Asthma

Patients with mild asthma who rely solely on short-acting beta2-agonists (SABAs) to control their asthma symptoms remain at increased risk of exacerbations, according to investigators.

Two recent studies presented at the American Thoracic Society’s international conference demonstrated the benefits of glucocorticoid therapy among patients with mild persistent or intermittent asthma while highlighting differential responses to steroids among patients with high versus low levels of eosinophils in sputum. Both studies were simultaneously published in the New England Journal of Medicine.

The first study, SIENA, led by Stephen C. Lazarus, MD of the University of California, San Francisco, and colleagues, involved 295 patients with mild, persistent asthma. Patients were classified as having either a high or low level of eosinophils in sputum, with a low level defined by two sputum samples consisting of less than 2% eosinophils. After a single-blind placebo run-in period of 6 weeks, patients were randomized to receive either mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist [LAMA]), or placebo for 12 weeks each, with subsequent crossover through the two remaining treatments. The primary outcome was the response to each active agent, compared with placebo among low-eosinophil patients who had a differential response to a trial agent.

Out of 295 patients, 221 (75%) had low eosinophils and 74 (25%) had high eosinophils. In the low-eosinophil subgroup, 59% of patients had a differential response to a trial agent; among these, 57% responded better to mometasone, compared with 43% who responded better to placebo, and 60% responded better to tiotropium, compared with 40% who responded better to placebo.

Turning to secondary analyses, among patients with high eosinophil levels who had a differential response, 74% responded better to mometasone, compared with 26% who responded better to placebo, and 57% responded better to tiotropium, compared with 43% who responded better to placebo.

In an additional exploratory analysis, adults with low eosinophil levels had better responses to tiotropium than placebo (62% vs 38%).

The researchers stated that a key finding of the study is that three-quarters of the mild, persistent asthma population had low eosinophil levels, far fewer than expected and that the difference in their response to mometasone compared to tiotropium was not significant.

“Our results raise the question of whether treatment guidelines should be reevaluated for patients with mild, persistent asthma for whom evidence of type 2 inflammation is lacking,” the investigators wrote. “The need for a change in treatment strategy is further highlighted by a growing body of literature suggesting that mild, persistent asthma can be managed safely without the daily use of inhaled glucocorticoids and by data showing that patients with a low eosinophil level may not have a favorable response to inhaled glucocorticoids” (New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1814917).

The second study, Novel START, conducted by lead author Richard Beasley, DSc, of the Medical Research Institute of New Zealand, Wellington, and colleagues, compared the efficacy of two inhaled glucocorticoid regimens and albuterol alone for patients with mild persistent or intermittent asthma, measured by annualized exacerbation rate.

Initial randomization involved 675 patients, of whom 668 were included in the final analysis. Patients were randomized into three groups: albuterol as needed (100 mcg, two inhalations as needed for asthma symptoms), budesonide maintenance (200 mcg, one inhalation twice daily with as-needed albuterol), or budesonide/formoterol (budesonide 200 mcg and formoterol 6 mcg, one inhalation as needed). Along with annualized exacerbation rate, several secondary outcomes assessed symptoms, respiratory function, and number of severe exacerbations.

Data analysis showed that patients in the budesonide groups had similar rates of annualized exacerbation, both of which were significantly better than the exacerbation rate in the albuterol-only group; the absolute rate of exacerbations per patient per year was 0.175, 0.195, and 0.400 for budesonide maintenance, budesonide/formoterol, and albuterol only, respectively. Similarly, the median fraction of exhaled nitric oxide (FENO) was lower in the budesonide groups than in the albuterol-only group. Patients in the budesonide/formoterol group had a 56% lower relative risk of severe pulmonary exacerbation than patients in the budesonide maintenance group and a 60% lower relative risk than the albuterol group. However, maintenance budesonide provided better symptom relief than budesonide/formoterol, “which suggests that for the patient for whom asthma symptoms rather than exacerbations are the most bothersome, maintenance treatment has value,” the investigators wrote (New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901963).

“The findings of our trial are consistent with evidence regarding the treatment of moderate and severe asthma – that maintenance and reliever therapy” with inhaled glucocorticoid/formoterol “results in a lower risk of severe exacerbations than maintenance therapy with an inhaled glucocorticoid–[long-acting beta agonist] and as-needed SABA,” the investigators concluded.

SIENA was funded by National Heart, Lung, and Blood Institute, with medications provided by Boehringer Ingelheim, Merck, and Teva; the investigators reported relationships with Sanofi, Vectura, Circassia, DBV Technologies, and others. Novel START was funded by AstraZeneca and the Health Research Council of New Zealand; the investigators reported relationships with GlaxoSmithKline, Genentech, Theravance Biopharma, and others.

SOURCES: Beasley et al. New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901963; Lazarus et al. New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1814917.

Patients with mild asthma who rely solely on short-acting beta2-agonists (SABAs) to control their asthma symptoms remain at increased risk of exacerbations, according to investigators.

Two recent studies presented at the American Thoracic Society’s international conference demonstrated the benefits of glucocorticoid therapy among patients with mild persistent or intermittent asthma while highlighting differential responses to steroids among patients with high versus low levels of eosinophils in sputum. Both studies were simultaneously published in the New England Journal of Medicine.

The first study, SIENA, led by Stephen C. Lazarus, MD of the University of California, San Francisco, and colleagues, involved 295 patients with mild, persistent asthma. Patients were classified as having either a high or low level of eosinophils in sputum, with a low level defined by two sputum samples consisting of less than 2% eosinophils. After a single-blind placebo run-in period of 6 weeks, patients were randomized to receive either mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist [LAMA]), or placebo for 12 weeks each, with subsequent crossover through the two remaining treatments. The primary outcome was the response to each active agent, compared with placebo among low-eosinophil patients who had a differential response to a trial agent.

Out of 295 patients, 221 (75%) had low eosinophils and 74 (25%) had high eosinophils. In the low-eosinophil subgroup, 59% of patients had a differential response to a trial agent; among these, 57% responded better to mometasone, compared with 43% who responded better to placebo, and 60% responded better to tiotropium, compared with 40% who responded better to placebo.

Turning to secondary analyses, among patients with high eosinophil levels who had a differential response, 74% responded better to mometasone, compared with 26% who responded better to placebo, and 57% responded better to tiotropium, compared with 43% who responded better to placebo.

In an additional exploratory analysis, adults with low eosinophil levels had better responses to tiotropium than placebo (62% vs 38%).

The researchers stated that a key finding of the study is that three-quarters of the mild, persistent asthma population had low eosinophil levels, far fewer than expected and that the difference in their response to mometasone compared to tiotropium was not significant.

“Our results raise the question of whether treatment guidelines should be reevaluated for patients with mild, persistent asthma for whom evidence of type 2 inflammation is lacking,” the investigators wrote. “The need for a change in treatment strategy is further highlighted by a growing body of literature suggesting that mild, persistent asthma can be managed safely without the daily use of inhaled glucocorticoids and by data showing that patients with a low eosinophil level may not have a favorable response to inhaled glucocorticoids” (New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1814917).

The second study, Novel START, conducted by lead author Richard Beasley, DSc, of the Medical Research Institute of New Zealand, Wellington, and colleagues, compared the efficacy of two inhaled glucocorticoid regimens and albuterol alone for patients with mild persistent or intermittent asthma, measured by annualized exacerbation rate.

Initial randomization involved 675 patients, of whom 668 were included in the final analysis. Patients were randomized into three groups: albuterol as needed (100 mcg, two inhalations as needed for asthma symptoms), budesonide maintenance (200 mcg, one inhalation twice daily with as-needed albuterol), or budesonide/formoterol (budesonide 200 mcg and formoterol 6 mcg, one inhalation as needed). Along with annualized exacerbation rate, several secondary outcomes assessed symptoms, respiratory function, and number of severe exacerbations.

Data analysis showed that patients in the budesonide groups had similar rates of annualized exacerbation, both of which were significantly better than the exacerbation rate in the albuterol-only group; the absolute rate of exacerbations per patient per year was 0.175, 0.195, and 0.400 for budesonide maintenance, budesonide/formoterol, and albuterol only, respectively. Similarly, the median fraction of exhaled nitric oxide (FENO) was lower in the budesonide groups than in the albuterol-only group. Patients in the budesonide/formoterol group had a 56% lower relative risk of severe pulmonary exacerbation than patients in the budesonide maintenance group and a 60% lower relative risk than the albuterol group. However, maintenance budesonide provided better symptom relief than budesonide/formoterol, “which suggests that for the patient for whom asthma symptoms rather than exacerbations are the most bothersome, maintenance treatment has value,” the investigators wrote (New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901963).

“The findings of our trial are consistent with evidence regarding the treatment of moderate and severe asthma – that maintenance and reliever therapy” with inhaled glucocorticoid/formoterol “results in a lower risk of severe exacerbations than maintenance therapy with an inhaled glucocorticoid–[long-acting beta agonist] and as-needed SABA,” the investigators concluded.

SIENA was funded by National Heart, Lung, and Blood Institute, with medications provided by Boehringer Ingelheim, Merck, and Teva; the investigators reported relationships with Sanofi, Vectura, Circassia, DBV Technologies, and others. Novel START was funded by AstraZeneca and the Health Research Council of New Zealand; the investigators reported relationships with GlaxoSmithKline, Genentech, Theravance Biopharma, and others.

SOURCES: Beasley et al. New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901963; Lazarus et al. New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1814917.

Patients with mild asthma who rely solely on short-acting beta2-agonists (SABAs) to control their asthma symptoms remain at increased risk of exacerbations, according to investigators.

Two recent studies presented at the American Thoracic Society’s international conference demonstrated the benefits of glucocorticoid therapy among patients with mild persistent or intermittent asthma while highlighting differential responses to steroids among patients with high versus low levels of eosinophils in sputum. Both studies were simultaneously published in the New England Journal of Medicine.

The first study, SIENA, led by Stephen C. Lazarus, MD of the University of California, San Francisco, and colleagues, involved 295 patients with mild, persistent asthma. Patients were classified as having either a high or low level of eosinophils in sputum, with a low level defined by two sputum samples consisting of less than 2% eosinophils. After a single-blind placebo run-in period of 6 weeks, patients were randomized to receive either mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist [LAMA]), or placebo for 12 weeks each, with subsequent crossover through the two remaining treatments. The primary outcome was the response to each active agent, compared with placebo among low-eosinophil patients who had a differential response to a trial agent.

Out of 295 patients, 221 (75%) had low eosinophils and 74 (25%) had high eosinophils. In the low-eosinophil subgroup, 59% of patients had a differential response to a trial agent; among these, 57% responded better to mometasone, compared with 43% who responded better to placebo, and 60% responded better to tiotropium, compared with 40% who responded better to placebo.

Turning to secondary analyses, among patients with high eosinophil levels who had a differential response, 74% responded better to mometasone, compared with 26% who responded better to placebo, and 57% responded better to tiotropium, compared with 43% who responded better to placebo.

In an additional exploratory analysis, adults with low eosinophil levels had better responses to tiotropium than placebo (62% vs 38%).

The researchers stated that a key finding of the study is that three-quarters of the mild, persistent asthma population had low eosinophil levels, far fewer than expected and that the difference in their response to mometasone compared to tiotropium was not significant.

“Our results raise the question of whether treatment guidelines should be reevaluated for patients with mild, persistent asthma for whom evidence of type 2 inflammation is lacking,” the investigators wrote. “The need for a change in treatment strategy is further highlighted by a growing body of literature suggesting that mild, persistent asthma can be managed safely without the daily use of inhaled glucocorticoids and by data showing that patients with a low eosinophil level may not have a favorable response to inhaled glucocorticoids” (New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1814917).

The second study, Novel START, conducted by lead author Richard Beasley, DSc, of the Medical Research Institute of New Zealand, Wellington, and colleagues, compared the efficacy of two inhaled glucocorticoid regimens and albuterol alone for patients with mild persistent or intermittent asthma, measured by annualized exacerbation rate.

Initial randomization involved 675 patients, of whom 668 were included in the final analysis. Patients were randomized into three groups: albuterol as needed (100 mcg, two inhalations as needed for asthma symptoms), budesonide maintenance (200 mcg, one inhalation twice daily with as-needed albuterol), or budesonide/formoterol (budesonide 200 mcg and formoterol 6 mcg, one inhalation as needed). Along with annualized exacerbation rate, several secondary outcomes assessed symptoms, respiratory function, and number of severe exacerbations.

Data analysis showed that patients in the budesonide groups had similar rates of annualized exacerbation, both of which were significantly better than the exacerbation rate in the albuterol-only group; the absolute rate of exacerbations per patient per year was 0.175, 0.195, and 0.400 for budesonide maintenance, budesonide/formoterol, and albuterol only, respectively. Similarly, the median fraction of exhaled nitric oxide (FENO) was lower in the budesonide groups than in the albuterol-only group. Patients in the budesonide/formoterol group had a 56% lower relative risk of severe pulmonary exacerbation than patients in the budesonide maintenance group and a 60% lower relative risk than the albuterol group. However, maintenance budesonide provided better symptom relief than budesonide/formoterol, “which suggests that for the patient for whom asthma symptoms rather than exacerbations are the most bothersome, maintenance treatment has value,” the investigators wrote (New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901963).

“The findings of our trial are consistent with evidence regarding the treatment of moderate and severe asthma – that maintenance and reliever therapy” with inhaled glucocorticoid/formoterol “results in a lower risk of severe exacerbations than maintenance therapy with an inhaled glucocorticoid–[long-acting beta agonist] and as-needed SABA,” the investigators concluded.

SIENA was funded by National Heart, Lung, and Blood Institute, with medications provided by Boehringer Ingelheim, Merck, and Teva; the investigators reported relationships with Sanofi, Vectura, Circassia, DBV Technologies, and others. Novel START was funded by AstraZeneca and the Health Research Council of New Zealand; the investigators reported relationships with GlaxoSmithKline, Genentech, Theravance Biopharma, and others.

SOURCES: Beasley et al. New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901963; Lazarus et al. New Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1814917.

NEW ORLEANS – When HIV-negative children born to mothers infected with HIV are evaluated in adolescence, they are found to have far higher rates of obesity and reactive airway disease than are those with no such exposure, according to research that provides a compelling link between inflammatory activity in utero and subsequent risk of metabolic disorders.

Most supportive of that link was a near-linear inverse relationship between CD4 counts during the time of pregnancy and risk of both obesity and reactive respiratory disease more than a decade later, according to research presented by Lindsay Fourman, MD, an instructor in medicine at Massachusetts General Hospital, Boston, during the annual meeting of the Endocrine Society.

