Asthma

Lower muscle mass was significantly associated with more airway obstruction and reduced functional exercise capacity in adults with asthma, based on data from 114 individuals.

Previous studies have shown reduced muscle mass in asthma patients, but the impact on clinical and functional outcomes has not been well studied, wrote Edith Visser, MSc, of Medical Centre Leeuwarden (the Netherlands) and colleagues.

“Many asthma patients, especially those with severe disease, report exercise intolerance and limitations in daily activities, severely affecting their quality of life,” they said. Research into the clinical consequences of low muscle mass and low muscle strength for patients with asthma and the role of inflammation could make muscle function a potential treatment target for those with asthma, they said.

In a study published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers recruited 114 consecutive adults aged 18 years and older with a diagnosis of moderate to severe asthma who were seen at a single center between Jun. 2019 and Oct. 2022. The mean age of the patients was 51.9 years, 36% were men, 70% were overweight or obese, and 34 were diagnosed with severe asthma.

Participants underwent clinical, functional, and laboratory assessments at one or two visits within a 2-week period. Assessment tools included the Asthma Quality of Life Questionnaire (AQLQ), the Asthma Control Questionnaire (ACQ-6), a questionnaire on health care use (HCU), and the ‘short questionnaire to assess health-enhancing physical activity’ (SQUASH).

Functional activity was based on the 6-minute walking distance (6MWD), and lung function tests included spirometry and fractional inhaled nitric oxide (FeNO). Muscle mass was based on fat-free mass index (FFMI) and urinary creatinine excretion rate (CER). Muscle strength was measured using hand-grip strength (HGS).

The researchers examined levels of muscle mass and strength and their relation to functional and clinical outcomes.

Overall, the mean measures of muscle mass and strength were higher in males, who had average FFMI, CER, and HGS measures of 20.1 kg/m², 15.3 mmol/day, and 48.8 kg, respectively. These measures in women were 17.3 kg/m², 10.8 mmol/day, and 29.3 kg, respectively.

After adjusting for confounding factors, patients in the lowest tertile for muscle mass based on FFMI had significantly more severe asthma based on postbronchodilator forced expiratory volume in 1 second and FEV₁/forced vital capacity, as well as lower functional exercise capacity based on the 6MWD compared to those in the highest tertile. A similar association appeared between CER and FEV₁, but not FEV₁/FVC.

However, no significant associations appeared between the muscle mass measures of FFMI or CER and scores on the ACQ, AQLQ, emergency department visits, or asthma exacerbations, the researchers noted.

No relationship appeared between muscle strength and functional outcomes. However, patients in the lowest tertile of HGS had worse asthma control, worse quality of life, and a higher probability of at least one visit to the emergency department compared to patients in the highest HGS tertile.

Higher leukocyte levels were significantly associated with lower muscle mass after adjusting for age, sex, weight, and physical activity, but no other inflammatory markers were significantly associated with FFMI.

The association between lower muscle strength and poorer asthma control, lower quality of life, and greater odds of emergency department visits reflect findings from previous studies, the researchers said. The mechanisms behind the loss of muscle strength in asthma remain unclear, but physical inactivity and daily oral corticosteroid use may play a role, they added.

The study findings were limited by the cross-sectional design and the possibility that muscle weakness may instead stem from reduced physical activity associated with poor lung function and asthma control, the researchers noted. Other limitations included the potential overestimation of FFMI and the lack of statistical power to show a relationship between FFMI and emergency department visits and asthma exacerbations, they said.

However, the current study is the first known to explore the relationship between lower muscle mass and strength and a range of both functional and clinical outcomes in patients with moderate to severe asthma, they said.

“Our findings encourage longitudinal studies into muscle function as a potential target for treatment to improve asthma outcomes,” they concluded.

The study was supported by unrestricted grants from Medical Centre Leeuwarden research fund. Ms. Visser had no financial conflicts to disclose.

Lower muscle mass was significantly associated with more airway obstruction and reduced functional exercise capacity in adults with asthma, based on data from 114 individuals.

Previous studies have shown reduced muscle mass in asthma patients, but the impact on clinical and functional outcomes has not been well studied, wrote Edith Visser, MSc, of Medical Centre Leeuwarden (the Netherlands) and colleagues.

“Many asthma patients, especially those with severe disease, report exercise intolerance and limitations in daily activities, severely affecting their quality of life,” they said. Research into the clinical consequences of low muscle mass and low muscle strength for patients with asthma and the role of inflammation could make muscle function a potential treatment target for those with asthma, they said.

In a study published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers recruited 114 consecutive adults aged 18 years and older with a diagnosis of moderate to severe asthma who were seen at a single center between Jun. 2019 and Oct. 2022. The mean age of the patients was 51.9 years, 36% were men, 70% were overweight or obese, and 34 were diagnosed with severe asthma.

Participants underwent clinical, functional, and laboratory assessments at one or two visits within a 2-week period. Assessment tools included the Asthma Quality of Life Questionnaire (AQLQ), the Asthma Control Questionnaire (ACQ-6), a questionnaire on health care use (HCU), and the ‘short questionnaire to assess health-enhancing physical activity’ (SQUASH).

Functional activity was based on the 6-minute walking distance (6MWD), and lung function tests included spirometry and fractional inhaled nitric oxide (FeNO). Muscle mass was based on fat-free mass index (FFMI) and urinary creatinine excretion rate (CER). Muscle strength was measured using hand-grip strength (HGS).

The researchers examined levels of muscle mass and strength and their relation to functional and clinical outcomes.

Overall, the mean measures of muscle mass and strength were higher in males, who had average FFMI, CER, and HGS measures of 20.1 kg/m², 15.3 mmol/day, and 48.8 kg, respectively. These measures in women were 17.3 kg/m², 10.8 mmol/day, and 29.3 kg, respectively.

After adjusting for confounding factors, patients in the lowest tertile for muscle mass based on FFMI had significantly more severe asthma based on postbronchodilator forced expiratory volume in 1 second and FEV₁/forced vital capacity, as well as lower functional exercise capacity based on the 6MWD compared to those in the highest tertile. A similar association appeared between CER and FEV₁, but not FEV₁/FVC.

However, no significant associations appeared between the muscle mass measures of FFMI or CER and scores on the ACQ, AQLQ, emergency department visits, or asthma exacerbations, the researchers noted.

No relationship appeared between muscle strength and functional outcomes. However, patients in the lowest tertile of HGS had worse asthma control, worse quality of life, and a higher probability of at least one visit to the emergency department compared to patients in the highest HGS tertile.

Higher leukocyte levels were significantly associated with lower muscle mass after adjusting for age, sex, weight, and physical activity, but no other inflammatory markers were significantly associated with FFMI.

The association between lower muscle strength and poorer asthma control, lower quality of life, and greater odds of emergency department visits reflect findings from previous studies, the researchers said. The mechanisms behind the loss of muscle strength in asthma remain unclear, but physical inactivity and daily oral corticosteroid use may play a role, they added.

The study findings were limited by the cross-sectional design and the possibility that muscle weakness may instead stem from reduced physical activity associated with poor lung function and asthma control, the researchers noted. Other limitations included the potential overestimation of FFMI and the lack of statistical power to show a relationship between FFMI and emergency department visits and asthma exacerbations, they said.

However, the current study is the first known to explore the relationship between lower muscle mass and strength and a range of both functional and clinical outcomes in patients with moderate to severe asthma, they said.

“Our findings encourage longitudinal studies into muscle function as a potential target for treatment to improve asthma outcomes,” they concluded.

The study was supported by unrestricted grants from Medical Centre Leeuwarden research fund. Ms. Visser had no financial conflicts to disclose.

Lower muscle mass was significantly associated with more airway obstruction and reduced functional exercise capacity in adults with asthma, based on data from 114 individuals.

Previous studies have shown reduced muscle mass in asthma patients, but the impact on clinical and functional outcomes has not been well studied, wrote Edith Visser, MSc, of Medical Centre Leeuwarden (the Netherlands) and colleagues.

“Many asthma patients, especially those with severe disease, report exercise intolerance and limitations in daily activities, severely affecting their quality of life,” they said. Research into the clinical consequences of low muscle mass and low muscle strength for patients with asthma and the role of inflammation could make muscle function a potential treatment target for those with asthma, they said.

In a study published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers recruited 114 consecutive adults aged 18 years and older with a diagnosis of moderate to severe asthma who were seen at a single center between Jun. 2019 and Oct. 2022. The mean age of the patients was 51.9 years, 36% were men, 70% were overweight or obese, and 34 were diagnosed with severe asthma.

Participants underwent clinical, functional, and laboratory assessments at one or two visits within a 2-week period. Assessment tools included the Asthma Quality of Life Questionnaire (AQLQ), the Asthma Control Questionnaire (ACQ-6), a questionnaire on health care use (HCU), and the ‘short questionnaire to assess health-enhancing physical activity’ (SQUASH).

Functional activity was based on the 6-minute walking distance (6MWD), and lung function tests included spirometry and fractional inhaled nitric oxide (FeNO). Muscle mass was based on fat-free mass index (FFMI) and urinary creatinine excretion rate (CER). Muscle strength was measured using hand-grip strength (HGS).

The researchers examined levels of muscle mass and strength and their relation to functional and clinical outcomes.

Overall, the mean measures of muscle mass and strength were higher in males, who had average FFMI, CER, and HGS measures of 20.1 kg/m², 15.3 mmol/day, and 48.8 kg, respectively. These measures in women were 17.3 kg/m², 10.8 mmol/day, and 29.3 kg, respectively.

After adjusting for confounding factors, patients in the lowest tertile for muscle mass based on FFMI had significantly more severe asthma based on postbronchodilator forced expiratory volume in 1 second and FEV₁/forced vital capacity, as well as lower functional exercise capacity based on the 6MWD compared to those in the highest tertile. A similar association appeared between CER and FEV₁, but not FEV₁/FVC.

However, no significant associations appeared between the muscle mass measures of FFMI or CER and scores on the ACQ, AQLQ, emergency department visits, or asthma exacerbations, the researchers noted.

No relationship appeared between muscle strength and functional outcomes. However, patients in the lowest tertile of HGS had worse asthma control, worse quality of life, and a higher probability of at least one visit to the emergency department compared to patients in the highest HGS tertile.

Higher leukocyte levels were significantly associated with lower muscle mass after adjusting for age, sex, weight, and physical activity, but no other inflammatory markers were significantly associated with FFMI.

The association between lower muscle strength and poorer asthma control, lower quality of life, and greater odds of emergency department visits reflect findings from previous studies, the researchers said. The mechanisms behind the loss of muscle strength in asthma remain unclear, but physical inactivity and daily oral corticosteroid use may play a role, they added.

The study findings were limited by the cross-sectional design and the possibility that muscle weakness may instead stem from reduced physical activity associated with poor lung function and asthma control, the researchers noted. Other limitations included the potential overestimation of FFMI and the lack of statistical power to show a relationship between FFMI and emergency department visits and asthma exacerbations, they said.

However, the current study is the first known to explore the relationship between lower muscle mass and strength and a range of both functional and clinical outcomes in patients with moderate to severe asthma, they said.

“Our findings encourage longitudinal studies into muscle function as a potential target for treatment to improve asthma outcomes,” they concluded.

The study was supported by unrestricted grants from Medical Centre Leeuwarden research fund. Ms. Visser had no financial conflicts to disclose.

The clinical features and inflammatory mediators of adult-onset asthma were associated with distinct endotype groups defined by eosinophil and neutrophil levels, based on data from a real-life long term study of 203 patients.

Asthma is a chronic condition from lower respiratory tract inflammation composed of complex, heterogeneous endotypes with T2 helper cells being one way to distinguish between them. Endotypes have previously been suggested to have differing risks for asthma exacerbations and severity. However, clinical and biomarker information used for recognizing and targeting treatment is largely lacking in those subgroups other than eosinophilic asthma, according to Ella Flinkman, faculty of medicine and health technology, of Tampere University (Finland), and colleagues.

In a study published in The Journal of Allergy and Clinical Immunology: In Practice the researchers reported on their single-center 12-year follow-up phase II Seinäjoki Adult Asthma Study (SAAS). The included cohort of 203 patients had a median age of 58 years and 58% were women; all participants were originally diagnosed by a respiratory specialist physician as having new adult-onset asthma during the years 1999-2000 using asthma symptoms and objective lung function measurements.

To evaluate the association between clinical features and inflammation mediators to venous blood granulocytes this cohort was divided into paucigranulocytic (n = 108), neutrophilic (n = 60), eosinophilic (n = 21), and mixed granulocytic (n = 14) endotype subgroups based on eosinophil and neutrophil levels. Objective comparisons between groups were made using measurements from forced expiratory volume in 1 second (FEV₁), fraction of exhaled nitric oxide (FeNO), immunoglobin E (IgE), high-sensitivity C-reactive protein (hsCRP), IL-6, resistin, MMP-9, plasma soluble urokinase plasminogen activator receptor (suPAR), leptin, HMW adiponectin, and periostin tests. Asthma-related medications and disease exacerbation data were collected from medical records accumulated over the 12-year study period.

The neutrophilic group was defined by high (≥ 4.4×10^9/L) neutrophil but low (< 0.30×10⁹/L) eosinophil counts and conversely the eosinophilic group had low (< 4.4×10⁹/L) neutrophil but high (≥ 0.30×10⁹/L) eosinophil counts. The paucigranulocytic was low and the mixed granulocytic group was high for both eosinophil and neutrophil levels, respectively. Each group was associated with a unique profile of features related to asthma prognosis and treatment. The paucigranulocytic endotype was used as the base comparison group in regression analysis as it was the least likely to meet the definition of severe asthma. This was indicated by the lowest use of inhaled corticosteroid (ICS), antibiotics, and occurrence of unplanned respiratory visits. The other three groups were more likely to fulfill a severe asthma classification.

Negative binomial regression analysis showed significant association of increased incidence rate ratio (IRR) of unplanned respiratory visits, highest body mass index (BMI), and highest dispensed doses of ICS with neutrophilic asthma. Additional significantly associated factors included smoking history and gender. Adjustment for dispensed ICS 2 years prior to the 12-year follow-up visit resulted in a change from borderline to significant association of increased IRR for the eosinophilic group. Both the eosinophilic and neutrophilic groups were associated with the most antibiotic use over the 12-year follow-up period. The authors suggested their data may indicate that antibiotics are overprescribed for asthma and further investigation is required.

Multiple linear regression analysis showed a decline in lung function associated with the eosinophilic but not the neutrophilic group. Connections between specific blood endotypes and molecular features were also identified. Highest periostin and FeNO levels found in the eosinophilic group were consistent with other studies on patients specifically diagnosed with eosinophilic asthma.

The neutrophilic group was distinguished by the highest hsCRP, MMP-9, IL-6, leptin, and suPAR levels. Highest resistin levels were found in both the mixed granulocyte and neutrophilic groups.

This study was strengthened by its real life long-term nature and method for cohort selection, according to the authors, though the value of a larger population to raise numbers particularly in the smaller sized groups was noted.

The authors concluded: “Our study indicates that assays of blood eosinophil and neutrophil counts provide useful information for assessing and treating patients with adult-onset asthma. These granulocyte counts reflect the underlying inflammatory pattern and reveal important differences in asthma clinical features and outcomes.” Additional research “regarding biomarkers used to identify different endotypes of asthma” is needed.

The study was sponsored by a number of research foundations in Finland as well as hospital research center funds. Several of the authors disclosed associations with pharmaceutical companies, including Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, and Sanofi.

The clinical features and inflammatory mediators of adult-onset asthma were associated with distinct endotype groups defined by eosinophil and neutrophil levels, based on data from a real-life long term study of 203 patients.

Asthma is a chronic condition from lower respiratory tract inflammation composed of complex, heterogeneous endotypes with T2 helper cells being one way to distinguish between them. Endotypes have previously been suggested to have differing risks for asthma exacerbations and severity. However, clinical and biomarker information used for recognizing and targeting treatment is largely lacking in those subgroups other than eosinophilic asthma, according to Ella Flinkman, faculty of medicine and health technology, of Tampere University (Finland), and colleagues.

In a study published in The Journal of Allergy and Clinical Immunology: In Practice the researchers reported on their single-center 12-year follow-up phase II Seinäjoki Adult Asthma Study (SAAS). The included cohort of 203 patients had a median age of 58 years and 58% were women; all participants were originally diagnosed by a respiratory specialist physician as having new adult-onset asthma during the years 1999-2000 using asthma symptoms and objective lung function measurements.

