Pulmonary Health Hub

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

NEW YORK – Fish oil supplementation, in daily doses of 2 g or more, may mitigate weight loss, increase appetite, and improve overall quality of life in people with lung cancer, according to a systematic review presented by Dr. Heidi Fritz, at the annual meeting of the Society for Integrative Oncology.

Fish oil supplementation may also have a small but significant impact on survival at higher doses of 18 g/day, said Dr. Fritz, a naturopathic physician at the Canadian College of Naturopathic Medicine in Toronto.

Dr. Fritz and her colleagues have undertaken a comprehensive effort to gather the best available data on the benefits and risks of various popular nutritional supplements in the management of lung cancer, among them vitamin A, green tea, selenium, and fish oils.

The Canadian team searched six medical literature databases, finding 50 papers including 6 randomized controlled trials, 11 observational studies, and 30 preclinical studies on the use of fish oil supplements as an adjunctive or supportive treatment for lung cancer.

For the most part, these studies focused on fish oil’s effects on cancer-associated cachexia or – in the case of the human clinical studies – on its use as a supportive therapy to improve quality of life. However, one phase II study looked at the impact on survival of supplementation with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid.

Dr. Fritz said that although the conclusions of individual studies varied, overall "modest clinical benefit from the use of fish oil and/or EPA alone was seen on parameters associated with cachexia – notably weight loss, appetite, and physical function – and there were also modest improvements seen in quality of life."

She added that one of the clinical trials showed a "significant benefit on survival with high-dose fish oil using 18 g/day." The generally recommended dose is 2 g/day.

No significant adverse effects were associated with the use of fish oils at any dosage in the human clinical studies in this systematic review, and no thromboembolic events – the biggest potentially life-threatening adverse effect associated with intensive omega-3 fatty acid supplementation – were reported.

"Fish oil, particularly EPA, appears safe and may be effective in the treatment of cachexia and related symptoms," Dr. Fritz concluded. "Use of EPA as part of a multifaceted approach to the treatment of cachexia may be advantageous in a clinical setting."

The Canadian team’s systematic review of 66 published studies on green tea and lung cancer concluded that although there is some evidence that compounds in green tea do have antitumor properties, there is no strong evidence that drinking green tea, even in large quantities, will prevent lung cancer or substantially improve treatment outcomes.

Their vitamin A/retinoids systematic review, based on 232 papers including 5 randomized controlled trials, does not support the use of this vitamin for either prevention or treatment of lung cancer. The available data indicate that beta-carotene should not be given to smokers; however, Dr. Fritz added, vitamin A and the retinoids deserve further study in other types of cancer, as the negative findings for lung cancer do not necessarily apply to all cancers.

Their analysis of selenium in the context of lung cancer was inconclusive. Available studies are conflicting in terms of both safety and efficacy, and there is little consensus about the appropriate form of supplemental selenium, the dosage, and the optimal level in humans.

"There may be potential benefit from selenium supplementation in populations with low baseline status, but increased risk of cancer and diabetes associated with supplementation in populations with higher baseline status," she said. Currently the evidence is insufficient to support a recommendation for routine use of selenium to prevent or treat lung cancer.

NEW YORK – Fish oil supplementation, in daily doses of 2 g or more, may mitigate weight loss, increase appetite, and improve overall quality of life in people with lung cancer, according to a systematic review presented by Dr. Heidi Fritz, at the annual meeting of the Society for Integrative Oncology.

Fish oil supplementation may also have a small but significant impact on survival at higher doses of 18 g/day, said Dr. Fritz, a naturopathic physician at the Canadian College of Naturopathic Medicine in Toronto.

Dr. Fritz and her colleagues have undertaken a comprehensive effort to gather the best available data on the benefits and risks of various popular nutritional supplements in the management of lung cancer, among them vitamin A, green tea, selenium, and fish oils.

The Canadian team searched six medical literature databases, finding 50 papers including 6 randomized controlled trials, 11 observational studies, and 30 preclinical studies on the use of fish oil supplements as an adjunctive or supportive treatment for lung cancer.

For the most part, these studies focused on fish oil’s effects on cancer-associated cachexia or – in the case of the human clinical studies – on its use as a supportive therapy to improve quality of life. However, one phase II study looked at the impact on survival of supplementation with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid.

Dr. Fritz said that although the conclusions of individual studies varied, overall "modest clinical benefit from the use of fish oil and/or EPA alone was seen on parameters associated with cachexia – notably weight loss, appetite, and physical function – and there were also modest improvements seen in quality of life."

She added that one of the clinical trials showed a "significant benefit on survival with high-dose fish oil using 18 g/day." The generally recommended dose is 2 g/day.

No significant adverse effects were associated with the use of fish oils at any dosage in the human clinical studies in this systematic review, and no thromboembolic events – the biggest potentially life-threatening adverse effect associated with intensive omega-3 fatty acid supplementation – were reported.

"Fish oil, particularly EPA, appears safe and may be effective in the treatment of cachexia and related symptoms," Dr. Fritz concluded. "Use of EPA as part of a multifaceted approach to the treatment of cachexia may be advantageous in a clinical setting."

The Canadian team’s systematic review of 66 published studies on green tea and lung cancer concluded that although there is some evidence that compounds in green tea do have antitumor properties, there is no strong evidence that drinking green tea, even in large quantities, will prevent lung cancer or substantially improve treatment outcomes.

Their vitamin A/retinoids systematic review, based on 232 papers including 5 randomized controlled trials, does not support the use of this vitamin for either prevention or treatment of lung cancer. The available data indicate that beta-carotene should not be given to smokers; however, Dr. Fritz added, vitamin A and the retinoids deserve further study in other types of cancer, as the negative findings for lung cancer do not necessarily apply to all cancers.

Their analysis of selenium in the context of lung cancer was inconclusive. Available studies are conflicting in terms of both safety and efficacy, and there is little consensus about the appropriate form of supplemental selenium, the dosage, and the optimal level in humans.

"There may be potential benefit from selenium supplementation in populations with low baseline status, but increased risk of cancer and diabetes associated with supplementation in populations with higher baseline status," she said. Currently the evidence is insufficient to support a recommendation for routine use of selenium to prevent or treat lung cancer.

NEW YORK – Fish oil supplementation, in daily doses of 2 g or more, may mitigate weight loss, increase appetite, and improve overall quality of life in people with lung cancer, according to a systematic review presented by Dr. Heidi Fritz, at the annual meeting of the Society for Integrative Oncology.

Fish oil supplementation may also have a small but significant impact on survival at higher doses of 18 g/day, said Dr. Fritz, a naturopathic physician at the Canadian College of Naturopathic Medicine in Toronto.

Dr. Fritz and her colleagues have undertaken a comprehensive effort to gather the best available data on the benefits and risks of various popular nutritional supplements in the management of lung cancer, among them vitamin A, green tea, selenium, and fish oils.

The Canadian team searched six medical literature databases, finding 50 papers including 6 randomized controlled trials, 11 observational studies, and 30 preclinical studies on the use of fish oil supplements as an adjunctive or supportive treatment for lung cancer.

For the most part, these studies focused on fish oil’s effects on cancer-associated cachexia or – in the case of the human clinical studies – on its use as a supportive therapy to improve quality of life. However, one phase II study looked at the impact on survival of supplementation with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid.

Dr. Fritz said that although the conclusions of individual studies varied, overall "modest clinical benefit from the use of fish oil and/or EPA alone was seen on parameters associated with cachexia – notably weight loss, appetite, and physical function – and there were also modest improvements seen in quality of life."

She added that one of the clinical trials showed a "significant benefit on survival with high-dose fish oil using 18 g/day." The generally recommended dose is 2 g/day.

No significant adverse effects were associated with the use of fish oils at any dosage in the human clinical studies in this systematic review, and no thromboembolic events – the biggest potentially life-threatening adverse effect associated with intensive omega-3 fatty acid supplementation – were reported.

"Fish oil, particularly EPA, appears safe and may be effective in the treatment of cachexia and related symptoms," Dr. Fritz concluded. "Use of EPA as part of a multifaceted approach to the treatment of cachexia may be advantageous in a clinical setting."

The Canadian team’s systematic review of 66 published studies on green tea and lung cancer concluded that although there is some evidence that compounds in green tea do have antitumor properties, there is no strong evidence that drinking green tea, even in large quantities, will prevent lung cancer or substantially improve treatment outcomes.

Their vitamin A/retinoids systematic review, based on 232 papers including 5 randomized controlled trials, does not support the use of this vitamin for either prevention or treatment of lung cancer. The available data indicate that beta-carotene should not be given to smokers; however, Dr. Fritz added, vitamin A and the retinoids deserve further study in other types of cancer, as the negative findings for lung cancer do not necessarily apply to all cancers.

Their analysis of selenium in the context of lung cancer was inconclusive. Available studies are conflicting in terms of both safety and efficacy, and there is little consensus about the appropriate form of supplemental selenium, the dosage, and the optimal level in humans.

"There may be potential benefit from selenium supplementation in populations with low baseline status, but increased risk of cancer and diabetes associated with supplementation in populations with higher baseline status," she said. Currently the evidence is insufficient to support a recommendation for routine use of selenium to prevent or treat lung cancer.

Children living on farms have a lower prevalence of asthma, likely due to a protective effect of their early exposure to a greater variety of environmental bacteria and fungi compared with what other children are exposed to, according to a report in the Feb. 24 issue of the New England Journal of Medicine.

