Terry L. Kamps, PhD

TOPLINE:

Immunological and quantitative mRNA assays support a pathogenesis role for histamine-releasing factor (HRF), its interaction with HRF-reactive immunoglobulin E and rhinovirus (RV) in asthma severity and exacerbation.

METHODOLOGY:

• Clinical data for healthy controls (HCs) were compared with data from patients with asthma for three distinct cohorts recruited from programs located in Pittsburg, Boston, and Virginia.
• Cohorts differed primarily by total number of participants, median age, description of asthma severity, RV status, and longitudinal follow-up.
• Enzyme-linked immunoassay tests quantified for comparisons total IgE, IgGs, and IgG1 levels occurring in human sera samples and for HRF-reactive IgE, IgG1, and IgG2b in sera from mice inoculated with mouse .
• Anti-IgE stimulation experiments characterized bronchoalveolar lavage (BAL) cell supernatants for tryptase and PGD2 by ELISA and the mRNAs for tryptase and FCER1A
• Effect of inoculated RV infections and/or house dust mite allergen on stimulating HRF secretion from respiratory epithelial cells and in vitro–grown lung BEAS-2B cells was evaluated by Western blots.

TAKEAWAY:

• HRF-reactive IgE and total IgE levels in serum were significantly higher from patients with severe asthma than from HCs and showed a rising trend as severity increased.
• HRF-reactive IgGs and IgG1 levels in serum were lower in people with asthma than in HCs.
• People with asthma with high HRF-reactive IgE, compared with those with low levels, tended to release more tryptase prostaglandin D2 with anti-IgE stimulation of BAL cells.
• RV infection induced HFR secretions from both in vivo– and in vitro–grown respiratory epithelial cells and was associated with higher levels of HRF-IgE at the time of asthma exacerbations, compared with after resolution.

IN PRACTICE:

Inhibiting HRF and HRF-reactive IgE interactions “can be a preventative/therapeutic target” for severe and RV-induced exacerbated asthma conditions.

SOURCE:

The study led by Yu Kawakami, MD, of La Jolla Institute for Allergy & Immunology, California, and colleagues was published in the Journal of Allergy and Clinical Immunology

LIMITATIONS:

Small sample sizes, large median age differences between cohorts, and lack of data for other demographic traits and variant asthma phenotypes or endotypes in some cohorts are noted limitations that may affect result extrapolations and conclusions.

DISCLOSURES:

The authors report there are no conflicts of interest directly related to this study.

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

TOPLINE:

Immunological and quantitative mRNA assays support a pathogenesis role for histamine-releasing factor (HRF), its interaction with HRF-reactive immunoglobulin E and rhinovirus (RV) in asthma severity and exacerbation.

METHODOLOGY:

• Clinical data for healthy controls (HCs) were compared with data from patients with asthma for three distinct cohorts recruited from programs located in Pittsburg, Boston, and Virginia.
• Cohorts differed primarily by total number of participants, median age, description of asthma severity, RV status, and longitudinal follow-up.
• Enzyme-linked immunoassay tests quantified for comparisons total IgE, IgGs, and IgG1 levels occurring in human sera samples and for HRF-reactive IgE, IgG1, and IgG2b in sera from mice inoculated with mouse .
• Anti-IgE stimulation experiments characterized bronchoalveolar lavage (BAL) cell supernatants for tryptase and PGD2 by ELISA and the mRNAs for tryptase and FCER1A
• Effect of inoculated RV infections and/or house dust mite allergen on stimulating HRF secretion from respiratory epithelial cells and in vitro–grown lung BEAS-2B cells was evaluated by Western blots.

TAKEAWAY:

• HRF-reactive IgE and total IgE levels in serum were significantly higher from patients with severe asthma than from HCs and showed a rising trend as severity increased.
• HRF-reactive IgGs and IgG1 levels in serum were lower in people with asthma than in HCs.
• People with asthma with high HRF-reactive IgE, compared with those with low levels, tended to release more tryptase prostaglandin D2 with anti-IgE stimulation of BAL cells.
• RV infection induced HFR secretions from both in vivo– and in vitro–grown respiratory epithelial cells and was associated with higher levels of HRF-IgE at the time of asthma exacerbations, compared with after resolution.

IN PRACTICE:

Inhibiting HRF and HRF-reactive IgE interactions “can be a preventative/therapeutic target” for severe and RV-induced exacerbated asthma conditions.

SOURCE:

The study led by Yu Kawakami, MD, of La Jolla Institute for Allergy & Immunology, California, and colleagues was published in the Journal of Allergy and Clinical Immunology

LIMITATIONS:

Small sample sizes, large median age differences between cohorts, and lack of data for other demographic traits and variant asthma phenotypes or endotypes in some cohorts are noted limitations that may affect result extrapolations and conclusions.

DISCLOSURES:

The authors report there are no conflicts of interest directly related to this study.

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

TOPLINE:

Immunological and quantitative mRNA assays support a pathogenesis role for histamine-releasing factor (HRF), its interaction with HRF-reactive immunoglobulin E and rhinovirus (RV) in asthma severity and exacerbation.