To evaluate the association between clinical features and inflammation mediators to venous blood granulocytes this cohort was divided into paucigranulocytic (n = 108), neutrophilic (n = 60), eosinophilic (n = 21), and mixed granulocytic (n = 14) endotype subgroups based on eosinophil and neutrophil levels. Objective comparisons between groups were made using measurements from forced expiratory volume in 1 second (FEV₁), fraction of exhaled nitric oxide (FeNO), immunoglobin E (IgE), high-sensitivity C-reactive protein (hsCRP), IL-6, resistin, MMP-9, plasma soluble urokinase plasminogen activator receptor (suPAR), leptin, HMW adiponectin, and periostin tests. Asthma-related medications and disease exacerbation data were collected from medical records accumulated over the 12-year study period.

The neutrophilic group was defined by high (≥ 4.4×10^9/L) neutrophil but low (< 0.30×10⁹/L) eosinophil counts and conversely the eosinophilic group had low (< 4.4×10⁹/L) neutrophil but high (≥ 0.30×10⁹/L) eosinophil counts. The paucigranulocytic was low and the mixed granulocytic group was high for both eosinophil and neutrophil levels, respectively. Each group was associated with a unique profile of features related to asthma prognosis and treatment. The paucigranulocytic endotype was used as the base comparison group in regression analysis as it was the least likely to meet the definition of severe asthma. This was indicated by the lowest use of inhaled corticosteroid (ICS), antibiotics, and occurrence of unplanned respiratory visits. The other three groups were more likely to fulfill a severe asthma classification.

Negative binomial regression analysis showed significant association of increased incidence rate ratio (IRR) of unplanned respiratory visits, highest body mass index (BMI), and highest dispensed doses of ICS with neutrophilic asthma. Additional significantly associated factors included smoking history and gender. Adjustment for dispensed ICS 2 years prior to the 12-year follow-up visit resulted in a change from borderline to significant association of increased IRR for the eosinophilic group. Both the eosinophilic and neutrophilic groups were associated with the most antibiotic use over the 12-year follow-up period. The authors suggested their data may indicate that antibiotics are overprescribed for asthma and further investigation is required.

Multiple linear regression analysis showed a decline in lung function associated with the eosinophilic but not the neutrophilic group. Connections between specific blood endotypes and molecular features were also identified. Highest periostin and FeNO levels found in the eosinophilic group were consistent with other studies on patients specifically diagnosed with eosinophilic asthma.

The neutrophilic group was distinguished by the highest hsCRP, MMP-9, IL-6, leptin, and suPAR levels. Highest resistin levels were found in both the mixed granulocyte and neutrophilic groups.

This study was strengthened by its real life long-term nature and method for cohort selection, according to the authors, though the value of a larger population to raise numbers particularly in the smaller sized groups was noted.

The authors concluded: “Our study indicates that assays of blood eosinophil and neutrophil counts provide useful information for assessing and treating patients with adult-onset asthma. These granulocyte counts reflect the underlying inflammatory pattern and reveal important differences in asthma clinical features and outcomes.” Additional research “regarding biomarkers used to identify different endotypes of asthma” is needed.

The study was sponsored by a number of research foundations in Finland as well as hospital research center funds. Several of the authors disclosed associations with pharmaceutical companies, including Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, and Sanofi.

The clinical features and inflammatory mediators of adult-onset asthma were associated with distinct endotype groups defined by eosinophil and neutrophil levels, based on data from a real-life long term study of 203 patients.

Asthma is a chronic condition from lower respiratory tract inflammation composed of complex, heterogeneous endotypes with T2 helper cells being one way to distinguish between them. Endotypes have previously been suggested to have differing risks for asthma exacerbations and severity. However, clinical and biomarker information used for recognizing and targeting treatment is largely lacking in those subgroups other than eosinophilic asthma, according to Ella Flinkman, faculty of medicine and health technology, of Tampere University (Finland), and colleagues.

In a study published in The Journal of Allergy and Clinical Immunology: In Practice the researchers reported on their single-center 12-year follow-up phase II Seinäjoki Adult Asthma Study (SAAS). The included cohort of 203 patients had a median age of 58 years and 58% were women; all participants were originally diagnosed by a respiratory specialist physician as having new adult-onset asthma during the years 1999-2000 using asthma symptoms and objective lung function measurements.

To evaluate the association between clinical features and inflammation mediators to venous blood granulocytes this cohort was divided into paucigranulocytic (n = 108), neutrophilic (n = 60), eosinophilic (n = 21), and mixed granulocytic (n = 14) endotype subgroups based on eosinophil and neutrophil levels. Objective comparisons between groups were made using measurements from forced expiratory volume in 1 second (FEV₁), fraction of exhaled nitric oxide (FeNO), immunoglobin E (IgE), high-sensitivity C-reactive protein (hsCRP), IL-6, resistin, MMP-9, plasma soluble urokinase plasminogen activator receptor (suPAR), leptin, HMW adiponectin, and periostin tests. Asthma-related medications and disease exacerbation data were collected from medical records accumulated over the 12-year study period.

The neutrophilic group was defined by high (≥ 4.4×10^9/L) neutrophil but low (< 0.30×10⁹/L) eosinophil counts and conversely the eosinophilic group had low (< 4.4×10⁹/L) neutrophil but high (≥ 0.30×10⁹/L) eosinophil counts. The paucigranulocytic was low and the mixed granulocytic group was high for both eosinophil and neutrophil levels, respectively. Each group was associated with a unique profile of features related to asthma prognosis and treatment. The paucigranulocytic endotype was used as the base comparison group in regression analysis as it was the least likely to meet the definition of severe asthma. This was indicated by the lowest use of inhaled corticosteroid (ICS), antibiotics, and occurrence of unplanned respiratory visits. The other three groups were more likely to fulfill a severe asthma classification.

Negative binomial regression analysis showed significant association of increased incidence rate ratio (IRR) of unplanned respiratory visits, highest body mass index (BMI), and highest dispensed doses of ICS with neutrophilic asthma. Additional significantly associated factors included smoking history and gender. Adjustment for dispensed ICS 2 years prior to the 12-year follow-up visit resulted in a change from borderline to significant association of increased IRR for the eosinophilic group. Both the eosinophilic and neutrophilic groups were associated with the most antibiotic use over the 12-year follow-up period. The authors suggested their data may indicate that antibiotics are overprescribed for asthma and further investigation is required.

Multiple linear regression analysis showed a decline in lung function associated with the eosinophilic but not the neutrophilic group. Connections between specific blood endotypes and molecular features were also identified. Highest periostin and FeNO levels found in the eosinophilic group were consistent with other studies on patients specifically diagnosed with eosinophilic asthma.

The neutrophilic group was distinguished by the highest hsCRP, MMP-9, IL-6, leptin, and suPAR levels. Highest resistin levels were found in both the mixed granulocyte and neutrophilic groups.

This study was strengthened by its real life long-term nature and method for cohort selection, according to the authors, though the value of a larger population to raise numbers particularly in the smaller sized groups was noted.

The authors concluded: “Our study indicates that assays of blood eosinophil and neutrophil counts provide useful information for assessing and treating patients with adult-onset asthma. These granulocyte counts reflect the underlying inflammatory pattern and reveal important differences in asthma clinical features and outcomes.” Additional research “regarding biomarkers used to identify different endotypes of asthma” is needed.

The study was sponsored by a number of research foundations in Finland as well as hospital research center funds. Several of the authors disclosed associations with pharmaceutical companies, including Astra Zeneca, Boehringer-Ingelheim, GSK, Novartis, and Sanofi.

Peripheral airway response to methacholine was similar among obese adults with and without asthma, although forced expiratory volume was lower for those with asthma, based on data from 53 individuals.

Obesity remains a risk factor for asthma, and obese individuals with asthma tend to have worse control and more severe disease, compared with nonobese asthma patients, wrote Anne E. Dixon, BM, BCh, of the University of Vermont, Burlington, and colleagues.

Previous studies have shown that airway reactivity can occur in obese individuals without airway inflammation, but studies characterizing obese asthma based on lung function are lacking, they said. “Combining spirometry and oscillometry might reveal abnormalities in lung mechanics particularly pertinent to people with obesity and asthma,” the researchers noted.

In a cross-sectional study published in the journal CHEST, the researchers reviewed data from 31 obese adults with asthma and 22 obese adults without asthma. The participants were aged 18 years and older, with forced expiratory volume (FEV₁) of at least 60% of predicted. All had class III obesity, with an average BMI of 47.2 kg/m² for those with asthma and 46.7 kg/m² for nonasthma controls. Demographic characteristics were similar between the groups.

Airway reactivity was defined as a 20% decrease in FEV₁ and/or a 50% change in resistance or reactance at 5 Hz (R5 and X5), at a concentration of 16 mg/mL or less of methacholine. Patients were assessed using spirometry and oscillometry.

Overall, most obese individuals with and without asthma showed significant changes in peripheral airway resistance. For those with asthma, the resistance at 5 Hz, measured by oscillometry, increased by 52% in response to the PC20 methacholine challenge, with an area under the reactance curve (AX) of 361%. For controls without asthma, the resistance at 5 Hz increased by 45%, with an AX of 268% in response to 16 mg/mL of methacholine.

This finding suggests that obesity predisposes individuals to peripheral airway reactivity regardless of asthma status, the researchers wrote in their discussion.

The researchers also identified two distinct groups of asthma patients categorized by respiratory system impedance based on more concordant vs. discordant bronchoconstriction in the central and peripheral airways. The baseline AX for these two groups was 11.8 and 46.7, respectively, with interquartile ranges of 9.9-23.4 and 23.2-53.7, respectively.

The discordant group included only women, and these patients reported significantly more gastroesophageal reflux, increased chest tightness, and more wheezing and asthma exacerbations than the concordant group, which may be related to air trapping, shown on previous studies of obese individuals with asthma, the researchers wrote.

The findings were limited by several factors, including the measurement of airway impedance only at the peak methacholine dose and the measurement of oscillometry after spirometry, the researchers noted. Other limitations included the relatively small study population at a single center, and the focus on obese individuals only.

More research is needed in larger and more diverse patient populations, but the results support the characterization of a subgroup of obese asthma patients with significant peripheral airway dysfunction, the researchers wrote.

“Oscillometry testing can reveal a physiologic phenotype of asthma in obesity that may be related to worse symptoms and more severe disease, and also reveal subclinical abnormalities in people with obesity, but without clinically diagnosed lung disease,” they concluded.

The study was supported in part by the National Institutes of Health. The researchers declared no financial conflicts.

A version of this article first appeared on Medscape.com.

Peripheral airway response to methacholine was similar among obese adults with and without asthma, although forced expiratory volume was lower for those with asthma, based on data from 53 individuals.

Obesity remains a risk factor for asthma, and obese individuals with asthma tend to have worse control and more severe disease, compared with nonobese asthma patients, wrote Anne E. Dixon, BM, BCh, of the University of Vermont, Burlington, and colleagues.

Previous studies have shown that airway reactivity can occur in obese individuals without airway inflammation, but studies characterizing obese asthma based on lung function are lacking, they said. “Combining spirometry and oscillometry might reveal abnormalities in lung mechanics particularly pertinent to people with obesity and asthma,” the researchers noted.

In a cross-sectional study published in the journal CHEST, the researchers reviewed data from 31 obese adults with asthma and 22 obese adults without asthma. The participants were aged 18 years and older, with forced expiratory volume (FEV₁) of at least 60% of predicted. All had class III obesity, with an average BMI of 47.2 kg/m² for those with asthma and 46.7 kg/m² for nonasthma controls. Demographic characteristics were similar between the groups.

Airway reactivity was defined as a 20% decrease in FEV₁ and/or a 50% change in resistance or reactance at 5 Hz (R5 and X5), at a concentration of 16 mg/mL or less of methacholine. Patients were assessed using spirometry and oscillometry.

Overall, most obese individuals with and without asthma showed significant changes in peripheral airway resistance. For those with asthma, the resistance at 5 Hz, measured by oscillometry, increased by 52% in response to the PC20 methacholine challenge, with an area under the reactance curve (AX) of 361%. For controls without asthma, the resistance at 5 Hz increased by 45%, with an AX of 268% in response to 16 mg/mL of methacholine.

This finding suggests that obesity predisposes individuals to peripheral airway reactivity regardless of asthma status, the researchers wrote in their discussion.

The researchers also identified two distinct groups of asthma patients categorized by respiratory system impedance based on more concordant vs. discordant bronchoconstriction in the central and peripheral airways. The baseline AX for these two groups was 11.8 and 46.7, respectively, with interquartile ranges of 9.9-23.4 and 23.2-53.7, respectively.

The discordant group included only women, and these patients reported significantly more gastroesophageal reflux, increased chest tightness, and more wheezing and asthma exacerbations than the concordant group, which may be related to air trapping, shown on previous studies of obese individuals with asthma, the researchers wrote.

The findings were limited by several factors, including the measurement of airway impedance only at the peak methacholine dose and the measurement of oscillometry after spirometry, the researchers noted. Other limitations included the relatively small study population at a single center, and the focus on obese individuals only.

More research is needed in larger and more diverse patient populations, but the results support the characterization of a subgroup of obese asthma patients with significant peripheral airway dysfunction, the researchers wrote.

“Oscillometry testing can reveal a physiologic phenotype of asthma in obesity that may be related to worse symptoms and more severe disease, and also reveal subclinical abnormalities in people with obesity, but without clinically diagnosed lung disease,” they concluded.

The study was supported in part by the National Institutes of Health. The researchers declared no financial conflicts.

A version of this article first appeared on Medscape.com.

Peripheral airway response to methacholine was similar among obese adults with and without asthma, although forced expiratory volume was lower for those with asthma, based on data from 53 individuals.

Obesity remains a risk factor for asthma, and obese individuals with asthma tend to have worse control and more severe disease, compared with nonobese asthma patients, wrote Anne E. Dixon, BM, BCh, of the University of Vermont, Burlington, and colleagues.

Previous studies have shown that airway reactivity can occur in obese individuals without airway inflammation, but studies characterizing obese asthma based on lung function are lacking, they said. “Combining spirometry and oscillometry might reveal abnormalities in lung mechanics particularly pertinent to people with obesity and asthma,” the researchers noted.

In a cross-sectional study published in the journal CHEST, the researchers reviewed data from 31 obese adults with asthma and 22 obese adults without asthma. The participants were aged 18 years and older, with forced expiratory volume (FEV₁) of at least 60% of predicted. All had class III obesity, with an average BMI of 47.2 kg/m² for those with asthma and 46.7 kg/m² for nonasthma controls. Demographic characteristics were similar between the groups.

Airway reactivity was defined as a 20% decrease in FEV₁ and/or a 50% change in resistance or reactance at 5 Hz (R5 and X5), at a concentration of 16 mg/mL or less of methacholine. Patients were assessed using spirometry and oscillometry.

Overall, most obese individuals with and without asthma showed significant changes in peripheral airway resistance. For those with asthma, the resistance at 5 Hz, measured by oscillometry, increased by 52% in response to the PC20 methacholine challenge, with an area under the reactance curve (AX) of 361%. For controls without asthma, the resistance at 5 Hz increased by 45%, with an AX of 268% in response to 16 mg/mL of methacholine.

This finding suggests that obesity predisposes individuals to peripheral airway reactivity regardless of asthma status, the researchers wrote in their discussion.

The researchers also identified two distinct groups of asthma patients categorized by respiratory system impedance based on more concordant vs. discordant bronchoconstriction in the central and peripheral airways. The baseline AX for these two groups was 11.8 and 46.7, respectively, with interquartile ranges of 9.9-23.4 and 23.2-53.7, respectively.

The discordant group included only women, and these patients reported significantly more gastroesophageal reflux, increased chest tightness, and more wheezing and asthma exacerbations than the concordant group, which may be related to air trapping, shown on previous studies of obese individuals with asthma, the researchers wrote.

The findings were limited by several factors, including the measurement of airway impedance only at the peak methacholine dose and the measurement of oscillometry after spirometry, the researchers noted. Other limitations included the relatively small study population at a single center, and the focus on obese individuals only.

More research is needed in larger and more diverse patient populations, but the results support the characterization of a subgroup of obese asthma patients with significant peripheral airway dysfunction, the researchers wrote.

“Oscillometry testing can reveal a physiologic phenotype of asthma in obesity that may be related to worse symptoms and more severe disease, and also reveal subclinical abnormalities in people with obesity, but without clinically diagnosed lung disease,” they concluded.