In this video interview, Dr. Fourman discusses the effort to understand the long-term health consequences of being exposed to HIV and antiretroviral therapies while in utero, a group known by the acronym HIV-exposed uninfected (HEU). With effective therapies now routinely preventing mother-to-child transmission, this population of children is growing quickly.

For this study, 50 HEU individuals were identified from a patient database. They were matched in a 3:1 ratio to a control group for a variety of demographic and socioeconomic variables. At a median age of 18 years, the HEU population was found to have a “strikingly” higher rate of obesity, compared with controls (42% vs. 25%, respectively; P = .04). The rate of reactive airway disease was similarly increased in the HEU group (40% vs. 24%; P = .04).

These data are important for considering health risks in an HEU population, but Dr. Fourman explained that it provides support for looking at metabolic risks from other in utero exposures linked to upregulated inflammation, such as gestational diabetes or obesity.

Dr Fourman and her colleagues reported no disclosures or financial conflicts of interest.

SOURCE: Fourman L et al. ENDO 2019, Session P10 (SAT-256).

NEW ORLEANS – When HIV-negative children born to mothers infected with HIV are evaluated in adolescence, they are found to have far higher rates of obesity and reactive airway disease than are those with no such exposure, according to research that provides a compelling link between inflammatory activity in utero and subsequent risk of metabolic disorders.

Most supportive of that link was a near-linear inverse relationship between CD4 counts during the time of pregnancy and risk of both obesity and reactive respiratory disease more than a decade later, according to research presented by Lindsay Fourman, MD, an instructor in medicine at Massachusetts General Hospital, Boston, during the annual meeting of the Endocrine Society.

In this video interview, Dr. Fourman discusses the effort to understand the long-term health consequences of being exposed to HIV and antiretroviral therapies while in utero, a group known by the acronym HIV-exposed uninfected (HEU). With effective therapies now routinely preventing mother-to-child transmission, this population of children is growing quickly.

For this study, 50 HEU individuals were identified from a patient database. They were matched in a 3:1 ratio to a control group for a variety of demographic and socioeconomic variables. At a median age of 18 years, the HEU population was found to have a “strikingly” higher rate of obesity, compared with controls (42% vs. 25%, respectively; P = .04). The rate of reactive airway disease was similarly increased in the HEU group (40% vs. 24%; P = .04).

These data are important for considering health risks in an HEU population, but Dr. Fourman explained that it provides support for looking at metabolic risks from other in utero exposures linked to upregulated inflammation, such as gestational diabetes or obesity.

Dr Fourman and her colleagues reported no disclosures or financial conflicts of interest.

SOURCE: Fourman L et al. ENDO 2019, Session P10 (SAT-256).

NEW ORLEANS – When HIV-negative children born to mothers infected with HIV are evaluated in adolescence, they are found to have far higher rates of obesity and reactive airway disease than are those with no such exposure, according to research that provides a compelling link between inflammatory activity in utero and subsequent risk of metabolic disorders.

Most supportive of that link was a near-linear inverse relationship between CD4 counts during the time of pregnancy and risk of both obesity and reactive respiratory disease more than a decade later, according to research presented by Lindsay Fourman, MD, an instructor in medicine at Massachusetts General Hospital, Boston, during the annual meeting of the Endocrine Society.

In this video interview, Dr. Fourman discusses the effort to understand the long-term health consequences of being exposed to HIV and antiretroviral therapies while in utero, a group known by the acronym HIV-exposed uninfected (HEU). With effective therapies now routinely preventing mother-to-child transmission, this population of children is growing quickly.

For this study, 50 HEU individuals were identified from a patient database. They were matched in a 3:1 ratio to a control group for a variety of demographic and socioeconomic variables. At a median age of 18 years, the HEU population was found to have a “strikingly” higher rate of obesity, compared with controls (42% vs. 25%, respectively; P = .04). The rate of reactive airway disease was similarly increased in the HEU group (40% vs. 24%; P = .04).

These data are important for considering health risks in an HEU population, but Dr. Fourman explained that it provides support for looking at metabolic risks from other in utero exposures linked to upregulated inflammation, such as gestational diabetes or obesity.

Dr Fourman and her colleagues reported no disclosures or financial conflicts of interest.

SOURCE: Fourman L et al. ENDO 2019, Session P10 (SAT-256).

NEW ORLEANS – A hormone that is oversecreted in obesity may provide a pathway from adipose to lung tissue in individuals with both obesity and asthma, according to new research presented at the annual meeting of the Endocrine Society.

“Obesity-related asthma is a really understudied and new phenomenon. It’s a unique complication of obesity,” said Furkan Burak, MD, in a video interview after an obesity-focused press conference.

“In addition to being a standalone disease, obesity mostly comes as a package. And that’s the problem,” said Dr. Burak, pointing to obesity-related asthma’s clustering with diseases such as diabetes and atherosclerosis.

Asthma affects 10% of the world population, and it’s becoming increasingly understood that obesity-related, adult-onset asthma is a separate disease entity from allergic asthma, which usually begins in childhood, said Dr. Burak, an endocrinology fellow at Brigham and Women’s Hospital, Boston.

“There are two types of asthma related to obesity,” he said. Classic allergic asthma can get worse with obesity; however, asthma can sometimes occur de novo in adults, particularly women, with obesity. “What is important is … that they are less responsive to classic treatments,” such as steroids and beta-agonists. “And the problem is not small: Of asthmatics, 40% are obese. It’s a therapeutic problem, and we are not able to treat them well.”

The fatty acid binding protein 4, aP2, a hormone that is released by adipose tissue, travels to distant organs and regulates metabolic responses. Levels of aP2 are known to be increased in obesity, particularly in individuals with asthma, said Dr. Burak.

Citing work done at Brigham and Women’s Hospital and at Boston’s Harvard Medical School, as well as elsewhere, Dr. Burak and his collaborators noted in the abstract accompanying the presentation that “increased serum aP2 levels strongly correlate with poor metabolic, inflammatory, and cardiovascular outcomes in multiple independent human studies.”

Dr. Burak said he and his colleagues are trying to sort out “how a fat-tissue–borne hormone could potentially cause a problem in the lung.”

A big clue came with the discovery that patients with asthma and obesity have elevated levels of aP2 within their airways when bronchoalveolar lavage is performed, suggesting that the hormone may be the pathological mediator linking obesity to asthma – “a direct link between the fat tissue and the lung,” he said.

Serum aP2 levels were available from the Nurse’s Health Study, so Dr. Burak and his colleagues looked at those levels in randomly selected study participants. “We found that aP2 levels were elevated 25.6% – significantly – in asthmatics, compared with nonasthmatics, but only in obese and overweight [participants, and] not in lean” participants, he said.

Dr. Burak and his colleagues compared 525 individuals with body mass indices of less than 25 kg/m², of whom 15 had asthma, with 385 individuals with body mass indices of more than 25, of whom 15 of whom had asthma.

Collecting bronchoalveolar lavage fluid from individuals with asthma showed a mean increase of 23% in aP2 levels in patients with obesity compared with lean individuals.

These data taken together show both systemic and local elevations of aP2 in human obesity. “That could contribute to the airway hyperreactivity and to the asthma pathogenesis,” which would confirm findings from animal studies, said Dr. Burak.

Further investigation will focus on individuals who are haploinsufficient for aP2. The group already is known to have lower risk for dyslipidemia, diabetes, and cardiovascular disease, but Dr. Burak and his collaborators also will determine whether asthma incidence is also lower.

The eventual goal is to attack aP2 as a therapeutic target. “Can we inhibit and target aP2 therapeutically in the context of obesity to treat obesity-related asthma? We have a big hope for that.”

Dr. Burak and his colleagues reported no disclosures or financial conflicts of interest.

[email protected]

SOURCE: Burak MF et al. ENDO 2019, Session OR01-1.

NEW ORLEANS – A hormone that is oversecreted in obesity may provide a pathway from adipose to lung tissue in individuals with both obesity and asthma, according to new research presented at the annual meeting of the Endocrine Society.

“Obesity-related asthma is a really understudied and new phenomenon. It’s a unique complication of obesity,” said Furkan Burak, MD, in a video interview after an obesity-focused press conference.

“In addition to being a standalone disease, obesity mostly comes as a package. And that’s the problem,” said Dr. Burak, pointing to obesity-related asthma’s clustering with diseases such as diabetes and atherosclerosis.

Asthma affects 10% of the world population, and it’s becoming increasingly understood that obesity-related, adult-onset asthma is a separate disease entity from allergic asthma, which usually begins in childhood, said Dr. Burak, an endocrinology fellow at Brigham and Women’s Hospital, Boston.

“There are two types of asthma related to obesity,” he said. Classic allergic asthma can get worse with obesity; however, asthma can sometimes occur de novo in adults, particularly women, with obesity. “What is important is … that they are less responsive to classic treatments,” such as steroids and beta-agonists. “And the problem is not small: Of asthmatics, 40% are obese. It’s a therapeutic problem, and we are not able to treat them well.”

The fatty acid binding protein 4, aP2, a hormone that is released by adipose tissue, travels to distant organs and regulates metabolic responses. Levels of aP2 are known to be increased in obesity, particularly in individuals with asthma, said Dr. Burak.

Citing work done at Brigham and Women’s Hospital and at Boston’s Harvard Medical School, as well as elsewhere, Dr. Burak and his collaborators noted in the abstract accompanying the presentation that “increased serum aP2 levels strongly correlate with poor metabolic, inflammatory, and cardiovascular outcomes in multiple independent human studies.”

Dr. Burak said he and his colleagues are trying to sort out “how a fat-tissue–borne hormone could potentially cause a problem in the lung.”

A big clue came with the discovery that patients with asthma and obesity have elevated levels of aP2 within their airways when bronchoalveolar lavage is performed, suggesting that the hormone may be the pathological mediator linking obesity to asthma – “a direct link between the fat tissue and the lung,” he said.

Serum aP2 levels were available from the Nurse’s Health Study, so Dr. Burak and his colleagues looked at those levels in randomly selected study participants. “We found that aP2 levels were elevated 25.6% – significantly – in asthmatics, compared with nonasthmatics, but only in obese and overweight [participants, and] not in lean” participants, he said.

Dr. Burak and his colleagues compared 525 individuals with body mass indices of less than 25 kg/m², of whom 15 had asthma, with 385 individuals with body mass indices of more than 25, of whom 15 of whom had asthma.

Collecting bronchoalveolar lavage fluid from individuals with asthma showed a mean increase of 23% in aP2 levels in patients with obesity compared with lean individuals.

These data taken together show both systemic and local elevations of aP2 in human obesity. “That could contribute to the airway hyperreactivity and to the asthma pathogenesis,” which would confirm findings from animal studies, said Dr. Burak.

Further investigation will focus on individuals who are haploinsufficient for aP2. The group already is known to have lower risk for dyslipidemia, diabetes, and cardiovascular disease, but Dr. Burak and his collaborators also will determine whether asthma incidence is also lower.

The eventual goal is to attack aP2 as a therapeutic target. “Can we inhibit and target aP2 therapeutically in the context of obesity to treat obesity-related asthma? We have a big hope for that.”

Dr. Burak and his colleagues reported no disclosures or financial conflicts of interest.

[email protected]

SOURCE: Burak MF et al. ENDO 2019, Session OR01-1.

NEW ORLEANS – A hormone that is oversecreted in obesity may provide a pathway from adipose to lung tissue in individuals with both obesity and asthma, according to new research presented at the annual meeting of the Endocrine Society.

“Obesity-related asthma is a really understudied and new phenomenon. It’s a unique complication of obesity,” said Furkan Burak, MD, in a video interview after an obesity-focused press conference.

“In addition to being a standalone disease, obesity mostly comes as a package. And that’s the problem,” said Dr. Burak, pointing to obesity-related asthma’s clustering with diseases such as diabetes and atherosclerosis.

Asthma affects 10% of the world population, and it’s becoming increasingly understood that obesity-related, adult-onset asthma is a separate disease entity from allergic asthma, which usually begins in childhood, said Dr. Burak, an endocrinology fellow at Brigham and Women’s Hospital, Boston.

“There are two types of asthma related to obesity,” he said. Classic allergic asthma can get worse with obesity; however, asthma can sometimes occur de novo in adults, particularly women, with obesity. “What is important is … that they are less responsive to classic treatments,” such as steroids and beta-agonists. “And the problem is not small: Of asthmatics, 40% are obese. It’s a therapeutic problem, and we are not able to treat them well.”

The fatty acid binding protein 4, aP2, a hormone that is released by adipose tissue, travels to distant organs and regulates metabolic responses. Levels of aP2 are known to be increased in obesity, particularly in individuals with asthma, said Dr. Burak.

Citing work done at Brigham and Women’s Hospital and at Boston’s Harvard Medical School, as well as elsewhere, Dr. Burak and his collaborators noted in the abstract accompanying the presentation that “increased serum aP2 levels strongly correlate with poor metabolic, inflammatory, and cardiovascular outcomes in multiple independent human studies.”

Dr. Burak said he and his colleagues are trying to sort out “how a fat-tissue–borne hormone could potentially cause a problem in the lung.”

A big clue came with the discovery that patients with asthma and obesity have elevated levels of aP2 within their airways when bronchoalveolar lavage is performed, suggesting that the hormone may be the pathological mediator linking obesity to asthma – “a direct link between the fat tissue and the lung,” he said.

Serum aP2 levels were available from the Nurse’s Health Study, so Dr. Burak and his colleagues looked at those levels in randomly selected study participants. “We found that aP2 levels were elevated 25.6% – significantly – in asthmatics, compared with nonasthmatics, but only in obese and overweight [participants, and] not in lean” participants, he said.

Dr. Burak and his colleagues compared 525 individuals with body mass indices of less than 25 kg/m², of whom 15 had asthma, with 385 individuals with body mass indices of more than 25, of whom 15 of whom had asthma.

Collecting bronchoalveolar lavage fluid from individuals with asthma showed a mean increase of 23% in aP2 levels in patients with obesity compared with lean individuals.

These data taken together show both systemic and local elevations of aP2 in human obesity. “That could contribute to the airway hyperreactivity and to the asthma pathogenesis,” which would confirm findings from animal studies, said Dr. Burak.

Further investigation will focus on individuals who are haploinsufficient for aP2. The group already is known to have lower risk for dyslipidemia, diabetes, and cardiovascular disease, but Dr. Burak and his collaborators also will determine whether asthma incidence is also lower.