Photo credit: © LindaYolanda/istock.com

In an epidemiologic analysis of data from two large observational studies of school-aged children in rural areas of central Europe, environmental samples from farmhouses showed a greater diversity of microbes than those from other homes. "The central finding of this analysis was the inverse association of the diversity scores with asthma [prevalence], which was not confounded by living on a farm," said Dr. Markus J. Ege of University Children’s Hospital, Munich, and his associates.

The analysis included data from a cross-sectional survey of 6,963 school children (aged 6-13 years), approximately half of whom lived on farms and the other half of whom lived in rural and suburban areas of Bavaria. Dust samples were collected from the mattresses of a randomly selected subgroup of 489 of the participants. Data also were obtained on the children’s respiratory and allergic symptoms, medical diagnoses, and potential confounders.

Children living on farms had a lower prevalence of asthma than did other children, with an adjusted odds ratio of 0.49. The percentage of dust samples that were positive for bacteria was significantly higher among farm dwellers, and the risk of asthma decreased significantly with an increasing number of detectable bands of bacterial DNA.

The analysis also included data from a second cross-sectional study involving 9,668 children attending elementary schools in rural areas of southern Germany, Switzerland, and Austria. Airborne dust samples were collected from the children’s bedrooms.

Again, children living on farms had a lower prevalence of asthma than did other children, with an odds ratio of 0.76. All bacterial and fungal taxa cultured from the dust samples were more prevalent among children living on farms than among other children, and the risk of asthma decreased significantly with an increasing number of fungal taxa, Dr. Ege and his colleagues said (N. Engl. J. Med. 2011;364:701-9).

In both studies, the diversity of microbes explained a substantial portion of the protective effect of the farming environment on asthma risk.

"Our methods do not allow us to identify specific microbes that may confer protection, but they have allowed us to identify broad families of species within microbial taxa that could be responsible for the effect of the farming environment.

"The challenge will be to identify these species with the precision needed to allow specific tests of the relationship between microbial exposure and protection against asthma," the investigators noted.

The analysis also could not determine the mechanism underlying this protective effect – how the diversity of microbial stimuli protects against asthma – but the researchers agreed with the prevailing view that perhaps micro-organisms trigger the innate immune system, which then bolsters resistance to asthma.

An alternative explanation may be that exposure to a broad rather than a narrow range of micro-organisms may prevent colonization of the lower airways with harmful bacteria. "Balanced colonization of the airways may parallel the beneficial effects of a diverse microbiome at other surfaces, such as the gut and skin," they added.

This study was funded by the Deutsche Forschungsgemeinschaft and the European Commission. Dr. Ege reported having a planned patent on asthma-protective bacteria. His associates reported ties to GlaxoSmithKline, Novartis, Protectimum, and ALK.

Children living on farms have a lower prevalence of asthma, likely due to a protective effect of their early exposure to a greater variety of environmental bacteria and fungi compared with what other children are exposed to, according to a report in the Feb. 24 issue of the New England Journal of Medicine.

Photo credit: © LindaYolanda/istock.com

In an epidemiologic analysis of data from two large observational studies of school-aged children in rural areas of central Europe, environmental samples from farmhouses showed a greater diversity of microbes than those from other homes. "The central finding of this analysis was the inverse association of the diversity scores with asthma [prevalence], which was not confounded by living on a farm," said Dr. Markus J. Ege of University Children’s Hospital, Munich, and his associates.

The analysis included data from a cross-sectional survey of 6,963 school children (aged 6-13 years), approximately half of whom lived on farms and the other half of whom lived in rural and suburban areas of Bavaria. Dust samples were collected from the mattresses of a randomly selected subgroup of 489 of the participants. Data also were obtained on the children’s respiratory and allergic symptoms, medical diagnoses, and potential confounders.

Children living on farms had a lower prevalence of asthma than did other children, with an adjusted odds ratio of 0.49. The percentage of dust samples that were positive for bacteria was significantly higher among farm dwellers, and the risk of asthma decreased significantly with an increasing number of detectable bands of bacterial DNA.

The analysis also included data from a second cross-sectional study involving 9,668 children attending elementary schools in rural areas of southern Germany, Switzerland, and Austria. Airborne dust samples were collected from the children’s bedrooms.

Again, children living on farms had a lower prevalence of asthma than did other children, with an odds ratio of 0.76. All bacterial and fungal taxa cultured from the dust samples were more prevalent among children living on farms than among other children, and the risk of asthma decreased significantly with an increasing number of fungal taxa, Dr. Ege and his colleagues said (N. Engl. J. Med. 2011;364:701-9).

In both studies, the diversity of microbes explained a substantial portion of the protective effect of the farming environment on asthma risk.

"Our methods do not allow us to identify specific microbes that may confer protection, but they have allowed us to identify broad families of species within microbial taxa that could be responsible for the effect of the farming environment.

"The challenge will be to identify these species with the precision needed to allow specific tests of the relationship between microbial exposure and protection against asthma," the investigators noted.

The analysis also could not determine the mechanism underlying this protective effect – how the diversity of microbial stimuli protects against asthma – but the researchers agreed with the prevailing view that perhaps micro-organisms trigger the innate immune system, which then bolsters resistance to asthma.

An alternative explanation may be that exposure to a broad rather than a narrow range of micro-organisms may prevent colonization of the lower airways with harmful bacteria. "Balanced colonization of the airways may parallel the beneficial effects of a diverse microbiome at other surfaces, such as the gut and skin," they added.

This study was funded by the Deutsche Forschungsgemeinschaft and the European Commission. Dr. Ege reported having a planned patent on asthma-protective bacteria. His associates reported ties to GlaxoSmithKline, Novartis, Protectimum, and ALK.

Children living on farms have a lower prevalence of asthma, likely due to a protective effect of their early exposure to a greater variety of environmental bacteria and fungi compared with what other children are exposed to, according to a report in the Feb. 24 issue of the New England Journal of Medicine.

Photo credit: © LindaYolanda/istock.com

In an epidemiologic analysis of data from two large observational studies of school-aged children in rural areas of central Europe, environmental samples from farmhouses showed a greater diversity of microbes than those from other homes. "The central finding of this analysis was the inverse association of the diversity scores with asthma [prevalence], which was not confounded by living on a farm," said Dr. Markus J. Ege of University Children’s Hospital, Munich, and his associates.

The analysis included data from a cross-sectional survey of 6,963 school children (aged 6-13 years), approximately half of whom lived on farms and the other half of whom lived in rural and suburban areas of Bavaria. Dust samples were collected from the mattresses of a randomly selected subgroup of 489 of the participants. Data also were obtained on the children’s respiratory and allergic symptoms, medical diagnoses, and potential confounders.

Children living on farms had a lower prevalence of asthma than did other children, with an adjusted odds ratio of 0.49. The percentage of dust samples that were positive for bacteria was significantly higher among farm dwellers, and the risk of asthma decreased significantly with an increasing number of detectable bands of bacterial DNA.

The analysis also included data from a second cross-sectional study involving 9,668 children attending elementary schools in rural areas of southern Germany, Switzerland, and Austria. Airborne dust samples were collected from the children’s bedrooms.

Again, children living on farms had a lower prevalence of asthma than did other children, with an odds ratio of 0.76. All bacterial and fungal taxa cultured from the dust samples were more prevalent among children living on farms than among other children, and the risk of asthma decreased significantly with an increasing number of fungal taxa, Dr. Ege and his colleagues said (N. Engl. J. Med. 2011;364:701-9).

In both studies, the diversity of microbes explained a substantial portion of the protective effect of the farming environment on asthma risk.

"Our methods do not allow us to identify specific microbes that may confer protection, but they have allowed us to identify broad families of species within microbial taxa that could be responsible for the effect of the farming environment.

"The challenge will be to identify these species with the precision needed to allow specific tests of the relationship between microbial exposure and protection against asthma," the investigators noted.

The analysis also could not determine the mechanism underlying this protective effect – how the diversity of microbial stimuli protects against asthma – but the researchers agreed with the prevailing view that perhaps micro-organisms trigger the innate immune system, which then bolsters resistance to asthma.

An alternative explanation may be that exposure to a broad rather than a narrow range of micro-organisms may prevent colonization of the lower airways with harmful bacteria. "Balanced colonization of the airways may parallel the beneficial effects of a diverse microbiome at other surfaces, such as the gut and skin," they added.

This study was funded by the Deutsche Forschungsgemeinschaft and the European Commission. Dr. Ege reported having a planned patent on asthma-protective bacteria. His associates reported ties to GlaxoSmithKline, Novartis, Protectimum, and ALK.

NEW YORK – Fish oil supplementation, in daily doses of 2 g or more, may mitigate weight loss, increase appetite, and improve overall quality of life in people with lung cancer, according to a systematic review presented by Dr. Heidi Fritz, at the annual meeting of the Society for Integrative Oncology.

Fish oil supplementation may also have a small but significant impact on survival at higher doses of 18 g/day, said Dr. Fritz, a naturopathic physician at the Canadian College of Naturopathic Medicine in Toronto.

Dr. Fritz and her colleagues have undertaken a comprehensive effort to gather the best available data on the benefits and risks of various popular nutritional supplements in the management of lung cancer, among them vitamin A, green tea, selenium, and fish oils.

The Canadian team searched six medical literature databases, finding 50 papers including 6 randomized controlled trials, 11 observational studies, and 30 preclinical studies on the use of fish oil supplements as an adjunctive or supportive treatment for lung cancer.