The study was supported in part by the National Institutes of Health. The researchers declared no financial conflicts.

A version of this article first appeared on Medscape.com.

Six subtypes of asthma that may facilitate personalized treatment were identified and confirmed in a large database review of approximately 50,000 patients, according to a recent study.

Previous studies of asthma subtypes have involved age of disease onset, the presence of allergies, and level of eosinophilic inflammation, and have been limited by factors including small sample size and lack of formal validation, Elsie M.F. Horne, MD, of the Asthma UK Centre for Applied Research, Edinburgh, and colleagues wrote.

In a study published in the International Journal of Medical Informatics, the researchers used data from two databases in the United Kingdom: the Optimum Patient Care Research Database (OPCRD) and the Secure Anonymised Information Linkage Database (SAIL). Each dataset included 50,000 randomly selected nonoverlapping adult asthma patients.

The researchers identified 45 categorical features from primary care electronic health records. The features included those directly linked to asthma, such as medications; and features indirectly linked to asthma, such as comorbidities.

The subtypes were defined by the clinically applicable features of level of inhaled corticosteroid use, level of health care use, and the presence of comorbidities, using multiple correspondence analysis and k-means cluster analysis.

The six asthma subtypes were identified in the OPCRD study population as follows: low inhaled corticosteroid use and low health care utilization (30%); low to medium ICS use (36%); low to medium ICS use and comorbidities (12%); varied ICS use and comorbid chronic obstructive pulmonary disease (4%); high ICS use (10%); and very high ICS use (7%).

The researchers replicated the subtypes with 91%-92% accuracy in an internal dataset and 84%-86% accuracy in an external dataset. “These subtypes generalized well at two future time points, and in an additional EHR database from a different U.K. nation (the SAIL Databank),” they wrote in their discussion.

The findings were limited by several factors including the retrospective design, the possible inclusion of people without asthma because of the cohort selection criteria, and the possible biases associated with the use of EHRs; however, the results were strengthened by the large dataset and the additional validations, the researchers noted.

“Using these subtypes to summarize asthma populations could help with management and resource planning at the practice level, and could be useful for understanding regional differences in the asthma population,” they noted. For example, key clinical implications for individuals in a low health care utilization subtype could include being flagged for barriers to care and misdiagnoses, while those in a high health care utilization subtype could be considered for reassessment of medication and other options.

The study received no outside funding. Lead author Dr. Horne had no financial conflicts to disclose.

Six subtypes of asthma that may facilitate personalized treatment were identified and confirmed in a large database review of approximately 50,000 patients, according to a recent study.

Previous studies of asthma subtypes have involved age of disease onset, the presence of allergies, and level of eosinophilic inflammation, and have been limited by factors including small sample size and lack of formal validation, Elsie M.F. Horne, MD, of the Asthma UK Centre for Applied Research, Edinburgh, and colleagues wrote.

In a study published in the International Journal of Medical Informatics, the researchers used data from two databases in the United Kingdom: the Optimum Patient Care Research Database (OPCRD) and the Secure Anonymised Information Linkage Database (SAIL). Each dataset included 50,000 randomly selected nonoverlapping adult asthma patients.

The researchers identified 45 categorical features from primary care electronic health records. The features included those directly linked to asthma, such as medications; and features indirectly linked to asthma, such as comorbidities.

The subtypes were defined by the clinically applicable features of level of inhaled corticosteroid use, level of health care use, and the presence of comorbidities, using multiple correspondence analysis and k-means cluster analysis.

The six asthma subtypes were identified in the OPCRD study population as follows: low inhaled corticosteroid use and low health care utilization (30%); low to medium ICS use (36%); low to medium ICS use and comorbidities (12%); varied ICS use and comorbid chronic obstructive pulmonary disease (4%); high ICS use (10%); and very high ICS use (7%).

The researchers replicated the subtypes with 91%-92% accuracy in an internal dataset and 84%-86% accuracy in an external dataset. “These subtypes generalized well at two future time points, and in an additional EHR database from a different U.K. nation (the SAIL Databank),” they wrote in their discussion.

The findings were limited by several factors including the retrospective design, the possible inclusion of people without asthma because of the cohort selection criteria, and the possible biases associated with the use of EHRs; however, the results were strengthened by the large dataset and the additional validations, the researchers noted.

“Using these subtypes to summarize asthma populations could help with management and resource planning at the practice level, and could be useful for understanding regional differences in the asthma population,” they noted. For example, key clinical implications for individuals in a low health care utilization subtype could include being flagged for barriers to care and misdiagnoses, while those in a high health care utilization subtype could be considered for reassessment of medication and other options.

The study received no outside funding. Lead author Dr. Horne had no financial conflicts to disclose.

Six subtypes of asthma that may facilitate personalized treatment were identified and confirmed in a large database review of approximately 50,000 patients, according to a recent study.

Previous studies of asthma subtypes have involved age of disease onset, the presence of allergies, and level of eosinophilic inflammation, and have been limited by factors including small sample size and lack of formal validation, Elsie M.F. Horne, MD, of the Asthma UK Centre for Applied Research, Edinburgh, and colleagues wrote.

In a study published in the International Journal of Medical Informatics, the researchers used data from two databases in the United Kingdom: the Optimum Patient Care Research Database (OPCRD) and the Secure Anonymised Information Linkage Database (SAIL). Each dataset included 50,000 randomly selected nonoverlapping adult asthma patients.

The researchers identified 45 categorical features from primary care electronic health records. The features included those directly linked to asthma, such as medications; and features indirectly linked to asthma, such as comorbidities.

The subtypes were defined by the clinically applicable features of level of inhaled corticosteroid use, level of health care use, and the presence of comorbidities, using multiple correspondence analysis and k-means cluster analysis.

The six asthma subtypes were identified in the OPCRD study population as follows: low inhaled corticosteroid use and low health care utilization (30%); low to medium ICS use (36%); low to medium ICS use and comorbidities (12%); varied ICS use and comorbid chronic obstructive pulmonary disease (4%); high ICS use (10%); and very high ICS use (7%).

The researchers replicated the subtypes with 91%-92% accuracy in an internal dataset and 84%-86% accuracy in an external dataset. “These subtypes generalized well at two future time points, and in an additional EHR database from a different U.K. nation (the SAIL Databank),” they wrote in their discussion.

The findings were limited by several factors including the retrospective design, the possible inclusion of people without asthma because of the cohort selection criteria, and the possible biases associated with the use of EHRs; however, the results were strengthened by the large dataset and the additional validations, the researchers noted.

“Using these subtypes to summarize asthma populations could help with management and resource planning at the practice level, and could be useful for understanding regional differences in the asthma population,” they noted. For example, key clinical implications for individuals in a low health care utilization subtype could include being flagged for barriers to care and misdiagnoses, while those in a high health care utilization subtype could be considered for reassessment of medication and other options.

The study received no outside funding. Lead author Dr. Horne had no financial conflicts to disclose.

A maternal or parental history of atopic dermatitis (AD) or asthma is associated with an increased risk of AD in offspring in the first 2 years of life, an analysis of a large birth cohort found.

“The prevalence of AD in children has increased dramatically in recent years, and most studies reporting the impact of parental atopic history on AD are based on older data,” wrote the study authors, led by Cathal O’Connor, MD. “Given the recent interest in early intervention to prevent AD and other allergic diseases, enhanced early identification of infants at risk of AD is increasingly important.”

The detailed analysis of AD risk associated with parental atopy in early life “may help to risk stratify infants to optimize early interventions for prevention or early treatment of AD,” they wrote.

LucaLorenzelli/Thinkstock

The study was published in Pediatric Dermatology.

For the analysis, Dr. O’Connor of the department of pediatrics and child health at University College Cork (Ireland) and colleagues conducted a secondary analysis of the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort Study.

The study recruited 2,183 healthy first-born babies between August 2009 and October 2011 to examine the effects of environmental factors during pregnancy and infancy on childhood health and development. Skin barrier assessments were performed at birth, 2 months, 6 months, 12 months, and 24 months using a validated open chamber system to measure transepidermal water loss.

Parental atopy was self-reported at 2 months. Parents were asked at 2 months if the infant had an “itchy rash on the face or in the folds of the arms or legs,” as a screening question for AD. Experienced health care personnel used UK Working Party criteria to diagnose AD at 6, 12, and 24 months.

Complete data on AD status was available for 1,505 children in the cohort. Dr. O’Connor and colleagues calculated an overall AD prevalence of 18.6% at 6 months, 15.2% at 12 months, and 16.5% at 24 months.

Overall prevalence of AD was highest at 6 months. The study showed a similar or slightly higher impact of paternal atopy on offspring AD development, compared to maternal atopy.

Multivariable logistic regression analysis revealed that the odds of AD were 1.57 at 6 months and 1.66 at 12 months for maternal AD; 1.90 at 6 months and 1.85 at 24 months for paternal AD; 1.76 at 6 months and 1.75 at 12 months for maternal asthma; and 1.70 at 6 months, 1.86 at 12 months, and 1.99 at 24 months for paternal asthma.

“Parental allergic rhinitis was not associated with AD in offspring in the first 2 years, except for maternal rhinitis at 24 months [an adjusted odds ratio of 1.79],” the authors wrote. “The genetic predisposition to allergic rhinitis, given the key role of aeroallergen sensitization in its pathogenesis, may not be associated with early onset AD, but may have a greater impact in later onset or persistent AD.”

The authors acknowledged certain limitations of the study, including the fact that it was a secondary data analysis, and that parental AD, asthma, and rhinitis were self-reported, “which may reduce reliability and may contribute to the differences seen between the impact of maternal and paternal reported atopy on offspring,” they wrote. “Data on siblings were not captured, as participants in the study were first-born children. Filaggrin mutational analysis was not performed, which would have provided richer detail.”

A maternal or parental history of atopic dermatitis (AD) or asthma is associated with an increased risk of AD in offspring in the first 2 years of life, an analysis of a large birth cohort found.

“The prevalence of AD in children has increased dramatically in recent years, and most studies reporting the impact of parental atopic history on AD are based on older data,” wrote the study authors, led by Cathal O’Connor, MD. “Given the recent interest in early intervention to prevent AD and other allergic diseases, enhanced early identification of infants at risk of AD is increasingly important.”

The detailed analysis of AD risk associated with parental atopy in early life “may help to risk stratify infants to optimize early interventions for prevention or early treatment of AD,” they wrote.

LucaLorenzelli/Thinkstock

The study was published in Pediatric Dermatology.

For the analysis, Dr. O’Connor of the department of pediatrics and child health at University College Cork (Ireland) and colleagues conducted a secondary analysis of the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort Study.

The study recruited 2,183 healthy first-born babies between August 2009 and October 2011 to examine the effects of environmental factors during pregnancy and infancy on childhood health and development. Skin barrier assessments were performed at birth, 2 months, 6 months, 12 months, and 24 months using a validated open chamber system to measure transepidermal water loss.

Parental atopy was self-reported at 2 months. Parents were asked at 2 months if the infant had an “itchy rash on the face or in the folds of the arms or legs,” as a screening question for AD. Experienced health care personnel used UK Working Party criteria to diagnose AD at 6, 12, and 24 months.

Complete data on AD status was available for 1,505 children in the cohort. Dr. O’Connor and colleagues calculated an overall AD prevalence of 18.6% at 6 months, 15.2% at 12 months, and 16.5% at 24 months.

Overall prevalence of AD was highest at 6 months. The study showed a similar or slightly higher impact of paternal atopy on offspring AD development, compared to maternal atopy.

Multivariable logistic regression analysis revealed that the odds of AD were 1.57 at 6 months and 1.66 at 12 months for maternal AD; 1.90 at 6 months and 1.85 at 24 months for paternal AD; 1.76 at 6 months and 1.75 at 12 months for maternal asthma; and 1.70 at 6 months, 1.86 at 12 months, and 1.99 at 24 months for paternal asthma.

“Parental allergic rhinitis was not associated with AD in offspring in the first 2 years, except for maternal rhinitis at 24 months [an adjusted odds ratio of 1.79],” the authors wrote. “The genetic predisposition to allergic rhinitis, given the key role of aeroallergen sensitization in its pathogenesis, may not be associated with early onset AD, but may have a greater impact in later onset or persistent AD.”

The authors acknowledged certain limitations of the study, including the fact that it was a secondary data analysis, and that parental AD, asthma, and rhinitis were self-reported, “which may reduce reliability and may contribute to the differences seen between the impact of maternal and paternal reported atopy on offspring,” they wrote. “Data on siblings were not captured, as participants in the study were first-born children. Filaggrin mutational analysis was not performed, which would have provided richer detail.”

A maternal or parental history of atopic dermatitis (AD) or asthma is associated with an increased risk of AD in offspring in the first 2 years of life, an analysis of a large birth cohort found.

“The prevalence of AD in children has increased dramatically in recent years, and most studies reporting the impact of parental atopic history on AD are based on older data,” wrote the study authors, led by Cathal O’Connor, MD. “Given the recent interest in early intervention to prevent AD and other allergic diseases, enhanced early identification of infants at risk of AD is increasingly important.”

The detailed analysis of AD risk associated with parental atopy in early life “may help to risk stratify infants to optimize early interventions for prevention or early treatment of AD,” they wrote.

LucaLorenzelli/Thinkstock

The study was published in Pediatric Dermatology.

For the analysis, Dr. O’Connor of the department of pediatrics and child health at University College Cork (Ireland) and colleagues conducted a secondary analysis of the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort Study.

The study recruited 2,183 healthy first-born babies between August 2009 and October 2011 to examine the effects of environmental factors during pregnancy and infancy on childhood health and development. Skin barrier assessments were performed at birth, 2 months, 6 months, 12 months, and 24 months using a validated open chamber system to measure transepidermal water loss.

Parental atopy was self-reported at 2 months. Parents were asked at 2 months if the infant had an “itchy rash on the face or in the folds of the arms or legs,” as a screening question for AD. Experienced health care personnel used UK Working Party criteria to diagnose AD at 6, 12, and 24 months.

Complete data on AD status was available for 1,505 children in the cohort. Dr. O’Connor and colleagues calculated an overall AD prevalence of 18.6% at 6 months, 15.2% at 12 months, and 16.5% at 24 months.

Overall prevalence of AD was highest at 6 months. The study showed a similar or slightly higher impact of paternal atopy on offspring AD development, compared to maternal atopy.

Multivariable logistic regression analysis revealed that the odds of AD were 1.57 at 6 months and 1.66 at 12 months for maternal AD; 1.90 at 6 months and 1.85 at 24 months for paternal AD; 1.76 at 6 months and 1.75 at 12 months for maternal asthma; and 1.70 at 6 months, 1.86 at 12 months, and 1.99 at 24 months for paternal asthma.

“Parental allergic rhinitis was not associated with AD in offspring in the first 2 years, except for maternal rhinitis at 24 months [an adjusted odds ratio of 1.79],” the authors wrote. “The genetic predisposition to allergic rhinitis, given the key role of aeroallergen sensitization in its pathogenesis, may not be associated with early onset AD, but may have a greater impact in later onset or persistent AD.”

The authors acknowledged certain limitations of the study, including the fact that it was a secondary data analysis, and that parental AD, asthma, and rhinitis were self-reported, “which may reduce reliability and may contribute to the differences seen between the impact of maternal and paternal reported atopy on offspring,” they wrote. “Data on siblings were not captured, as participants in the study were first-born children. Filaggrin mutational analysis was not performed, which would have provided richer detail.”

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

A version of this article first appeared on Medscape.com.

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

A version of this article first appeared on Medscape.com.

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

A version of this article first appeared on Medscape.com.

Persistent asthma is associated with increased carotid plaque burden and higher levels of inflammation, putting these patients at risk for atherosclerotic cardiovascular disease (ASCVD) events, new research suggests.

Using data from the MESA study, investigators analyzed more than 5,000 individuals, comparing carotid plaque and inflammatory markers in those with and without asthma.

They found that carotid plaque was present in half of participants without asthma and half of those with intermittent asthma but in close to 70% of participants with persistent asthma.

Moreover, those with persistent asthma had higher interleukin-6 (IL-6) levels, compared with those without asthma or those with intermittent asthma.

“The take-home message is that the current study, paired with prior studies, highlights that individuals with more significant forms of asthma may be at higher cardiovascular risk and makes it imperative to address modifiable risk factors among patients with asthma,” lead author Matthew Tattersall, DO, MS, assistant professor of cardiovascular medicine, University of Wisconsin School of Medicine and Public Health, Madison, told this news organization.