METHODOLOGY:

• Clinical data for healthy controls (HCs) were compared with data from patients with asthma for three distinct cohorts recruited from programs located in Pittsburg, Boston, and Virginia.
• Cohorts differed primarily by total number of participants, median age, description of asthma severity, RV status, and longitudinal follow-up.
• Enzyme-linked immunoassay tests quantified for comparisons total IgE, IgGs, and IgG1 levels occurring in human sera samples and for HRF-reactive IgE, IgG1, and IgG2b in sera from mice inoculated with mouse .
• Anti-IgE stimulation experiments characterized bronchoalveolar lavage (BAL) cell supernatants for tryptase and PGD2 by ELISA and the mRNAs for tryptase and FCER1A
• Effect of inoculated RV infections and/or house dust mite allergen on stimulating HRF secretion from respiratory epithelial cells and in vitro–grown lung BEAS-2B cells was evaluated by Western blots.

TAKEAWAY:

• HRF-reactive IgE and total IgE levels in serum were significantly higher from patients with severe asthma than from HCs and showed a rising trend as severity increased.
• HRF-reactive IgGs and IgG1 levels in serum were lower in people with asthma than in HCs.
• People with asthma with high HRF-reactive IgE, compared with those with low levels, tended to release more tryptase prostaglandin D2 with anti-IgE stimulation of BAL cells.
• RV infection induced HFR secretions from both in vivo– and in vitro–grown respiratory epithelial cells and was associated with higher levels of HRF-IgE at the time of asthma exacerbations, compared with after resolution.

IN PRACTICE:

Inhibiting HRF and HRF-reactive IgE interactions “can be a preventative/therapeutic target” for severe and RV-induced exacerbated asthma conditions.

SOURCE:

The study led by Yu Kawakami, MD, of La Jolla Institute for Allergy & Immunology, California, and colleagues was published in the Journal of Allergy and Clinical Immunology

LIMITATIONS:

Small sample sizes, large median age differences between cohorts, and lack of data for other demographic traits and variant asthma phenotypes or endotypes in some cohorts are noted limitations that may affect result extrapolations and conclusions.

DISCLOSURES:

The authors report there are no conflicts of interest directly related to this study.

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

TOPLINE:

Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis. 

METHODOLOGY:

Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.

Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.

Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.

Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.

TAKEAWAYS:

DR-TB patients tended to be older than NDR-TB patients.

Isolated plasma exosomes were morphologically characterized as being “close to pure.”

Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.

Protein-protein interaction modeling suggests that downregulated apolipoproteins APOA1, APOB, and APOC1 have a role in mediating DR-TB development through their functions in lipid metabolism and protein transport.

IN PRACTICE:

Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.” 

STUDY DETAILS:

The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.

LIMITATIONS:

This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.

DISCLOSURES:

The authors report no relevant financial relationships.
 

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

TOPLINE:

Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis. 

METHODOLOGY:

Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.

Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.

Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.

Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.

TAKEAWAYS:

DR-TB patients tended to be older than NDR-TB patients.

Isolated plasma exosomes were morphologically characterized as being “close to pure.”

Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.

Protein-protein interaction modeling suggests that downregulated apolipoproteins APOA1, APOB, and APOC1 have a role in mediating DR-TB development through their functions in lipid metabolism and protein transport.

IN PRACTICE:

Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.” 

STUDY DETAILS:

The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.

LIMITATIONS:

This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.

DISCLOSURES:

The authors report no relevant financial relationships.
 

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

TOPLINE:

Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis. 

METHODOLOGY:

Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.

Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.

Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.

Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.

TAKEAWAYS:

DR-TB patients tended to be older than NDR-TB patients.

Isolated plasma exosomes were morphologically characterized as being “close to pure.”

Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.

Protein-protein interaction modeling suggests that downregulated apolipoproteins APOA1, APOB, and APOC1 have a role in mediating DR-TB development through their functions in lipid metabolism and protein transport.

IN PRACTICE:

Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.” 

STUDY DETAILS:

The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.

LIMITATIONS:

This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.

DISCLOSURES:

The authors report no relevant financial relationships.
 

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

The real-world Zephyr 2 study, which assessed benralizumab for effectiveness in treating severe eosinophilic asthma, was extended with an analysis of a larger population stratified into three cohorts of participants who were aged 12 years or older. Pre- and posttreatment data showed an improvement in asthma control for each group.

Immunotherapy with monoclonal antibodies designed to block specific inflammatory pathways is a recommended add-on treatment option for adults to manage severe, uncontrolled eosinophilic-dependent (> 150 cells/µl) and corticosteroid-dependent asthma. One such biologic, benralizumab, targets the interleukin-5 receptor alpha chain (IL-5Rα).

For asthma patients who had previously been treated with benralizumab, there were significant reductions in exacerbation rates in the ZEPHYR 1 study. However, information regarding benefit associated with specific profiles was limited, warranting a larger study to address effectiveness when considering various blood eosinophil counts, prior treatments with other biologics, or benralizumab use for up to 24 months, Donna Carstens, MD, of AstraZeneca, Wilmington, Del., and colleagues write.
 

Study details

In the retrospective cohort Zephyr 2 study, which was published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers retrieved deidentified patient information from medical, laboratory, and pharmacy U.S. insurance claims records from the PatientSource and DiagnosticSource databases and compared asthma exacerbation rates before and after treatment with benralizumab.

Age, asthma diagnosis, number of exacerbations, and number of benralizumab treatment records within specified periods were used to identify a total of 1,795 participants for inclusion in the study. The index date for establishing before-treatment and after-treatment index time intervals of 12 months each was defined as the day after the initial benralizumab treatment occurring between November 2017 and June 2019.