For the most part, these studies focused on fish oil’s effects on cancer-associated cachexia or – in the case of the human clinical studies – on its use as a supportive therapy to improve quality of life. However, one phase II study looked at the impact on survival of supplementation with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid.

Dr. Fritz said that although the conclusions of individual studies varied, overall "modest clinical benefit from the use of fish oil and/or EPA alone was seen on parameters associated with cachexia – notably weight loss, appetite, and physical function – and there were also modest improvements seen in quality of life."

She added that one of the clinical trials showed a "significant benefit on survival with high-dose fish oil using 18 g/day." The generally recommended dose is 2 g/day.

No significant adverse effects were associated with the use of fish oils at any dosage in the human clinical studies in this systematic review, and no thromboembolic events – the biggest potentially life-threatening adverse effect associated with intensive omega-3 fatty acid supplementation – were reported.

"Fish oil, particularly EPA, appears safe and may be effective in the treatment of cachexia and related symptoms," Dr. Fritz concluded. "Use of EPA as part of a multifaceted approach to the treatment of cachexia may be advantageous in a clinical setting."

The Canadian team’s systematic review of 66 published studies on green tea and lung cancer concluded that although there is some evidence that compounds in green tea do have antitumor properties, there is no strong evidence that drinking green tea, even in large quantities, will prevent lung cancer or substantially improve treatment outcomes.

Their vitamin A/retinoids systematic review, based on 232 papers including 5 randomized controlled trials, does not support the use of this vitamin for either prevention or treatment of lung cancer. The available data indicate that beta-carotene should not be given to smokers; however, Dr. Fritz added, vitamin A and the retinoids deserve further study in other types of cancer, as the negative findings for lung cancer do not necessarily apply to all cancers.

Their analysis of selenium in the context of lung cancer was inconclusive. Available studies are conflicting in terms of both safety and efficacy, and there is little consensus about the appropriate form of supplemental selenium, the dosage, and the optimal level in humans.

"There may be potential benefit from selenium supplementation in populations with low baseline status, but increased risk of cancer and diabetes associated with supplementation in populations with higher baseline status," she said. Currently the evidence is insufficient to support a recommendation for routine use of selenium to prevent or treat lung cancer.

NEW YORK – Fish oil supplementation, in daily doses of 2 g or more, may mitigate weight loss, increase appetite, and improve overall quality of life in people with lung cancer, according to a systematic review presented by Dr. Heidi Fritz, at the annual meeting of the Society for Integrative Oncology.

Fish oil supplementation may also have a small but significant impact on survival at higher doses of 18 g/day, said Dr. Fritz, a naturopathic physician at the Canadian College of Naturopathic Medicine in Toronto.

Dr. Fritz and her colleagues have undertaken a comprehensive effort to gather the best available data on the benefits and risks of various popular nutritional supplements in the management of lung cancer, among them vitamin A, green tea, selenium, and fish oils.

The Canadian team searched six medical literature databases, finding 50 papers including 6 randomized controlled trials, 11 observational studies, and 30 preclinical studies on the use of fish oil supplements as an adjunctive or supportive treatment for lung cancer.

For the most part, these studies focused on fish oil’s effects on cancer-associated cachexia or – in the case of the human clinical studies – on its use as a supportive therapy to improve quality of life. However, one phase II study looked at the impact on survival of supplementation with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid.

Dr. Fritz said that although the conclusions of individual studies varied, overall "modest clinical benefit from the use of fish oil and/or EPA alone was seen on parameters associated with cachexia – notably weight loss, appetite, and physical function – and there were also modest improvements seen in quality of life."

She added that one of the clinical trials showed a "significant benefit on survival with high-dose fish oil using 18 g/day." The generally recommended dose is 2 g/day.

No significant adverse effects were associated with the use of fish oils at any dosage in the human clinical studies in this systematic review, and no thromboembolic events – the biggest potentially life-threatening adverse effect associated with intensive omega-3 fatty acid supplementation – were reported.

"Fish oil, particularly EPA, appears safe and may be effective in the treatment of cachexia and related symptoms," Dr. Fritz concluded. "Use of EPA as part of a multifaceted approach to the treatment of cachexia may be advantageous in a clinical setting."

The Canadian team’s systematic review of 66 published studies on green tea and lung cancer concluded that although there is some evidence that compounds in green tea do have antitumor properties, there is no strong evidence that drinking green tea, even in large quantities, will prevent lung cancer or substantially improve treatment outcomes.

Their vitamin A/retinoids systematic review, based on 232 papers including 5 randomized controlled trials, does not support the use of this vitamin for either prevention or treatment of lung cancer. The available data indicate that beta-carotene should not be given to smokers; however, Dr. Fritz added, vitamin A and the retinoids deserve further study in other types of cancer, as the negative findings for lung cancer do not necessarily apply to all cancers.

Their analysis of selenium in the context of lung cancer was inconclusive. Available studies are conflicting in terms of both safety and efficacy, and there is little consensus about the appropriate form of supplemental selenium, the dosage, and the optimal level in humans.

"There may be potential benefit from selenium supplementation in populations with low baseline status, but increased risk of cancer and diabetes associated with supplementation in populations with higher baseline status," she said. Currently the evidence is insufficient to support a recommendation for routine use of selenium to prevent or treat lung cancer.

NEW YORK – Fish oil supplementation, in daily doses of 2 g or more, may mitigate weight loss, increase appetite, and improve overall quality of life in people with lung cancer, according to a systematic review presented by Dr. Heidi Fritz, at the annual meeting of the Society for Integrative Oncology.

Fish oil supplementation may also have a small but significant impact on survival at higher doses of 18 g/day, said Dr. Fritz, a naturopathic physician at the Canadian College of Naturopathic Medicine in Toronto.

Dr. Fritz and her colleagues have undertaken a comprehensive effort to gather the best available data on the benefits and risks of various popular nutritional supplements in the management of lung cancer, among them vitamin A, green tea, selenium, and fish oils.

The Canadian team searched six medical literature databases, finding 50 papers including 6 randomized controlled trials, 11 observational studies, and 30 preclinical studies on the use of fish oil supplements as an adjunctive or supportive treatment for lung cancer.

For the most part, these studies focused on fish oil’s effects on cancer-associated cachexia or – in the case of the human clinical studies – on its use as a supportive therapy to improve quality of life. However, one phase II study looked at the impact on survival of supplementation with eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid.

Dr. Fritz said that although the conclusions of individual studies varied, overall "modest clinical benefit from the use of fish oil and/or EPA alone was seen on parameters associated with cachexia – notably weight loss, appetite, and physical function – and there were also modest improvements seen in quality of life."

She added that one of the clinical trials showed a "significant benefit on survival with high-dose fish oil using 18 g/day." The generally recommended dose is 2 g/day.

No significant adverse effects were associated with the use of fish oils at any dosage in the human clinical studies in this systematic review, and no thromboembolic events – the biggest potentially life-threatening adverse effect associated with intensive omega-3 fatty acid supplementation – were reported.

"Fish oil, particularly EPA, appears safe and may be effective in the treatment of cachexia and related symptoms," Dr. Fritz concluded. "Use of EPA as part of a multifaceted approach to the treatment of cachexia may be advantageous in a clinical setting."

The Canadian team’s systematic review of 66 published studies on green tea and lung cancer concluded that although there is some evidence that compounds in green tea do have antitumor properties, there is no strong evidence that drinking green tea, even in large quantities, will prevent lung cancer or substantially improve treatment outcomes.

Their vitamin A/retinoids systematic review, based on 232 papers including 5 randomized controlled trials, does not support the use of this vitamin for either prevention or treatment of lung cancer. The available data indicate that beta-carotene should not be given to smokers; however, Dr. Fritz added, vitamin A and the retinoids deserve further study in other types of cancer, as the negative findings for lung cancer do not necessarily apply to all cancers.

Their analysis of selenium in the context of lung cancer was inconclusive. Available studies are conflicting in terms of both safety and efficacy, and there is little consensus about the appropriate form of supplemental selenium, the dosage, and the optimal level in humans.

"There may be potential benefit from selenium supplementation in populations with low baseline status, but increased risk of cancer and diabetes associated with supplementation in populations with higher baseline status," she said. Currently the evidence is insufficient to support a recommendation for routine use of selenium to prevent or treat lung cancer.

The European Medicines Agency, following its February monthly meeting, said that, while there remained "concern" about a possible link between the Pandemrix influenza vaccine and reports of narcolepsy among young people in Finland and Sweden, the data were "insufficient to establish a causal relationship."

Moreover, EMA said in a press release Feb. 18, other non-Nordic countries have not reported similar increased narcolepsy rates following vaccination with Pandemrix. The agency pointed to Canada as one country where Pandemrix use was widespread during the 2009 H1N1 pandemic, but increased narcolepsy reports did not follow.

The agency therefore elected not to change its recommendations on Pandemrix unless it receives more compelling data to suggest a link. The study submitted to EMA by the Finnish government had compared the incidence of narcolepsy in people aged 4-19 years who were vaccinated with Pandemrix between Jan. 1, 2009 and Dec. 31, 2010, with unvaccinated people the same age. The Finnish study also reported a ninefold increase in reports of narcolepsy in the vaccinated population (an increase from 1 to 9 cases per 100,000 vaccinated).

"One possible explanation for the results is that Pandemrix may have interacted with an unknown local environmental and/or genetic factor in contributing to an increased risk," EMA said. An ongoing study epidemiologic study of narcolepsy and pandemic vaccines is currently being conducted by the European Centre for Disease Control and Prevention in nine E.U. countries, with final results expected in June.