The study was published online  in the Journal of the American Heart Association.
 

Limited data

Asthma and ASCVD are “highly prevalent inflammatory diseases,” the authors write. Carotid artery plaque detected by B-mode ultrasound “represents advanced, typically subclinical atherosclerosis that is a strong independent predictor of incident ASCVD events,” with inflammation playing a “key role” in precipitating these events, they note.

Serum inflammatory markers such as C-reactive protein (CRP) and IL-6 are associated with increased ASCVD events, and in asthma, CRP and other inflammatory biomarkers are elevated and tend to further increase during exacerbations.

Currently, there are limited data looking at the associations of asthma, asthma severity, and atherosclerotic plaque burden, they note, so the researchers turned to the MESA study – a multiethnic population of individuals free of prevalent ASCVD at baseline. They hypothesized that persistent asthma would be associated with higher carotid plaque presence and burden.

They also wanted to explore “whether these associations would be attenuated after adjustment for baseline inflammatory biomarkers.”

Dr. Tattersall said the current study “links our previous work studying the manifestations of asthma,” in which he and his colleagues demonstrated increased cardiovascular events among MESA participants with persistent asthma, as well as late-onset asthma participants in the Wisconsin Sleep Cohort. His group also showed that early arterial injury occurs in adolescents with asthma. 

However, there are also few data looking at the association with carotid plaque, “a late manifestation of arterial injury and a strong predictor of future cardiovascular events and asthma,” Dr. Tattersall added.

He and his group therefore “wanted to explore the entire spectrum of arterial injury, from the initial increase in the carotid media thickness to plaque formation to cardiovascular events.”

To do so, they studied participants in MESA, a study of close to 7,000 adults that began in the year 2000 and continues to follow participants today. At the time of enrollment, all were free from CVD.

The current analysis looked at 5,029 MESA participants (mean age 61.6 years, 53% female, 26% Black, 23% Hispanic, 12% Asian), comparing those with persistent asthma, defined as “asthma requiring use of controller medications,” intermittent asthma, defined as “asthma without controller medications,” and no asthma.

Participants underwent B-mode carotid ultrasound to detect carotid plaques, with a total plaque score (TPS) ranging from 0-12. The researchers used multivariable regression modeling to evaluate the association of asthma subtype and carotid plaque burden.
 

Interpret cautiously

Participants with persistent asthma were more likely to be female, have higher body mass index (BMI), and higher high-density lipoprotein (HDL) cholesterol levels, compared with those without asthma.

Participants with persistent asthma had the highest burden of carotid plaque (P ≤ .003 for comparison of proportions and .002 for comparison of means).

Heightened awareness

Robert Brook, MD, professor and director of cardiovascular disease prevention, Wayne State University, Detroit, said the “main contribution of this study is the novel demonstration of a significant association between persistent (but not intermittent) asthma with carotid atherosclerosis in the MESA cohort, a large multi-ethnic population.”

These findings “support the biological plausibility of the growing epidemiological evidence that asthma independently increases the risk for cardiovascular morbidity and mortality,” added Dr. Brook, who was not involved with the study.

“The main take-home message for clinicians is that, just like in COPD (which is well-established), asthma is often a systemic condition in that the inflammation and disease process can impact the whole body,” he said.

“Health care providers should have a heightened awareness of the potentially increased cardiovascular risk of their patients with asthma and pay special attention to controlling their heart disease risk factors (for example, hyperlipidemia, hypertension),” Dr. Brook stated.

Dr. Tattersall was supported by an American Heart Association Career Development Award. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Tattersall and co-authors and Dr. Brook declare no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Persistent asthma is associated with increased carotid plaque burden and higher levels of inflammation, putting these patients at risk for atherosclerotic cardiovascular disease (ASCVD) events, new research suggests.

Using data from the MESA study, investigators analyzed more than 5,000 individuals, comparing carotid plaque and inflammatory markers in those with and without asthma.

They found that carotid plaque was present in half of participants without asthma and half of those with intermittent asthma but in close to 70% of participants with persistent asthma.

Moreover, those with persistent asthma had higher interleukin-6 (IL-6) levels, compared with those without asthma or those with intermittent asthma.

“The take-home message is that the current study, paired with prior studies, highlights that individuals with more significant forms of asthma may be at higher cardiovascular risk and makes it imperative to address modifiable risk factors among patients with asthma,” lead author Matthew Tattersall, DO, MS, assistant professor of cardiovascular medicine, University of Wisconsin School of Medicine and Public Health, Madison, told this news organization.

The study was published online  in the Journal of the American Heart Association.
 

Limited data

Asthma and ASCVD are “highly prevalent inflammatory diseases,” the authors write. Carotid artery plaque detected by B-mode ultrasound “represents advanced, typically subclinical atherosclerosis that is a strong independent predictor of incident ASCVD events,” with inflammation playing a “key role” in precipitating these events, they note.

Serum inflammatory markers such as C-reactive protein (CRP) and IL-6 are associated with increased ASCVD events, and in asthma, CRP and other inflammatory biomarkers are elevated and tend to further increase during exacerbations.

Currently, there are limited data looking at the associations of asthma, asthma severity, and atherosclerotic plaque burden, they note, so the researchers turned to the MESA study – a multiethnic population of individuals free of prevalent ASCVD at baseline. They hypothesized that persistent asthma would be associated with higher carotid plaque presence and burden.

They also wanted to explore “whether these associations would be attenuated after adjustment for baseline inflammatory biomarkers.”

Dr. Tattersall said the current study “links our previous work studying the manifestations of asthma,” in which he and his colleagues demonstrated increased cardiovascular events among MESA participants with persistent asthma, as well as late-onset asthma participants in the Wisconsin Sleep Cohort. His group also showed that early arterial injury occurs in adolescents with asthma. 

However, there are also few data looking at the association with carotid plaque, “a late manifestation of arterial injury and a strong predictor of future cardiovascular events and asthma,” Dr. Tattersall added.

He and his group therefore “wanted to explore the entire spectrum of arterial injury, from the initial increase in the carotid media thickness to plaque formation to cardiovascular events.”

To do so, they studied participants in MESA, a study of close to 7,000 adults that began in the year 2000 and continues to follow participants today. At the time of enrollment, all were free from CVD.

The current analysis looked at 5,029 MESA participants (mean age 61.6 years, 53% female, 26% Black, 23% Hispanic, 12% Asian), comparing those with persistent asthma, defined as “asthma requiring use of controller medications,” intermittent asthma, defined as “asthma without controller medications,” and no asthma.

Participants underwent B-mode carotid ultrasound to detect carotid plaques, with a total plaque score (TPS) ranging from 0-12. The researchers used multivariable regression modeling to evaluate the association of asthma subtype and carotid plaque burden.
 

Interpret cautiously

Participants with persistent asthma were more likely to be female, have higher body mass index (BMI), and higher high-density lipoprotein (HDL) cholesterol levels, compared with those without asthma.

Participants with persistent asthma had the highest burden of carotid plaque (P ≤ .003 for comparison of proportions and .002 for comparison of means).

Heightened awareness

Robert Brook, MD, professor and director of cardiovascular disease prevention, Wayne State University, Detroit, said the “main contribution of this study is the novel demonstration of a significant association between persistent (but not intermittent) asthma with carotid atherosclerosis in the MESA cohort, a large multi-ethnic population.”

These findings “support the biological plausibility of the growing epidemiological evidence that asthma independently increases the risk for cardiovascular morbidity and mortality,” added Dr. Brook, who was not involved with the study.

“The main take-home message for clinicians is that, just like in COPD (which is well-established), asthma is often a systemic condition in that the inflammation and disease process can impact the whole body,” he said.

“Health care providers should have a heightened awareness of the potentially increased cardiovascular risk of their patients with asthma and pay special attention to controlling their heart disease risk factors (for example, hyperlipidemia, hypertension),” Dr. Brook stated.

Dr. Tattersall was supported by an American Heart Association Career Development Award. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Tattersall and co-authors and Dr. Brook declare no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Persistent asthma is associated with increased carotid plaque burden and higher levels of inflammation, putting these patients at risk for atherosclerotic cardiovascular disease (ASCVD) events, new research suggests.

Using data from the MESA study, investigators analyzed more than 5,000 individuals, comparing carotid plaque and inflammatory markers in those with and without asthma.

They found that carotid plaque was present in half of participants without asthma and half of those with intermittent asthma but in close to 70% of participants with persistent asthma.

Moreover, those with persistent asthma had higher interleukin-6 (IL-6) levels, compared with those without asthma or those with intermittent asthma.

“The take-home message is that the current study, paired with prior studies, highlights that individuals with more significant forms of asthma may be at higher cardiovascular risk and makes it imperative to address modifiable risk factors among patients with asthma,” lead author Matthew Tattersall, DO, MS, assistant professor of cardiovascular medicine, University of Wisconsin School of Medicine and Public Health, Madison, told this news organization.

The study was published online  in the Journal of the American Heart Association.
 

Limited data

Asthma and ASCVD are “highly prevalent inflammatory diseases,” the authors write. Carotid artery plaque detected by B-mode ultrasound “represents advanced, typically subclinical atherosclerosis that is a strong independent predictor of incident ASCVD events,” with inflammation playing a “key role” in precipitating these events, they note.

Serum inflammatory markers such as C-reactive protein (CRP) and IL-6 are associated with increased ASCVD events, and in asthma, CRP and other inflammatory biomarkers are elevated and tend to further increase during exacerbations.

Currently, there are limited data looking at the associations of asthma, asthma severity, and atherosclerotic plaque burden, they note, so the researchers turned to the MESA study – a multiethnic population of individuals free of prevalent ASCVD at baseline. They hypothesized that persistent asthma would be associated with higher carotid plaque presence and burden.

They also wanted to explore “whether these associations would be attenuated after adjustment for baseline inflammatory biomarkers.”

Dr. Tattersall said the current study “links our previous work studying the manifestations of asthma,” in which he and his colleagues demonstrated increased cardiovascular events among MESA participants with persistent asthma, as well as late-onset asthma participants in the Wisconsin Sleep Cohort. His group also showed that early arterial injury occurs in adolescents with asthma. 

However, there are also few data looking at the association with carotid plaque, “a late manifestation of arterial injury and a strong predictor of future cardiovascular events and asthma,” Dr. Tattersall added.

He and his group therefore “wanted to explore the entire spectrum of arterial injury, from the initial increase in the carotid media thickness to plaque formation to cardiovascular events.”

To do so, they studied participants in MESA, a study of close to 7,000 adults that began in the year 2000 and continues to follow participants today. At the time of enrollment, all were free from CVD.

The current analysis looked at 5,029 MESA participants (mean age 61.6 years, 53% female, 26% Black, 23% Hispanic, 12% Asian), comparing those with persistent asthma, defined as “asthma requiring use of controller medications,” intermittent asthma, defined as “asthma without controller medications,” and no asthma.

Participants underwent B-mode carotid ultrasound to detect carotid plaques, with a total plaque score (TPS) ranging from 0-12. The researchers used multivariable regression modeling to evaluate the association of asthma subtype and carotid plaque burden.
 

Interpret cautiously

Participants with persistent asthma were more likely to be female, have higher body mass index (BMI), and higher high-density lipoprotein (HDL) cholesterol levels, compared with those without asthma.

Participants with persistent asthma had the highest burden of carotid plaque (P ≤ .003 for comparison of proportions and .002 for comparison of means).

Heightened awareness

Robert Brook, MD, professor and director of cardiovascular disease prevention, Wayne State University, Detroit, said the “main contribution of this study is the novel demonstration of a significant association between persistent (but not intermittent) asthma with carotid atherosclerosis in the MESA cohort, a large multi-ethnic population.”

These findings “support the biological plausibility of the growing epidemiological evidence that asthma independently increases the risk for cardiovascular morbidity and mortality,” added Dr. Brook, who was not involved with the study.

“The main take-home message for clinicians is that, just like in COPD (which is well-established), asthma is often a systemic condition in that the inflammation and disease process can impact the whole body,” he said.

“Health care providers should have a heightened awareness of the potentially increased cardiovascular risk of their patients with asthma and pay special attention to controlling their heart disease risk factors (for example, hyperlipidemia, hypertension),” Dr. Brook stated.

Dr. Tattersall was supported by an American Heart Association Career Development Award. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Tattersall and co-authors and Dr. Brook declare no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CASE

Erica S*, age 22, has intermittent asthma and presents to your clinic to discuss refills of her albuterol inhaler. Two years ago, she was hospitalized for a severe asthma exacerbation because she was unable to afford medications. Since then, her asthma has generally been well controlled, and she needs to use albuterol only 1 or 2 times per month. Ms. S says she has no morning chest tightness or nocturnal coughing, but she does experience increased wheezing and shortness of breath with activity.

What would you recommend? Would your recommendation differ if she had persistent asthma?

* The patient’s name has been changed to protect her identity .

As of 2020, more than 20 million adults and 4 million children younger than 18 years of age in the United States were living with asthma.¹ In 2019 alone, there were more than 1.8 million asthma-related emergency department visits for adults, and more than 790,000 asthma-related emergency department visits for children. Asthma caused more than 4000 deaths in the United States in 2020.¹ Given the scale of the burden of asthma, it is not surprising that approximately 60% of all asthma visits occur in primary care settings,² making it essential that primary care physicians stay abreast of recent developments in asthma diagnosis and management.

Since 1991, the major guidance on best practices for asthma management in the United States has been provided by the National Heart, Lung, and Blood Institute (NHLBI)’s National Asthma Education and Prevention Program (NAEPP). Its last major update on asthma was released in 2007 as the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3).³ Since that time, there has been significant progress in our understanding of asthma as a complex spectrum of phenotypes, which has advanced our knowledge of pathophysiology and helped refine treatment. In contrast to the NAEPP, the Global Initiative for Asthma (GINA) has published annual updates on asthma management incorporating up-to-date information.⁴ In response to the continuously evolving body of knowledge on asthma, the NAEPP Coordinating Committee Expert Panel Working Group published the 2020 Focused Updates to the Asthma Management Guidelines.⁵

Given the vast resources available on asthma, our purpose in this article is not to provide a comprehensive review of the stepwise approach to asthma management, but instead to summarize the major points presented in the 2020 Focused Updates and how these compare and contrast with the latest guidance from GINA.

A heterogeneous disease

Asthma is a chronic respiratory disease characterized by both variable symptoms and airflow limitation that change over time, often in response to external triggers such as exercise, allergens, and viral respiratory infections. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Despite the common symptomatology, asthma is a heterogeneous disease with several recognizable phenotypes including allergic, nonallergic, and asthma with persistent airflow limitation.

Continue to: The airflow limitation...

The airflow limitation in asthma occurs through both airway hyperresponsiveness to external stimuli and chronic airway inflammation. Airway constriction is regulated by nerves to the smooth muscles of the airway. Beta-2 nerve receptors have long been the target of asthma therapy with both short-acting beta-2 agonists (SABAs) as rescue treatment and long-acting beta-2 agonists (LABAs) as maintenance therapy.^3,4 However, there is increasing evidence that cholinergic nerves also have a role in airway regulation in asthma, and long-acting muscarinic antagonists (LAMAs) have recently shown benefit as add-on therapy in some types of asthma.^4-6 Inhaled corticosteroids (ICSs) have long held an important role in reducing airway inflammation, especially in the setting of allergic or eosinophilic inflammation.^3-5

Spirometry is essential to asthma Dx—but what about FeNO?

The mainstay of asthma diagnosis is confirming both a history of variable respiratory symptoms and variable expiratory airflow limitation exhibited by spirometry. Obstruction is defined as a reduced forced expiratory volume in 1 second (FEV₁) and as a decreased ratio of FEV₁ over forced vital capacity (FVC) based on predicted values. An increase of at least 12% in FEV₁ post bronchodilator use indicates asthma for adolescents and adults.

A fractional exhaled nitric oxide level > 50 ppb makes eosinophilic inflammation and treatment response to an inhaled corticosteroid more likely.

More recently, studies have examined the role of fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma. The 2020 Focused Updates report states that FeNO may be useful when the diagnosis of asthma is uncertain using initial history, physical exam, and spirometry findings, or when spirometry cannot be performed reliably.⁵ Levels of FeNO > 50 ppb make eosinophilic inflammation and treatment response to an ICS more likely. FeNO levels < 25 ppb make inflammatory asthma less likely and should prompt a search for an alternate diagnosis.⁵ For patients with FeNO of 25 to 50 ppb, more detailed clinical context is needed. In contrast, the 2022 GINA updates conclude that FeNO is not yet an established diagnostic tool for asthma.⁴

Management

When to start and adjust an ICS

ICSs continue to be the primary controller treatment for patients with asthma. However, the NAEPP and GINA have provided different guidance on how to initiate step therapy (TABLE^3-5). NAEPP focuses on severity classification, while GINA recommends treatment initiation based on presenting symptoms. Since both guidelines recommend early ­follow-up and adjustment of therapy according to level of control, this difference becomes less apparent in ongoing care.