The cohort was stratified into three nonmutually exclusive groups consisting of 349 patients who had switched primarily from either omalizumab or mepolizumab biologics to benralizumab; 429 patients subdivided by closest to the index date blood eosinophil counts of less than 150, greater than or equal to 150, 150-299, less than 300, and greater than or equal to 300, and 419 patients with post data collection extended beyond 12 months to 18 or 24 months.

Similarities in baseline patient characteristics that were were observed across the three cohorts included a mean age range of 51-53 years, preponderance of women (67%-69%), obesity diagnosis (31.5%-32.9%), and a mean Charlson Comorbidity Index of 1.47-1.52. Allergic rhinitis was the most frequently reported (60%-67%) comorbidity, followed by hypertension and gastroesophageal reflex.
 

Effectiveness

Benralizumab was found to be a significantly effective treatment for managing severe eosinophilic asthma for all three evaluated cohorts, as evidenced by reductions in asthma exacerbations post-index, compared with pre-index. Specifically, the exacerbation rate for all five subgroups of the blood eosinophil cohort significantly decreased from the pre-index 3.10-3.55 person per year (PPY) rate to a 1.11-1.72 PPY post-index rate, equivalent to a 52%-64% decrease in exacerbations (P < .001 for all pre-index vs. post-index comparisons).

Comparable reductions also occurred with the cohort in which the biologic treatment was changed to benralizumab. A greater effect was observed when the switch was made from omalizumab to benralizumab with a pre-post PPY rate reduction of 3.25-1.25 (62%) than when the switch was made from mepolizumab (pre-post PPY rate reduction was 3.81-1.78 [53%], but both resulted in significant post-treatment improvements (P < .001).

Results from the extended follow-up analysis cohort showed consistency for significant exacerbation rate decline going from a pre-index rate of 3.38 PPY down to 1.34 PPY (60% rate reduction vs. pre-index) in the first 12 post-index months, continuing to decline to 1.18 PPY (65% reduction) over the following six months (both significant at P < .001).

Likewise, the results from the extended follow-up 24-month subgroup presented significant down trending exacerbation rates from pre-index 3.38 PPY to 1.38 (comparative 59% reduction) for the first 12 months continuing down to 1.08 PPY (68% reduction) over the 12-24 month post-index period (both P < .001). In the first and second 12 post-index months for the 24-month subgroup, 39% and 49% of the patients, respectively, experienced no exacerbations.

Following treatment with benralizumab, in addition to the observed decline in asthma exacerbation rates, the need for concomitant asthma medications was also significantly reduced for all three cohorts.

This retrospective ZEPHYR 2 study contributes evidence supporting the significant effectiveness of benralizumab in improving disease management for “specific subsets of severe asthma patients that are frequently seen in real-world practice and may be excluded from clinical trials,” according to the authors. The treatment resulted in reduced rates of asthma exacerbations with defined standards for hospitalizations, visits to emergency department or urgent care, or outpatient visits with separate exacerbations occurring at greater than or equal to 14 days, as reported in database records. Reduction in the rate of asthma exacerbations when benralizumab is switched for another biologic increases the disease management options for achieving optimal patient care, the authors add.

The authors have financial relationships with AstraZeneca, the source of funding for the study.

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

The real-world Zephyr 2 study, which assessed benralizumab for effectiveness in treating severe eosinophilic asthma, was extended with an analysis of a larger population stratified into three cohorts of participants who were aged 12 years or older. Pre- and posttreatment data showed an improvement in asthma control for each group.

Immunotherapy with monoclonal antibodies designed to block specific inflammatory pathways is a recommended add-on treatment option for adults to manage severe, uncontrolled eosinophilic-dependent (> 150 cells/µl) and corticosteroid-dependent asthma. One such biologic, benralizumab, targets the interleukin-5 receptor alpha chain (IL-5Rα).

For asthma patients who had previously been treated with benralizumab, there were significant reductions in exacerbation rates in the ZEPHYR 1 study. However, information regarding benefit associated with specific profiles was limited, warranting a larger study to address effectiveness when considering various blood eosinophil counts, prior treatments with other biologics, or benralizumab use for up to 24 months, Donna Carstens, MD, of AstraZeneca, Wilmington, Del., and colleagues write.
 

Study details

In the retrospective cohort Zephyr 2 study, which was published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers retrieved deidentified patient information from medical, laboratory, and pharmacy U.S. insurance claims records from the PatientSource and DiagnosticSource databases and compared asthma exacerbation rates before and after treatment with benralizumab.

Age, asthma diagnosis, number of exacerbations, and number of benralizumab treatment records within specified periods were used to identify a total of 1,795 participants for inclusion in the study. The index date for establishing before-treatment and after-treatment index time intervals of 12 months each was defined as the day after the initial benralizumab treatment occurring between November 2017 and June 2019.

The cohort was stratified into three nonmutually exclusive groups consisting of 349 patients who had switched primarily from either omalizumab or mepolizumab biologics to benralizumab; 429 patients subdivided by closest to the index date blood eosinophil counts of less than 150, greater than or equal to 150, 150-299, less than 300, and greater than or equal to 300, and 419 patients with post data collection extended beyond 12 months to 18 or 24 months.

