurrence of asthma exacerbations requiring medical attention is a key health outcome, and may be an indicator of the quality of asthma care," Dr. Louis Vernacchio reported at the annual meeting of the Pediatric Academic Societies. "Exacerbations that are cared for in the office setting may be more common than hospital admissions or ED visits, but there is currently no standard methodology for defining exacerbations cared for in the office setting. It would be nice to develop process measures that relate to asthma outcomes, particularly to exacerbations," he said.

Dr. Vernacchio, of the Pediatric Physicians’ Organization at Children’s (PPOC) and the general pediatrics division at Children’s Hospital Boston, and his associate, Jennifer M. Muto, set out to assess the accuracy of claims-based definitions of asthma exacerbations cared for in the office setting and to evaluate potential risk factors for asthma exacerbations that could serve as process measures for quality improvement. They analyzed medical claims from a large not-for-profit insurer for patients of the PPOC, a large independent practice association affiliated with Children’s Hospital Boston. The study population included 19,469 patients aged 5-17 years who were continuously enrolled in 2008 and 19,779 patients aged 5-17 years who were continuously enrolled in 2009. Of these, 530 (2.7%) met Healthcare Effectiveness Data and Information Set (HEDIS) criteria for persistent asthma in 2008 and 507 (2.6%) did so in 2009.

Proposed definitions of asthma exacerbations cared for in an office setting included office visits for asthma with oral steroid prescription filled the day of or the day after a visit (definition 1); office visits for asthma with oral steroid prescription filled the day of or the day after a visit or with nebulizer treatment given in the office (definition 2); office visits for asthma with oral steroid prescription filled the day of or the day after a visit or with oral steroid prescription filled the day of or the day after a visit or with nebulizer treatment given in the office, or coded as "with status asthmaticus" or "with acute exacerbation" (definition 3).

The researchers compared each of those three definitions to a chart review, which was considered the gold standard. Two clinicians independently reviewed 144 asthma visits and evaluated three elements in each chart: history of present illness, physical examination, and assessment. "If they found evidence of exacerbation in two of those three areas, we counted the visit as an exacerbation visit," Dr. Vernacchio said.

Receiver operating characteristic curve analysis revealed that definition 1 had a sensitivity of 24.7% and a specificity of 90.5%, definition 2 had a sensitivity of 56.8% and a specificity of 76.2%, and definition 3 had a sensitivity of 95.1% and a specificity of 68.3%. "The overall area under the curve is best with the third definition, but there’s a tradeoff in sensitivity and specificity," he said.

Logistic regression analysis of associations with exacerbations revealed that the ratio of controller to total asthma prescription fills was the process measure that correlated most closely to the risk of asthma exacerbations, with risk ratios near 2.0 for those in the third and fourth quartiles of controller to total asthma prescription fills ratio (corresponding to ratios of 0.5-0.8 and less than 0.5, respectively).

"This ratio can serve as the basis for quality improvement projects in pediatric asthma," Dr. Vernacchio said. He noted that the proposed 2012 HEDIS measure uses a cutoff value of 0.5, "which is well below what appears optimal in our data."

Dr. Vernacchio said that he had no relevant financial conflicts to disclose.

DENVER – The ratio of controller to total asthma medication fills predicts the risk of exacerbations in pediatric patients with persistent asthma, results from a large study demonstrated.

"The occurrence of asthma exacerbations requiring medical attention is a key health outcome, and may be an indicator of the quality of asthma care," Dr. Louis Vernacchio reported at the annual meeting of the Pediatric Academic Societies. "Exacerbations that are cared for in the office setting may be more common than hospital admissions or ED visits, but there is currently no standard methodology for defining exacerbations cared for in the office setting. It would be nice to develop process measures that relate to asthma outcomes, particularly to exacerbations," he said.

Dr. Vernacchio, of the Pediatric Physicians’ Organization at Children’s (PPOC) and the general pediatrics division at Children’s Hospital Boston, and his associate, Jennifer M. Muto, set out to assess the accuracy of claims-based definitions of asthma exacerbations cared for in the office setting and to evaluate potential risk factors for asthma exacerbations that could serve as process measures for quality improvement. They analyzed medical claims from a large not-for-profit insurer for patients of the PPOC, a large independent practice association affiliated with Children’s Hospital Boston. The study population included 19,469 patients aged 5-17 years who were continuously enrolled in 2008 and 19,779 patients aged 5-17 years who were continuously enrolled in 2009. Of these, 530 (2.7%) met Healthcare Effectiveness Data and Information Set (HEDIS) criteria for persistent asthma in 2008 and 507 (2.6%) did so in 2009.

Proposed definitions of asthma exacerbations cared for in an office setting included office visits for asthma with oral steroid prescription filled the day of or the day after a visit (definition 1); office visits for asthma with oral steroid prescription filled the day of or the day after a visit or with nebulizer treatment given in the office (definition 2); office visits for asthma with oral steroid prescription filled the day of or the day after a visit or with oral steroid prescription filled the day of or the day after a visit or with nebulizer treatment given in the office, or coded as "with status asthmaticus" or "with acute exacerbation" (definition 3).

The researchers compared each of those three definitions to a chart review, which was considered the gold standard. Two clinicians independently reviewed 144 asthma visits and evaluated three elements in each chart: history of present illness, physical examination, and assessment. "If they found evidence of exacerbation in two of those three areas, we counted the visit as an exacerbation visit," Dr. Vernacchio said.

Receiver operating characteristic curve analysis revealed that definition 1 had a sensitivity of 24.7% and a specificity of 90.5%, definition 2 had a sensitivity of 56.8% and a specificity of 76.2%, and definition 3 had a sensitivity of 95.1% and a specificity of 68.3%. "The overall area under the curve is best with the third definition, but there’s a tradeoff in sensitivity and specificity," he said.

Logistic regression analysis of associations with exacerbations revealed that the ratio of controller to total asthma prescription fills was the process measure that correlated most closely to the risk of asthma exacerbations, with risk ratios near 2.0 for those in the third and fourth quartiles of controller to total asthma prescription fills ratio (corresponding to ratios of 0.5-0.8 and less than 0.5, respectively).

"This ratio can serve as the basis for quality improvement projects in pediatric asthma," Dr. Vernacchio said. He noted that the proposed 2012 HEDIS measure uses a cutoff value of 0.5, "which is well below what appears optimal in our data."

Dr. Vernacchio said that he had no relevant financial conflicts to disclose.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.