The eventual goal is to attack aP2 as a therapeutic target. “Can we inhibit and target aP2 therapeutically in the context of obesity to treat obesity-related asthma? We have a big hope for that.”

Dr. Burak and his colleagues reported no disclosures or financial conflicts of interest.

[email protected]

SOURCE: Burak MF et al. ENDO 2019, Session OR01-1.

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Even the best physicians make mistakes.

Each of us can recall a patient for whom our initial diagnosis was incorrect, or conversely, where we uncovered the correct diagnosis. My memorable mistake was missing an obvious case of hypothyroidism, and my happier encounter was correcting an incorrect diagnosis of asthma when the patient actually had primary pulmonary fibrosis. These patients came to mind as I read this month’s cover story, “COPD and asthma: Diagnostic accuracy requires spirometry.”

In a previous editorial, “When our biases derail the diagnosis,”¹ I discussed types of cognitive bias that can lead us to the wrong conclusion. Today, I want to address diagnostic errors in medicine as a patient safety issue.

Listening closely to the patient's and family's concerns can lead in a direction other than my initial impression.

The patient safety movement gained traction in 1999 with the publication of the Institute of Medicine (IOM, now National Academy of Medicine) report, To Err is Human: Building a Safer Health System. That report focused on health care system issues and had little to offer regarding improving diagnoses. It was not until 2015, with the publication of the IOM report Improving Diagnosis in Health Care, that serious national attention was directed to accurate diagnosis. It is worth reading the summary of this report, which includes 8 goals and is available at nas.edu/improvingdiagnosis.

The recommendations most pertinent to family physicians are to: 1) facilitate more effective teamwork among health care professionals, patients, and families, 2) teach health care professionals about the diagnostic process, 3) ensure that technology supports proper diagnosis, 4) establish a work culture that supports diagnostic processes, and 5) identify diagnostic errors and learn from them.

Teamwork. The first recommendation is intriguing because the focus on teamwork includes patients and their families. I have found that listening closely to the patient’s and family’s concerns can lead me in a direction other than my initial impression—especially when they are insistent about a particular diagnosis.

Technology. Despite all of their “warts,” electronic health records are gradually incorporating clinical decision support tools that really do help steer us in the right direction. I have found that electronic point-of-care references can be very helpful in establishing an accurate diagnosis in the exam room—and can help convince patients that my diagnosis is correct when they read it for themselves!

Continue to: Finally, discussing our mistakes...

Finally, discussing our mistakes openly with our colleagues helps us—and them—to avoid that mistake in the future. Let’s be sure to keep that dialogue open. And let’s continue to refine our diagnostic skills so that we can continue to keep our patients safe.

Even the best physicians make mistakes.

Each of us can recall a patient for whom our initial diagnosis was incorrect, or conversely, where we uncovered the correct diagnosis. My memorable mistake was missing an obvious case of hypothyroidism, and my happier encounter was correcting an incorrect diagnosis of asthma when the patient actually had primary pulmonary fibrosis. These patients came to mind as I read this month’s cover story, “COPD and asthma: Diagnostic accuracy requires spirometry.”

In a previous editorial, “When our biases derail the diagnosis,”¹ I discussed types of cognitive bias that can lead us to the wrong conclusion. Today, I want to address diagnostic errors in medicine as a patient safety issue.

Listening closely to the patient's and family's concerns can lead in a direction other than my initial impression.

The patient safety movement gained traction in 1999 with the publication of the Institute of Medicine (IOM, now National Academy of Medicine) report, To Err is Human: Building a Safer Health System. That report focused on health care system issues and had little to offer regarding improving diagnoses. It was not until 2015, with the publication of the IOM report Improving Diagnosis in Health Care, that serious national attention was directed to accurate diagnosis. It is worth reading the summary of this report, which includes 8 goals and is available at nas.edu/improvingdiagnosis.

The recommendations most pertinent to family physicians are to: 1) facilitate more effective teamwork among health care professionals, patients, and families, 2) teach health care professionals about the diagnostic process, 3) ensure that technology supports proper diagnosis, 4) establish a work culture that supports diagnostic processes, and 5) identify diagnostic errors and learn from them.

Teamwork. The first recommendation is intriguing because the focus on teamwork includes patients and their families. I have found that listening closely to the patient’s and family’s concerns can lead me in a direction other than my initial impression—especially when they are insistent about a particular diagnosis.

Technology. Despite all of their “warts,” electronic health records are gradually incorporating clinical decision support tools that really do help steer us in the right direction. I have found that electronic point-of-care references can be very helpful in establishing an accurate diagnosis in the exam room—and can help convince patients that my diagnosis is correct when they read it for themselves!

Continue to: Finally, discussing our mistakes...

Finally, discussing our mistakes openly with our colleagues helps us—and them—to avoid that mistake in the future. Let’s be sure to keep that dialogue open. And let’s continue to refine our diagnostic skills so that we can continue to keep our patients safe.

Even the best physicians make mistakes.

Each of us can recall a patient for whom our initial diagnosis was incorrect, or conversely, where we uncovered the correct diagnosis. My memorable mistake was missing an obvious case of hypothyroidism, and my happier encounter was correcting an incorrect diagnosis of asthma when the patient actually had primary pulmonary fibrosis. These patients came to mind as I read this month’s cover story, “COPD and asthma: Diagnostic accuracy requires spirometry.”

In a previous editorial, “When our biases derail the diagnosis,”¹ I discussed types of cognitive bias that can lead us to the wrong conclusion. Today, I want to address diagnostic errors in medicine as a patient safety issue.

Listening closely to the patient's and family's concerns can lead in a direction other than my initial impression.

The patient safety movement gained traction in 1999 with the publication of the Institute of Medicine (IOM, now National Academy of Medicine) report, To Err is Human: Building a Safer Health System. That report focused on health care system issues and had little to offer regarding improving diagnoses. It was not until 2015, with the publication of the IOM report Improving Diagnosis in Health Care, that serious national attention was directed to accurate diagnosis. It is worth reading the summary of this report, which includes 8 goals and is available at nas.edu/improvingdiagnosis.

The recommendations most pertinent to family physicians are to: 1) facilitate more effective teamwork among health care professionals, patients, and families, 2) teach health care professionals about the diagnostic process, 3) ensure that technology supports proper diagnosis, 4) establish a work culture that supports diagnostic processes, and 5) identify diagnostic errors and learn from them.

Teamwork. The first recommendation is intriguing because the focus on teamwork includes patients and their families. I have found that listening closely to the patient’s and family’s concerns can lead me in a direction other than my initial impression—especially when they are insistent about a particular diagnosis.

Technology. Despite all of their “warts,” electronic health records are gradually incorporating clinical decision support tools that really do help steer us in the right direction. I have found that electronic point-of-care references can be very helpful in establishing an accurate diagnosis in the exam room—and can help convince patients that my diagnosis is correct when they read it for themselves!

Continue to: Finally, discussing our mistakes...

Finally, discussing our mistakes openly with our colleagues helps us—and them—to avoid that mistake in the future. Let’s be sure to keep that dialogue open. And let’s continue to refine our diagnostic skills so that we can continue to keep our patients safe.

SAN FRANCISCO – Less than 4% of people who undergo drug-allergy testing are positive and need to avoid the drug in the future, but many patients who undergo drug-allergy testing and have a negative result cling to their allergic status and struggle with letting go.

Mitchel L. Zoler/MDedge News

New findings suggest that preexisting anxiety or depression plays a role in some people who refuse to believe a negative drug-allergy result, which suggests that these people may need a more tailored intervention to drug-allergy testing and its aftermath, including some type of behavioral intervention.

“Underlying anxiety and depression may reduce the effectiveness of negative drug-allergy evaluation and functional delabeling,” Christine Rukasin, MD, said while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “In the future, tailored drug-allergy evaluation, behavioral interventions, targeted follow-up communication, and patient education appear necessary to improve the sustained effectiveness of a negative drug-allergy and functional delabeling,” said Dr. Rukasin, an allergy immunology physician at Vanderbilt University in Nashville, Tenn.

The results showed that some people who undergo drug allergy testing “have a high anxiety state and don’t feel comfortable regardless of their test result,” she said in an interview. “This is not where one size fits all. We usually perform a single, oral drug challenge and then pronounce the person free of allergy if the result was negative. We need to better anticipate how effective a drug evaluation will be for someone; will they believe the result?” Individual patients, especially those with diagnosed anxiety or depression, may need multiple challenge tests, both oral and skin, before they believe a negative result, and they may also need referral to a behavioral health specialist, she said.

Dr. Rukasin and her associates ran their study with 100 people who underwent assessment at the Vanderbilt drug-allergy clinic and completed a set of questionnaires. The range of suspected drug allergies included 40% with a suspected reaction to penicillin, 22% to a sulfa-containing drug, 17% to a cephalosporin, 8% to another antibiotic, 7% to an NSAID, and the remainder to other drugs. The 100 participants included 57 people without diagnosed anxiety or depression, 31 diagnosed with anxiety, and 33 diagnosed with depression; some patients had diagnoses for both anxiety and depression.

The questionnaire results from before and after drug-allergy testing showed an apparent association between anxiety, depression, and a decreased willingness to believe the results of a negative drug-allergy test. For example, when posed with the prospect of finding out they were not allergic to the tested drug, 24% of the people with anxiety and 20% of those with depression said that they still would not take the medication if it were prescribed to them, compared with 7% of those without anxiety or depression who gave this response.

Many patients who come to the drug-allergy clinic are scared and worried. “We want to dig deeper, to better help these patients,” Dr. Rukasin said. This is the first reported study to evaluate anxiety in the setting of drug-allergy testing. Further insight into ways to improve the effectiveness of drug-allergy testing hopefully will come from additional analysis of the findings.

Dr. Rukasin had no relevant financial disclosures.

[email protected]

SOURCE: Rukasin C et al. J Allergy Clin Immunol. 2019 Feb;143(2):AB428.

SAN FRANCISCO – Less than 4% of people who undergo drug-allergy testing are positive and need to avoid the drug in the future, but many patients who undergo drug-allergy testing and have a negative result cling to their allergic status and struggle with letting go.

Mitchel L. Zoler/MDedge News

New findings suggest that preexisting anxiety or depression plays a role in some people who refuse to believe a negative drug-allergy result, which suggests that these people may need a more tailored intervention to drug-allergy testing and its aftermath, including some type of behavioral intervention.

“Underlying anxiety and depression may reduce the effectiveness of negative drug-allergy evaluation and functional delabeling,” Christine Rukasin, MD, said while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “In the future, tailored drug-allergy evaluation, behavioral interventions, targeted follow-up communication, and patient education appear necessary to improve the sustained effectiveness of a negative drug-allergy and functional delabeling,” said Dr. Rukasin, an allergy immunology physician at Vanderbilt University in Nashville, Tenn.

The results showed that some people who undergo drug allergy testing “have a high anxiety state and don’t feel comfortable regardless of their test result,” she said in an interview. “This is not where one size fits all. We usually perform a single, oral drug challenge and then pronounce the person free of allergy if the result was negative. We need to better anticipate how effective a drug evaluation will be for someone; will they believe the result?” Individual patients, especially those with diagnosed anxiety or depression, may need multiple challenge tests, both oral and skin, before they believe a negative result, and they may also need referral to a behavioral health specialist, she said.

Dr. Rukasin and her associates ran their study with 100 people who underwent assessment at the Vanderbilt drug-allergy clinic and completed a set of questionnaires. The range of suspected drug allergies included 40% with a suspected reaction to penicillin, 22% to a sulfa-containing drug, 17% to a cephalosporin, 8% to another antibiotic, 7% to an NSAID, and the remainder to other drugs. The 100 participants included 57 people without diagnosed anxiety or depression, 31 diagnosed with anxiety, and 33 diagnosed with depression; some patients had diagnoses for both anxiety and depression.

The questionnaire results from before and after drug-allergy testing showed an apparent association between anxiety, depression, and a decreased willingness to believe the results of a negative drug-allergy test. For example, when posed with the prospect of finding out they were not allergic to the tested drug, 24% of the people with anxiety and 20% of those with depression said that they still would not take the medication if it were prescribed to them, compared with 7% of those without anxiety or depression who gave this response.

Many patients who come to the drug-allergy clinic are scared and worried. “We want to dig deeper, to better help these patients,” Dr. Rukasin said. This is the first reported study to evaluate anxiety in the setting of drug-allergy testing. Further insight into ways to improve the effectiveness of drug-allergy testing hopefully will come from additional analysis of the findings.

Dr. Rukasin had no relevant financial disclosures.

[email protected]

SOURCE: Rukasin C et al. J Allergy Clin Immunol. 2019 Feb;143(2):AB428.

SAN FRANCISCO – Less than 4% of people who undergo drug-allergy testing are positive and need to avoid the drug in the future, but many patients who undergo drug-allergy testing and have a negative result cling to their allergic status and struggle with letting go.

Mitchel L. Zoler/MDedge News

New findings suggest that preexisting anxiety or depression plays a role in some people who refuse to believe a negative drug-allergy result, which suggests that these people may need a more tailored intervention to drug-allergy testing and its aftermath, including some type of behavioral intervention.

“Underlying anxiety and depression may reduce the effectiveness of negative drug-allergy evaluation and functional delabeling,” Christine Rukasin, MD, said while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. “In the future, tailored drug-allergy evaluation, behavioral interventions, targeted follow-up communication, and patient education appear necessary to improve the sustained effectiveness of a negative drug-allergy and functional delabeling,” said Dr. Rukasin, an allergy immunology physician at Vanderbilt University in Nashville, Tenn.

The results showed that some people who undergo drug allergy testing “have a high anxiety state and don’t feel comfortable regardless of their test result,” she said in an interview. “This is not where one size fits all. We usually perform a single, oral drug challenge and then pronounce the person free of allergy if the result was negative. We need to better anticipate how effective a drug evaluation will be for someone; will they believe the result?” Individual patients, especially those with diagnosed anxiety or depression, may need multiple challenge tests, both oral and skin, before they believe a negative result, and they may also need referral to a behavioral health specialist, she said.

Dr. Rukasin and her associates ran their study with 100 people who underwent assessment at the Vanderbilt drug-allergy clinic and completed a set of questionnaires. The range of suspected drug allergies included 40% with a suspected reaction to penicillin, 22% to a sulfa-containing drug, 17% to a cephalosporin, 8% to another antibiotic, 7% to an NSAID, and the remainder to other drugs. The 100 participants included 57 people without diagnosed anxiety or depression, 31 diagnosed with anxiety, and 33 diagnosed with depression; some patients had diagnoses for both anxiety and depression.