The European Medicines Agency, following its February monthly meeting, said that, while there remained "concern" about a possible link between the Pandemrix influenza vaccine and reports of narcolepsy among young people in Finland and Sweden, the data were "insufficient to establish a causal relationship."

Moreover, EMA said in a press release Feb. 18, other non-Nordic countries have not reported similar increased narcolepsy rates following vaccination with Pandemrix. The agency pointed to Canada as one country where Pandemrix use was widespread during the 2009 H1N1 pandemic, but increased narcolepsy reports did not follow.

The agency therefore elected not to change its recommendations on Pandemrix unless it receives more compelling data to suggest a link. The study submitted to EMA by the Finnish government had compared the incidence of narcolepsy in people aged 4-19 years who were vaccinated with Pandemrix between Jan. 1, 2009 and Dec. 31, 2010, with unvaccinated people the same age. The Finnish study also reported a ninefold increase in reports of narcolepsy in the vaccinated population (an increase from 1 to 9 cases per 100,000 vaccinated).

"One possible explanation for the results is that Pandemrix may have interacted with an unknown local environmental and/or genetic factor in contributing to an increased risk," EMA said. An ongoing study epidemiologic study of narcolepsy and pandemic vaccines is currently being conducted by the European Centre for Disease Control and Prevention in nine E.U. countries, with final results expected in June.

The European Medicines Agency, following its February monthly meeting, said that, while there remained "concern" about a possible link between the Pandemrix influenza vaccine and reports of narcolepsy among young people in Finland and Sweden, the data were "insufficient to establish a causal relationship."

Moreover, EMA said in a press release Feb. 18, other non-Nordic countries have not reported similar increased narcolepsy rates following vaccination with Pandemrix. The agency pointed to Canada as one country where Pandemrix use was widespread during the 2009 H1N1 pandemic, but increased narcolepsy reports did not follow.

The agency therefore elected not to change its recommendations on Pandemrix unless it receives more compelling data to suggest a link. The study submitted to EMA by the Finnish government had compared the incidence of narcolepsy in people aged 4-19 years who were vaccinated with Pandemrix between Jan. 1, 2009 and Dec. 31, 2010, with unvaccinated people the same age. The Finnish study also reported a ninefold increase in reports of narcolepsy in the vaccinated population (an increase from 1 to 9 cases per 100,000 vaccinated).

"One possible explanation for the results is that Pandemrix may have interacted with an unknown local environmental and/or genetic factor in contributing to an increased risk," EMA said. An ongoing study epidemiologic study of narcolepsy and pandemic vaccines is currently being conducted by the European Centre for Disease Control and Prevention in nine E.U. countries, with final results expected in June.

The choice of treatment for the management of adult pulmonary fungal infections should be based on diagnostic findings and individual risk factors, according to a new policy statement issued by the American Thoracic Society. "In most cases, treatment of fungal infections must be based on the causative fungus, the severity of disease, and the clinical features of each patient," the authors wrote.

The policy statement provides organism- and infection-site specific guidelines for therapy, including dosing recommendations, and incorporates the range of novel antifungal medications, such as the extended-spectrum triazoles and echinocandins, that have been introduced since the previous guidelines were published in 1988, according to Dr. Andrew Limper of the Mayo Clinic in Rochester, Minn., and his colleagues on the American Thoracic Society (ATS) Fungal Infections Working Group.

In particular, the recommendations outline the management of endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections with increased prevalence in immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections, such as zygomycoses, hyalohyphomycoses, the phaeohyphomycoses, and infections related to Trichosporon species (Am. J. Respir. Crit. Care. Med. 2011;183:96-128).

Endemic Mycoses. The guidelines recommend treatment with itraconazole for mild to moderate histoplasmosis, sporotrichosis, and blastomycosis, and treatment with amphotericin B for severe disease (followed by itraconazole in patients with sporotrichosis). Patients with severe histoplasmosis with diffuse pulmonary infiltrates and critically ill patients with severe pulmonary blastomycosis may require systemic steroid therapy, as well. Further, for patients with pulmonary blastomycosis and concomitant CNS involvement, combination therapy with liposomal amphotericin B (vs. amphotericin B deoxycholate) and fluconazole "should be considered due to theoretic better CNS penetration," the authors wrote.

Antifungal therapy is not recommended for primary pulmonary coccidioidomycosis in immunocompetent patients who have no risk factors for dissemination, while patients with disseminated infection should be treated with an extended-spectrum triazole, according to the guidelines, which also specify that critically ill patients with disseminated paracoccidioidomycosis should be treated initially with amphotericin B, followed by ketoconazole, itraconazole, or sulfadiazine.

Immunocompromised Patients. The treatment options for fungal infections in patients with compromised immune systems, including transplant patients, those being treated for autoimmune inflammatory conditions, and HIV-infected patients, include oral trimethoprim and sulfamethoxazole, oral primaquine plus clindamycin, or oral atovaquone for mild to moderate Pneumocystis pneumonia. Patients with moderate to severe disease should be given trimethoprim, sulfamethoxazole, and possibly prednisone, the guidelines recommend.

Emerging Fungal Infections. "The management of emerging or rare fungi is supported by limited evidence-based studies with no randomized, blinded comparative studies," the authors wrote, noting that treatment recommendations are thus based on clinical experience and in vitro susceptibility testing. Because the majority of affected patients are immunocompromised, "a primary strategy for management of these infections with underlying diseases is to maximally reduce immunosuppressive drugs, provide immunostimulants, and/or rapidly control the underlying diseases or conditions, such as HIV infection, diabetes, and/or chemotherapy-induced neutropenia," they stated.

Secondarily, particularly in the angioinvasive zygomycoses, necrotic tissues, cysts, or true abscesses should be debulked or debrided, they emphasized.

The third management strategy includes specific antifungal recommendations, such as amphotericin B for zygomycosis; voriconazole, posaconazole, or lipid formulations of amphotericin B for fusariosis; voriconazole or posaconazole for scedosporiosis; itraconazole, voriconazole, or posaconazole for phaeohyphomycoses; and, possibly, voriconazole, posaconazole, or itraconazole for trichosporonis and Paecilomyces infections.

"The exact dosing and duration of treatment for these emerging, rare infections are not precise, and consultation with an expert in infectious disease regarding these clinical decisions should be considered," the authors stressed.

The policy statement also includes recommendations for the treatment of Candida and Aspergillus infections, which are becoming increasingly common in the intensive care unit, the authors stated. For candidemia, the guidelines recommend that all existing central venous catheters should be removed, if possible, or a new placement site should be obtained and initial antifungal treatment should be with fluconazole, an amphotericin B formulation, an echinocandin, or a combination of fluconazole and amphotericin. With respect to Aspergillus infections, the guidelines recommend intravenous voriconazole or liposomal amphotericin B for invasive pulmonary aspergillosis; voriconazole or itraconazole for mild to moderate chronic necrotizing aspergillosis; and liposomal amphotericin B or intravenous voriconazole for severe chronic necrotizing aspergillosis.

The authors reported financial relationships with AlphaMed Pharmaceuticals, Pfizer, Ortho-McNeil, MiraBella Technologies, AstraZeneca, GlaxoSmithKline, Bayer, Novartis, Aradigm, Astellas, Enzon, Merck, and Schering-Plough.

The choice of treatment for the management of adult pulmonary fungal infections should be based on diagnostic findings and individual risk factors, according to a new policy statement issued by the American Thoracic Society. "In most cases, treatment of fungal infections must be based on the causative fungus, the severity of disease, and the clinical features of each patient," the authors wrote.

The policy statement provides organism- and infection-site specific guidelines for therapy, including dosing recommendations, and incorporates the range of novel antifungal medications, such as the extended-spectrum triazoles and echinocandins, that have been introduced since the previous guidelines were published in 1988, according to Dr. Andrew Limper of the Mayo Clinic in Rochester, Minn., and his colleagues on the American Thoracic Society (ATS) Fungal Infections Working Group.

In particular, the recommendations outline the management of endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections with increased prevalence in immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections, such as zygomycoses, hyalohyphomycoses, the phaeohyphomycoses, and infections related to Trichosporon species (Am. J. Respir. Crit. Care. Med. 2011;183:96-128).

Endemic Mycoses. The guidelines recommend treatment with itraconazole for mild to moderate histoplasmosis, sporotrichosis, and blastomycosis, and treatment with amphotericin B for severe disease (followed by itraconazole in patients with sporotrichosis). Patients with severe histoplasmosis with diffuse pulmonary infiltrates and critically ill patients with severe pulmonary blastomycosis may require systemic steroid therapy, as well. Further, for patients with pulmonary blastomycosis and concomitant CNS involvement, combination therapy with liposomal amphotericin B (vs. amphotericin B deoxycholate) and fluconazole "should be considered due to theoretic better CNS penetration," the authors wrote.

Antifungal therapy is not recommended for primary pulmonary coccidioidomycosis in immunocompetent patients who have no risk factors for dissemination, while patients with disseminated infection should be treated with an extended-spectrum triazole, according to the guidelines, which also specify that critically ill patients with disseminated paracoccidioidomycosis should be treated initially with amphotericin B, followed by ketoconazole, itraconazole, or sulfadiazine.