A more fundamental difference is seen in the recommended therapies for each step (TABLE^3-5). Whereas the 2020 Focused Updates prefers a SABA as needed in step 1, GINA favors a low-dose combination of ICS-formoterol as needed. The GINA recommendation is driven by supportive evidence for early initiation of low-dose ICS in any patient with asthma for greater improvement in lung function. This also addresses concerns that overuse of as-needed SABAs may increase the risk for severe exacerbations. Evidence also indicates that the risk for asthma-­related death and urgent asthma-related health care increases when a patient takes a SABA as needed as monotherapy compared with ICS therapy, even with good symptom control.^7,8

Continue to: Dosing of an ICS

Dosing of an ICS is based on step therapy regardless of the guideline used and is given at a total daily amount—low, medium, and high—for each age group. When initiating an ICS, consider differences between available treatment options (eg, cost, administration technique, likely patient adherence, patient preferences) and employ shared decision-making strategies. Dosing may need to be limited depending on the commercially available product, especially when used in combination with a LABA. However, as GINA emphasizes, a low-dose ICS provides the most clinical benefit. A high-dose ICS is needed by very few patients and is associated with greater risk for local and systemic adverse effects, such as adrenal suppression. With these considerations, both guidelines recommend using the lowest effective ICS dose and stepping up and down according to the patient’s comfort level.

Give an ICS time to work. Although an ICS can begin to reduce inflammation within days of initiation, the full benefit may be evident only after 2 to 3 months.⁴ Once the patient’s asthma is well controlled for 3 months, stepping down the dose can be considered and approached carefully. Complete cessation of ICSs is associated with significantly higher risk for exacerbations. Therefore, a general recommendation is to step down an ICS by 50% or reduce ICS-LABA from twice-daily administration to once daily. Risk for exacerbation after step-down therapy is heightened if the patient has a history of exacerbation or an emergency department visit in the past 12 months, a low baseline FEV₁, or a loss of control during a dose reduction (ie, airway hyperresponsiveness and sputum eosinophilia).

Weigh the utility of FeNO measurement. The 2020 Focused Updates also recommend considering FeNO measurement to guide treatment choice and monitoring, although this is based on overall low certainty of evidence.⁵ GINA affirms the mixed evidence for FeNO, stating that while a few studies have shown significantly reduced exacerbations among children, adolescents, and pregnant women with FeNO-guided treatment, other studies have shown no significant difference in exacerbations.^4,9-15 At this time, the role for FeNO in asthma management remains inconclusive, and access to it is limited across primary care settings.

Inhaled corticosteroids can begin to reduce inflammation within days, but the full benefit may be evident only after 2 to 3 months.

When assessing response to ICS therapy (and before stepping up therapy), consider patient adherence, inhaler technique, whether allergen exposure is persistent, and possible comorbidities. Inhaler technique can be especially challenging, as each inhaler varies in appearance and operation. Employ patient education strategies (eg, videos, demonstration, teach-back methods). If stepping up therapy is indicated, adding a LABA is recommended over increasing the ICS dose. Since asthma is variable, stepping up therapy can be tried and reassessed in 2 to 3 months.

SMART is preferred

Single maintenance and reliever therapy (SMART) with ICS-formoterol, used as needed, is the preferred therapy for steps 3 and 4 in both GINA recommendations and the 2020 Focused Updates (TABLE^3-5). GINA also prefers SMART for step 5. The recommended SMART combination that has been studied contains budesonide (or beclomethasone, not available in combination in the United States) for the ICS and formoterol for the LABA in a single inhaler that is used both daily for control and as needed for rescue therapy.

Continue to: Other ICS-formoterol...

Other ICS-formoterol or ICS-LABA combinations can be considered for controller therapy, especially those described in the NAEPP and GINA alternative step therapy recommendations. However, SMART has been more effective than other combinations in reducing exacerbations and provides similar or better levels of control at lower average ICS doses (compared with ICS-LABA with SABA or ICS with SABA) for adolescent and adult patients.^3,4 As patients use greater amounts of ICS-formoterol during episodes of increased symptoms, this additional ICS may augment the anti-inflammatory effects. SMART may also improve adherence, especially among those who confuse multiple inhalers.

SMART is also recommended for use in children. Specifically, from the 2020 Focused Updates, any patient ≥ 4 years of age with a severe exacerbation in the past year is a good SMART candidate. Also consider SMART before higher-dose ICS-LABA and SABA as needed. Additional benefits in this younger patient population are fewer medical visits or less systemic corticosteroid use with improved control and quality of life.

Caveats. Patients who have a difficult time recognizing symptoms may not be good candidates for SMART, due to the potential for taking higher or lower ICS doses than necessary.

SMART specifically refers to formoterol combinations that produce bronchodilation within 1 to 3 minutes.¹⁶ For example, the SMART strategy is not recommended for patients using ICS-salmeterol as controller therapy.

Although guideline supported, SMART options are not approved by the US Food and Drug Administration for use as reliever therapy.

Continue to: With the single combination...

With the single combination inhaler, consider the dosing limits of formoterol. The maximum daily amount of formoterol for ­adolescents and adults is 54 μg (12 puffs) delivered with the budesonide-formoterol metered dose inhaler. When using SMART as reliever therapy, the low-dose ICS-­formoterol recommendation remains. However, depending on insurance coverage, a 1-month supply of ­ICS-formoterol may not be sufficient for additional reliever therapy use.

The role of LAMAs as add-on therapy

Bronchiolar smooth muscle tone is mediated by complex mechanisms that include cholinergic stimulation at muscarinic (M3) receptors.¹⁷ LAMAs, a mainstay in the management of chronic obstructive pulmonary disease (COPD), are likely to be effective in reducing asthma exacerbations and the need for oral steroids. When patients have not achieved control at step 4 of asthma therapy, both the 2020 Focused Updates and GINA now recommend considering a LAMA (eg, tiotropium) as add-on therapy for patients > 12 years of age already taking medium-dose ICS-LABA for modest improvements in lung function and reductions in severe exacerbations. GINA recommendations also now include a LAMA as add-on treatment for those ages 6 to 11 years, as some evidence supports the use in school-aged children.¹⁸ It is important to note that LAMAs should not replace a LABA for treatment, as the ICS-LABA combination is likely more effective than ICS-LAMA.

Addressing asthma-COPD overlap

Asthma and COPD are frequently and frustratingly intertwined without clear demarcation. This tends to occur as patients age and chronic lung changes appear from longstanding asthma. However, it is important to distinguish between these conditions, because there are clearly delineated treatments for each that can improve outcomes.

The priority in addressing asthma-COPD overlap (ACO) is to evaluate symptoms and determine if asthma or COPD is predominant.¹⁹ This includes establishing patient age at which symptoms began, variation and triggers of symptoms, and history of exposures to smoke/environmental respiratory toxins. Age 40 years is often used as the tipping point at which symptom onset favors a diagnosis of COPD. Serial spirometry may also be used to evaluate lung function over time and persistence of disease. If a firm diagnosis is evasive, consider a referral to a pulmonary specialist for further testing.

The priority in addressing asthma-COPD overlap is to evaluate symptoms and determine if asthma or COPD is predominant.

Choosing to use an ICS or LAMA depends on which underlying disorder is more likely. While early COPD management includes LAMA + LABA, the addition of an ICS is reserved for more severe disease. High-dose ICSs, particularly fluticasone, should be limited in COPD due to an increased risk for pneumonia. For asthma or ACO, the addition of an ICS is critical and prioritized to reduce airway inflammation and risk for exacerbations and death. While a LAMA is likely useful earlier in ACO, it is not used until step 5 of asthma therapy. Given the complexities of ACO treatment, further research is needed to provide adequate guidance.

CASE

For Ms. S, you would be wise to use an ICS-formoterol combination for as-needed symptom relief. If symptoms were more persistent, you could consider recommending the ICS-­formoterol inhaler as SMART therapy, with regular doses taken twice daily and extra ­doses taken as needed.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota School of Medicine, Department of Family Medicine and Community Health, 2426 West Broadway Avenue, Minneapolis, MN 55411; [email protected]

CASE

Erica S*, age 22, has intermittent asthma and presents to your clinic to discuss refills of her albuterol inhaler. Two years ago, she was hospitalized for a severe asthma exacerbation because she was unable to afford medications. Since then, her asthma has generally been well controlled, and she needs to use albuterol only 1 or 2 times per month. Ms. S says she has no morning chest tightness or nocturnal coughing, but she does experience increased wheezing and shortness of breath with activity.

What would you recommend? Would your recommendation differ if she had persistent asthma?

* The patient’s name has been changed to protect her identity .

As of 2020, more than 20 million adults and 4 million children younger than 18 years of age in the United States were living with asthma.¹ In 2019 alone, there were more than 1.8 million asthma-related emergency department visits for adults, and more than 790,000 asthma-related emergency department visits for children. Asthma caused more than 4000 deaths in the United States in 2020.¹ Given the scale of the burden of asthma, it is not surprising that approximately 60% of all asthma visits occur in primary care settings,² making it essential that primary care physicians stay abreast of recent developments in asthma diagnosis and management.

Since 1991, the major guidance on best practices for asthma management in the United States has been provided by the National Heart, Lung, and Blood Institute (NHLBI)’s National Asthma Education and Prevention Program (NAEPP). Its last major update on asthma was released in 2007 as the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3).³ Since that time, there has been significant progress in our understanding of asthma as a complex spectrum of phenotypes, which has advanced our knowledge of pathophysiology and helped refine treatment. In contrast to the NAEPP, the Global Initiative for Asthma (GINA) has published annual updates on asthma management incorporating up-to-date information.⁴ In response to the continuously evolving body of knowledge on asthma, the NAEPP Coordinating Committee Expert Panel Working Group published the 2020 Focused Updates to the Asthma Management Guidelines.⁵

Given the vast resources available on asthma, our purpose in this article is not to provide a comprehensive review of the stepwise approach to asthma management, but instead to summarize the major points presented in the 2020 Focused Updates and how these compare and contrast with the latest guidance from GINA.

A heterogeneous disease

Asthma is a chronic respiratory disease characterized by both variable symptoms and airflow limitation that change over time, often in response to external triggers such as exercise, allergens, and viral respiratory infections. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Despite the common symptomatology, asthma is a heterogeneous disease with several recognizable phenotypes including allergic, nonallergic, and asthma with persistent airflow limitation.

Continue to: The airflow limitation...

The airflow limitation in asthma occurs through both airway hyperresponsiveness to external stimuli and chronic airway inflammation. Airway constriction is regulated by nerves to the smooth muscles of the airway. Beta-2 nerve receptors have long been the target of asthma therapy with both short-acting beta-2 agonists (SABAs) as rescue treatment and long-acting beta-2 agonists (LABAs) as maintenance therapy.^3,4 However, there is increasing evidence that cholinergic nerves also have a role in airway regulation in asthma, and long-acting muscarinic antagonists (LAMAs) have recently shown benefit as add-on therapy in some types of asthma.^4-6 Inhaled corticosteroids (ICSs) have long held an important role in reducing airway inflammation, especially in the setting of allergic or eosinophilic inflammation.^3-5

Spirometry is essential to asthma Dx—but what about FeNO?

The mainstay of asthma diagnosis is confirming both a history of variable respiratory symptoms and variable expiratory airflow limitation exhibited by spirometry. Obstruction is defined as a reduced forced expiratory volume in 1 second (FEV₁) and as a decreased ratio of FEV₁ over forced vital capacity (FVC) based on predicted values. An increase of at least 12% in FEV₁ post bronchodilator use indicates asthma for adolescents and adults.

A fractional exhaled nitric oxide level > 50 ppb makes eosinophilic inflammation and treatment response to an inhaled corticosteroid more likely.

More recently, studies have examined the role of fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma. The 2020 Focused Updates report states that FeNO may be useful when the diagnosis of asthma is uncertain using initial history, physical exam, and spirometry findings, or when spirometry cannot be performed reliably.⁵ Levels of FeNO > 50 ppb make eosinophilic inflammation and treatment response to an ICS more likely. FeNO levels < 25 ppb make inflammatory asthma less likely and should prompt a search for an alternate diagnosis.⁵ For patients with FeNO of 25 to 50 ppb, more detailed clinical context is needed. In contrast, the 2022 GINA updates conclude that FeNO is not yet an established diagnostic tool for asthma.⁴

Management

When to start and adjust an ICS

ICSs continue to be the primary controller treatment for patients with asthma. However, the NAEPP and GINA have provided different guidance on how to initiate step therapy (TABLE^3-5). NAEPP focuses on severity classification, while GINA recommends treatment initiation based on presenting symptoms. Since both guidelines recommend early ­follow-up and adjustment of therapy according to level of control, this difference becomes less apparent in ongoing care.

A more fundamental difference is seen in the recommended therapies for each step (TABLE^3-5). Whereas the 2020 Focused Updates prefers a SABA as needed in step 1, GINA favors a low-dose combination of ICS-formoterol as needed. The GINA recommendation is driven by supportive evidence for early initiation of low-dose ICS in any patient with asthma for greater improvement in lung function. This also addresses concerns that overuse of as-needed SABAs may increase the risk for severe exacerbations. Evidence also indicates that the risk for asthma-­related death and urgent asthma-related health care increases when a patient takes a SABA as needed as monotherapy compared with ICS therapy, even with good symptom control.^7,8

Continue to: Dosing of an ICS

Dosing of an ICS is based on step therapy regardless of the guideline used and is given at a total daily amount—low, medium, and high—for each age group. When initiating an ICS, consider differences between available treatment options (eg, cost, administration technique, likely patient adherence, patient preferences) and employ shared decision-making strategies. Dosing may need to be limited depending on the commercially available product, especially when used in combination with a LABA. However, as GINA emphasizes, a low-dose ICS provides the most clinical benefit. A high-dose ICS is needed by very few patients and is associated with greater risk for local and systemic adverse effects, such as adrenal suppression. With these considerations, both guidelines recommend using the lowest effective ICS dose and stepping up and down according to the patient’s comfort level.

Give an ICS time to work. Although an ICS can begin to reduce inflammation within days of initiation, the full benefit may be evident only after 2 to 3 months.⁴ Once the patient’s asthma is well controlled for 3 months, stepping down the dose can be considered and approached carefully. Complete cessation of ICSs is associated with significantly higher risk for exacerbations. Therefore, a general recommendation is to step down an ICS by 50% or reduce ICS-LABA from twice-daily administration to once daily. Risk for exacerbation after step-down therapy is heightened if the patient has a history of exacerbation or an emergency department visit in the past 12 months, a low baseline FEV₁, or a loss of control during a dose reduction (ie, airway hyperresponsiveness and sputum eosinophilia).

Weigh the utility of FeNO measurement. The 2020 Focused Updates also recommend considering FeNO measurement to guide treatment choice and monitoring, although this is based on overall low certainty of evidence.⁵ GINA affirms the mixed evidence for FeNO, stating that while a few studies have shown significantly reduced exacerbations among children, adolescents, and pregnant women with FeNO-guided treatment, other studies have shown no significant difference in exacerbations.^4,9-15 At this time, the role for FeNO in asthma management remains inconclusive, and access to it is limited across primary care settings.

Inhaled corticosteroids can begin to reduce inflammation within days, but the full benefit may be evident only after 2 to 3 months.

When assessing response to ICS therapy (and before stepping up therapy), consider patient adherence, inhaler technique, whether allergen exposure is persistent, and possible comorbidities. Inhaler technique can be especially challenging, as each inhaler varies in appearance and operation. Employ patient education strategies (eg, videos, demonstration, teach-back methods). If stepping up therapy is indicated, adding a LABA is recommended over increasing the ICS dose. Since asthma is variable, stepping up therapy can be tried and reassessed in 2 to 3 months.

SMART is preferred

Single maintenance and reliever therapy (SMART) with ICS-formoterol, used as needed, is the preferred therapy for steps 3 and 4 in both GINA recommendations and the 2020 Focused Updates (TABLE^3-5). GINA also prefers SMART for step 5. The recommended SMART combination that has been studied contains budesonide (or beclomethasone, not available in combination in the United States) for the ICS and formoterol for the LABA in a single inhaler that is used both daily for control and as needed for rescue therapy.