The questionnaire results from before and after drug-allergy testing showed an apparent association between anxiety, depression, and a decreased willingness to believe the results of a negative drug-allergy test. For example, when posed with the prospect of finding out they were not allergic to the tested drug, 24% of the people with anxiety and 20% of those with depression said that they still would not take the medication if it were prescribed to them, compared with 7% of those without anxiety or depression who gave this response.

Many patients who come to the drug-allergy clinic are scared and worried. “We want to dig deeper, to better help these patients,” Dr. Rukasin said. This is the first reported study to evaluate anxiety in the setting of drug-allergy testing. Further insight into ways to improve the effectiveness of drug-allergy testing hopefully will come from additional analysis of the findings.

Dr. Rukasin had no relevant financial disclosures.

[email protected]

SOURCE: Rukasin C et al. J Allergy Clin Immunol. 2019 Feb;143(2):AB428.

SAN FRANCISCO – Clinicians safely used epicutaneous immunotherapy to resolve eosinophilic esophagitis in children and teens secondary to milk consumption in a placebo-controlled, pilot study that included 20 patients.

Mitchel L. Zoler/MDedge News

Following the randomized phase of the study, all 19 patients who continued to participate began an 11-month open-label phase of epicutaneous immunotherapy to milk. At the end of this open-label phase, nine patients (47%) followed in this phase showed a substantial cut in their eosinophilic esophagitis (EoE) response to milk, with fewer than 15 eosinophils in a high-powered field, said Jonathan M. Spergel, MD, chief of the allergy section and Stuart E. Starr Chair of Pediatrics at the Children’s Hospital of Philadelphia, while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. An immunologic response of this sort would likely correlate with substantial clinical benefit.

“I’m happy with a 47% response,” Dr. Spergel said, adding that the responding patients “tolerate milk without symptoms, and there is really no risk” from this form of immunotherapy, which produced no serious adverse effects and caused 1 of 15 patients to stop treatment because of a treatment-related effect during the randomized phase. The most common adverse reaction was gastrointestinal symptoms, but these were just marginally more common among patients on active treatment than in control patients.

In contrast, oral immunotherapy with milk has been ineffective in children with an EoE milk reaction, and results from subcutaneous or sublingual immunotherapy for this form of milk allergy haven’t been reported, he said. The most common, current approaches to managing EoE from milk in children are either milk avoidance or treatment to reduce inflammation.

The epicutaneous approach “uses substantially lower dosing [micrograms vs. milligrams], avoids oral allergen ingestion, and may have a more advantageous adverse event profile and better adherence than other therapies,” according to a recent report that tested epicutaneous immunotherapy for peanut allergy in a phase 3 trial with 356 children (JAMA. 2019 Feb 22. doi: 10.1001/jama.2019.1113). The Viaskin Milk system tested in the current milk study involves placing a disc coated with 500 mcg of lyophilized milk protein on the skin for a gradually increasing number of hours daily until the disc is worn continuously, with daily changes of the disk. On the skin, the protein on the disk interacts with epidermal Langerhans cells to trigger desensitization.

The Milk Patch for Eosinophilic Esophagitis (SMILEE) study enrolled 20 patients at Children’s Hospital aged 4-17 years old and had milk-induced EoE, and randomized 15 to receive active epicutaneous immunotherapy to milk and 5 to receive placebo treatment. The protocol called for 9 month of epicutaneous immunotherapy without any milk exposure, followed by 2 months of continued treatment coupled with at least 240 mL of milk consumption daily. At the end of 2 months the researchers performed an esophageal biopsy on each patient to determine eosinophil density in the tissue. The study’s primary endpoint was the number of eosinophils in a high-powered field.

During the randomized phase, 8 of the 15 patients assigned to active treatment and 3 of 5 patients assigned to the placebo arm had violations of the treatment protocol, the diet protocol, or both. A per protocol analysis that focused on the seven actively treated and two placebo patients who adhered to the protocol showed a mean eosinophil count of 26 cells in patients on active treatment and 95 cells among the controls, a statistically significant difference. However, for the intention-to-treat analysis, which included all 20 enrolled patients, the primary endpoint showed no significant difference in eosinophil counts between the two study arms.

Although Dr. Spergel said that he was not aware of the developing company’s plans for further study of epicutaneous milk immunotherapy, from a scientific standpoint the next step should be a phase 2 or phase 2/3 trial for safety and efficacy. EoE was historically considered a rare disease, but a 2015 review of the condition called it “one of the most common conditions diagnosed during the assessment of feeding problems in children” (New Engl J Med. 2015 Oct 22;373[17]:1640-8).

The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.

[email protected]

SOURCE: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.

SAN FRANCISCO – Clinicians safely used epicutaneous immunotherapy to resolve eosinophilic esophagitis in children and teens secondary to milk consumption in a placebo-controlled, pilot study that included 20 patients.

Mitchel L. Zoler/MDedge News

Following the randomized phase of the study, all 19 patients who continued to participate began an 11-month open-label phase of epicutaneous immunotherapy to milk. At the end of this open-label phase, nine patients (47%) followed in this phase showed a substantial cut in their eosinophilic esophagitis (EoE) response to milk, with fewer than 15 eosinophils in a high-powered field, said Jonathan M. Spergel, MD, chief of the allergy section and Stuart E. Starr Chair of Pediatrics at the Children’s Hospital of Philadelphia, while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. An immunologic response of this sort would likely correlate with substantial clinical benefit.

“I’m happy with a 47% response,” Dr. Spergel said, adding that the responding patients “tolerate milk without symptoms, and there is really no risk” from this form of immunotherapy, which produced no serious adverse effects and caused 1 of 15 patients to stop treatment because of a treatment-related effect during the randomized phase. The most common adverse reaction was gastrointestinal symptoms, but these were just marginally more common among patients on active treatment than in control patients.

In contrast, oral immunotherapy with milk has been ineffective in children with an EoE milk reaction, and results from subcutaneous or sublingual immunotherapy for this form of milk allergy haven’t been reported, he said. The most common, current approaches to managing EoE from milk in children are either milk avoidance or treatment to reduce inflammation.

The epicutaneous approach “uses substantially lower dosing [micrograms vs. milligrams], avoids oral allergen ingestion, and may have a more advantageous adverse event profile and better adherence than other therapies,” according to a recent report that tested epicutaneous immunotherapy for peanut allergy in a phase 3 trial with 356 children (JAMA. 2019 Feb 22. doi: 10.1001/jama.2019.1113). The Viaskin Milk system tested in the current milk study involves placing a disc coated with 500 mcg of lyophilized milk protein on the skin for a gradually increasing number of hours daily until the disc is worn continuously, with daily changes of the disk. On the skin, the protein on the disk interacts with epidermal Langerhans cells to trigger desensitization.

The Milk Patch for Eosinophilic Esophagitis (SMILEE) study enrolled 20 patients at Children’s Hospital aged 4-17 years old and had milk-induced EoE, and randomized 15 to receive active epicutaneous immunotherapy to milk and 5 to receive placebo treatment. The protocol called for 9 month of epicutaneous immunotherapy without any milk exposure, followed by 2 months of continued treatment coupled with at least 240 mL of milk consumption daily. At the end of 2 months the researchers performed an esophageal biopsy on each patient to determine eosinophil density in the tissue. The study’s primary endpoint was the number of eosinophils in a high-powered field.

During the randomized phase, 8 of the 15 patients assigned to active treatment and 3 of 5 patients assigned to the placebo arm had violations of the treatment protocol, the diet protocol, or both. A per protocol analysis that focused on the seven actively treated and two placebo patients who adhered to the protocol showed a mean eosinophil count of 26 cells in patients on active treatment and 95 cells among the controls, a statistically significant difference. However, for the intention-to-treat analysis, which included all 20 enrolled patients, the primary endpoint showed no significant difference in eosinophil counts between the two study arms.

Although Dr. Spergel said that he was not aware of the developing company’s plans for further study of epicutaneous milk immunotherapy, from a scientific standpoint the next step should be a phase 2 or phase 2/3 trial for safety and efficacy. EoE was historically considered a rare disease, but a 2015 review of the condition called it “one of the most common conditions diagnosed during the assessment of feeding problems in children” (New Engl J Med. 2015 Oct 22;373[17]:1640-8).

The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.

[email protected]

SOURCE: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.

SAN FRANCISCO – Clinicians safely used epicutaneous immunotherapy to resolve eosinophilic esophagitis in children and teens secondary to milk consumption in a placebo-controlled, pilot study that included 20 patients.

Mitchel L. Zoler/MDedge News

Following the randomized phase of the study, all 19 patients who continued to participate began an 11-month open-label phase of epicutaneous immunotherapy to milk. At the end of this open-label phase, nine patients (47%) followed in this phase showed a substantial cut in their eosinophilic esophagitis (EoE) response to milk, with fewer than 15 eosinophils in a high-powered field, said Jonathan M. Spergel, MD, chief of the allergy section and Stuart E. Starr Chair of Pediatrics at the Children’s Hospital of Philadelphia, while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. An immunologic response of this sort would likely correlate with substantial clinical benefit.

“I’m happy with a 47% response,” Dr. Spergel said, adding that the responding patients “tolerate milk without symptoms, and there is really no risk” from this form of immunotherapy, which produced no serious adverse effects and caused 1 of 15 patients to stop treatment because of a treatment-related effect during the randomized phase. The most common adverse reaction was gastrointestinal symptoms, but these were just marginally more common among patients on active treatment than in control patients.

In contrast, oral immunotherapy with milk has been ineffective in children with an EoE milk reaction, and results from subcutaneous or sublingual immunotherapy for this form of milk allergy haven’t been reported, he said. The most common, current approaches to managing EoE from milk in children are either milk avoidance or treatment to reduce inflammation.

The epicutaneous approach “uses substantially lower dosing [micrograms vs. milligrams], avoids oral allergen ingestion, and may have a more advantageous adverse event profile and better adherence than other therapies,” according to a recent report that tested epicutaneous immunotherapy for peanut allergy in a phase 3 trial with 356 children (JAMA. 2019 Feb 22. doi: 10.1001/jama.2019.1113). The Viaskin Milk system tested in the current milk study involves placing a disc coated with 500 mcg of lyophilized milk protein on the skin for a gradually increasing number of hours daily until the disc is worn continuously, with daily changes of the disk. On the skin, the protein on the disk interacts with epidermal Langerhans cells to trigger desensitization.

The Milk Patch for Eosinophilic Esophagitis (SMILEE) study enrolled 20 patients at Children’s Hospital aged 4-17 years old and had milk-induced EoE, and randomized 15 to receive active epicutaneous immunotherapy to milk and 5 to receive placebo treatment. The protocol called for 9 month of epicutaneous immunotherapy without any milk exposure, followed by 2 months of continued treatment coupled with at least 240 mL of milk consumption daily. At the end of 2 months the researchers performed an esophageal biopsy on each patient to determine eosinophil density in the tissue. The study’s primary endpoint was the number of eosinophils in a high-powered field.

During the randomized phase, 8 of the 15 patients assigned to active treatment and 3 of 5 patients assigned to the placebo arm had violations of the treatment protocol, the diet protocol, or both. A per protocol analysis that focused on the seven actively treated and two placebo patients who adhered to the protocol showed a mean eosinophil count of 26 cells in patients on active treatment and 95 cells among the controls, a statistically significant difference. However, for the intention-to-treat analysis, which included all 20 enrolled patients, the primary endpoint showed no significant difference in eosinophil counts between the two study arms.

Although Dr. Spergel said that he was not aware of the developing company’s plans for further study of epicutaneous milk immunotherapy, from a scientific standpoint the next step should be a phase 2 or phase 2/3 trial for safety and efficacy. EoE was historically considered a rare disease, but a 2015 review of the condition called it “one of the most common conditions diagnosed during the assessment of feeding problems in children” (New Engl J Med. 2015 Oct 22;373[17]:1640-8).

The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.

[email protected]

SOURCE: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.

SAN FRANCISCO – Women with poorly-controlled asthma during pregnancy had a substantially decreased rate of live births, and among the live births had a significantly increased rate of both preterm delivery and neonatal intensive care admissions, according to a review of insurance claims data for more than 1 million American women during 2011-2015.

Mitchel L. Zoler/MDedge News

On the other hand, asthma severity, which the researchers inferred based on the type and amount of treatment patients received, showed essentially no link with the live birth rate, Jennifer Yland said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

“The findings add to the body of evidence that relate poor asthma control to an increased risk for pregnancy complications.” explained Michael X. Schatz, MD, an allergist at Kaiser Permanente of Southern California, in San Diego, and a coauthor of the study.

Results from several prior studies had shown links between asthma and an increased rate of preterm birth, “but the larger, more generalizable population is a strength of the current findings. Results from prior studies have less frequently shown a link between asthma during pregnancy and neonatal ICU admissions,” he added.“The findings strengthen the case for good asthma control during pregnancy.”

For their review, Ms. Yland and her coauthors used insurance claims data from privately-insured American women aged 12-55 years who were pregnant and had drug prescription records during the study period. The database included 996,861 women without an asthma diagnosis and 29,882 women diagnosed with asthma. The analysis excluded women diagnosed with chronic obstructive pulmonary disease at least twice during pregnancy.

To analyze the pregnancy outcomes by asthma severity Ms. Yland and her associates divided the asthma patients into five subgroups based on the drug regimens they were on during pregnancy as a surrogate marker of disease severity. This analysis showed no relationship between disease severity and live birth rate.

The researchers also ran an analysis that divided patients into the quality of their management during pregnancy – either good or poor – based on either of two markers of poor control: filling five or more prescriptions for a short-acting beta-antagonist, or at least one exacerbation episode defined as an asthma-related emergency department visit, hospitalization, or need for oral corticosteroid treatment. By these criteria 7,135 (24%) of the pregnant women with asthma were poorly controlled. The live birth rate was 74% among women without asthma, 71% among those with well-controlled asthma, and 68% among women with poorly-controlled asthma, reported Ms. Yland, a researcher at the Harvard T.H. Chan School of Public Health in Boston.

In a multivariate analysis that adjusted for demographic differences and comorbidities, women with poorly-controlled asthma had preterm delivery a statistically significant 30% more often than did women with well-controlled asthma, and the rate of neonatal ICU admissions was a significant 24% higher in women with poorly-controlled asthma, compared with women who had well-controlled asthma. However, the rates of small-for-gestational-age infants and infants with congenital malformations was not significantly different between the well-controlled and poorly-controlled subgroups.

The finding that almost a quarter of the pregnant women in the study were poorly controlled wasn’t surprising, Dr. Schatz said in an interview. In some studies as many as half the asthma patients have poor control.