Immunocompromised Patients. The treatment options for fungal infections in patients with compromised immune systems, including transplant patients, those being treated for autoimmune inflammatory conditions, and HIV-infected patients, include oral trimethoprim and sulfamethoxazole, oral primaquine plus clindamycin, or oral atovaquone for mild to moderate Pneumocystis pneumonia. Patients with moderate to severe disease should be given trimethoprim, sulfamethoxazole, and possibly prednisone, the guidelines recommend.

Emerging Fungal Infections. "The management of emerging or rare fungi is supported by limited evidence-based studies with no randomized, blinded comparative studies," the authors wrote, noting that treatment recommendations are thus based on clinical experience and in vitro susceptibility testing. Because the majority of affected patients are immunocompromised, "a primary strategy for management of these infections with underlying diseases is to maximally reduce immunosuppressive drugs, provide immunostimulants, and/or rapidly control the underlying diseases or conditions, such as HIV infection, diabetes, and/or chemotherapy-induced neutropenia," they stated.

Secondarily, particularly in the angioinvasive zygomycoses, necrotic tissues, cysts, or true abscesses should be debulked or debrided, they emphasized.

The third management strategy includes specific antifungal recommendations, such as amphotericin B for zygomycosis; voriconazole, posaconazole, or lipid formulations of amphotericin B for fusariosis; voriconazole or posaconazole for scedosporiosis; itraconazole, voriconazole, or posaconazole for phaeohyphomycoses; and, possibly, voriconazole, posaconazole, or itraconazole for trichosporonis and Paecilomyces infections.

"The exact dosing and duration of treatment for these emerging, rare infections are not precise, and consultation with an expert in infectious disease regarding these clinical decisions should be considered," the authors stressed.

The policy statement also includes recommendations for the treatment of Candida and Aspergillus infections, which are becoming increasingly common in the intensive care unit, the authors stated. For candidemia, the guidelines recommend that all existing central venous catheters should be removed, if possible, or a new placement site should be obtained and initial antifungal treatment should be with fluconazole, an amphotericin B formulation, an echinocandin, or a combination of fluconazole and amphotericin. With respect to Aspergillus infections, the guidelines recommend intravenous voriconazole or liposomal amphotericin B for invasive pulmonary aspergillosis; voriconazole or itraconazole for mild to moderate chronic necrotizing aspergillosis; and liposomal amphotericin B or intravenous voriconazole for severe chronic necrotizing aspergillosis.

The authors reported financial relationships with AlphaMed Pharmaceuticals, Pfizer, Ortho-McNeil, MiraBella Technologies, AstraZeneca, GlaxoSmithKline, Bayer, Novartis, Aradigm, Astellas, Enzon, Merck, and Schering-Plough.

The choice of treatment for the management of adult pulmonary fungal infections should be based on diagnostic findings and individual risk factors, according to a new policy statement issued by the American Thoracic Society. "In most cases, treatment of fungal infections must be based on the causative fungus, the severity of disease, and the clinical features of each patient," the authors wrote.

The policy statement provides organism- and infection-site specific guidelines for therapy, including dosing recommendations, and incorporates the range of novel antifungal medications, such as the extended-spectrum triazoles and echinocandins, that have been introduced since the previous guidelines were published in 1988, according to Dr. Andrew Limper of the Mayo Clinic in Rochester, Minn., and his colleagues on the American Thoracic Society (ATS) Fungal Infections Working Group.

In particular, the recommendations outline the management of endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections with increased prevalence in immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections, such as zygomycoses, hyalohyphomycoses, the phaeohyphomycoses, and infections related to Trichosporon species (Am. J. Respir. Crit. Care. Med. 2011;183:96-128).

Endemic Mycoses. The guidelines recommend treatment with itraconazole for mild to moderate histoplasmosis, sporotrichosis, and blastomycosis, and treatment with amphotericin B for severe disease (followed by itraconazole in patients with sporotrichosis). Patients with severe histoplasmosis with diffuse pulmonary infiltrates and critically ill patients with severe pulmonary blastomycosis may require systemic steroid therapy, as well. Further, for patients with pulmonary blastomycosis and concomitant CNS involvement, combination therapy with liposomal amphotericin B (vs. amphotericin B deoxycholate) and fluconazole "should be considered due to theoretic better CNS penetration," the authors wrote.

Antifungal therapy is not recommended for primary pulmonary coccidioidomycosis in immunocompetent patients who have no risk factors for dissemination, while patients with disseminated infection should be treated with an extended-spectrum triazole, according to the guidelines, which also specify that critically ill patients with disseminated paracoccidioidomycosis should be treated initially with amphotericin B, followed by ketoconazole, itraconazole, or sulfadiazine.

Immunocompromised Patients. The treatment options for fungal infections in patients with compromised immune systems, including transplant patients, those being treated for autoimmune inflammatory conditions, and HIV-infected patients, include oral trimethoprim and sulfamethoxazole, oral primaquine plus clindamycin, or oral atovaquone for mild to moderate Pneumocystis pneumonia. Patients with moderate to severe disease should be given trimethoprim, sulfamethoxazole, and possibly prednisone, the guidelines recommend.

Emerging Fungal Infections. "The management of emerging or rare fungi is supported by limited evidence-based studies with no randomized, blinded comparative studies," the authors wrote, noting that treatment recommendations are thus based on clinical experience and in vitro susceptibility testing. Because the majority of affected patients are immunocompromised, "a primary strategy for management of these infections with underlying diseases is to maximally reduce immunosuppressive drugs, provide immunostimulants, and/or rapidly control the underlying diseases or conditions, such as HIV infection, diabetes, and/or chemotherapy-induced neutropenia," they stated.

Secondarily, particularly in the angioinvasive zygomycoses, necrotic tissues, cysts, or true abscesses should be debulked or debrided, they emphasized.

The third management strategy includes specific antifungal recommendations, such as amphotericin B for zygomycosis; voriconazole, posaconazole, or lipid formulations of amphotericin B for fusariosis; voriconazole or posaconazole for scedosporiosis; itraconazole, voriconazole, or posaconazole for phaeohyphomycoses; and, possibly, voriconazole, posaconazole, or itraconazole for trichosporonis and Paecilomyces infections.

"The exact dosing and duration of treatment for these emerging, rare infections are not precise, and consultation with an expert in infectious disease regarding these clinical decisions should be considered," the authors stressed.

The policy statement also includes recommendations for the treatment of Candida and Aspergillus infections, which are becoming increasingly common in the intensive care unit, the authors stated. For candidemia, the guidelines recommend that all existing central venous catheters should be removed, if possible, or a new placement site should be obtained and initial antifungal treatment should be with fluconazole, an amphotericin B formulation, an echinocandin, or a combination of fluconazole and amphotericin. With respect to Aspergillus infections, the guidelines recommend intravenous voriconazole or liposomal amphotericin B for invasive pulmonary aspergillosis; voriconazole or itraconazole for mild to moderate chronic necrotizing aspergillosis; and liposomal amphotericin B or intravenous voriconazole for severe chronic necrotizing aspergillosis.

The authors reported financial relationships with AlphaMed Pharmaceuticals, Pfizer, Ortho-McNeil, MiraBella Technologies, AstraZeneca, GlaxoSmithKline, Bayer, Novartis, Aradigm, Astellas, Enzon, Merck, and Schering-Plough.

LONDON – Primary care and emergency physicians face significant difficulties in the diagnosis and treatment of bronchiolitis, particularly during the winter months when the prevalence of the condition rises.

Part of the problem is making a differential diagnosis, compounded by the lack of available evidence-based treatments, experts said at the Excellence in Paediatrics annual meeting in London.

Primary care physicians and general practitioners (GPs) are often not comfortable making a diagnosis of bronchiolitis, said Dr. Mike Thomas, an Asthma UK senior research fellow at the University of Aberdeen (Scotland). "There isn’t a simple, gold-standard diagnostic test, which makes things rather difficult," he observed.

Bronchiolitis typically occurs in infants aged 3-6 months, and a diagnosis is often based on the presenting symptoms, which may include difficulty in breathing, wheeze, crackles on auscultation, cough, and even apnea in very young babies. General irritability and poor feeding may also be apparent.

These symptoms are shared with several other respiratory conditions, such as asthma, viral-induced wheeze, bacterial lower respiratory tract infection, pneumonia, and some rarer lung diseases such as cystic fibrosis.

Investigations – chest x-ray, hematology, and virology – are not routinely recommended, and even when a diagnosis is made, "we’re not 100% sure what to do," Dr. Thomas said.

Evidence-based treatments for the condition are lacking, Dr. Thomas said, with current practice guidelines set in 2006 in both the United Kingdom and United States tending to give advice on what not to do rather than what treatment to give.

"The bottom line is that there is no evidence-based specific treatment in prehospitalized infants ... and we’re left giving standard advice to children with viral illness on the use of fluids and antipyretics."

Dr. Joan L. Robinson, professor of pediatrics at Stollery Children’s Hospital in Edmonton, Alberta, noted that problems in diagnosing and treating bronchiolitis also exist in the ED.

Indeed, evidence shows that ED physicians and radiologists may interpret chest X-rays very differently, often misdiagnosing bronchiolitis as bacterial pneumonia (J. Pediatr. 2007;150:429-33; Pediatr. Pulmonol. 2009;44:122-7).

"Chest x-ray in a typical case of bronchiolitis leads to overdiagnosis of pneumonia and therefore overuse of antibiotics," Dr. Robinson cautioned.

Viral testing has its pros and cons, but it is probably not cost effective in the majority of non–high-risk outpatient cases, she added. "There is no clear correct answer as to whether hospitals should encourage routine testing for inpatients," Dr. Robinson observed.