Similarities in baseline patient characteristics that were were observed across the three cohorts included a mean age range of 51-53 years, preponderance of women (67%-69%), obesity diagnosis (31.5%-32.9%), and a mean Charlson Comorbidity Index of 1.47-1.52. Allergic rhinitis was the most frequently reported (60%-67%) comorbidity, followed by hypertension and gastroesophageal reflex.
 

Effectiveness

Benralizumab was found to be a significantly effective treatment for managing severe eosinophilic asthma for all three evaluated cohorts, as evidenced by reductions in asthma exacerbations post-index, compared with pre-index. Specifically, the exacerbation rate for all five subgroups of the blood eosinophil cohort significantly decreased from the pre-index 3.10-3.55 person per year (PPY) rate to a 1.11-1.72 PPY post-index rate, equivalent to a 52%-64% decrease in exacerbations (P < .001 for all pre-index vs. post-index comparisons).

Comparable reductions also occurred with the cohort in which the biologic treatment was changed to benralizumab. A greater effect was observed when the switch was made from omalizumab to benralizumab with a pre-post PPY rate reduction of 3.25-1.25 (62%) than when the switch was made from mepolizumab (pre-post PPY rate reduction was 3.81-1.78 [53%], but both resulted in significant post-treatment improvements (P < .001).

Results from the extended follow-up analysis cohort showed consistency for significant exacerbation rate decline going from a pre-index rate of 3.38 PPY down to 1.34 PPY (60% rate reduction vs. pre-index) in the first 12 post-index months, continuing to decline to 1.18 PPY (65% reduction) over the following six months (both significant at P < .001).

Likewise, the results from the extended follow-up 24-month subgroup presented significant down trending exacerbation rates from pre-index 3.38 PPY to 1.38 (comparative 59% reduction) for the first 12 months continuing down to 1.08 PPY (68% reduction) over the 12-24 month post-index period (both P < .001). In the first and second 12 post-index months for the 24-month subgroup, 39% and 49% of the patients, respectively, experienced no exacerbations.

Following treatment with benralizumab, in addition to the observed decline in asthma exacerbation rates, the need for concomitant asthma medications was also significantly reduced for all three cohorts.

This retrospective ZEPHYR 2 study contributes evidence supporting the significant effectiveness of benralizumab in improving disease management for “specific subsets of severe asthma patients that are frequently seen in real-world practice and may be excluded from clinical trials,” according to the authors. The treatment resulted in reduced rates of asthma exacerbations with defined standards for hospitalizations, visits to emergency department or urgent care, or outpatient visits with separate exacerbations occurring at greater than or equal to 14 days, as reported in database records. Reduction in the rate of asthma exacerbations when benralizumab is switched for another biologic increases the disease management options for achieving optimal patient care, the authors add.

The authors have financial relationships with AstraZeneca, the source of funding for the study.

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

The real-world Zephyr 2 study, which assessed benralizumab for effectiveness in treating severe eosinophilic asthma, was extended with an analysis of a larger population stratified into three cohorts of participants who were aged 12 years or older. Pre- and posttreatment data showed an improvement in asthma control for each group.

Immunotherapy with monoclonal antibodies designed to block specific inflammatory pathways is a recommended add-on treatment option for adults to manage severe, uncontrolled eosinophilic-dependent (> 150 cells/µl) and corticosteroid-dependent asthma. One such biologic, benralizumab, targets the interleukin-5 receptor alpha chain (IL-5Rα).

For asthma patients who had previously been treated with benralizumab, there were significant reductions in exacerbation rates in the ZEPHYR 1 study. However, information regarding benefit associated with specific profiles was limited, warranting a larger study to address effectiveness when considering various blood eosinophil counts, prior treatments with other biologics, or benralizumab use for up to 24 months, Donna Carstens, MD, of AstraZeneca, Wilmington, Del., and colleagues write.
 

Study details

In the retrospective cohort Zephyr 2 study, which was published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers retrieved deidentified patient information from medical, laboratory, and pharmacy U.S. insurance claims records from the PatientSource and DiagnosticSource databases and compared asthma exacerbation rates before and after treatment with benralizumab.

Age, asthma diagnosis, number of exacerbations, and number of benralizumab treatment records within specified periods were used to identify a total of 1,795 participants for inclusion in the study. The index date for establishing before-treatment and after-treatment index time intervals of 12 months each was defined as the day after the initial benralizumab treatment occurring between November 2017 and June 2019.

The cohort was stratified into three nonmutually exclusive groups consisting of 349 patients who had switched primarily from either omalizumab or mepolizumab biologics to benralizumab; 429 patients subdivided by closest to the index date blood eosinophil counts of less than 150, greater than or equal to 150, 150-299, less than 300, and greater than or equal to 300, and 419 patients with post data collection extended beyond 12 months to 18 or 24 months.

Similarities in baseline patient characteristics that were were observed across the three cohorts included a mean age range of 51-53 years, preponderance of women (67%-69%), obesity diagnosis (31.5%-32.9%), and a mean Charlson Comorbidity Index of 1.47-1.52. Allergic rhinitis was the most frequently reported (60%-67%) comorbidity, followed by hypertension and gastroesophageal reflex.
 

Effectiveness

Benralizumab was found to be a significantly effective treatment for managing severe eosinophilic asthma for all three evaluated cohorts, as evidenced by reductions in asthma exacerbations post-index, compared with pre-index. Specifically, the exacerbation rate for all five subgroups of the blood eosinophil cohort significantly decreased from the pre-index 3.10-3.55 person per year (PPY) rate to a 1.11-1.72 PPY post-index rate, equivalent to a 52%-64% decrease in exacerbations (P < .001 for all pre-index vs. post-index comparisons).