The 24% rate of poor asthma control during pregnancy in the studied women is “most likely an underestimate of poor control in the general population” because the study used data from women with commercial health insurance, noted Sonia Hernandez-Diaz, MD, lead investigator for the study and professor of epidemiology at Harvard T.H. Chan School of Public Health. “More disadvantaged populations, such as pregnant women on Medicaid, tend to have worse control.”

Barriers to good asthma control during pregnancy include smoking, weight gain, undertreatment, poor adherence, and viral infection. The overall approach to managing asthma during pregnancy is the same as when women are not pregnant, although certain asthma medications have a better safety record during pregnancy. “The most reassuring data exist for albuterol and inhaled steroids, particularly budesonide and fluticasone. Reassuring data also exist for the long-acting beta agonists salmeterol and formoterol, which are combined with inhaled steroids, and for montelukast,” Dr. Schatz said.

This is the first study to assess the impact of asthma management on pregnancy outcome in such a large population. The large number of women included provided a lot of statistical power and allowed the analyses to control for several potential confounders, Ms. Yland noted in an interview. She plans to expand the analysis with Medicaid data to try to further increase the generalizability and precision of the findings.

The study was funded by GlaxoSmithKline, and a coauthor of the study is a company employee. Ms. Yland had no disclosures. Dr. Schatz has received research funding from ALK, AstraZeneca, Medimmune, GlaxoSmithKline, and Merck. Dr. Hernandez-Diaz has been a consultant to Boehringer Ingelheim, Roche, and UCB, and has received research funding from GlaxoSmithKline, Lilly, and Pfizer.

[email protected]

SOURCE: Yland J et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB422.

SAN FRANCISCO – Women with poorly-controlled asthma during pregnancy had a substantially decreased rate of live births, and among the live births had a significantly increased rate of both preterm delivery and neonatal intensive care admissions, according to a review of insurance claims data for more than 1 million American women during 2011-2015.

Mitchel L. Zoler/MDedge News

On the other hand, asthma severity, which the researchers inferred based on the type and amount of treatment patients received, showed essentially no link with the live birth rate, Jennifer Yland said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

“The findings add to the body of evidence that relate poor asthma control to an increased risk for pregnancy complications.” explained Michael X. Schatz, MD, an allergist at Kaiser Permanente of Southern California, in San Diego, and a coauthor of the study.

Results from several prior studies had shown links between asthma and an increased rate of preterm birth, “but the larger, more generalizable population is a strength of the current findings. Results from prior studies have less frequently shown a link between asthma during pregnancy and neonatal ICU admissions,” he added.“The findings strengthen the case for good asthma control during pregnancy.”

For their review, Ms. Yland and her coauthors used insurance claims data from privately-insured American women aged 12-55 years who were pregnant and had drug prescription records during the study period. The database included 996,861 women without an asthma diagnosis and 29,882 women diagnosed with asthma. The analysis excluded women diagnosed with chronic obstructive pulmonary disease at least twice during pregnancy.

To analyze the pregnancy outcomes by asthma severity Ms. Yland and her associates divided the asthma patients into five subgroups based on the drug regimens they were on during pregnancy as a surrogate marker of disease severity. This analysis showed no relationship between disease severity and live birth rate.

The researchers also ran an analysis that divided patients into the quality of their management during pregnancy – either good or poor – based on either of two markers of poor control: filling five or more prescriptions for a short-acting beta-antagonist, or at least one exacerbation episode defined as an asthma-related emergency department visit, hospitalization, or need for oral corticosteroid treatment. By these criteria 7,135 (24%) of the pregnant women with asthma were poorly controlled. The live birth rate was 74% among women without asthma, 71% among those with well-controlled asthma, and 68% among women with poorly-controlled asthma, reported Ms. Yland, a researcher at the Harvard T.H. Chan School of Public Health in Boston.

In a multivariate analysis that adjusted for demographic differences and comorbidities, women with poorly-controlled asthma had preterm delivery a statistically significant 30% more often than did women with well-controlled asthma, and the rate of neonatal ICU admissions was a significant 24% higher in women with poorly-controlled asthma, compared with women who had well-controlled asthma. However, the rates of small-for-gestational-age infants and infants with congenital malformations was not significantly different between the well-controlled and poorly-controlled subgroups.

The finding that almost a quarter of the pregnant women in the study were poorly controlled wasn’t surprising, Dr. Schatz said in an interview. In some studies as many as half the asthma patients have poor control.

The 24% rate of poor asthma control during pregnancy in the studied women is “most likely an underestimate of poor control in the general population” because the study used data from women with commercial health insurance, noted Sonia Hernandez-Diaz, MD, lead investigator for the study and professor of epidemiology at Harvard T.H. Chan School of Public Health. “More disadvantaged populations, such as pregnant women on Medicaid, tend to have worse control.”

Barriers to good asthma control during pregnancy include smoking, weight gain, undertreatment, poor adherence, and viral infection. The overall approach to managing asthma during pregnancy is the same as when women are not pregnant, although certain asthma medications have a better safety record during pregnancy. “The most reassuring data exist for albuterol and inhaled steroids, particularly budesonide and fluticasone. Reassuring data also exist for the long-acting beta agonists salmeterol and formoterol, which are combined with inhaled steroids, and for montelukast,” Dr. Schatz said.

This is the first study to assess the impact of asthma management on pregnancy outcome in such a large population. The large number of women included provided a lot of statistical power and allowed the analyses to control for several potential confounders, Ms. Yland noted in an interview. She plans to expand the analysis with Medicaid data to try to further increase the generalizability and precision of the findings.

The study was funded by GlaxoSmithKline, and a coauthor of the study is a company employee. Ms. Yland had no disclosures. Dr. Schatz has received research funding from ALK, AstraZeneca, Medimmune, GlaxoSmithKline, and Merck. Dr. Hernandez-Diaz has been a consultant to Boehringer Ingelheim, Roche, and UCB, and has received research funding from GlaxoSmithKline, Lilly, and Pfizer.

[email protected]

SOURCE: Yland J et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB422.

SAN FRANCISCO – Women with poorly-controlled asthma during pregnancy had a substantially decreased rate of live births, and among the live births had a significantly increased rate of both preterm delivery and neonatal intensive care admissions, according to a review of insurance claims data for more than 1 million American women during 2011-2015.

Mitchel L. Zoler/MDedge News

On the other hand, asthma severity, which the researchers inferred based on the type and amount of treatment patients received, showed essentially no link with the live birth rate, Jennifer Yland said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

“The findings add to the body of evidence that relate poor asthma control to an increased risk for pregnancy complications.” explained Michael X. Schatz, MD, an allergist at Kaiser Permanente of Southern California, in San Diego, and a coauthor of the study.

Results from several prior studies had shown links between asthma and an increased rate of preterm birth, “but the larger, more generalizable population is a strength of the current findings. Results from prior studies have less frequently shown a link between asthma during pregnancy and neonatal ICU admissions,” he added.“The findings strengthen the case for good asthma control during pregnancy.”

For their review, Ms. Yland and her coauthors used insurance claims data from privately-insured American women aged 12-55 years who were pregnant and had drug prescription records during the study period. The database included 996,861 women without an asthma diagnosis and 29,882 women diagnosed with asthma. The analysis excluded women diagnosed with chronic obstructive pulmonary disease at least twice during pregnancy.

To analyze the pregnancy outcomes by asthma severity Ms. Yland and her associates divided the asthma patients into five subgroups based on the drug regimens they were on during pregnancy as a surrogate marker of disease severity. This analysis showed no relationship between disease severity and live birth rate.

The researchers also ran an analysis that divided patients into the quality of their management during pregnancy – either good or poor – based on either of two markers of poor control: filling five or more prescriptions for a short-acting beta-antagonist, or at least one exacerbation episode defined as an asthma-related emergency department visit, hospitalization, or need for oral corticosteroid treatment. By these criteria 7,135 (24%) of the pregnant women with asthma were poorly controlled. The live birth rate was 74% among women without asthma, 71% among those with well-controlled asthma, and 68% among women with poorly-controlled asthma, reported Ms. Yland, a researcher at the Harvard T.H. Chan School of Public Health in Boston.

In a multivariate analysis that adjusted for demographic differences and comorbidities, women with poorly-controlled asthma had preterm delivery a statistically significant 30% more often than did women with well-controlled asthma, and the rate of neonatal ICU admissions was a significant 24% higher in women with poorly-controlled asthma, compared with women who had well-controlled asthma. However, the rates of small-for-gestational-age infants and infants with congenital malformations was not significantly different between the well-controlled and poorly-controlled subgroups.

The finding that almost a quarter of the pregnant women in the study were poorly controlled wasn’t surprising, Dr. Schatz said in an interview. In some studies as many as half the asthma patients have poor control.

The 24% rate of poor asthma control during pregnancy in the studied women is “most likely an underestimate of poor control in the general population” because the study used data from women with commercial health insurance, noted Sonia Hernandez-Diaz, MD, lead investigator for the study and professor of epidemiology at Harvard T.H. Chan School of Public Health. “More disadvantaged populations, such as pregnant women on Medicaid, tend to have worse control.”

Barriers to good asthma control during pregnancy include smoking, weight gain, undertreatment, poor adherence, and viral infection. The overall approach to managing asthma during pregnancy is the same as when women are not pregnant, although certain asthma medications have a better safety record during pregnancy. “The most reassuring data exist for albuterol and inhaled steroids, particularly budesonide and fluticasone. Reassuring data also exist for the long-acting beta agonists salmeterol and formoterol, which are combined with inhaled steroids, and for montelukast,” Dr. Schatz said.

This is the first study to assess the impact of asthma management on pregnancy outcome in such a large population. The large number of women included provided a lot of statistical power and allowed the analyses to control for several potential confounders, Ms. Yland noted in an interview. She plans to expand the analysis with Medicaid data to try to further increase the generalizability and precision of the findings.

The study was funded by GlaxoSmithKline, and a coauthor of the study is a company employee. Ms. Yland had no disclosures. Dr. Schatz has received research funding from ALK, AstraZeneca, Medimmune, GlaxoSmithKline, and Merck. Dr. Hernandez-Diaz has been a consultant to Boehringer Ingelheim, Roche, and UCB, and has received research funding from GlaxoSmithKline, Lilly, and Pfizer.

[email protected]

SOURCE: Yland J et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB422.

A study of diagnostic accuracy in the primary care setting showed that among patients receiving inhaled therapies, most had not received an accurate diagnosis of chronic obstructive pulmonary disease (COPD) or asthma according to international guidelines.^1,2 Other studies have shown that up to one-third of patients with a diagnosis of asthma³ or COPD⁴ may not actually have disease based on subsequent lung function testing.

Diagnostic error in medicine leads to numerous lost opportunities including the opportunity to: identify chronic conditions that are the true sources of patients’ symptoms, prevent morbidity and mortality, reduce unnecessary costs to patients and health systems, and deliver high-quality care.^5-7 The reasons for diagnostic error in COPD and asthma are multifactorial, stemming from insufficient knowledge of clinical practice guidelines and underutilization of spirometry testing. Spirometry is recommended as part of the workup for suspected COPD and is the preferred test for diagnosing asthma. Spirometry, combined with clinical findings, can help differentiate between these diseases.

IMAGE © JOE GORMAN

In this article, we review the definitions and characteristics of COPD and asthma, address the potential causes for diagnostic error, and explain how current clinical practice guidelines can steer examinations to the right diagnosis, improve clinical management, and contribute to better patient outcomes and quality of life.^8,9

COPD and asthma characteristics

COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as a common lung disease characterized by persistent respiratory symptoms and airflow obstruction caused by airway or alveolar abnormalities secondary to significant exposure to noxious particles or gases.¹⁰ The most common COPD-risk exposure in the United States is tobacco smoke, chiefly from cigarettes. Risk is also heightened with use of other types of tobacco (pipe, cigar, water pipe), indoor and outdoor air pollution (including second-hand tobacco smoke exposure), and occupational exposures. (Consider testing for alpha-1 antitrypsin deficiency—a known genetic risk factor for COPD—especially when an individual with COPD is younger and has a limited smoking history.)

If COPD is suspected, perform spirometry to determine the presence of fixed airflow limitation and confirm the diagnosis.

The most common symptom of COPD is chronic, progressive dyspnea — an increased effort to breathe, with chest heaviness, air hunger, or gasping. About one-third of people with COPD have a chronic cough with sputum production.¹⁰ There may be wheezing and chest tightness. Fatigue, weight loss, and anorexia can be seen in severe COPD. Consider this disorder in any individual older than 40 years of age who has dyspnea and chronic cough with sputum production, as well as a history of risk factors. If COPD is suspected, perform spirometry to determine the presence of fixed airflow limitation and confirm the diagnosis.

Asthma is usually characterized by variable airway hyperresponsiveness and chronic inflammation. A typical clinical presentation is an individual with a history of wheezing, shortness of breath, chest tightness, and cough that vary in intensity over time and are coupled with variable expiratory flow limitation. Asthma symptoms are often triggered by allergen or irritant exposure, exercise, weather changes, or viral respiratory infections.² Symptoms may also be worse at night or first thing in the morning. Once asthma is suspected, document the presence of airflow variability with spirometry to confirm the diagnosis.

[polldaddy:10261486]

Diagnostic error in suspected COPD and asthma

Numerous studies have demonstrated the prevalence of diagnostic error when testing of lung function is neglected.^11-14 Using spirometry to confirm a prior clinical diagnosis of COPD, researchers found that:

• 35% to 50% of patients did not have objective evidence of COPD^12,13;
• 37% with an asthma-only diagnosis had persistent obstruction, which may indicate COPD or chronic obstructive asthma¹²; and
• 31% of patients thought to have asthma-COPD overlap did not have a COPD component.¹²

Continue to: In 2 longitudinal studies...

In 2 longitudinal studies, patients with a diagnosis of asthma were recruited to undergo medication reduction and serial lung function testing. Asthma was excluded in approximately 30% of patients.^15,16 Diagnostic error has also been seen in patients hospitalized with exacerbations of COPD and asthma. One study found that only 31% of patients admitted with a diagnosis of COPD exacerbation had undergone a spirometry test prior to hospitalization.¹⁷ And of those patients with a diagnosis of COPD who underwent spirometry, 30% had results inconsistent with COPD.¹⁷

In another study, 22% of adults hospitalized for COPD or asthma exacerbations had no evidence of obstruction on spirometry at the time of hospitalization.¹⁸ This finding refutes a diagnosis of COPD and, in the midst of an exacerbation, challenges an asthma diagnosis as well. Increased awareness of clinical practice guidelines, coupled with the use and accurate interpretation of spirometry are needed for optimal management and treatment of COPD and asthma.