Dr. Steve Cunningham, a consultant respiratory pediatrician at the Royal Hospital for Sick Children in Edinburgh, commented that treatments for bronchiolitis range from those that aim to improve airflow to those that reduce mucosal inflammation, lessen edema, or improve mucous movement.

Of all available treatments, however, only continuous positive airway pressure and nasal hypertonic saline had any, although still questionable, effect.

With the difficulties in diagnosis and treatment, it becomes all the more important for parents and other caregivers to be well informed about bronchiolitis and how to recognize the signs of a child’s possible deterioration.

"Most infants with bronchiolitis will have a mild illness that can be managed at home," Dr. Thomas said. Caregivers need to know, however, that there is "no cure," and that while symptoms may disappear at around 2 weeks in half of all affected infants, prolonged illness can result in others. It is unclear if there is a higher risk of developing asthma later in life.

Together with general advice on hygiene and regular hand-washing, physicians should remind caregivers that other factors, such as breast-feeding and passive smoking, can have an effect on the child’s health.

"There is also need for better education for GPs and a better evidence base for management," Dr. Thomas suggested. Primary care and general practitioners are uniquely placed to help monitor infants and young children, possibly preventing the need for emergency hospital admission.

Dr. Thomas, Dr. Robinson, and Dr. Cunningham said that they had no conflicts of interest.

LONDON – Primary care and emergency physicians face significant difficulties in the diagnosis and treatment of bronchiolitis, particularly during the winter months when the prevalence of the condition rises.

Part of the problem is making a differential diagnosis, compounded by the lack of available evidence-based treatments, experts said at the Excellence in Paediatrics annual meeting in London.

Primary care physicians and general practitioners (GPs) are often not comfortable making a diagnosis of bronchiolitis, said Dr. Mike Thomas, an Asthma UK senior research fellow at the University of Aberdeen (Scotland). "There isn’t a simple, gold-standard diagnostic test, which makes things rather difficult," he observed.

Bronchiolitis typically occurs in infants aged 3-6 months, and a diagnosis is often based on the presenting symptoms, which may include difficulty in breathing, wheeze, crackles on auscultation, cough, and even apnea in very young babies. General irritability and poor feeding may also be apparent.

These symptoms are shared with several other respiratory conditions, such as asthma, viral-induced wheeze, bacterial lower respiratory tract infection, pneumonia, and some rarer lung diseases such as cystic fibrosis.

Investigations – chest x-ray, hematology, and virology – are not routinely recommended, and even when a diagnosis is made, "we’re not 100% sure what to do," Dr. Thomas said.

Evidence-based treatments for the condition are lacking, Dr. Thomas said, with current practice guidelines set in 2006 in both the United Kingdom and United States tending to give advice on what not to do rather than what treatment to give.

"The bottom line is that there is no evidence-based specific treatment in prehospitalized infants ... and we’re left giving standard advice to children with viral illness on the use of fluids and antipyretics."

Dr. Joan L. Robinson, professor of pediatrics at Stollery Children’s Hospital in Edmonton, Alberta, noted that problems in diagnosing and treating bronchiolitis also exist in the ED.

Indeed, evidence shows that ED physicians and radiologists may interpret chest X-rays very differently, often misdiagnosing bronchiolitis as bacterial pneumonia (J. Pediatr. 2007;150:429-33; Pediatr. Pulmonol. 2009;44:122-7).

"Chest x-ray in a typical case of bronchiolitis leads to overdiagnosis of pneumonia and therefore overuse of antibiotics," Dr. Robinson cautioned.

Viral testing has its pros and cons, but it is probably not cost effective in the majority of non–high-risk outpatient cases, she added. "There is no clear correct answer as to whether hospitals should encourage routine testing for inpatients," Dr. Robinson observed.

Dr. Steve Cunningham, a consultant respiratory pediatrician at the Royal Hospital for Sick Children in Edinburgh, commented that treatments for bronchiolitis range from those that aim to improve airflow to those that reduce mucosal inflammation, lessen edema, or improve mucous movement.

Of all available treatments, however, only continuous positive airway pressure and nasal hypertonic saline had any, although still questionable, effect.

With the difficulties in diagnosis and treatment, it becomes all the more important for parents and other caregivers to be well informed about bronchiolitis and how to recognize the signs of a child’s possible deterioration.

"Most infants with bronchiolitis will have a mild illness that can be managed at home," Dr. Thomas said. Caregivers need to know, however, that there is "no cure," and that while symptoms may disappear at around 2 weeks in half of all affected infants, prolonged illness can result in others. It is unclear if there is a higher risk of developing asthma later in life.

Together with general advice on hygiene and regular hand-washing, physicians should remind caregivers that other factors, such as breast-feeding and passive smoking, can have an effect on the child’s health.

"There is also need for better education for GPs and a better evidence base for management," Dr. Thomas suggested. Primary care and general practitioners are uniquely placed to help monitor infants and young children, possibly preventing the need for emergency hospital admission.

Dr. Thomas, Dr. Robinson, and Dr. Cunningham said that they had no conflicts of interest.

LONDON – Primary care and emergency physicians face significant difficulties in the diagnosis and treatment of bronchiolitis, particularly during the winter months when the prevalence of the condition rises.

Part of the problem is making a differential diagnosis, compounded by the lack of available evidence-based treatments, experts said at the Excellence in Paediatrics annual meeting in London.

Primary care physicians and general practitioners (GPs) are often not comfortable making a diagnosis of bronchiolitis, said Dr. Mike Thomas, an Asthma UK senior research fellow at the University of Aberdeen (Scotland). "There isn’t a simple, gold-standard diagnostic test, which makes things rather difficult," he observed.

Bronchiolitis typically occurs in infants aged 3-6 months, and a diagnosis is often based on the presenting symptoms, which may include difficulty in breathing, wheeze, crackles on auscultation, cough, and even apnea in very young babies. General irritability and poor feeding may also be apparent.

These symptoms are shared with several other respiratory conditions, such as asthma, viral-induced wheeze, bacterial lower respiratory tract infection, pneumonia, and some rarer lung diseases such as cystic fibrosis.

Investigations – chest x-ray, hematology, and virology – are not routinely recommended, and even when a diagnosis is made, "we’re not 100% sure what to do," Dr. Thomas said.

Evidence-based treatments for the condition are lacking, Dr. Thomas said, with current practice guidelines set in 2006 in both the United Kingdom and United States tending to give advice on what not to do rather than what treatment to give.

"The bottom line is that there is no evidence-based specific treatment in prehospitalized infants ... and we’re left giving standard advice to children with viral illness on the use of fluids and antipyretics."

Dr. Joan L. Robinson, professor of pediatrics at Stollery Children’s Hospital in Edmonton, Alberta, noted that problems in diagnosing and treating bronchiolitis also exist in the ED.

Indeed, evidence shows that ED physicians and radiologists may interpret chest X-rays very differently, often misdiagnosing bronchiolitis as bacterial pneumonia (J. Pediatr. 2007;150:429-33; Pediatr. Pulmonol. 2009;44:122-7).

"Chest x-ray in a typical case of bronchiolitis leads to overdiagnosis of pneumonia and therefore overuse of antibiotics," Dr. Robinson cautioned.

Viral testing has its pros and cons, but it is probably not cost effective in the majority of non–high-risk outpatient cases, she added. "There is no clear correct answer as to whether hospitals should encourage routine testing for inpatients," Dr. Robinson observed.

Dr. Steve Cunningham, a consultant respiratory pediatrician at the Royal Hospital for Sick Children in Edinburgh, commented that treatments for bronchiolitis range from those that aim to improve airflow to those that reduce mucosal inflammation, lessen edema, or improve mucous movement.

Of all available treatments, however, only continuous positive airway pressure and nasal hypertonic saline had any, although still questionable, effect.

With the difficulties in diagnosis and treatment, it becomes all the more important for parents and other caregivers to be well informed about bronchiolitis and how to recognize the signs of a child’s possible deterioration.

"Most infants with bronchiolitis will have a mild illness that can be managed at home," Dr. Thomas said. Caregivers need to know, however, that there is "no cure," and that while symptoms may disappear at around 2 weeks in half of all affected infants, prolonged illness can result in others. It is unclear if there is a higher risk of developing asthma later in life.

Together with general advice on hygiene and regular hand-washing, physicians should remind caregivers that other factors, such as breast-feeding and passive smoking, can have an effect on the child’s health.

"There is also need for better education for GPs and a better evidence base for management," Dr. Thomas suggested. Primary care and general practitioners are uniquely placed to help monitor infants and young children, possibly preventing the need for emergency hospital admission.

Dr. Thomas, Dr. Robinson, and Dr. Cunningham said that they had no conflicts of interest.

KEYSTONE, COLO. – It doesn’t take a long stretch of the imagination to surmise that chronic airway remodeling has an impact on airway obstruction in persistent asthma. But to what degree? And should steroid dosing be adjusted to mediate its progression at younger ages?

Biopsies alone don’t adequately address these questions. The impact of airway narrowing is more of a "reasonable correlation" that physicians must formulate by evaluating asthma-related damage and epithelial tissue thickening over time, then comparing it to airway constriction in the patient, said Dr. Anthony N. Gerber of the University of California, San Francisco.