Comparable reductions also occurred with the cohort in which the biologic treatment was changed to benralizumab. A greater effect was observed when the switch was made from omalizumab to benralizumab with a pre-post PPY rate reduction of 3.25-1.25 (62%) than when the switch was made from mepolizumab (pre-post PPY rate reduction was 3.81-1.78 [53%], but both resulted in significant post-treatment improvements (P < .001).

Results from the extended follow-up analysis cohort showed consistency for significant exacerbation rate decline going from a pre-index rate of 3.38 PPY down to 1.34 PPY (60% rate reduction vs. pre-index) in the first 12 post-index months, continuing to decline to 1.18 PPY (65% reduction) over the following six months (both significant at P < .001).

Likewise, the results from the extended follow-up 24-month subgroup presented significant down trending exacerbation rates from pre-index 3.38 PPY to 1.38 (comparative 59% reduction) for the first 12 months continuing down to 1.08 PPY (68% reduction) over the 12-24 month post-index period (both P < .001). In the first and second 12 post-index months for the 24-month subgroup, 39% and 49% of the patients, respectively, experienced no exacerbations.

Following treatment with benralizumab, in addition to the observed decline in asthma exacerbation rates, the need for concomitant asthma medications was also significantly reduced for all three cohorts.

This retrospective ZEPHYR 2 study contributes evidence supporting the significant effectiveness of benralizumab in improving disease management for “specific subsets of severe asthma patients that are frequently seen in real-world practice and may be excluded from clinical trials,” according to the authors. The treatment resulted in reduced rates of asthma exacerbations with defined standards for hospitalizations, visits to emergency department or urgent care, or outpatient visits with separate exacerbations occurring at greater than or equal to 14 days, as reported in database records. Reduction in the rate of asthma exacerbations when benralizumab is switched for another biologic increases the disease management options for achieving optimal patient care, the authors add.

The authors have financial relationships with AstraZeneca, the source of funding for the study.

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

A recent Swedish study found that both abdominal and general obesity were independently associated with respiratory illnesses, including asthma and self-reported chronic obstructive pulmonary disease.

Relationships between respiratory conditions with characterized obesity types in adults were assessed using self-report surveys from participants originally enrolled in the European Community Respiratory Health Survey (ECRHS) investigating asthma, allergy, and risk factors. The Respiratory Health in Northern Europe (RHINE) III provides a second follow-up substudy of ECRHS focused on two forms of obesity associated with respiratory illnesses.

Obesity is a characteristic risk factor linked to respiratory ailments such as asthma and COPD. High body mass index (BMI) and waist circumference (WC) provide quantitative measurements for defining conditions of comprehensive general and abdominal obesity, respectively.

Although both types of obesity have been associated with asthma incidence, studies on their independent impact on this disease have been limited. Previous reports on abdominal obesity associated with asthma have been inconsistent when considering sexes in the analysis. Additionally, COPD and related outcomes differed between abdominal and general obesity, indicating a need to discover whether self-reported WC abdominal obesity and BMI-based general obesity are independently associated with respiratory symptoms, early- and late-onset asthma, COPD, chronic bronchitis, rhinitis, and sex, Marta A. Kisiel, MD, PhD, of the department of environmental and occupational medicine, Uppsala University, Sweden, and colleagues write.

In a prospective study published in the journal Respiratory Medicine, the researchers report on a cross-sectional investigation of responses to a questionnaire similar to one utilized 10 years earlier in the RHINE II study. Questions required simple yes/no responses that covered asthma, respiratory symptoms, allergic rhinitis, chronic bronchitis, and COPD. Additional requested information included age of asthma onset, potential confounding variables of age, smoking, physical activity, and highest education level, weight and height for BMI calculation, and WC measurement with instructions and a provided tape measure.

The population of the RHINE III study conducted from 2010 to 2012 was composed of 12,290 participants (53% response frequency) obtained from a total of seven research centers located in five northern European countries. Obesity categorization classified 1,837 (6.7%) participants as generally obese based on a high BMI ≥ 30 kg/m² and 4,261 (34.7%) as abdominally obese by WC measurements of ≥ 102 cm for men and ≥ 88 cm for women. Of the 4,261 total participants, 1,669 met both general and abdominal obesity criteria. Mean age was in the low 50s range and the obese population consisted of more women than men.

Simple linear regression revealed that BMI and WC were highly correlated, and both were associated with tested respiratory conditions when adjusted for confounding variables. Differences with respect to WC and BMI were independently associated with most of the examined respiratory conditions when WC was adjusted for BMI and vice versa. Neither early-onset asthma nor allergic rhinitis were associated with WC, BMI, or abdominal or general obesity.

A significantly high proportion of individuals with general and abdominal obesity experienced a variety of defined respiratory symptoms, and asthma, chronic bronchitis, or COPD. An independent association of abdominal obesity (with or without general obesity) was found to occur with respiratory symptoms, asthma, late-onset asthma, and chronic bronchitis.