Continue to: Other ICS-formoterol...

Other ICS-formoterol or ICS-LABA combinations can be considered for controller therapy, especially those described in the NAEPP and GINA alternative step therapy recommendations. However, SMART has been more effective than other combinations in reducing exacerbations and provides similar or better levels of control at lower average ICS doses (compared with ICS-LABA with SABA or ICS with SABA) for adolescent and adult patients.^3,4 As patients use greater amounts of ICS-formoterol during episodes of increased symptoms, this additional ICS may augment the anti-inflammatory effects. SMART may also improve adherence, especially among those who confuse multiple inhalers.

SMART is also recommended for use in children. Specifically, from the 2020 Focused Updates, any patient ≥ 4 years of age with a severe exacerbation in the past year is a good SMART candidate. Also consider SMART before higher-dose ICS-LABA and SABA as needed. Additional benefits in this younger patient population are fewer medical visits or less systemic corticosteroid use with improved control and quality of life.

Caveats. Patients who have a difficult time recognizing symptoms may not be good candidates for SMART, due to the potential for taking higher or lower ICS doses than necessary.

SMART specifically refers to formoterol combinations that produce bronchodilation within 1 to 3 minutes.¹⁶ For example, the SMART strategy is not recommended for patients using ICS-salmeterol as controller therapy.

Although guideline supported, SMART options are not approved by the US Food and Drug Administration for use as reliever therapy.

Continue to: With the single combination...

With the single combination inhaler, consider the dosing limits of formoterol. The maximum daily amount of formoterol for ­adolescents and adults is 54 μg (12 puffs) delivered with the budesonide-formoterol metered dose inhaler. When using SMART as reliever therapy, the low-dose ICS-­formoterol recommendation remains. However, depending on insurance coverage, a 1-month supply of ­ICS-formoterol may not be sufficient for additional reliever therapy use.

The role of LAMAs as add-on therapy

Bronchiolar smooth muscle tone is mediated by complex mechanisms that include cholinergic stimulation at muscarinic (M3) receptors.¹⁷ LAMAs, a mainstay in the management of chronic obstructive pulmonary disease (COPD), are likely to be effective in reducing asthma exacerbations and the need for oral steroids. When patients have not achieved control at step 4 of asthma therapy, both the 2020 Focused Updates and GINA now recommend considering a LAMA (eg, tiotropium) as add-on therapy for patients > 12 years of age already taking medium-dose ICS-LABA for modest improvements in lung function and reductions in severe exacerbations. GINA recommendations also now include a LAMA as add-on treatment for those ages 6 to 11 years, as some evidence supports the use in school-aged children.¹⁸ It is important to note that LAMAs should not replace a LABA for treatment, as the ICS-LABA combination is likely more effective than ICS-LAMA.

Addressing asthma-COPD overlap

Asthma and COPD are frequently and frustratingly intertwined without clear demarcation. This tends to occur as patients age and chronic lung changes appear from longstanding asthma. However, it is important to distinguish between these conditions, because there are clearly delineated treatments for each that can improve outcomes.

The priority in addressing asthma-COPD overlap (ACO) is to evaluate symptoms and determine if asthma or COPD is predominant.¹⁹ This includes establishing patient age at which symptoms began, variation and triggers of symptoms, and history of exposures to smoke/environmental respiratory toxins. Age 40 years is often used as the tipping point at which symptom onset favors a diagnosis of COPD. Serial spirometry may also be used to evaluate lung function over time and persistence of disease. If a firm diagnosis is evasive, consider a referral to a pulmonary specialist for further testing.

The priority in addressing asthma-COPD overlap is to evaluate symptoms and determine if asthma or COPD is predominant.

Choosing to use an ICS or LAMA depends on which underlying disorder is more likely. While early COPD management includes LAMA + LABA, the addition of an ICS is reserved for more severe disease. High-dose ICSs, particularly fluticasone, should be limited in COPD due to an increased risk for pneumonia. For asthma or ACO, the addition of an ICS is critical and prioritized to reduce airway inflammation and risk for exacerbations and death. While a LAMA is likely useful earlier in ACO, it is not used until step 5 of asthma therapy. Given the complexities of ACO treatment, further research is needed to provide adequate guidance.

CASE

For Ms. S, you would be wise to use an ICS-formoterol combination for as-needed symptom relief. If symptoms were more persistent, you could consider recommending the ICS-­formoterol inhaler as SMART therapy, with regular doses taken twice daily and extra ­doses taken as needed.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota School of Medicine, Department of Family Medicine and Community Health, 2426 West Broadway Avenue, Minneapolis, MN 55411; [email protected]

CASE

Erica S*, age 22, has intermittent asthma and presents to your clinic to discuss refills of her albuterol inhaler. Two years ago, she was hospitalized for a severe asthma exacerbation because she was unable to afford medications. Since then, her asthma has generally been well controlled, and she needs to use albuterol only 1 or 2 times per month. Ms. S says she has no morning chest tightness or nocturnal coughing, but she does experience increased wheezing and shortness of breath with activity.

What would you recommend? Would your recommendation differ if she had persistent asthma?

* The patient’s name has been changed to protect her identity .

As of 2020, more than 20 million adults and 4 million children younger than 18 years of age in the United States were living with asthma.¹ In 2019 alone, there were more than 1.8 million asthma-related emergency department visits for adults, and more than 790,000 asthma-related emergency department visits for children. Asthma caused more than 4000 deaths in the United States in 2020.¹ Given the scale of the burden of asthma, it is not surprising that approximately 60% of all asthma visits occur in primary care settings,² making it essential that primary care physicians stay abreast of recent developments in asthma diagnosis and management.

Since 1991, the major guidance on best practices for asthma management in the United States has been provided by the National Heart, Lung, and Blood Institute (NHLBI)’s National Asthma Education and Prevention Program (NAEPP). Its last major update on asthma was released in 2007 as the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3).³ Since that time, there has been significant progress in our understanding of asthma as a complex spectrum of phenotypes, which has advanced our knowledge of pathophysiology and helped refine treatment. In contrast to the NAEPP, the Global Initiative for Asthma (GINA) has published annual updates on asthma management incorporating up-to-date information.⁴ In response to the continuously evolving body of knowledge on asthma, the NAEPP Coordinating Committee Expert Panel Working Group published the 2020 Focused Updates to the Asthma Management Guidelines.⁵

Given the vast resources available on asthma, our purpose in this article is not to provide a comprehensive review of the stepwise approach to asthma management, but instead to summarize the major points presented in the 2020 Focused Updates and how these compare and contrast with the latest guidance from GINA.

A heterogeneous disease

Asthma is a chronic respiratory disease characterized by both variable symptoms and airflow limitation that change over time, often in response to external triggers such as exercise, allergens, and viral respiratory infections. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Despite the common symptomatology, asthma is a heterogeneous disease with several recognizable phenotypes including allergic, nonallergic, and asthma with persistent airflow limitation.

Continue to: The airflow limitation...

The airflow limitation in asthma occurs through both airway hyperresponsiveness to external stimuli and chronic airway inflammation. Airway constriction is regulated by nerves to the smooth muscles of the airway. Beta-2 nerve receptors have long been the target of asthma therapy with both short-acting beta-2 agonists (SABAs) as rescue treatment and long-acting beta-2 agonists (LABAs) as maintenance therapy.^3,4 However, there is increasing evidence that cholinergic nerves also have a role in airway regulation in asthma, and long-acting muscarinic antagonists (LAMAs) have recently shown benefit as add-on therapy in some types of asthma.^4-6 Inhaled corticosteroids (ICSs) have long held an important role in reducing airway inflammation, especially in the setting of allergic or eosinophilic inflammation.^3-5

Spirometry is essential to asthma Dx—but what about FeNO?

The mainstay of asthma diagnosis is confirming both a history of variable respiratory symptoms and variable expiratory airflow limitation exhibited by spirometry. Obstruction is defined as a reduced forced expiratory volume in 1 second (FEV₁) and as a decreased ratio of FEV₁ over forced vital capacity (FVC) based on predicted values. An increase of at least 12% in FEV₁ post bronchodilator use indicates asthma for adolescents and adults.

A fractional exhaled nitric oxide level > 50 ppb makes eosinophilic inflammation and treatment response to an inhaled corticosteroid more likely.

More recently, studies have examined the role of fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma. The 2020 Focused Updates report states that FeNO may be useful when the diagnosis of asthma is uncertain using initial history, physical exam, and spirometry findings, or when spirometry cannot be performed reliably.⁵ Levels of FeNO > 50 ppb make eosinophilic inflammation and treatment response to an ICS more likely. FeNO levels < 25 ppb make inflammatory asthma less likely and should prompt a search for an alternate diagnosis.⁵ For patients with FeNO of 25 to 50 ppb, more detailed clinical context is needed. In contrast, the 2022 GINA updates conclude that FeNO is not yet an established diagnostic tool for asthma.⁴

Management

When to start and adjust an ICS

ICSs continue to be the primary controller treatment for patients with asthma. However, the NAEPP and GINA have provided different guidance on how to initiate step therapy (TABLE^3-5). NAEPP focuses on severity classification, while GINA recommends treatment initiation based on presenting symptoms. Since both guidelines recommend early ­follow-up and adjustment of therapy according to level of control, this difference becomes less apparent in ongoing care.

A more fundamental difference is seen in the recommended therapies for each step (TABLE^3-5). Whereas the 2020 Focused Updates prefers a SABA as needed in step 1, GINA favors a low-dose combination of ICS-formoterol as needed. The GINA recommendation is driven by supportive evidence for early initiation of low-dose ICS in any patient with asthma for greater improvement in lung function. This also addresses concerns that overuse of as-needed SABAs may increase the risk for severe exacerbations. Evidence also indicates that the risk for asthma-­related death and urgent asthma-related health care increases when a patient takes a SABA as needed as monotherapy compared with ICS therapy, even with good symptom control.^7,8

Continue to: Dosing of an ICS

Dosing of an ICS is based on step therapy regardless of the guideline used and is given at a total daily amount—low, medium, and high—for each age group. When initiating an ICS, consider differences between available treatment options (eg, cost, administration technique, likely patient adherence, patient preferences) and employ shared decision-making strategies. Dosing may need to be limited depending on the commercially available product, especially when used in combination with a LABA. However, as GINA emphasizes, a low-dose ICS provides the most clinical benefit. A high-dose ICS is needed by very few patients and is associated with greater risk for local and systemic adverse effects, such as adrenal suppression. With these considerations, both guidelines recommend using the lowest effective ICS dose and stepping up and down according to the patient’s comfort level.

Give an ICS time to work. Although an ICS can begin to reduce inflammation within days of initiation, the full benefit may be evident only after 2 to 3 months.⁴ Once the patient’s asthma is well controlled for 3 months, stepping down the dose can be considered and approached carefully. Complete cessation of ICSs is associated with significantly higher risk for exacerbations. Therefore, a general recommendation is to step down an ICS by 50% or reduce ICS-LABA from twice-daily administration to once daily. Risk for exacerbation after step-down therapy is heightened if the patient has a history of exacerbation or an emergency department visit in the past 12 months, a low baseline FEV₁, or a loss of control during a dose reduction (ie, airway hyperresponsiveness and sputum eosinophilia).

Weigh the utility of FeNO measurement. The 2020 Focused Updates also recommend considering FeNO measurement to guide treatment choice and monitoring, although this is based on overall low certainty of evidence.⁵ GINA affirms the mixed evidence for FeNO, stating that while a few studies have shown significantly reduced exacerbations among children, adolescents, and pregnant women with FeNO-guided treatment, other studies have shown no significant difference in exacerbations.^4,9-15 At this time, the role for FeNO in asthma management remains inconclusive, and access to it is limited across primary care settings.

Inhaled corticosteroids can begin to reduce inflammation within days, but the full benefit may be evident only after 2 to 3 months.

When assessing response to ICS therapy (and before stepping up therapy), consider patient adherence, inhaler technique, whether allergen exposure is persistent, and possible comorbidities. Inhaler technique can be especially challenging, as each inhaler varies in appearance and operation. Employ patient education strategies (eg, videos, demonstration, teach-back methods). If stepping up therapy is indicated, adding a LABA is recommended over increasing the ICS dose. Since asthma is variable, stepping up therapy can be tried and reassessed in 2 to 3 months.

SMART is preferred

Single maintenance and reliever therapy (SMART) with ICS-formoterol, used as needed, is the preferred therapy for steps 3 and 4 in both GINA recommendations and the 2020 Focused Updates (TABLE^3-5). GINA also prefers SMART for step 5. The recommended SMART combination that has been studied contains budesonide (or beclomethasone, not available in combination in the United States) for the ICS and formoterol for the LABA in a single inhaler that is used both daily for control and as needed for rescue therapy.

Continue to: Other ICS-formoterol...

Other ICS-formoterol or ICS-LABA combinations can be considered for controller therapy, especially those described in the NAEPP and GINA alternative step therapy recommendations. However, SMART has been more effective than other combinations in reducing exacerbations and provides similar or better levels of control at lower average ICS doses (compared with ICS-LABA with SABA or ICS with SABA) for adolescent and adult patients.^3,4 As patients use greater amounts of ICS-formoterol during episodes of increased symptoms, this additional ICS may augment the anti-inflammatory effects. SMART may also improve adherence, especially among those who confuse multiple inhalers.

SMART is also recommended for use in children. Specifically, from the 2020 Focused Updates, any patient ≥ 4 years of age with a severe exacerbation in the past year is a good SMART candidate. Also consider SMART before higher-dose ICS-LABA and SABA as needed. Additional benefits in this younger patient population are fewer medical visits or less systemic corticosteroid use with improved control and quality of life.

Caveats. Patients who have a difficult time recognizing symptoms may not be good candidates for SMART, due to the potential for taking higher or lower ICS doses than necessary.

SMART specifically refers to formoterol combinations that produce bronchodilation within 1 to 3 minutes.¹⁶ For example, the SMART strategy is not recommended for patients using ICS-salmeterol as controller therapy.

Although guideline supported, SMART options are not approved by the US Food and Drug Administration for use as reliever therapy.

Continue to: With the single combination...

With the single combination inhaler, consider the dosing limits of formoterol. The maximum daily amount of formoterol for ­adolescents and adults is 54 μg (12 puffs) delivered with the budesonide-formoterol metered dose inhaler. When using SMART as reliever therapy, the low-dose ICS-­formoterol recommendation remains. However, depending on insurance coverage, a 1-month supply of ­ICS-formoterol may not be sufficient for additional reliever therapy use.

The role of LAMAs as add-on therapy

Bronchiolar smooth muscle tone is mediated by complex mechanisms that include cholinergic stimulation at muscarinic (M3) receptors.¹⁷ LAMAs, a mainstay in the management of chronic obstructive pulmonary disease (COPD), are likely to be effective in reducing asthma exacerbations and the need for oral steroids. When patients have not achieved control at step 4 of asthma therapy, both the 2020 Focused Updates and GINA now recommend considering a LAMA (eg, tiotropium) as add-on therapy for patients > 12 years of age already taking medium-dose ICS-LABA for modest improvements in lung function and reductions in severe exacerbations. GINA recommendations also now include a LAMA as add-on treatment for those ages 6 to 11 years, as some evidence supports the use in school-aged children.¹⁸ It is important to note that LAMAs should not replace a LABA for treatment, as the ICS-LABA combination is likely more effective than ICS-LAMA.

Addressing asthma-COPD overlap

Asthma and COPD are frequently and frustratingly intertwined without clear demarcation. This tends to occur as patients age and chronic lung changes appear from longstanding asthma. However, it is important to distinguish between these conditions, because there are clearly delineated treatments for each that can improve outcomes.

The priority in addressing asthma-COPD overlap (ACO) is to evaluate symptoms and determine if asthma or COPD is predominant.¹⁹ This includes establishing patient age at which symptoms began, variation and triggers of symptoms, and history of exposures to smoke/environmental respiratory toxins. Age 40 years is often used as the tipping point at which symptom onset favors a diagnosis of COPD. Serial spirometry may also be used to evaluate lung function over time and persistence of disease. If a firm diagnosis is evasive, consider a referral to a pulmonary specialist for further testing.

The priority in addressing asthma-COPD overlap is to evaluate symptoms and determine if asthma or COPD is predominant.