"What [physicians] are forced to do is perform biopsies and correlate the amount of airway smooth muscle thickening or the quantity of basement membrane thickening with the severity of airway obstruction," he said at a meeting on allergy and respiratory diseases, which was sponsored by National Jewish Health. "I don’t know if it’s really possible to deconvolute the precise amount that airway remodeling is contributing to airway obstruction."

Correlating CT scans with bronchial biopsies and histologic analysis sets the stage for a comparison of findings with forced expiratory volume in 1 second (FEV1 ) readings. The physician can then evaluate remodeling in a more relative sense by analyzing how actively it conspires with three additional airway obstruction components – acute asthmatic inflammation, airway hyperreactivity, and mucus formation.

The central hallmarks of chronic remodeling are increased airway smooth muscle mass and subepithelial fibrosis, or thickening in the lamina reticularis from dense fibrotic responses as a result of accumulated collagens. Inflamed airway smooth muscle mass has been associated with a decline in FEV1 (Am. J. Respir. Crit. Care Med. 2010;182:317-24) and is characterized by abnormal cell turnover and proliferation, presumably in response to the chronic inflammatory stimuli that trigger the patient’s asthma. The proliferating cell nuclear antigen (PCNA) is an acknowledged marker for this part of the process, with patients more likely to demonstrate higher levels of PCNA-positive cells as their asthma severity scores increase, Dr. Gerber said.

In addition, subepithelial fibrosis progression may be chronic, with increased smooth muscle narrowing seen in older patients (Am. J. Respir. Crit. Care Med. 2000;162:663-9).

"The real question I think that comes up is, should we treat people with airway remodeling differently than you would treat a typical asthmatic, where you’re just trying to manage their symptoms? I think that the unfortunate answer to this is that we really don’t know enough about the natural history of airway remodeling. Nor do we know enough about the effects of giving high doses of inhaled corticosteroids to potentially reverse airway remodeling," the pathologist said. "But I do think that there’s evidence to maybe give pause to the idea that we should try and find the lowest corticosteroid dose that effectively controls symptoms."

Dr. Gerber’s presentation didn’t explicitly address the chicken-or-egg quandary: Does persistent asthma bring on airway remodeling, or does remodeling worsen an existing case of asthma?

"In general, asthma comes first and leads to remodeling over time," he said in an interview. "However, some people appear more prone to develop remodeling than others. And for some, they may eventually have more symptoms from the remodeling than they ever had from acute asthma attacks."

Only after quantifying the impact of airway remodeling can the physician make an informed decision on adjustments to steroid therapy. Glucocorticoid use remains something of a gamble in consideration of the fact that many of the genes that glucocorticoids act on to control catabolism are not inflammatory regulators. But some early findings have identified KLF15 as a possible glucocorticoid target and regulator of airway remodeling, he said.

Dr. Gerber sits on the advisory board and consults for Breathe Technologies.

KEYSTONE, COLO. – It doesn’t take a long stretch of the imagination to surmise that chronic airway remodeling has an impact on airway obstruction in persistent asthma. But to what degree? And should steroid dosing be adjusted to mediate its progression at younger ages?

Biopsies alone don’t adequately address these questions. The impact of airway narrowing is more of a "reasonable correlation" that physicians must formulate by evaluating asthma-related damage and epithelial tissue thickening over time, then comparing it to airway constriction in the patient, said Dr. Anthony N. Gerber of the University of California, San Francisco.

"What [physicians] are forced to do is perform biopsies and correlate the amount of airway smooth muscle thickening or the quantity of basement membrane thickening with the severity of airway obstruction," he said at a meeting on allergy and respiratory diseases, which was sponsored by National Jewish Health. "I don’t know if it’s really possible to deconvolute the precise amount that airway remodeling is contributing to airway obstruction."

Correlating CT scans with bronchial biopsies and histologic analysis sets the stage for a comparison of findings with forced expiratory volume in 1 second (FEV1 ) readings. The physician can then evaluate remodeling in a more relative sense by analyzing how actively it conspires with three additional airway obstruction components – acute asthmatic inflammation, airway hyperreactivity, and mucus formation.

The central hallmarks of chronic remodeling are increased airway smooth muscle mass and subepithelial fibrosis, or thickening in the lamina reticularis from dense fibrotic responses as a result of accumulated collagens. Inflamed airway smooth muscle mass has been associated with a decline in FEV1 (Am. J. Respir. Crit. Care Med. 2010;182:317-24) and is characterized by abnormal cell turnover and proliferation, presumably in response to the chronic inflammatory stimuli that trigger the patient’s asthma. The proliferating cell nuclear antigen (PCNA) is an acknowledged marker for this part of the process, with patients more likely to demonstrate higher levels of PCNA-positive cells as their asthma severity scores increase, Dr. Gerber said.

In addition, subepithelial fibrosis progression may be chronic, with increased smooth muscle narrowing seen in older patients (Am. J. Respir. Crit. Care Med. 2000;162:663-9).

"The real question I think that comes up is, should we treat people with airway remodeling differently than you would treat a typical asthmatic, where you’re just trying to manage their symptoms? I think that the unfortunate answer to this is that we really don’t know enough about the natural history of airway remodeling. Nor do we know enough about the effects of giving high doses of inhaled corticosteroids to potentially reverse airway remodeling," the pathologist said. "But I do think that there’s evidence to maybe give pause to the idea that we should try and find the lowest corticosteroid dose that effectively controls symptoms."

Dr. Gerber’s presentation didn’t explicitly address the chicken-or-egg quandary: Does persistent asthma bring on airway remodeling, or does remodeling worsen an existing case of asthma?

"In general, asthma comes first and leads to remodeling over time," he said in an interview. "However, some people appear more prone to develop remodeling than others. And for some, they may eventually have more symptoms from the remodeling than they ever had from acute asthma attacks."

Only after quantifying the impact of airway remodeling can the physician make an informed decision on adjustments to steroid therapy. Glucocorticoid use remains something of a gamble in consideration of the fact that many of the genes that glucocorticoids act on to control catabolism are not inflammatory regulators. But some early findings have identified KLF15 as a possible glucocorticoid target and regulator of airway remodeling, he said.

Dr. Gerber sits on the advisory board and consults for Breathe Technologies.

KEYSTONE, COLO. – It doesn’t take a long stretch of the imagination to surmise that chronic airway remodeling has an impact on airway obstruction in persistent asthma. But to what degree? And should steroid dosing be adjusted to mediate its progression at younger ages?

Biopsies alone don’t adequately address these questions. The impact of airway narrowing is more of a "reasonable correlation" that physicians must formulate by evaluating asthma-related damage and epithelial tissue thickening over time, then comparing it to airway constriction in the patient, said Dr. Anthony N. Gerber of the University of California, San Francisco.

"What [physicians] are forced to do is perform biopsies and correlate the amount of airway smooth muscle thickening or the quantity of basement membrane thickening with the severity of airway obstruction," he said at a meeting on allergy and respiratory diseases, which was sponsored by National Jewish Health. "I don’t know if it’s really possible to deconvolute the precise amount that airway remodeling is contributing to airway obstruction."

Correlating CT scans with bronchial biopsies and histologic analysis sets the stage for a comparison of findings with forced expiratory volume in 1 second (FEV1 ) readings. The physician can then evaluate remodeling in a more relative sense by analyzing how actively it conspires with three additional airway obstruction components – acute asthmatic inflammation, airway hyperreactivity, and mucus formation.

The central hallmarks of chronic remodeling are increased airway smooth muscle mass and subepithelial fibrosis, or thickening in the lamina reticularis from dense fibrotic responses as a result of accumulated collagens. Inflamed airway smooth muscle mass has been associated with a decline in FEV1 (Am. J. Respir. Crit. Care Med. 2010;182:317-24) and is characterized by abnormal cell turnover and proliferation, presumably in response to the chronic inflammatory stimuli that trigger the patient’s asthma. The proliferating cell nuclear antigen (PCNA) is an acknowledged marker for this part of the process, with patients more likely to demonstrate higher levels of PCNA-positive cells as their asthma severity scores increase, Dr. Gerber said.

In addition, subepithelial fibrosis progression may be chronic, with increased smooth muscle narrowing seen in older patients (Am. J. Respir. Crit. Care Med. 2000;162:663-9).

"The real question I think that comes up is, should we treat people with airway remodeling differently than you would treat a typical asthmatic, where you’re just trying to manage their symptoms? I think that the unfortunate answer to this is that we really don’t know enough about the natural history of airway remodeling. Nor do we know enough about the effects of giving high doses of inhaled corticosteroids to potentially reverse airway remodeling," the pathologist said. "But I do think that there’s evidence to maybe give pause to the idea that we should try and find the lowest corticosteroid dose that effectively controls symptoms."

Dr. Gerber’s presentation didn’t explicitly address the chicken-or-egg quandary: Does persistent asthma bring on airway remodeling, or does remodeling worsen an existing case of asthma?

"In general, asthma comes first and leads to remodeling over time," he said in an interview. "However, some people appear more prone to develop remodeling than others. And for some, they may eventually have more symptoms from the remodeling than they ever had from acute asthma attacks."

Only after quantifying the impact of airway remodeling can the physician make an informed decision on adjustments to steroid therapy. Glucocorticoid use remains something of a gamble in consideration of the fact that many of the genes that glucocorticoids act on to control catabolism are not inflammatory regulators. But some early findings have identified KLF15 as a possible glucocorticoid target and regulator of airway remodeling, he said.

Dr. Gerber sits on the advisory board and consults for Breathe Technologies.