After adjusting for abdominal obesity, general obesity showed an independent and significant association with respiratory symptoms, asthma, adult-onset asthma, and COPD. An analysis stratified by sex indicated a significant association of abdominal and general obesity with asthma in women presented as an odds ratio of 1.56 (95% confidence interval, 1.30-1.87) and 1.95 (95% CI, 1.56-2.43), respectively, compared with men, with an OR of 1.22 (95% CI, 0.97-3.17) and 1.28 (95% CI, 0.97-1.68), respectively. The association of abdominal and general obesity with COPD was also stronger in women, compared with men.

The researchers conclude that “both general and abdominal obesity [were], independent of each other, associated with respiratory symptoms in adults.” There is also a distinct difference between women and men for the association of self-reported asthma and COPD with abdominal and general obesity.

The large randomly selected sample size of participants from research centers located in five northern European countries was considered a major strength of this study as it permitted simultaneous adjustment for multiple potential confounders. Several limitations were acknowledged, including absence of data on obstructive respiratory disease severity, WC measurements not being performed by trained staff, and self-reported height and weight measurements.

The authors have disclosed no relevant financial relationships.

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

A recent Swedish study found that both abdominal and general obesity were independently associated with respiratory illnesses, including asthma and self-reported chronic obstructive pulmonary disease.

Relationships between respiratory conditions with characterized obesity types in adults were assessed using self-report surveys from participants originally enrolled in the European Community Respiratory Health Survey (ECRHS) investigating asthma, allergy, and risk factors. The Respiratory Health in Northern Europe (RHINE) III provides a second follow-up substudy of ECRHS focused on two forms of obesity associated with respiratory illnesses.

Obesity is a characteristic risk factor linked to respiratory ailments such as asthma and COPD. High body mass index (BMI) and waist circumference (WC) provide quantitative measurements for defining conditions of comprehensive general and abdominal obesity, respectively.

Although both types of obesity have been associated with asthma incidence, studies on their independent impact on this disease have been limited. Previous reports on abdominal obesity associated with asthma have been inconsistent when considering sexes in the analysis. Additionally, COPD and related outcomes differed between abdominal and general obesity, indicating a need to discover whether self-reported WC abdominal obesity and BMI-based general obesity are independently associated with respiratory symptoms, early- and late-onset asthma, COPD, chronic bronchitis, rhinitis, and sex, Marta A. Kisiel, MD, PhD, of the department of environmental and occupational medicine, Uppsala University, Sweden, and colleagues write.

In a prospective study published in the journal Respiratory Medicine, the researchers report on a cross-sectional investigation of responses to a questionnaire similar to one utilized 10 years earlier in the RHINE II study. Questions required simple yes/no responses that covered asthma, respiratory symptoms, allergic rhinitis, chronic bronchitis, and COPD. Additional requested information included age of asthma onset, potential confounding variables of age, smoking, physical activity, and highest education level, weight and height for BMI calculation, and WC measurement with instructions and a provided tape measure.

The population of the RHINE III study conducted from 2010 to 2012 was composed of 12,290 participants (53% response frequency) obtained from a total of seven research centers located in five northern European countries. Obesity categorization classified 1,837 (6.7%) participants as generally obese based on a high BMI ≥ 30 kg/m² and 4,261 (34.7%) as abdominally obese by WC measurements of ≥ 102 cm for men and ≥ 88 cm for women. Of the 4,261 total participants, 1,669 met both general and abdominal obesity criteria. Mean age was in the low 50s range and the obese population consisted of more women than men.

Simple linear regression revealed that BMI and WC were highly correlated, and both were associated with tested respiratory conditions when adjusted for confounding variables. Differences with respect to WC and BMI were independently associated with most of the examined respiratory conditions when WC was adjusted for BMI and vice versa. Neither early-onset asthma nor allergic rhinitis were associated with WC, BMI, or abdominal or general obesity.

A significantly high proportion of individuals with general and abdominal obesity experienced a variety of defined respiratory symptoms, and asthma, chronic bronchitis, or COPD. An independent association of abdominal obesity (with or without general obesity) was found to occur with respiratory symptoms, asthma, late-onset asthma, and chronic bronchitis.

After adjusting for abdominal obesity, general obesity showed an independent and significant association with respiratory symptoms, asthma, adult-onset asthma, and COPD. An analysis stratified by sex indicated a significant association of abdominal and general obesity with asthma in women presented as an odds ratio of 1.56 (95% confidence interval, 1.30-1.87) and 1.95 (95% CI, 1.56-2.43), respectively, compared with men, with an OR of 1.22 (95% CI, 0.97-3.17) and 1.28 (95% CI, 0.97-1.68), respectively. The association of abdominal and general obesity with COPD was also stronger in women, compared with men.

The researchers conclude that “both general and abdominal obesity [were], independent of each other, associated with respiratory symptoms in adults.” There is also a distinct difference between women and men for the association of self-reported asthma and COPD with abdominal and general obesity.

The large randomly selected sample size of participants from research centers located in five northern European countries was considered a major strength of this study as it permitted simultaneous adjustment for multiple potential confounders. Several limitations were acknowledged, including absence of data on obstructive respiratory disease severity, WC measurements not being performed by trained staff, and self-reported height and weight measurements.

The authors have disclosed no relevant financial relationships.

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

A recent Swedish study found that both abdominal and general obesity were independently associated with respiratory illnesses, including asthma and self-reported chronic obstructive pulmonary disease.

Relationships between respiratory conditions with characterized obesity types in adults were assessed using self-report surveys from participants originally enrolled in the European Community Respiratory Health Survey (ECRHS) investigating asthma, allergy, and risk factors. The Respiratory Health in Northern Europe (RHINE) III provides a second follow-up substudy of ECRHS focused on two forms of obesity associated with respiratory illnesses.