Choosing to use an ICS or LAMA depends on which underlying disorder is more likely. While early COPD management includes LAMA + LABA, the addition of an ICS is reserved for more severe disease. High-dose ICSs, particularly fluticasone, should be limited in COPD due to an increased risk for pneumonia. For asthma or ACO, the addition of an ICS is critical and prioritized to reduce airway inflammation and risk for exacerbations and death. While a LAMA is likely useful earlier in ACO, it is not used until step 5 of asthma therapy. Given the complexities of ACO treatment, further research is needed to provide adequate guidance.

CASE

For Ms. S, you would be wise to use an ICS-formoterol combination for as-needed symptom relief. If symptoms were more persistent, you could consider recommending the ICS-­formoterol inhaler as SMART therapy, with regular doses taken twice daily and extra ­doses taken as needed.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota School of Medicine, Department of Family Medicine and Community Health, 2426 West Broadway Avenue, Minneapolis, MN 55411; [email protected]

The asthma medication tezepelumab, added to subcutaneous immunotherapy treatment (SCIT), may provide better, longer-lasting symptom relief than allergy shots alone for patients with allergic rhinitis caused by cat allergens, according to results of a phase 1/2 clinical trial.

“One year of allergen immunotherapy [AIT] combined with tezepelumab was significantly more effective than SCIT alone in reducing the nasal response to allergen challenge both at the end of treatment and one year after stopping treatment,” lead study author Jonathan Corren, MD, of the University of California, Los Angeles, and his colleagues wrote in The Journal of Allergy and Clinical Immunology.

“This persistent improvement in clinical response was paralleled by reductions in nasal transcripts for multiple immunologic pathways, including mast cell activation.”

The study was cited in a news release from the National Institutes of Health that said that the approach may work in a similar way with other allergens.

The Food and Drug Administration recently approved tezepelumab for the treatment of severe asthma in people aged 12 years and older. Tezelumab, a monoclonal antibody, works by blocking the cytokine thymic stromal lymphopoietin (TSLP).

“Cells that cover the surface of organs like the skin and intestines or that line the inside of the nose and lungs rapidly secrete TSLP in response to signals of potential danger,” according to the NIH news release. “In allergic disease, TSLP helps initiate an overreactive immune response to otherwise harmless substances like cat dander, provoking airway inflammation that leads to the symptoms of allergic rhinitis.”
 

Testing an enhanced strategy

The double-blind CATNIP trial was conducted by Dr. Corren and colleagues at nine sites in the United States. The trial included patients aged 18-65 years who’d had moderate to severe cat-induced allergic rhinitis for at least 2 years from 2015 to 2019.

The researchers excluded patients with recurrent acute or chronic sinusitis. They excluded patients who had undergone SCIT with cat allergen within the past 10 years or seasonal or perennial allergen sensitivity during nasal challenges. They also excluded persons with a history of persistent asthma.

In the parallel-design study, 121 participants were randomly allocated into four groups: 32 patients were treated with intravenous tezepelumab plus cat SCIT, 31 received the allergy shots alone, 30 received tezepelumab alone, and 28 received placebo alone for 52 weeks, followed by 52 weeks of observation.

Participants received SCIT (10,000 bioequivalent allergy units per milliliter) or matched placebo via subcutaneous injections weekly in increasing doses for around 12 weeks, followed by monthly maintenance injections (4,000 BAU or maximum tolerated dose) until week 48.

They received tezepelumab (700 mg IV) or matched placebo 1-3 days prior to the SCIT or placebo SCIT injections once every 4 weeks through week 24, then before or on the same day as the SCIT or placebo injections through week 48.
 

Measures of effectiveness

Participants were also given nasal allergy challenges – one spritz of a nasal spray containing cat allergen extract in each nostril at screening, baseline, and weeks 26, 52, 78, and 104. The researchers recorded participants’ total nasal symptom score (TNSS) and peak nasal inspiratory flow at 5, 15, 30, and 60 minutes after being sprayed and hourly for up to 6 hours post challenge. Blood and nasal cell samples were also collected.

The research team performed skin prick tests using serial dilutions of cat extract and an intradermal skin test (IDST) using the concentration of allergen that produced an early response of at least 15 mm at baseline. They measured early-phase responses for the both tests at 15 minutes and late-phase response to the IDST at 6 hours.

They measured serum levels of cat dander–specific IgE, IgG4, and total IgE using fluoroenzyme immunoassay. They measured serum interleukin-5 and IL-13 using high-sensitivity single-molecule digital immunoassay and performed nasal brushing using a 3-mm cytology brush 6 hours after a nasal allergy challenge. They performed whole-genome transcriptional profiling on the extracted RNA.
 

Combination therapy worked better and longer

The combined therapy worked better while being administered. Although the allergy shots alone stopped working after they were discontinued, the combination continued to benefit participants 1 year after that therapy ended.

At week 52, statistically significant reductions in TNSS induced by nasal allergy challenges occurred in patients receiving tezepelumab plus SCIT compared with patients receiving SCIT alone.

At week 104, 1 year after treatment ended, the primary endpoint TNSS was not significantly different in the tezepelumab-plus-SCIT group than in the SCIT-alone group, but TNSS peak 0–1 hour was significantly lower in the combination treatment group than in the SCIT-alone group.

In analysis of gene expression from nasal epithelial samples, participants who had been treated with the combination but not with either therapy by itself showed persistent modulation of the nasal immunologic environment, including diminished mast cell function. This was explained in large part by decreased transcription of the gene TPSAB1 (tryptase). Tryptase protein in nasal fluid was also decreased in the combination group, compared with the SCIT-alone group.

Adverse and serious adverse events, including infections and infestations as well as respiratory, thoracic, mediastinal, gastrointestinal, immune system, and nervous system disorders, did not differ significantly between treatment groups.
 

Four independent experts welcome the results

Patricia Lynne Lugar, MD, associate professor of medicine in the division of pulmonology, allergy, and critical care medicine at Duke University, Durham, N.C., found the results, especially the 1-year posttreatment response durability, surprising.

“AIT is a very effective treatment that often provides prolonged symptom improvement and is ‘curative’ in many cases,” she said in an interview. “If further studies show that tezepelumab offers long-term results, more patients might opt for combination therapy.

“A significant strength of the study is its evaluation of responses of the combination therapy on cellular output and gene expression,” Dr. Lugar added. “The mechanism by which AIT modulates the allergic response is largely understood. Tezepelumab may augment this modulation to alter the Th2 response upon exposure to the allergens.”
 

Will payors cover the prohibitively costly biologic?

Scott Frank, MD, associate professor in the department of family medicine and community health at Case Western Reserve University, Cleveland, called the study well designed and rigorous.

“The practicality of the approach may be limited by the need for intravenous administration of tezepelumab in addition to the traditional allergy shot,” he noted by email, “and the cost of this therapeutic approach is not addressed.”

Christopher Brooks, MD, clinical assistant professor of allergy and immunology in the department of otolaryngology at Ohio State University Wexner Medical Center, Columbus, also pointed out the drug’s cost.

“Tezepelumab is currently an expensive biologic, so it remains to be seen whether patients and payors will be willing to pay for this add-on medication when AIT by itself still remains very effective,” he said by email.

“AIT is most effective when given for 5 years, so it also remains to be seen whether the results and conclusions of this study would still hold true if done for the typical 5-year treatment period,” he added.

Stokes Peebles, MD, professor of medicine in the division of allergy, pulmonary, and critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., called the study “very well designed by a highly respected group of investigators using well-matched study populations.

“Tezepelumab has been shown to work in asthma, and there is no reason to think it would not work in allergic rhinitis,” he said in an interview.

“However, while the results of the combined therapy were statistically significant, their clinical significance was not clear. Patients do not care about statistical significance. They want to know whether a drug will be clinically significant,” he added.

Many people avoid cat allergy symptoms by avoiding cats and, in some cases, by avoiding people who live with cats, he said. Medical therapy, usually involving nasal corticosteroids and antihistamines, helps most people avoid cat allergy symptoms.

“Patients with bad allergies who have not done well with SCIT may consider adding tezepelumab, but it incurs a major cost. If medical therapy doesn’t work, allergy shots are available at roughly $3,000 per year. Adding tezepelumab costs around $40,000 more per year,” he explained. “Does the slight clinical benefit justify the greatly increased cost?”

The authors and uninvolved experts recommend further related research.

The research was supported by the National Institute of Allergy and Infectious Diseases. AstraZeneca and Amgen donated the drug used in the study. Dr. Corren reported financial relationships with AstraZeneca, and one coauthor reported relevant financial relationships with Amgen and other pharmaceutical companies. The remaining coauthors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The asthma medication tezepelumab, added to subcutaneous immunotherapy treatment (SCIT), may provide better, longer-lasting symptom relief than allergy shots alone for patients with allergic rhinitis caused by cat allergens, according to results of a phase 1/2 clinical trial.

“One year of allergen immunotherapy [AIT] combined with tezepelumab was significantly more effective than SCIT alone in reducing the nasal response to allergen challenge both at the end of treatment and one year after stopping treatment,” lead study author Jonathan Corren, MD, of the University of California, Los Angeles, and his colleagues wrote in The Journal of Allergy and Clinical Immunology.

“This persistent improvement in clinical response was paralleled by reductions in nasal transcripts for multiple immunologic pathways, including mast cell activation.”

The study was cited in a news release from the National Institutes of Health that said that the approach may work in a similar way with other allergens.

The Food and Drug Administration recently approved tezepelumab for the treatment of severe asthma in people aged 12 years and older. Tezelumab, a monoclonal antibody, works by blocking the cytokine thymic stromal lymphopoietin (TSLP).

“Cells that cover the surface of organs like the skin and intestines or that line the inside of the nose and lungs rapidly secrete TSLP in response to signals of potential danger,” according to the NIH news release. “In allergic disease, TSLP helps initiate an overreactive immune response to otherwise harmless substances like cat dander, provoking airway inflammation that leads to the symptoms of allergic rhinitis.”
 

Testing an enhanced strategy

The double-blind CATNIP trial was conducted by Dr. Corren and colleagues at nine sites in the United States. The trial included patients aged 18-65 years who’d had moderate to severe cat-induced allergic rhinitis for at least 2 years from 2015 to 2019.

The researchers excluded patients with recurrent acute or chronic sinusitis. They excluded patients who had undergone SCIT with cat allergen within the past 10 years or seasonal or perennial allergen sensitivity during nasal challenges. They also excluded persons with a history of persistent asthma.

In the parallel-design study, 121 participants were randomly allocated into four groups: 32 patients were treated with intravenous tezepelumab plus cat SCIT, 31 received the allergy shots alone, 30 received tezepelumab alone, and 28 received placebo alone for 52 weeks, followed by 52 weeks of observation.

Participants received SCIT (10,000 bioequivalent allergy units per milliliter) or matched placebo via subcutaneous injections weekly in increasing doses for around 12 weeks, followed by monthly maintenance injections (4,000 BAU or maximum tolerated dose) until week 48.

They received tezepelumab (700 mg IV) or matched placebo 1-3 days prior to the SCIT or placebo SCIT injections once every 4 weeks through week 24, then before or on the same day as the SCIT or placebo injections through week 48.
 

Measures of effectiveness

Participants were also given nasal allergy challenges – one spritz of a nasal spray containing cat allergen extract in each nostril at screening, baseline, and weeks 26, 52, 78, and 104. The researchers recorded participants’ total nasal symptom score (TNSS) and peak nasal inspiratory flow at 5, 15, 30, and 60 minutes after being sprayed and hourly for up to 6 hours post challenge. Blood and nasal cell samples were also collected.

The research team performed skin prick tests using serial dilutions of cat extract and an intradermal skin test (IDST) using the concentration of allergen that produced an early response of at least 15 mm at baseline. They measured early-phase responses for the both tests at 15 minutes and late-phase response to the IDST at 6 hours.

They measured serum levels of cat dander–specific IgE, IgG4, and total IgE using fluoroenzyme immunoassay. They measured serum interleukin-5 and IL-13 using high-sensitivity single-molecule digital immunoassay and performed nasal brushing using a 3-mm cytology brush 6 hours after a nasal allergy challenge. They performed whole-genome transcriptional profiling on the extracted RNA.
 

Combination therapy worked better and longer

The combined therapy worked better while being administered. Although the allergy shots alone stopped working after they were discontinued, the combination continued to benefit participants 1 year after that therapy ended.

At week 52, statistically significant reductions in TNSS induced by nasal allergy challenges occurred in patients receiving tezepelumab plus SCIT compared with patients receiving SCIT alone.

At week 104, 1 year after treatment ended, the primary endpoint TNSS was not significantly different in the tezepelumab-plus-SCIT group than in the SCIT-alone group, but TNSS peak 0–1 hour was significantly lower in the combination treatment group than in the SCIT-alone group.

In analysis of gene expression from nasal epithelial samples, participants who had been treated with the combination but not with either therapy by itself showed persistent modulation of the nasal immunologic environment, including diminished mast cell function. This was explained in large part by decreased transcription of the gene TPSAB1 (tryptase). Tryptase protein in nasal fluid was also decreased in the combination group, compared with the SCIT-alone group.

Adverse and serious adverse events, including infections and infestations as well as respiratory, thoracic, mediastinal, gastrointestinal, immune system, and nervous system disorders, did not differ significantly between treatment groups.
 

Four independent experts welcome the results

Patricia Lynne Lugar, MD, associate professor of medicine in the division of pulmonology, allergy, and critical care medicine at Duke University, Durham, N.C., found the results, especially the 1-year posttreatment response durability, surprising.

“AIT is a very effective treatment that often provides prolonged symptom improvement and is ‘curative’ in many cases,” she said in an interview. “If further studies show that tezepelumab offers long-term results, more patients might opt for combination therapy.

“A significant strength of the study is its evaluation of responses of the combination therapy on cellular output and gene expression,” Dr. Lugar added. “The mechanism by which AIT modulates the allergic response is largely understood. Tezepelumab may augment this modulation to alter the Th2 response upon exposure to the allergens.”
 

Will payors cover the prohibitively costly biologic?

Scott Frank, MD, associate professor in the department of family medicine and community health at Case Western Reserve University, Cleveland, called the study well designed and rigorous.

“The practicality of the approach may be limited by the need for intravenous administration of tezepelumab in addition to the traditional allergy shot,” he noted by email, “and the cost of this therapeutic approach is not addressed.”

Christopher Brooks, MD, clinical assistant professor of allergy and immunology in the department of otolaryngology at Ohio State University Wexner Medical Center, Columbus, also pointed out the drug’s cost.

“Tezepelumab is currently an expensive biologic, so it remains to be seen whether patients and payors will be willing to pay for this add-on medication when AIT by itself still remains very effective,” he said by email.

“AIT is most effective when given for 5 years, so it also remains to be seen whether the results and conclusions of this study would still hold true if done for the typical 5-year treatment period,” he added.

Stokes Peebles, MD, professor of medicine in the division of allergy, pulmonary, and critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., called the study “very well designed by a highly respected group of investigators using well-matched study populations.

“Tezepelumab has been shown to work in asthma, and there is no reason to think it would not work in allergic rhinitis,” he said in an interview.

“However, while the results of the combined therapy were statistically significant, their clinical significance was not clear. Patients do not care about statistical significance. They want to know whether a drug will be clinically significant,” he added.

Many people avoid cat allergy symptoms by avoiding cats and, in some cases, by avoiding people who live with cats, he said. Medical therapy, usually involving nasal corticosteroids and antihistamines, helps most people avoid cat allergy symptoms.

“Patients with bad allergies who have not done well with SCIT may consider adding tezepelumab, but it incurs a major cost. If medical therapy doesn’t work, allergy shots are available at roughly $3,000 per year. Adding tezepelumab costs around $40,000 more per year,” he explained. “Does the slight clinical benefit justify the greatly increased cost?”

The authors and uninvolved experts recommend further related research.

The research was supported by the National Institute of Allergy and Infectious Diseases. AstraZeneca and Amgen donated the drug used in the study. Dr. Corren reported financial relationships with AstraZeneca, and one coauthor reported relevant financial relationships with Amgen and other pharmaceutical companies. The remaining coauthors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The asthma medication tezepelumab, added to subcutaneous immunotherapy treatment (SCIT), may provide better, longer-lasting symptom relief than allergy shots alone for patients with allergic rhinitis caused by cat allergens, according to results of a phase 1/2 clinical trial.