Airflow measurement is decisive in diagnosing COPD and asthma

Clinical practice guidelines recommend spirometry for the diagnosis of COPD and asthma and have been issued by GOLD¹⁰; the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and the European Respiratory Society¹⁹; the Global Initiative for Asthma (GINA)²; and the National Heart, Lung, and Blood Institute.²⁰

When a patient’s symptoms and risk factors suggest COPD, spirometry is needed to show persistent post-bronchodilator airflow obstruction and thereby confirm the diagnosis. However, in the United States, confirmatory spirometry is used only in about one third of patients newly diagnosed with COPD.^21,22 Similarly for asthma, in the presence of suggestive symptoms, spirometry is the preferred and most reliable and reproducible test to detect the variable expiratory airflow limitation consistent with this diagnosis.

An alternative to spirometry for the diagnosis of asthma (if needed) is a peak flow meter, a simple tool to measure peak expiratory flow. When compared with spirometry, peak flow measurements are less time consuming, less costly, and not dependent on trained staff to perform.²³ However, this option does require that patients perform and document multiple measurements over several days without an objective assessment of their efforts. Unlike spirometry, the peak flow meter has no reference values or reliability and reproducibility standards, and measurements can differ from one peak flow meter to another. Thus, a peak flow meter is less reliable than spirometry for diagnosing asthma. But it can be useful for monitoring asthma control at home and in the clinic setting,²⁴ or for diagnosis if spirometry is unavailable.²³

Continue to: Barriers to the use of spirometry...

Barriers to the use of spirometry in the primary care setting exist on several levels. Providers may lack knowledge of clinical practice guidelines that recommend spirometry in the diagnosis of COPD, and they may lack general awareness of the utility of spirometry.^25-29 In 2 studies of primary care practices that offered office spirometry, lack of knowledge in conducting and interpreting the test was a barrier to its use.^28,30 Primary care physicians also struggle with logistical challenges when clinical visits last just 10 to 15 minutes for patients with multiple comorbidities,²⁷ and maintenance of an office spirometry program may not always be feasible.

Getting to the right diagnosis

Guideline-based treatment recommendations differ for COPD and asthma, and mistakenly treating the wrong condition can lead to adverse events (AEs). For instance, while inhaled corticosteroids use is common in patients with persistent asthma, its use in COPD increases the risk of pneumonia³¹ and thus is usually reserved for add-on treatment mainly if patients experience continued exacerbations. Use of long-acting beta-agonists (LABAs) as monotherapy is appropriate in COPD but not so in the management of asthma. In 2006, a large randomized controlled trial evaluated a LABA (salmeterol) vs placebo added to usual care and found more serious AEs and asthma-related deaths in the salmeterol group.^32,33 Thus LABA monotherapy is not recommended in asthma guidelines.

Likewise, nonpharmacologic interventions may be misused or go unused when needed if the diagnosis is inaccurate. For patients with COPD, outcomes are improved with pulmonary rehabilitation and supplemental oxygen in the setting of resting hypoxemia, but these resources will not be considered if patients are misdiagnosed as having asthma. A patient with undetected heart failure or obstructive sleep apnea who has been misdiagnosed with COPD or asthma may not receive appropriate diagnostic testing or treatment until asthma or COPD has been ruled out with lung function testing.

Objectively documenting the right diagnosis helps ensure guideline-based management of COPD or asthma. Ruling out these 2 disorders prompts further investigation into other conditions (eg, coronary artery disease, heart failure, gastroesophageal reflux disease, pulmonary hypertension, interstitial lung diseases) that can cause symptoms such as shortness of breath, wheezing, or cough.

The TABLE^2,10,34 summarizes some of the more common clinical and spirometric features of COPD and asthma. Onset of COPD usually occurs in those over age 40. Asthma can present in younger individuals, including children. Tobacco use or exposure to noxious substances is more often associated with COPD. Patients with asthma are more likely to have atopy. Symptoms in COPD usually progress with increasing activity or exertion. Symptoms in asthma may vary with certain activities, such as exercise, and with various triggers. These features represent “typical” cases of COPD or asthma, but some patients may have clinical characteristics that do not fit easily into one disease pattern, making diagnostic testing of lung function even more essential.

Continue to: The utility of spirometry in measuring lung function

The utility of spirometry in measuring lung function. Spirometry is the most reproducible and objective measurement of airflow limitation,¹⁰ and it should precede any treatment decisions. This technique—in which the patient performs maximal inhalation followed by forced exhalation—measures airflow over time and determines the lung volume exhaled at any time point. Because this respiratory exercise is patient dependent, a well-trained technician is needed to ensure reproducibility and reliability of results based on technical standards.

Asthma was excluded in about 30% of patients studied longitudinally who subsequently underwent spirometry.

Spirometry measures forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁), from which the FEV₁/FVC ratio is calculated. FVC is the total amount of air from total lung volume that can be exhaled in one breath. FEV₁ is the total amount of air exhaled in the first second after initiation of exhalation. Thus, the FEV₁/FVC ratio is the percentage of the total amount of air in a single breath that is exhaled in the first second. On average, an individual with normal lungs can exhale approximately 80% of their FVC in the first second, thereby resulting in a FEV₁/FVC ratio of 80%.

Spirometry findings with COPD. A post-bronchodilator FEV₁/FVC ratio of less than 70% confirms airflow obstruction and is consistent with COPD according to GOLD criteria.¹⁰ Post-bronchodilator spirometry is performed after the patient has received a specified dose of an inhaled bronchodilator per lab protocols. In patients with COPD, the FEV₁/FVC ratio is persistently low even after administration of a bronchodilator.

Another means of using spirometry to diagnose COPD is referring to age-dependent cutoff values below the lower fifth percentile of the FEV₁/FVC ratio (ie, lower limit of normal [LLN]), which differs from the GOLD strategy but is consistent with the American Thoracic Society/European Respiratory Society guidelines.³⁵ Because the FEV₁/FVC ratio declines with age, older adults may have a normal post-bronchodilator ratio less than 70%. Admittedly, applying GOLD criteria to older adults could result in overdiagnosis, while using the LLN could lead to underdiagnosis. Although there is no consensus on which method to use, the best approach may be the one that most strongly correlates with pretest probability of disease. In a large Canadian study, the approach that most strongly predicted poor patient outcomes was using a FEV₁/FVC based on fixed (70%) and/or LLN criteria, and a low FEV₁³⁴

Spirometry findings with asthma. According to the American Thoracic Society, a post-bronchodilator response is defined as an increase in FEV₁ (or FVC) of 12% if that volume is also ≥200 mL. In patients with suspected asthma, an increase in FEV₁ ≥12% and 200 mL is consistent with variable airflow limitation² and supports the diagnosis. Of note, lung function in patients with asthma may be normal when patients are not symptomatic or when they are receiving therapy. Spirometry is therefore ideally performed before initiating therapy and when maintenance therapy is being considered due to symptoms. If therapy is clinically indicated, a short-acting bronchodilator may be prescribed alone and then held 6 to 8 hours before conducting spirometry. If a trial of a maintenance medication is prescribed before spirometry, consider de-escalation of therapy once the patient is more stable and then perform spirometry to confirm the presence of airflow variability consistent with asthma. (In COPD, there can be a positive bronchodilator response; however, the post-bronchodilator FEV₁/FVC ratio remains low.)

Continue to: Don't use in isolation

Don’t use in isolation. Use spirometry to support a clinical suspicion of asthma³⁶ or COPD after a thorough history and physical exam, and not in isolation.

Special consideration: Asthma-COPD overlap syndrome

Some patients have features characteristic of both asthma and COPD and are said to have asthma-COPD overlap syndrome (ACOS). Between 15% and 20% of patients with COPD may in fact have ACOS.³⁶ While there is no specific definition of ACOS, GOLD and GINA describe ACOS as persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.^2,10,37 ACOS becomes more prevalent with advancing age.

In the United States, confirmatory spirometry is used in only about one-third of patients newly diagnosed with COPD.

In ACOS, patients with COPD present with increased reversibility or patients with asthma and smoking history develop non-fully reversible airway obstruction at an older age.³⁸ Patients with ACOS have worse lung function, more respiratory symptoms, and lower health-related quality of life than individuals with asthma or COPD alone,^39,40 leading to more consumption of medical resources.⁴¹ In patients with ACOS, the FEV₁/FVC ratio is low and consistent with the diagnosis of COPD. The post-bronchodilator response may be variable, depending on the stage of disease and predominant clinical features. It is still unclear whether ACOS is a separate disease entity, a representation of severe asthma that has morphed into COPD, or not a syndrome but simply 2 separate comorbid disease states.

CORRESPONDENCE
Christina D. Wells, MD, University of Illinois Mile Square Health Center, 1220 S. Wood Street, Chicago, IL 60612; [email protected].

A study of diagnostic accuracy in the primary care setting showed that among patients receiving inhaled therapies, most had not received an accurate diagnosis of chronic obstructive pulmonary disease (COPD) or asthma according to international guidelines.^1,2 Other studies have shown that up to one-third of patients with a diagnosis of asthma³ or COPD⁴ may not actually have disease based on subsequent lung function testing.

Diagnostic error in medicine leads to numerous lost opportunities including the opportunity to: identify chronic conditions that are the true sources of patients’ symptoms, prevent morbidity and mortality, reduce unnecessary costs to patients and health systems, and deliver high-quality care.^5-7 The reasons for diagnostic error in COPD and asthma are multifactorial, stemming from insufficient knowledge of clinical practice guidelines and underutilization of spirometry testing. Spirometry is recommended as part of the workup for suspected COPD and is the preferred test for diagnosing asthma. Spirometry, combined with clinical findings, can help differentiate between these diseases.

IMAGE © JOE GORMAN

In this article, we review the definitions and characteristics of COPD and asthma, address the potential causes for diagnostic error, and explain how current clinical practice guidelines can steer examinations to the right diagnosis, improve clinical management, and contribute to better patient outcomes and quality of life.^8,9

COPD and asthma characteristics

COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as a common lung disease characterized by persistent respiratory symptoms and airflow obstruction caused by airway or alveolar abnormalities secondary to significant exposure to noxious particles or gases.¹⁰ The most common COPD-risk exposure in the United States is tobacco smoke, chiefly from cigarettes. Risk is also heightened with use of other types of tobacco (pipe, cigar, water pipe), indoor and outdoor air pollution (including second-hand tobacco smoke exposure), and occupational exposures. (Consider testing for alpha-1 antitrypsin deficiency—a known genetic risk factor for COPD—especially when an individual with COPD is younger and has a limited smoking history.)

If COPD is suspected, perform spirometry to determine the presence of fixed airflow limitation and confirm the diagnosis.

The most common symptom of COPD is chronic, progressive dyspnea — an increased effort to breathe, with chest heaviness, air hunger, or gasping. About one-third of people with COPD have a chronic cough with sputum production.¹⁰ There may be wheezing and chest tightness. Fatigue, weight loss, and anorexia can be seen in severe COPD. Consider this disorder in any individual older than 40 years of age who has dyspnea and chronic cough with sputum production, as well as a history of risk factors. If COPD is suspected, perform spirometry to determine the presence of fixed airflow limitation and confirm the diagnosis.

Asthma is usually characterized by variable airway hyperresponsiveness and chronic inflammation. A typical clinical presentation is an individual with a history of wheezing, shortness of breath, chest tightness, and cough that vary in intensity over time and are coupled with variable expiratory flow limitation. Asthma symptoms are often triggered by allergen or irritant exposure, exercise, weather changes, or viral respiratory infections.² Symptoms may also be worse at night or first thing in the morning. Once asthma is suspected, document the presence of airflow variability with spirometry to confirm the diagnosis.

[polldaddy:10261486]

Diagnostic error in suspected COPD and asthma

Numerous studies have demonstrated the prevalence of diagnostic error when testing of lung function is neglected.^11-14 Using spirometry to confirm a prior clinical diagnosis of COPD, researchers found that:

• 35% to 50% of patients did not have objective evidence of COPD^12,13;
• 37% with an asthma-only diagnosis had persistent obstruction, which may indicate COPD or chronic obstructive asthma¹²; and
• 31% of patients thought to have asthma-COPD overlap did not have a COPD component.¹²

Continue to: In 2 longitudinal studies...

In 2 longitudinal studies, patients with a diagnosis of asthma were recruited to undergo medication reduction and serial lung function testing. Asthma was excluded in approximately 30% of patients.^15,16 Diagnostic error has also been seen in patients hospitalized with exacerbations of COPD and asthma. One study found that only 31% of patients admitted with a diagnosis of COPD exacerbation had undergone a spirometry test prior to hospitalization.¹⁷ And of those patients with a diagnosis of COPD who underwent spirometry, 30% had results inconsistent with COPD.¹⁷

In another study, 22% of adults hospitalized for COPD or asthma exacerbations had no evidence of obstruction on spirometry at the time of hospitalization.¹⁸ This finding refutes a diagnosis of COPD and, in the midst of an exacerbation, challenges an asthma diagnosis as well. Increased awareness of clinical practice guidelines, coupled with the use and accurate interpretation of spirometry are needed for optimal management and treatment of COPD and asthma.

Airflow measurement is decisive in diagnosing COPD and asthma

Clinical practice guidelines recommend spirometry for the diagnosis of COPD and asthma and have been issued by GOLD¹⁰; the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and the European Respiratory Society¹⁹; the Global Initiative for Asthma (GINA)²; and the National Heart, Lung, and Blood Institute.²⁰

When a patient’s symptoms and risk factors suggest COPD, spirometry is needed to show persistent post-bronchodilator airflow obstruction and thereby confirm the diagnosis. However, in the United States, confirmatory spirometry is used only in about one third of patients newly diagnosed with COPD.^21,22 Similarly for asthma, in the presence of suggestive symptoms, spirometry is the preferred and most reliable and reproducible test to detect the variable expiratory airflow limitation consistent with this diagnosis.

An alternative to spirometry for the diagnosis of asthma (if needed) is a peak flow meter, a simple tool to measure peak expiratory flow. When compared with spirometry, peak flow measurements are less time consuming, less costly, and not dependent on trained staff to perform.²³ However, this option does require that patients perform and document multiple measurements over several days without an objective assessment of their efforts. Unlike spirometry, the peak flow meter has no reference values or reliability and reproducibility standards, and measurements can differ from one peak flow meter to another. Thus, a peak flow meter is less reliable than spirometry for diagnosing asthma. But it can be useful for monitoring asthma control at home and in the clinic setting,²⁴ or for diagnosis if spirometry is unavailable.²³

Continue to: Barriers to the use of spirometry...