Obesity is a characteristic risk factor linked to respiratory ailments such as asthma and COPD. High body mass index (BMI) and waist circumference (WC) provide quantitative measurements for defining conditions of comprehensive general and abdominal obesity, respectively.

Although both types of obesity have been associated with asthma incidence, studies on their independent impact on this disease have been limited. Previous reports on abdominal obesity associated with asthma have been inconsistent when considering sexes in the analysis. Additionally, COPD and related outcomes differed between abdominal and general obesity, indicating a need to discover whether self-reported WC abdominal obesity and BMI-based general obesity are independently associated with respiratory symptoms, early- and late-onset asthma, COPD, chronic bronchitis, rhinitis, and sex, Marta A. Kisiel, MD, PhD, of the department of environmental and occupational medicine, Uppsala University, Sweden, and colleagues write.

In a prospective study published in the journal Respiratory Medicine, the researchers report on a cross-sectional investigation of responses to a questionnaire similar to one utilized 10 years earlier in the RHINE II study. Questions required simple yes/no responses that covered asthma, respiratory symptoms, allergic rhinitis, chronic bronchitis, and COPD. Additional requested information included age of asthma onset, potential confounding variables of age, smoking, physical activity, and highest education level, weight and height for BMI calculation, and WC measurement with instructions and a provided tape measure.

The population of the RHINE III study conducted from 2010 to 2012 was composed of 12,290 participants (53% response frequency) obtained from a total of seven research centers located in five northern European countries. Obesity categorization classified 1,837 (6.7%) participants as generally obese based on a high BMI ≥ 30 kg/m² and 4,261 (34.7%) as abdominally obese by WC measurements of ≥ 102 cm for men and ≥ 88 cm for women. Of the 4,261 total participants, 1,669 met both general and abdominal obesity criteria. Mean age was in the low 50s range and the obese population consisted of more women than men.

Simple linear regression revealed that BMI and WC were highly correlated, and both were associated with tested respiratory conditions when adjusted for confounding variables. Differences with respect to WC and BMI were independently associated with most of the examined respiratory conditions when WC was adjusted for BMI and vice versa. Neither early-onset asthma nor allergic rhinitis were associated with WC, BMI, or abdominal or general obesity.

A significantly high proportion of individuals with general and abdominal obesity experienced a variety of defined respiratory symptoms, and asthma, chronic bronchitis, or COPD. An independent association of abdominal obesity (with or without general obesity) was found to occur with respiratory symptoms, asthma, late-onset asthma, and chronic bronchitis.

After adjusting for abdominal obesity, general obesity showed an independent and significant association with respiratory symptoms, asthma, adult-onset asthma, and COPD. An analysis stratified by sex indicated a significant association of abdominal and general obesity with asthma in women presented as an odds ratio of 1.56 (95% confidence interval, 1.30-1.87) and 1.95 (95% CI, 1.56-2.43), respectively, compared with men, with an OR of 1.22 (95% CI, 0.97-3.17) and 1.28 (95% CI, 0.97-1.68), respectively. The association of abdominal and general obesity with COPD was also stronger in women, compared with men.

The researchers conclude that “both general and abdominal obesity [were], independent of each other, associated with respiratory symptoms in adults.” There is also a distinct difference between women and men for the association of self-reported asthma and COPD with abdominal and general obesity.

The large randomly selected sample size of participants from research centers located in five northern European countries was considered a major strength of this study as it permitted simultaneous adjustment for multiple potential confounders. Several limitations were acknowledged, including absence of data on obstructive respiratory disease severity, WC measurements not being performed by trained staff, and self-reported height and weight measurements.

The authors have disclosed no relevant financial relationships.

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

Relationships between 22 unique comorbidities and idiopathic pulmonary fibrosis (IPF) were assessed by a bidirectional Mendelian randomization (MR) approach in a retrospective study. Three of the comorbidities that were examined appeared causally associated with an increased risk of IPF.

Researchers used summary statistics of large-scale genomewide association studies (GWAS) obtained from the IPF Genetics Consortium. For replication, they used data from the Global Biobank Meta-Analysis Initiative.

Pulmonary or extrapulmonary illnesses are regularly observed to be comorbidities associated with IPF. Although randomized control trials can provide strong deductive evidence of causal relationships between diseases, they are also often subject to inherent practical and ethical limitations. MR is an alternative approach that exploits genetic variants of genes with known function as a means to infer a causal effect of a modifiable exposure on disease and minimizes possible confounding issues from unrelated environmental factors and reverse causation. Bidirectional MR extends the exposure-outcome association analysis of MR to both directions, producing a higher level of evidence for causality, Jiahao Zhu, of the Department of Epidemiology and Health Statistics, Hangzhou, China, and colleagues wrote.
 

Study details

In a study published in the journal Chest, the researchers reported on direction and causal associations between IPF and comorbidities, as determined by bidirectional MR analysis of GWAS summary statistics from five studies included in the IPF Genetics Consortium (4,125 patients and 20,464 control participants). For replication, they extracted IPF GWAS summary statistics from the nine biobanks from the GBMI (6,257 patients and 947,616 control participants). All individuals were of European ancestry.