“One year of allergen immunotherapy [AIT] combined with tezepelumab was significantly more effective than SCIT alone in reducing the nasal response to allergen challenge both at the end of treatment and one year after stopping treatment,” lead study author Jonathan Corren, MD, of the University of California, Los Angeles, and his colleagues wrote in The Journal of Allergy and Clinical Immunology.

“This persistent improvement in clinical response was paralleled by reductions in nasal transcripts for multiple immunologic pathways, including mast cell activation.”

The study was cited in a news release from the National Institutes of Health that said that the approach may work in a similar way with other allergens.

The Food and Drug Administration recently approved tezepelumab for the treatment of severe asthma in people aged 12 years and older. Tezelumab, a monoclonal antibody, works by blocking the cytokine thymic stromal lymphopoietin (TSLP).

“Cells that cover the surface of organs like the skin and intestines or that line the inside of the nose and lungs rapidly secrete TSLP in response to signals of potential danger,” according to the NIH news release. “In allergic disease, TSLP helps initiate an overreactive immune response to otherwise harmless substances like cat dander, provoking airway inflammation that leads to the symptoms of allergic rhinitis.”
 

Testing an enhanced strategy

The double-blind CATNIP trial was conducted by Dr. Corren and colleagues at nine sites in the United States. The trial included patients aged 18-65 years who’d had moderate to severe cat-induced allergic rhinitis for at least 2 years from 2015 to 2019.

The researchers excluded patients with recurrent acute or chronic sinusitis. They excluded patients who had undergone SCIT with cat allergen within the past 10 years or seasonal or perennial allergen sensitivity during nasal challenges. They also excluded persons with a history of persistent asthma.

In the parallel-design study, 121 participants were randomly allocated into four groups: 32 patients were treated with intravenous tezepelumab plus cat SCIT, 31 received the allergy shots alone, 30 received tezepelumab alone, and 28 received placebo alone for 52 weeks, followed by 52 weeks of observation.

Participants received SCIT (10,000 bioequivalent allergy units per milliliter) or matched placebo via subcutaneous injections weekly in increasing doses for around 12 weeks, followed by monthly maintenance injections (4,000 BAU or maximum tolerated dose) until week 48.

They received tezepelumab (700 mg IV) or matched placebo 1-3 days prior to the SCIT or placebo SCIT injections once every 4 weeks through week 24, then before or on the same day as the SCIT or placebo injections through week 48.
 

Measures of effectiveness

Participants were also given nasal allergy challenges – one spritz of a nasal spray containing cat allergen extract in each nostril at screening, baseline, and weeks 26, 52, 78, and 104. The researchers recorded participants’ total nasal symptom score (TNSS) and peak nasal inspiratory flow at 5, 15, 30, and 60 minutes after being sprayed and hourly for up to 6 hours post challenge. Blood and nasal cell samples were also collected.

The research team performed skin prick tests using serial dilutions of cat extract and an intradermal skin test (IDST) using the concentration of allergen that produced an early response of at least 15 mm at baseline. They measured early-phase responses for the both tests at 15 minutes and late-phase response to the IDST at 6 hours.

They measured serum levels of cat dander–specific IgE, IgG4, and total IgE using fluoroenzyme immunoassay. They measured serum interleukin-5 and IL-13 using high-sensitivity single-molecule digital immunoassay and performed nasal brushing using a 3-mm cytology brush 6 hours after a nasal allergy challenge. They performed whole-genome transcriptional profiling on the extracted RNA.
 

Combination therapy worked better and longer

The combined therapy worked better while being administered. Although the allergy shots alone stopped working after they were discontinued, the combination continued to benefit participants 1 year after that therapy ended.

At week 52, statistically significant reductions in TNSS induced by nasal allergy challenges occurred in patients receiving tezepelumab plus SCIT compared with patients receiving SCIT alone.

At week 104, 1 year after treatment ended, the primary endpoint TNSS was not significantly different in the tezepelumab-plus-SCIT group than in the SCIT-alone group, but TNSS peak 0–1 hour was significantly lower in the combination treatment group than in the SCIT-alone group.

In analysis of gene expression from nasal epithelial samples, participants who had been treated with the combination but not with either therapy by itself showed persistent modulation of the nasal immunologic environment, including diminished mast cell function. This was explained in large part by decreased transcription of the gene TPSAB1 (tryptase). Tryptase protein in nasal fluid was also decreased in the combination group, compared with the SCIT-alone group.

Adverse and serious adverse events, including infections and infestations as well as respiratory, thoracic, mediastinal, gastrointestinal, immune system, and nervous system disorders, did not differ significantly between treatment groups.
 

Four independent experts welcome the results

Patricia Lynne Lugar, MD, associate professor of medicine in the division of pulmonology, allergy, and critical care medicine at Duke University, Durham, N.C., found the results, especially the 1-year posttreatment response durability, surprising.

“AIT is a very effective treatment that often provides prolonged symptom improvement and is ‘curative’ in many cases,” she said in an interview. “If further studies show that tezepelumab offers long-term results, more patients might opt for combination therapy.

“A significant strength of the study is its evaluation of responses of the combination therapy on cellular output and gene expression,” Dr. Lugar added. “The mechanism by which AIT modulates the allergic response is largely understood. Tezepelumab may augment this modulation to alter the Th2 response upon exposure to the allergens.”
 

Will payors cover the prohibitively costly biologic?

Scott Frank, MD, associate professor in the department of family medicine and community health at Case Western Reserve University, Cleveland, called the study well designed and rigorous.

“The practicality of the approach may be limited by the need for intravenous administration of tezepelumab in addition to the traditional allergy shot,” he noted by email, “and the cost of this therapeutic approach is not addressed.”

Christopher Brooks, MD, clinical assistant professor of allergy and immunology in the department of otolaryngology at Ohio State University Wexner Medical Center, Columbus, also pointed out the drug’s cost.

“Tezepelumab is currently an expensive biologic, so it remains to be seen whether patients and payors will be willing to pay for this add-on medication when AIT by itself still remains very effective,” he said by email.

“AIT is most effective when given for 5 years, so it also remains to be seen whether the results and conclusions of this study would still hold true if done for the typical 5-year treatment period,” he added.

Stokes Peebles, MD, professor of medicine in the division of allergy, pulmonary, and critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., called the study “very well designed by a highly respected group of investigators using well-matched study populations.

“Tezepelumab has been shown to work in asthma, and there is no reason to think it would not work in allergic rhinitis,” he said in an interview.

“However, while the results of the combined therapy were statistically significant, their clinical significance was not clear. Patients do not care about statistical significance. They want to know whether a drug will be clinically significant,” he added.

Many people avoid cat allergy symptoms by avoiding cats and, in some cases, by avoiding people who live with cats, he said. Medical therapy, usually involving nasal corticosteroids and antihistamines, helps most people avoid cat allergy symptoms.

“Patients with bad allergies who have not done well with SCIT may consider adding tezepelumab, but it incurs a major cost. If medical therapy doesn’t work, allergy shots are available at roughly $3,000 per year. Adding tezepelumab costs around $40,000 more per year,” he explained. “Does the slight clinical benefit justify the greatly increased cost?”

The authors and uninvolved experts recommend further related research.

The research was supported by the National Institute of Allergy and Infectious Diseases. AstraZeneca and Amgen donated the drug used in the study. Dr. Corren reported financial relationships with AstraZeneca, and one coauthor reported relevant financial relationships with Amgen and other pharmaceutical companies. The remaining coauthors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

From the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Clinical inertia is defined as the failure of clinicians to initiate or escalate guideline-directed medical therapy to achieve treatment goals for well-defined clinical conditions.^1,2 Evidence-based guidelines recommend optimal disease management with readily available medical therapies throughout the phases of clinical care. Unfortunately, the care provided to individual patients undergoes multiple modifications throughout the disease course, resulting in divergent pathways, significant deviations from treatment guidelines, and failure of “safeguard” checkpoints to reinstate, initiate, optimize, or stop treatments. Clinical inertia generally describes rigidity or resistance to change around implementing evidence-based guidelines. Furthermore, this term describes treatment behavior on the part of an individual clinician, not organizational inertia, which generally encompasses both internal (immediate clinical practice settings) and external factors (national and international guidelines and recommendations), eventually leading to resistance to optimizing disease treatment and therapeutic regimens. Individual clinicians’ clinical inertia in the form of resistance to guideline implementation and evidence-based principles can be one factor that drives organizational inertia. In turn, such individual behavior can be dictated by personal beliefs, knowledge, interpretation, skills, management principles, and biases. The terms therapeutic inertia or clinical inertia should not be confused with nonadherence from the patient’s standpoint when the clinician follows the best practice guidelines.³

Clinical inertia has been described in several clinical domains, including diabetes,^4,5 hypertension,^6,7 heart failure,⁸ depression,⁹ pulmonary medicine,¹⁰ and complex disease management.¹¹ Clinicians can set suboptimal treatment goals due to specific beliefs and attitudes around optimal therapeutic goals. For example, when treating a patient with a chronic disease that is presently stable, a clinician could elect to initiate suboptimal treatment, as escalation of treatment might not be the priority in stable disease; they also may have concerns about overtreatment. Other factors that can contribute to clinical inertia (ie, undertreatment in the presence of indications for treatment) include those related to the patient, the clinical setting, and the organization, along with the importance of individualizing therapies in specific patients. Organizational inertia is the initial global resistance by the system to implementation, which can slow the dissemination and adaptation of best practices but eventually declines over time. Individual clinical inertia, on the other hand, will likely persist after the system-level rollout of guideline-based approaches.

The trajectory of dissemination, implementation, and adaptation of innovations and best practices is illustrated in the Figure. When the guidelines and medical societies endorse the adaptation of innovations or practice change after the benefits of such innovations/change have been established by the regulatory bodies, uptake can be hindered by both organizational and clinical inertia. Overcoming inertia to system-level changes requires addressing individual clinicians, along with practice and organizational factors, in order to ensure systematic adaptations. From the clinicians’ view, training and cognitive interventions to improve the adaptation and coping skills can improve understanding of treatment options through standardized educational and behavioral modification tools, direct and indirect feedback around performance, and decision support through a continuous improvement approach on both individual and system levels.

Addressing inertia in clinical practice requires a deep understanding of the individual and organizational elements that foster resistance to adapting best practice models. Research that explores tools and approaches to overcome inertia in managing complex diseases is a key step in advancing clinical innovation and disseminating best practices.

Corresponding author: Ebrahim Barkoudah, MD, MPH; [email protected]

Disclosures: None reported.

From the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Clinical inertia is defined as the failure of clinicians to initiate or escalate guideline-directed medical therapy to achieve treatment goals for well-defined clinical conditions.^1,2 Evidence-based guidelines recommend optimal disease management with readily available medical therapies throughout the phases of clinical care. Unfortunately, the care provided to individual patients undergoes multiple modifications throughout the disease course, resulting in divergent pathways, significant deviations from treatment guidelines, and failure of “safeguard” checkpoints to reinstate, initiate, optimize, or stop treatments. Clinical inertia generally describes rigidity or resistance to change around implementing evidence-based guidelines. Furthermore, this term describes treatment behavior on the part of an individual clinician, not organizational inertia, which generally encompasses both internal (immediate clinical practice settings) and external factors (national and international guidelines and recommendations), eventually leading to resistance to optimizing disease treatment and therapeutic regimens. Individual clinicians’ clinical inertia in the form of resistance to guideline implementation and evidence-based principles can be one factor that drives organizational inertia. In turn, such individual behavior can be dictated by personal beliefs, knowledge, interpretation, skills, management principles, and biases. The terms therapeutic inertia or clinical inertia should not be confused with nonadherence from the patient’s standpoint when the clinician follows the best practice guidelines.³

Clinical inertia has been described in several clinical domains, including diabetes,^4,5 hypertension,^6,7 heart failure,⁸ depression,⁹ pulmonary medicine,¹⁰ and complex disease management.¹¹ Clinicians can set suboptimal treatment goals due to specific beliefs and attitudes around optimal therapeutic goals. For example, when treating a patient with a chronic disease that is presently stable, a clinician could elect to initiate suboptimal treatment, as escalation of treatment might not be the priority in stable disease; they also may have concerns about overtreatment. Other factors that can contribute to clinical inertia (ie, undertreatment in the presence of indications for treatment) include those related to the patient, the clinical setting, and the organization, along with the importance of individualizing therapies in specific patients. Organizational inertia is the initial global resistance by the system to implementation, which can slow the dissemination and adaptation of best practices but eventually declines over time. Individual clinical inertia, on the other hand, will likely persist after the system-level rollout of guideline-based approaches.

The trajectory of dissemination, implementation, and adaptation of innovations and best practices is illustrated in the Figure. When the guidelines and medical societies endorse the adaptation of innovations or practice change after the benefits of such innovations/change have been established by the regulatory bodies, uptake can be hindered by both organizational and clinical inertia. Overcoming inertia to system-level changes requires addressing individual clinicians, along with practice and organizational factors, in order to ensure systematic adaptations. From the clinicians’ view, training and cognitive interventions to improve the adaptation and coping skills can improve understanding of treatment options through standardized educational and behavioral modification tools, direct and indirect feedback around performance, and decision support through a continuous improvement approach on both individual and system levels.

Addressing inertia in clinical practice requires a deep understanding of the individual and organizational elements that foster resistance to adapting best practice models. Research that explores tools and approaches to overcome inertia in managing complex diseases is a key step in advancing clinical innovation and disseminating best practices.

Corresponding author: Ebrahim Barkoudah, MD, MPH; [email protected]

Disclosures: None reported.

From the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA.

Clinical inertia is defined as the failure of clinicians to initiate or escalate guideline-directed medical therapy to achieve treatment goals for well-defined clinical conditions.^1,2 Evidence-based guidelines recommend optimal disease management with readily available medical therapies throughout the phases of clinical care. Unfortunately, the care provided to individual patients undergoes multiple modifications throughout the disease course, resulting in divergent pathways, significant deviations from treatment guidelines, and failure of “safeguard” checkpoints to reinstate, initiate, optimize, or stop treatments. Clinical inertia generally describes rigidity or resistance to change around implementing evidence-based guidelines. Furthermore, this term describes treatment behavior on the part of an individual clinician, not organizational inertia, which generally encompasses both internal (immediate clinical practice settings) and external factors (national and international guidelines and recommendations), eventually leading to resistance to optimizing disease treatment and therapeutic regimens. Individual clinicians’ clinical inertia in the form of resistance to guideline implementation and evidence-based principles can be one factor that drives organizational inertia. In turn, such individual behavior can be dictated by personal beliefs, knowledge, interpretation, skills, management principles, and biases. The terms therapeutic inertia or clinical inertia should not be confused with nonadherence from the patient’s standpoint when the clinician follows the best practice guidelines.³

Clinical inertia has been described in several clinical domains, including diabetes,^4,5 hypertension,^6,7 heart failure,⁸ depression,⁹ pulmonary medicine,¹⁰ and complex disease management.¹¹ Clinicians can set suboptimal treatment goals due to specific beliefs and attitudes around optimal therapeutic goals. For example, when treating a patient with a chronic disease that is presently stable, a clinician could elect to initiate suboptimal treatment, as escalation of treatment might not be the priority in stable disease; they also may have concerns about overtreatment. Other factors that can contribute to clinical inertia (ie, undertreatment in the presence of indications for treatment) include those related to the patient, the clinical setting, and the organization, along with the importance of individualizing therapies in specific patients. Organizational inertia is the initial global resistance by the system to implementation, which can slow the dissemination and adaptation of best practices but eventually declines over time. Individual clinical inertia, on the other hand, will likely persist after the system-level rollout of guideline-based approaches.

The trajectory of dissemination, implementation, and adaptation of innovations and best practices is illustrated in the Figure. When the guidelines and medical societies endorse the adaptation of innovations or practice change after the benefits of such innovations/change have been established by the regulatory bodies, uptake can be hindered by both organizational and clinical inertia. Overcoming inertia to system-level changes requires addressing individual clinicians, along with practice and organizational factors, in order to ensure systematic adaptations. From the clinicians’ view, training and cognitive interventions to improve the adaptation and coping skills can improve understanding of treatment options through standardized educational and behavioral modification tools, direct and indirect feedback around performance, and decision support through a continuous improvement approach on both individual and system levels.

Addressing inertia in clinical practice requires a deep understanding of the individual and organizational elements that foster resistance to adapting best practice models. Research that explores tools and approaches to overcome inertia in managing complex diseases is a key step in advancing clinical innovation and disseminating best practices.

Corresponding author: Ebrahim Barkoudah, MD, MPH; [email protected]

Disclosures: None reported.