KEYSTONE, Colo. – Physicians would do well to add habituation, neuropathic triggers, and laryngopharyngeal reflux to the list of factors they assess when tracing the origins of a cough that has persisted for longer than 8 weeks, advised a Colorado pulmonary specialist.

The usually recognized initiators of chronic refractory cough include asthma, upper airway cough syndrome (postnasal drip), and gastroesophageal reflux disease. But looking beyond these common culprits and analyzing combined etiologic factors on a case-by-case basis may be necessary, emphasized Dr. Ronald C. Balkissoon of the division of pulmonary and critical care medicine at National Jewish Health in Denver.

"Most people who have chronic cough have at least two or more underlying problems that are contributing to it," Dr. Balkissoon said at a meeting on allergy and respiratory diseases, sponsored by National Jewish Health. "Often [physicians] will just try to treat one issue like acid reflux and it doesn’t work, so they presume that’s not part of the problem. But you really have to have a multidisciplinary approach and consider all the relative contributing factors."

An especially underappreciated complication is laryngopharyngeal reflux (LPR), he said. Physicians using both classic pH probes or impedance probes often shortchange their diagnoses by missing clues, in large part because LPR is not specific in its presentation. The role LPR plays can be obfuscated by the presence of supraglottic edema or erythema, glottic abnormalities, epiglottic malformations, and lingual tonsillar hypertrophy, among other factors.

Moreover, the cobblestoning of epithelial tissue, an obvious sign of LPR, is not exclusive to that disease. It is also seen in cases where chronic cough derives mostly from a postnasal drip. Bronchoscopy will often reveal a transformation of tissue from normal columnar epithelium into squamous epithelium, even when the reflux is nonacidic, but beyond that, finding the proper context for tissue changes such as cobblestoning and ruling out non-LPR origins can be a challenge.

Chronic cough has a detrimental effect on the lives of many, with almost 30 million clinical visits reported annually in the United States. Females demonstrate a higher cough reflex sensitivity than do males, and the condition is driven by several additional originating factors that range from ACE inhibitor use to chronic bronchitis and bronchiectasis.

The learned and neuropathic origins of persistent cough stand as additional elements that may be more important in the big picture than many clinicians realize.

"Habituation, I think, is a very, very big part of what happens to people who have chronic cough," Dr. Balkissoon said. "They may have postnasal drainage issues. They may have gastroesophageal reflux disease issues and even ongoing asthma, but by the time they develop this cough that’s been going on for 15 or 25 years, there’s clearly habituation."

At another level, neuropathic manifestations of chronic cough are due to the irritant receptors that thrive in the lungs and throat. These include nociceptive C fibers, G protein, transient receptor potential vanilloid 1, and transient receptor potential A1.

The jury is still out on newer receptor antagonists, as well as surgical procedures such as fundoplication and other nonpharmacologic management approaches. But a diagnosis that acknowledges the likelihood of a more complex group of reasons for chronic cough may be the most logical way to seek better-tailored therapies.

"Most of the people who have chronic cough really have the common etiologies, but understanding that they’re often in combination and they have one or more reasons for it being refractory is the most important point," Dr. Balkissoon said.

Dr. Balkissoon disclosed speaking on behalf of AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, and Novartis.

KEYSTONE, Colo. – Physicians would do well to add habituation, neuropathic triggers, and laryngopharyngeal reflux to the list of factors they assess when tracing the origins of a cough that has persisted for longer than 8 weeks, advised a Colorado pulmonary specialist.

The usually recognized initiators of chronic refractory cough include asthma, upper airway cough syndrome (postnasal drip), and gastroesophageal reflux disease. But looking beyond these common culprits and analyzing combined etiologic factors on a case-by-case basis may be necessary, emphasized Dr. Ronald C. Balkissoon of the division of pulmonary and critical care medicine at National Jewish Health in Denver.

"Most people who have chronic cough have at least two or more underlying problems that are contributing to it," Dr. Balkissoon said at a meeting on allergy and respiratory diseases, sponsored by National Jewish Health. "Often [physicians] will just try to treat one issue like acid reflux and it doesn’t work, so they presume that’s not part of the problem. But you really have to have a multidisciplinary approach and consider all the relative contributing factors."

An especially underappreciated complication is laryngopharyngeal reflux (LPR), he said. Physicians using both classic pH probes or impedance probes often shortchange their diagnoses by missing clues, in large part because LPR is not specific in its presentation. The role LPR plays can be obfuscated by the presence of supraglottic edema or erythema, glottic abnormalities, epiglottic malformations, and lingual tonsillar hypertrophy, among other factors.

Moreover, the cobblestoning of epithelial tissue, an obvious sign of LPR, is not exclusive to that disease. It is also seen in cases where chronic cough derives mostly from a postnasal drip. Bronchoscopy will often reveal a transformation of tissue from normal columnar epithelium into squamous epithelium, even when the reflux is nonacidic, but beyond that, finding the proper context for tissue changes such as cobblestoning and ruling out non-LPR origins can be a challenge.

Chronic cough has a detrimental effect on the lives of many, with almost 30 million clinical visits reported annually in the United States. Females demonstrate a higher cough reflex sensitivity than do males, and the condition is driven by several additional originating factors that range from ACE inhibitor use to chronic bronchitis and bronchiectasis.

The learned and neuropathic origins of persistent cough stand as additional elements that may be more important in the big picture than many clinicians realize.

"Habituation, I think, is a very, very big part of what happens to people who have chronic cough," Dr. Balkissoon said. "They may have postnasal drainage issues. They may have gastroesophageal reflux disease issues and even ongoing asthma, but by the time they develop this cough that’s been going on for 15 or 25 years, there’s clearly habituation."

At another level, neuropathic manifestations of chronic cough are due to the irritant receptors that thrive in the lungs and throat. These include nociceptive C fibers, G protein, transient receptor potential vanilloid 1, and transient receptor potential A1.

The jury is still out on newer receptor antagonists, as well as surgical procedures such as fundoplication and other nonpharmacologic management approaches. But a diagnosis that acknowledges the likelihood of a more complex group of reasons for chronic cough may be the most logical way to seek better-tailored therapies.

"Most of the people who have chronic cough really have the common etiologies, but understanding that they’re often in combination and they have one or more reasons for it being refractory is the most important point," Dr. Balkissoon said.

Dr. Balkissoon disclosed speaking on behalf of AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, and Novartis.

KEYSTONE, Colo. – Physicians would do well to add habituation, neuropathic triggers, and laryngopharyngeal reflux to the list of factors they assess when tracing the origins of a cough that has persisted for longer than 8 weeks, advised a Colorado pulmonary specialist.

The usually recognized initiators of chronic refractory cough include asthma, upper airway cough syndrome (postnasal drip), and gastroesophageal reflux disease. But looking beyond these common culprits and analyzing combined etiologic factors on a case-by-case basis may be necessary, emphasized Dr. Ronald C. Balkissoon of the division of pulmonary and critical care medicine at National Jewish Health in Denver.

"Most people who have chronic cough have at least two or more underlying problems that are contributing to it," Dr. Balkissoon said at a meeting on allergy and respiratory diseases, sponsored by National Jewish Health. "Often [physicians] will just try to treat one issue like acid reflux and it doesn’t work, so they presume that’s not part of the problem. But you really have to have a multidisciplinary approach and consider all the relative contributing factors."

An especially underappreciated complication is laryngopharyngeal reflux (LPR), he said. Physicians using both classic pH probes or impedance probes often shortchange their diagnoses by missing clues, in large part because LPR is not specific in its presentation. The role LPR plays can be obfuscated by the presence of supraglottic edema or erythema, glottic abnormalities, epiglottic malformations, and lingual tonsillar hypertrophy, among other factors.

Moreover, the cobblestoning of epithelial tissue, an obvious sign of LPR, is not exclusive to that disease. It is also seen in cases where chronic cough derives mostly from a postnasal drip. Bronchoscopy will often reveal a transformation of tissue from normal columnar epithelium into squamous epithelium, even when the reflux is nonacidic, but beyond that, finding the proper context for tissue changes such as cobblestoning and ruling out non-LPR origins can be a challenge.

Chronic cough has a detrimental effect on the lives of many, with almost 30 million clinical visits reported annually in the United States. Females demonstrate a higher cough reflex sensitivity than do males, and the condition is driven by several additional originating factors that range from ACE inhibitor use to chronic bronchitis and bronchiectasis.

The learned and neuropathic origins of persistent cough stand as additional elements that may be more important in the big picture than many clinicians realize.

"Habituation, I think, is a very, very big part of what happens to people who have chronic cough," Dr. Balkissoon said. "They may have postnasal drainage issues. They may have gastroesophageal reflux disease issues and even ongoing asthma, but by the time they develop this cough that’s been going on for 15 or 25 years, there’s clearly habituation."

At another level, neuropathic manifestations of chronic cough are due to the irritant receptors that thrive in the lungs and throat. These include nociceptive C fibers, G protein, transient receptor potential vanilloid 1, and transient receptor potential A1.

The jury is still out on newer receptor antagonists, as well as surgical procedures such as fundoplication and other nonpharmacologic management approaches. But a diagnosis that acknowledges the likelihood of a more complex group of reasons for chronic cough may be the most logical way to seek better-tailored therapies.

"Most of the people who have chronic cough really have the common etiologies, but understanding that they’re often in combination and they have one or more reasons for it being refractory is the most important point," Dr. Balkissoon said.

Dr. Balkissoon disclosed speaking on behalf of AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, and Novartis.