Barriers to the use of spirometry in the primary care setting exist on several levels. Providers may lack knowledge of clinical practice guidelines that recommend spirometry in the diagnosis of COPD, and they may lack general awareness of the utility of spirometry.^25-29 In 2 studies of primary care practices that offered office spirometry, lack of knowledge in conducting and interpreting the test was a barrier to its use.^28,30 Primary care physicians also struggle with logistical challenges when clinical visits last just 10 to 15 minutes for patients with multiple comorbidities,²⁷ and maintenance of an office spirometry program may not always be feasible.

Getting to the right diagnosis

Guideline-based treatment recommendations differ for COPD and asthma, and mistakenly treating the wrong condition can lead to adverse events (AEs). For instance, while inhaled corticosteroids use is common in patients with persistent asthma, its use in COPD increases the risk of pneumonia³¹ and thus is usually reserved for add-on treatment mainly if patients experience continued exacerbations. Use of long-acting beta-agonists (LABAs) as monotherapy is appropriate in COPD but not so in the management of asthma. In 2006, a large randomized controlled trial evaluated a LABA (salmeterol) vs placebo added to usual care and found more serious AEs and asthma-related deaths in the salmeterol group.^32,33 Thus LABA monotherapy is not recommended in asthma guidelines.

Likewise, nonpharmacologic interventions may be misused or go unused when needed if the diagnosis is inaccurate. For patients with COPD, outcomes are improved with pulmonary rehabilitation and supplemental oxygen in the setting of resting hypoxemia, but these resources will not be considered if patients are misdiagnosed as having asthma. A patient with undetected heart failure or obstructive sleep apnea who has been misdiagnosed with COPD or asthma may not receive appropriate diagnostic testing or treatment until asthma or COPD has been ruled out with lung function testing.

Objectively documenting the right diagnosis helps ensure guideline-based management of COPD or asthma. Ruling out these 2 disorders prompts further investigation into other conditions (eg, coronary artery disease, heart failure, gastroesophageal reflux disease, pulmonary hypertension, interstitial lung diseases) that can cause symptoms such as shortness of breath, wheezing, or cough.

The TABLE^2,10,34 summarizes some of the more common clinical and spirometric features of COPD and asthma. Onset of COPD usually occurs in those over age 40. Asthma can present in younger individuals, including children. Tobacco use or exposure to noxious substances is more often associated with COPD. Patients with asthma are more likely to have atopy. Symptoms in COPD usually progress with increasing activity or exertion. Symptoms in asthma may vary with certain activities, such as exercise, and with various triggers. These features represent “typical” cases of COPD or asthma, but some patients may have clinical characteristics that do not fit easily into one disease pattern, making diagnostic testing of lung function even more essential.

Continue to: The utility of spirometry in measuring lung function

The utility of spirometry in measuring lung function. Spirometry is the most reproducible and objective measurement of airflow limitation,¹⁰ and it should precede any treatment decisions. This technique—in which the patient performs maximal inhalation followed by forced exhalation—measures airflow over time and determines the lung volume exhaled at any time point. Because this respiratory exercise is patient dependent, a well-trained technician is needed to ensure reproducibility and reliability of results based on technical standards.

Asthma was excluded in about 30% of patients studied longitudinally who subsequently underwent spirometry.

Spirometry measures forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁), from which the FEV₁/FVC ratio is calculated. FVC is the total amount of air from total lung volume that can be exhaled in one breath. FEV₁ is the total amount of air exhaled in the first second after initiation of exhalation. Thus, the FEV₁/FVC ratio is the percentage of the total amount of air in a single breath that is exhaled in the first second. On average, an individual with normal lungs can exhale approximately 80% of their FVC in the first second, thereby resulting in a FEV₁/FVC ratio of 80%.

Spirometry findings with COPD. A post-bronchodilator FEV₁/FVC ratio of less than 70% confirms airflow obstruction and is consistent with COPD according to GOLD criteria.¹⁰ Post-bronchodilator spirometry is performed after the patient has received a specified dose of an inhaled bronchodilator per lab protocols. In patients with COPD, the FEV₁/FVC ratio is persistently low even after administration of a bronchodilator.

Another means of using spirometry to diagnose COPD is referring to age-dependent cutoff values below the lower fifth percentile of the FEV₁/FVC ratio (ie, lower limit of normal [LLN]), which differs from the GOLD strategy but is consistent with the American Thoracic Society/European Respiratory Society guidelines.³⁵ Because the FEV₁/FVC ratio declines with age, older adults may have a normal post-bronchodilator ratio less than 70%. Admittedly, applying GOLD criteria to older adults could result in overdiagnosis, while using the LLN could lead to underdiagnosis. Although there is no consensus on which method to use, the best approach may be the one that most strongly correlates with pretest probability of disease. In a large Canadian study, the approach that most strongly predicted poor patient outcomes was using a FEV₁/FVC based on fixed (70%) and/or LLN criteria, and a low FEV₁³⁴

Spirometry findings with asthma. According to the American Thoracic Society, a post-bronchodilator response is defined as an increase in FEV₁ (or FVC) of 12% if that volume is also ≥200 mL. In patients with suspected asthma, an increase in FEV₁ ≥12% and 200 mL is consistent with variable airflow limitation² and supports the diagnosis. Of note, lung function in patients with asthma may be normal when patients are not symptomatic or when they are receiving therapy. Spirometry is therefore ideally performed before initiating therapy and when maintenance therapy is being considered due to symptoms. If therapy is clinically indicated, a short-acting bronchodilator may be prescribed alone and then held 6 to 8 hours before conducting spirometry. If a trial of a maintenance medication is prescribed before spirometry, consider de-escalation of therapy once the patient is more stable and then perform spirometry to confirm the presence of airflow variability consistent with asthma. (In COPD, there can be a positive bronchodilator response; however, the post-bronchodilator FEV₁/FVC ratio remains low.)

Continue to: Don't use in isolation

Don’t use in isolation. Use spirometry to support a clinical suspicion of asthma³⁶ or COPD after a thorough history and physical exam, and not in isolation.

Special consideration: Asthma-COPD overlap syndrome

Some patients have features characteristic of both asthma and COPD and are said to have asthma-COPD overlap syndrome (ACOS). Between 15% and 20% of patients with COPD may in fact have ACOS.³⁶ While there is no specific definition of ACOS, GOLD and GINA describe ACOS as persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.^2,10,37 ACOS becomes more prevalent with advancing age.

In the United States, confirmatory spirometry is used in only about one-third of patients newly diagnosed with COPD.

In ACOS, patients with COPD present with increased reversibility or patients with asthma and smoking history develop non-fully reversible airway obstruction at an older age.³⁸ Patients with ACOS have worse lung function, more respiratory symptoms, and lower health-related quality of life than individuals with asthma or COPD alone,^39,40 leading to more consumption of medical resources.⁴¹ In patients with ACOS, the FEV₁/FVC ratio is low and consistent with the diagnosis of COPD. The post-bronchodilator response may be variable, depending on the stage of disease and predominant clinical features. It is still unclear whether ACOS is a separate disease entity, a representation of severe asthma that has morphed into COPD, or not a syndrome but simply 2 separate comorbid disease states.

CORRESPONDENCE
Christina D. Wells, MD, University of Illinois Mile Square Health Center, 1220 S. Wood Street, Chicago, IL 60612; [email protected].

A study of diagnostic accuracy in the primary care setting showed that among patients receiving inhaled therapies, most had not received an accurate diagnosis of chronic obstructive pulmonary disease (COPD) or asthma according to international guidelines.^1,2 Other studies have shown that up to one-third of patients with a diagnosis of asthma³ or COPD⁴ may not actually have disease based on subsequent lung function testing.

Diagnostic error in medicine leads to numerous lost opportunities including the opportunity to: identify chronic conditions that are the true sources of patients’ symptoms, prevent morbidity and mortality, reduce unnecessary costs to patients and health systems, and deliver high-quality care.^5-7 The reasons for diagnostic error in COPD and asthma are multifactorial, stemming from insufficient knowledge of clinical practice guidelines and underutilization of spirometry testing. Spirometry is recommended as part of the workup for suspected COPD and is the preferred test for diagnosing asthma. Spirometry, combined with clinical findings, can help differentiate between these diseases.

IMAGE © JOE GORMAN

In this article, we review the definitions and characteristics of COPD and asthma, address the potential causes for diagnostic error, and explain how current clinical practice guidelines can steer examinations to the right diagnosis, improve clinical management, and contribute to better patient outcomes and quality of life.^8,9

COPD and asthma characteristics

COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as a common lung disease characterized by persistent respiratory symptoms and airflow obstruction caused by airway or alveolar abnormalities secondary to significant exposure to noxious particles or gases.¹⁰ The most common COPD-risk exposure in the United States is tobacco smoke, chiefly from cigarettes. Risk is also heightened with use of other types of tobacco (pipe, cigar, water pipe), indoor and outdoor air pollution (including second-hand tobacco smoke exposure), and occupational exposures. (Consider testing for alpha-1 antitrypsin deficiency—a known genetic risk factor for COPD—especially when an individual with COPD is younger and has a limited smoking history.)

If COPD is suspected, perform spirometry to determine the presence of fixed airflow limitation and confirm the diagnosis.

The most common symptom of COPD is chronic, progressive dyspnea — an increased effort to breathe, with chest heaviness, air hunger, or gasping. About one-third of people with COPD have a chronic cough with sputum production.¹⁰ There may be wheezing and chest tightness. Fatigue, weight loss, and anorexia can be seen in severe COPD. Consider this disorder in any individual older than 40 years of age who has dyspnea and chronic cough with sputum production, as well as a history of risk factors. If COPD is suspected, perform spirometry to determine the presence of fixed airflow limitation and confirm the diagnosis.

Asthma is usually characterized by variable airway hyperresponsiveness and chronic inflammation. A typical clinical presentation is an individual with a history of wheezing, shortness of breath, chest tightness, and cough that vary in intensity over time and are coupled with variable expiratory flow limitation. Asthma symptoms are often triggered by allergen or irritant exposure, exercise, weather changes, or viral respiratory infections.² Symptoms may also be worse at night or first thing in the morning. Once asthma is suspected, document the presence of airflow variability with spirometry to confirm the diagnosis.

[polldaddy:10261486]

Diagnostic error in suspected COPD and asthma

Numerous studies have demonstrated the prevalence of diagnostic error when testing of lung function is neglected.^11-14 Using spirometry to confirm a prior clinical diagnosis of COPD, researchers found that:

• 35% to 50% of patients did not have objective evidence of COPD^12,13;
• 37% with an asthma-only diagnosis had persistent obstruction, which may indicate COPD or chronic obstructive asthma¹²; and
• 31% of patients thought to have asthma-COPD overlap did not have a COPD component.¹²

Continue to: In 2 longitudinal studies...

In 2 longitudinal studies, patients with a diagnosis of asthma were recruited to undergo medication reduction and serial lung function testing. Asthma was excluded in approximately 30% of patients.^15,16 Diagnostic error has also been seen in patients hospitalized with exacerbations of COPD and asthma. One study found that only 31% of patients admitted with a diagnosis of COPD exacerbation had undergone a spirometry test prior to hospitalization.¹⁷ And of those patients with a diagnosis of COPD who underwent spirometry, 30% had results inconsistent with COPD.¹⁷

In another study, 22% of adults hospitalized for COPD or asthma exacerbations had no evidence of obstruction on spirometry at the time of hospitalization.¹⁸ This finding refutes a diagnosis of COPD and, in the midst of an exacerbation, challenges an asthma diagnosis as well. Increased awareness of clinical practice guidelines, coupled with the use and accurate interpretation of spirometry are needed for optimal management and treatment of COPD and asthma.

Airflow measurement is decisive in diagnosing COPD and asthma

Clinical practice guidelines recommend spirometry for the diagnosis of COPD and asthma and have been issued by GOLD¹⁰; the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and the European Respiratory Society¹⁹; the Global Initiative for Asthma (GINA)²; and the National Heart, Lung, and Blood Institute.²⁰

When a patient’s symptoms and risk factors suggest COPD, spirometry is needed to show persistent post-bronchodilator airflow obstruction and thereby confirm the diagnosis. However, in the United States, confirmatory spirometry is used only in about one third of patients newly diagnosed with COPD.^21,22 Similarly for asthma, in the presence of suggestive symptoms, spirometry is the preferred and most reliable and reproducible test to detect the variable expiratory airflow limitation consistent with this diagnosis.

An alternative to spirometry for the diagnosis of asthma (if needed) is a peak flow meter, a simple tool to measure peak expiratory flow. When compared with spirometry, peak flow measurements are less time consuming, less costly, and not dependent on trained staff to perform.²³ However, this option does require that patients perform and document multiple measurements over several days without an objective assessment of their efforts. Unlike spirometry, the peak flow meter has no reference values or reliability and reproducibility standards, and measurements can differ from one peak flow meter to another. Thus, a peak flow meter is less reliable than spirometry for diagnosing asthma. But it can be useful for monitoring asthma control at home and in the clinic setting,²⁴ or for diagnosis if spirometry is unavailable.²³

Continue to: Barriers to the use of spirometry...

Barriers to the use of spirometry in the primary care setting exist on several levels. Providers may lack knowledge of clinical practice guidelines that recommend spirometry in the diagnosis of COPD, and they may lack general awareness of the utility of spirometry.^25-29 In 2 studies of primary care practices that offered office spirometry, lack of knowledge in conducting and interpreting the test was a barrier to its use.^28,30 Primary care physicians also struggle with logistical challenges when clinical visits last just 10 to 15 minutes for patients with multiple comorbidities,²⁷ and maintenance of an office spirometry program may not always be feasible.

Getting to the right diagnosis

Guideline-based treatment recommendations differ for COPD and asthma, and mistakenly treating the wrong condition can lead to adverse events (AEs). For instance, while inhaled corticosteroids use is common in patients with persistent asthma, its use in COPD increases the risk of pneumonia³¹ and thus is usually reserved for add-on treatment mainly if patients experience continued exacerbations. Use of long-acting beta-agonists (LABAs) as monotherapy is appropriate in COPD but not so in the management of asthma. In 2006, a large randomized controlled trial evaluated a LABA (salmeterol) vs placebo added to usual care and found more serious AEs and asthma-related deaths in the salmeterol group.^32,33 Thus LABA monotherapy is not recommended in asthma guidelines.

Likewise, nonpharmacologic interventions may be misused or go unused when needed if the diagnosis is inaccurate. For patients with COPD, outcomes are improved with pulmonary rehabilitation and supplemental oxygen in the setting of resting hypoxemia, but these resources will not be considered if patients are misdiagnosed as having asthma. A patient with undetected heart failure or obstructive sleep apnea who has been misdiagnosed with COPD or asthma may not receive appropriate diagnostic testing or treatment until asthma or COPD has been ruled out with lung function testing.

Objectively documenting the right diagnosis helps ensure guideline-based management of COPD or asthma. Ruling out these 2 disorders prompts further investigation into other conditions (eg, coronary artery disease, heart failure, gastroesophageal reflux disease, pulmonary hypertension, interstitial lung diseases) that can cause symptoms such as shortness of breath, wheezing, or cough.

The TABLE^2,10,34 summarizes some of the more common clinical and spirometric features of COPD and asthma. Onset of COPD usually occurs in those over age 40. Asthma can present in younger individuals, including children. Tobacco use or exposure to noxious substances is more often associated with COPD. Patients with asthma are more likely to have atopy. Symptoms in COPD usually progress with increasing activity or exertion. Symptoms in asthma may vary with certain activities, such as exercise, and with various triggers. These features represent “typical” cases of COPD or asthma, but some patients may have clinical characteristics that do not fit easily into one disease pattern, making diagnostic testing of lung function even more essential.

Continue to: The utility of spirometry in measuring lung function

The utility of spirometry in measuring lung function. Spirometry is the most reproducible and objective measurement of airflow limitation,¹⁰ and it should precede any treatment decisions. This technique—in which the patient performs maximal inhalation followed by forced exhalation—measures airflow over time and determines the lung volume exhaled at any time point. Because this respiratory exercise is patient dependent, a well-trained technician is needed to ensure reproducibility and reliability of results based on technical standards.

Asthma was excluded in about 30% of patients studied longitudinally who subsequently underwent spirometry.

Spirometry measures forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁), from which the FEV₁/FVC ratio is calculated. FVC is the total amount of air from total lung volume that can be exhaled in one breath. FEV₁ is the total amount of air exhaled in the first second after initiation of exhalation. Thus, the FEV₁/FVC ratio is the percentage of the total amount of air in a single breath that is exhaled in the first second. On average, an individual with normal lungs can exhale approximately 80% of their FVC in the first second, thereby resulting in a FEV₁/FVC ratio of 80%.

Spirometry findings with COPD. A post-bronchodilator FEV₁/FVC ratio of less than 70% confirms airflow obstruction and is consistent with COPD according to GOLD criteria.¹⁰ Post-bronchodilator spirometry is performed after the patient has received a specified dose of an inhaled bronchodilator per lab protocols. In patients with COPD, the FEV₁/FVC ratio is persistently low even after administration of a bronchodilator.

Another means of using spirometry to diagnose COPD is referring to age-dependent cutoff values below the lower fifth percentile of the FEV₁/FVC ratio (ie, lower limit of normal [LLN]), which differs from the GOLD strategy but is consistent with the American Thoracic Society/European Respiratory Society guidelines.³⁵ Because the FEV₁/FVC ratio declines with age, older adults may have a normal post-bronchodilator ratio less than 70%. Admittedly, applying GOLD criteria to older adults could result in overdiagnosis, while using the LLN could lead to underdiagnosis. Although there is no consensus on which method to use, the best approach may be the one that most strongly correlates with pretest probability of disease. In a large Canadian study, the approach that most strongly predicted poor patient outcomes was using a FEV₁/FVC based on fixed (70%) and/or LLN criteria, and a low FEV₁³⁴

Spirometry findings with asthma. According to the American Thoracic Society, a post-bronchodilator response is defined as an increase in FEV₁ (or FVC) of 12% if that volume is also ≥200 mL. In patients with suspected asthma, an increase in FEV₁ ≥12% and 200 mL is consistent with variable airflow limitation² and supports the diagnosis. Of note, lung function in patients with asthma may be normal when patients are not symptomatic or when they are receiving therapy. Spirometry is therefore ideally performed before initiating therapy and when maintenance therapy is being considered due to symptoms. If therapy is clinically indicated, a short-acting bronchodilator may be prescribed alone and then held 6 to 8 hours before conducting spirometry. If a trial of a maintenance medication is prescribed before spirometry, consider de-escalation of therapy once the patient is more stable and then perform spirometry to confirm the presence of airflow variability consistent with asthma. (In COPD, there can be a positive bronchodilator response; however, the post-bronchodilator FEV₁/FVC ratio remains low.)

Continue to: Don't use in isolation

Don’t use in isolation. Use spirometry to support a clinical suspicion of asthma³⁶ or COPD after a thorough history and physical exam, and not in isolation.

Special consideration: Asthma-COPD overlap syndrome

Some patients have features characteristic of both asthma and COPD and are said to have asthma-COPD overlap syndrome (ACOS). Between 15% and 20% of patients with COPD may in fact have ACOS.³⁶ While there is no specific definition of ACOS, GOLD and GINA describe ACOS as persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.^2,10,37 ACOS becomes more prevalent with advancing age.

In the United States, confirmatory spirometry is used in only about one-third of patients newly diagnosed with COPD.

In ACOS, patients with COPD present with increased reversibility or patients with asthma and smoking history develop non-fully reversible airway obstruction at an older age.³⁸ Patients with ACOS have worse lung function, more respiratory symptoms, and lower health-related quality of life than individuals with asthma or COPD alone,^39,40 leading to more consumption of medical resources.⁴¹ In patients with ACOS, the FEV₁/FVC ratio is low and consistent with the diagnosis of COPD. The post-bronchodilator response may be variable, depending on the stage of disease and predominant clinical features. It is still unclear whether ACOS is a separate disease entity, a representation of severe asthma that has morphed into COPD, or not a syndrome but simply 2 separate comorbid disease states.

CORRESPONDENCE
Christina D. Wells, MD, University of Illinois Mile Square Health Center, 1220 S. Wood Street, Chicago, IL 60612; [email protected].

SAN FRANCISCO – Children diagnosed with atopic dermatitis when they were 1 year old were significantly more likely to have active food allergies and to have those allergies persist throughout childhood to age 18 years, based on findings from a prospective, longitudinal study of 287 Wisconsin children.

Mitchel L. Zoler/MDedge News

The link between atopic dermatitis (AD) and food allergy was especially strong in children who displayed early and recurrent AD; the link was weaker or essentially nonexistent for children with early transient AD or AD that first appeared later in childhood, Anne Marie Singh, MD, said while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

The results also showed that even mild AD linked with an increased prevalence of food allergy when it appeared early and persisted, but more severe AD with this onset and recurrence pattern led to an even greater prevalence of food allergy, said Dr. Singh, a pediatric allergist and asthma specialist at the University of Wisconsin–Madison.

“The data suggest that something about early, recurrent AD increases the risk for food allergy throughout childhood,” Dr. Singh said in an interview. The findings suggest that surveillance for food allergies need to be intensified in infants who present with AD by the time they’re 1 year old and that food allergy surveillance should continue as these children age as long as their AD recurs.

The results also hint that these children might potentially benefit from steps aimed at desensitizing the allergy, although this must be proven in a future intervention study, she said.

The results suggest that a food allergy prevention regimen like the one used in the Learning Early About Peanut Allergy (LEAP) trial (New Engl J Med. 2015 Feb 26;372[9]:803-13) to prevent peanut allergy may be appropriate for selected, high-risk children with early AD, but this hypothesis needs testing, Dr. Singh said. She noted that some important differences exist between the patients enrolled in LEAP and the children studied in the current report: In LEAP, all enrolled children had severe eczema, an established egg allergy, or both. The findings reported by Dr. Singh came from children with AD, but only about 30% had moderate or severe eczema, and her analysis did not subdivide the observed food allergies by the type of food that caused a reaction.

She and her associates used data collected in the Childhood Origins of Asthma (COAST) study, begun in 1998, which enrolled 287 infants prior to birth who had at least one parent who was allergic, asthmatic, or both (Pediatr Allergy Immunol. 2002 Dec;13[s15]:38-43). The data showed that 62% of the infants had either no AD or transient AD, 14% had late onset AD, and 24% had early, recurrent AD. Although the data showed a statistically significant link between AD at 1 year old and food allergies throughout childhood, further analysis that broke the population into three different patterns of AD showed that the link with food allergy primarily existed among children with the early, recurrent form. Children with early, recurrent atopic dermatitis had a food allergy prevalence of 12%-27% annually through the age of 18 years.

“The data suggest that immunologic changes early in life are critical to food allergy development and that these changes have long-lasting effects throughout childhood,” Dr. Singh concluded. “The immunologic mechanisms by which early AD affects food allergy development and disease expression require further investigation.”

COAST received no commercial funding. Dr. Singh reported no relevant financial disclosures.

[email protected]

SOURCE: Singh AM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB125.

SAN FRANCISCO – Children diagnosed with atopic dermatitis when they were 1 year old were significantly more likely to have active food allergies and to have those allergies persist throughout childhood to age 18 years, based on findings from a prospective, longitudinal study of 287 Wisconsin children.

Mitchel L. Zoler/MDedge News

The link between atopic dermatitis (AD) and food allergy was especially strong in children who displayed early and recurrent AD; the link was weaker or essentially nonexistent for children with early transient AD or AD that first appeared later in childhood, Anne Marie Singh, MD, said while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

The results also showed that even mild AD linked with an increased prevalence of food allergy when it appeared early and persisted, but more severe AD with this onset and recurrence pattern led to an even greater prevalence of food allergy, said Dr. Singh, a pediatric allergist and asthma specialist at the University of Wisconsin–Madison.

“The data suggest that something about early, recurrent AD increases the risk for food allergy throughout childhood,” Dr. Singh said in an interview. The findings suggest that surveillance for food allergies need to be intensified in infants who present with AD by the time they’re 1 year old and that food allergy surveillance should continue as these children age as long as their AD recurs.

The results also hint that these children might potentially benefit from steps aimed at desensitizing the allergy, although this must be proven in a future intervention study, she said.

The results suggest that a food allergy prevention regimen like the one used in the Learning Early About Peanut Allergy (LEAP) trial (New Engl J Med. 2015 Feb 26;372[9]:803-13) to prevent peanut allergy may be appropriate for selected, high-risk children with early AD, but this hypothesis needs testing, Dr. Singh said. She noted that some important differences exist between the patients enrolled in LEAP and the children studied in the current report: In LEAP, all enrolled children had severe eczema, an established egg allergy, or both. The findings reported by Dr. Singh came from children with AD, but only about 30% had moderate or severe eczema, and her analysis did not subdivide the observed food allergies by the type of food that caused a reaction.

She and her associates used data collected in the Childhood Origins of Asthma (COAST) study, begun in 1998, which enrolled 287 infants prior to birth who had at least one parent who was allergic, asthmatic, or both (Pediatr Allergy Immunol. 2002 Dec;13[s15]:38-43). The data showed that 62% of the infants had either no AD or transient AD, 14% had late onset AD, and 24% had early, recurrent AD. Although the data showed a statistically significant link between AD at 1 year old and food allergies throughout childhood, further analysis that broke the population into three different patterns of AD showed that the link with food allergy primarily existed among children with the early, recurrent form. Children with early, recurrent atopic dermatitis had a food allergy prevalence of 12%-27% annually through the age of 18 years.

“The data suggest that immunologic changes early in life are critical to food allergy development and that these changes have long-lasting effects throughout childhood,” Dr. Singh concluded. “The immunologic mechanisms by which early AD affects food allergy development and disease expression require further investigation.”

COAST received no commercial funding. Dr. Singh reported no relevant financial disclosures.

[email protected]

SOURCE: Singh AM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB125.

SAN FRANCISCO – Children diagnosed with atopic dermatitis when they were 1 year old were significantly more likely to have active food allergies and to have those allergies persist throughout childhood to age 18 years, based on findings from a prospective, longitudinal study of 287 Wisconsin children.

Mitchel L. Zoler/MDedge News

The link between atopic dermatitis (AD) and food allergy was especially strong in children who displayed early and recurrent AD; the link was weaker or essentially nonexistent for children with early transient AD or AD that first appeared later in childhood, Anne Marie Singh, MD, said while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

The results also showed that even mild AD linked with an increased prevalence of food allergy when it appeared early and persisted, but more severe AD with this onset and recurrence pattern led to an even greater prevalence of food allergy, said Dr. Singh, a pediatric allergist and asthma specialist at the University of Wisconsin–Madison.

“The data suggest that something about early, recurrent AD increases the risk for food allergy throughout childhood,” Dr. Singh said in an interview. The findings suggest that surveillance for food allergies need to be intensified in infants who present with AD by the time they’re 1 year old and that food allergy surveillance should continue as these children age as long as their AD recurs.

The results also hint that these children might potentially benefit from steps aimed at desensitizing the allergy, although this must be proven in a future intervention study, she said.

The results suggest that a food allergy prevention regimen like the one used in the Learning Early About Peanut Allergy (LEAP) trial (New Engl J Med. 2015 Feb 26;372[9]:803-13) to prevent peanut allergy may be appropriate for selected, high-risk children with early AD, but this hypothesis needs testing, Dr. Singh said. She noted that some important differences exist between the patients enrolled in LEAP and the children studied in the current report: In LEAP, all enrolled children had severe eczema, an established egg allergy, or both. The findings reported by Dr. Singh came from children with AD, but only about 30% had moderate or severe eczema, and her analysis did not subdivide the observed food allergies by the type of food that caused a reaction.

She and her associates used data collected in the Childhood Origins of Asthma (COAST) study, begun in 1998, which enrolled 287 infants prior to birth who had at least one parent who was allergic, asthmatic, or both (Pediatr Allergy Immunol. 2002 Dec;13[s15]:38-43). The data showed that 62% of the infants had either no AD or transient AD, 14% had late onset AD, and 24% had early, recurrent AD. Although the data showed a statistically significant link between AD at 1 year old and food allergies throughout childhood, further analysis that broke the population into three different patterns of AD showed that the link with food allergy primarily existed among children with the early, recurrent form. Children with early, recurrent atopic dermatitis had a food allergy prevalence of 12%-27% annually through the age of 18 years.

“The data suggest that immunologic changes early in life are critical to food allergy development and that these changes have long-lasting effects throughout childhood,” Dr. Singh concluded. “The immunologic mechanisms by which early AD affects food allergy development and disease expression require further investigation.”

COAST received no commercial funding. Dr. Singh reported no relevant financial disclosures.

[email protected]

SOURCE: Singh AM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB125.