The 22 comorbidities examined for a relationship to IPF were identified through a combination of a PubMed database literature search limited to English-language articles concerning IPF as either an exposure or an outcome and having an available full GWAS summary statistic. The number of patients in these studies ranged from a minimum of 3,203 for osteoporosis to a maximum of 246,363 for major depressive disorder.

To estimate causal relationships, single-nucleotide polymorphism selection for IPF and each comorbidity genetic instrument were based on a genomewide significance value (P < 5x10^–8) and were clumped by linkage disequilibrium (r² < 0.001 within a 10,000 kB clumping distance). Evidence from analysis associating each comorbidity with IPF was categorized as either convincing, suggestive, or weak. Follow-up studies examined the causal effects of measured lung and thyroid variables on IPF and IPF effects on blood pressure variables.
 

Convincing evidence

The bidirectional MR and follow-up analysis revealed “convincing evidence” of causal relationships between IPF and 2 of the evaluated 22 comorbidities. A higher risk of IPF was associated with gastroesophageal reflux disease (GERD). Importantly, a multivariable MR analysis conditioning for smoking continued to show the causal linkage between GERD and a higher risk of IPF. In contrast, the genetic liability of COPD appeared to confer a protective role, as indicated by an associated decrease in risk for IPF. The researchers suggest that this negative relationship may be caused by their distinct genetic architecture.

Suggestive evidence

“Suggestive evidence” of underlying relationships between IPF and lung cancer or blood pressure phenotype comorbidities was also found with this study. The MR results give support to existing evidence that IPF has a causal effect for a higher lung cancer risk. In contrast, IPF appeared to have a protective effect on hypertension and BP phenotypes. This contrasted with VTE: On the basis of bidirectional MR analysis, the researchers suggest that VTE was more likely to be a cause rather than a consequence of IPF. Evidence suggestive that genetic liability to hypothyroidism could lead to IPF was also found (International IPF Genetics Consortium, P < .040; MR PRESSO method; and GBMI, P < .002; IVW method).

Limitations

The primary strengths of the study was the ability of MR design to enhance causal inference, particularly when large cohorts for perspective investigations would be inherently difficult to obtain. Several noted limitations include the fact that causal estimates may not be well matched to observational or interventional studies and there was a low number of single-nucleotide polymorphisms available as genetic instruments for some diseases. In addition, there was a potential bias because of some sample overlap among the utilized databases, and it is unknown whether the results are applicable to ethnicities other than those of European ancestry.

Conclusion

Overall, this study showed that a bidirectional MR analysis approach could leverage genetic information from large databases to reveal causative associations between IPF and several different comorbidities. This included an apparent causal relationship of GERD, venous thromboembolism, and hypothyroidism with IPF, according to the researchers. These provide the basis to obtain “a deeper understanding of the pathways underlying these diverse associations” that may have valuable “implications for enhanced prevention and treatment strategies for comorbidities.”

The authors disclosed no relevant financial relationships.

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

Relationships between 22 unique comorbidities and idiopathic pulmonary fibrosis (IPF) were assessed by a bidirectional Mendelian randomization (MR) approach in a retrospective study. Three of the comorbidities that were examined appeared causally associated with an increased risk of IPF.

Researchers used summary statistics of large-scale genomewide association studies (GWAS) obtained from the IPF Genetics Consortium. For replication, they used data from the Global Biobank Meta-Analysis Initiative.

Pulmonary or extrapulmonary illnesses are regularly observed to be comorbidities associated with IPF. Although randomized control trials can provide strong deductive evidence of causal relationships between diseases, they are also often subject to inherent practical and ethical limitations. MR is an alternative approach that exploits genetic variants of genes with known function as a means to infer a causal effect of a modifiable exposure on disease and minimizes possible confounding issues from unrelated environmental factors and reverse causation. Bidirectional MR extends the exposure-outcome association analysis of MR to both directions, producing a higher level of evidence for causality, Jiahao Zhu, of the Department of Epidemiology and Health Statistics, Hangzhou, China, and colleagues wrote.
 

Study details

In a study published in the journal Chest, the researchers reported on direction and causal associations between IPF and comorbidities, as determined by bidirectional MR analysis of GWAS summary statistics from five studies included in the IPF Genetics Consortium (4,125 patients and 20,464 control participants). For replication, they extracted IPF GWAS summary statistics from the nine biobanks from the GBMI (6,257 patients and 947,616 control participants). All individuals were of European ancestry.

The 22 comorbidities examined for a relationship to IPF were identified through a combination of a PubMed database literature search limited to English-language articles concerning IPF as either an exposure or an outcome and having an available full GWAS summary statistic. The number of patients in these studies ranged from a minimum of 3,203 for osteoporosis to a maximum of 246,363 for major depressive disorder.

To estimate causal relationships, single-nucleotide polymorphism selection for IPF and each comorbidity genetic instrument were based on a genomewide significance value (P < 5x10^–8) and were clumped by linkage disequilibrium (r² < 0.001 within a 10,000 kB clumping distance). Evidence from analysis associating each comorbidity with IPF was categorized as either convincing, suggestive, or weak. Follow-up studies examined the causal effects of measured lung and thyroid variables on IPF and IPF effects on blood pressure variables.
 

Convincing evidence

The bidirectional MR and follow-up analysis revealed “convincing evidence” of causal relationships between IPF and 2 of the evaluated 22 comorbidities. A higher risk of IPF was associated with gastroesophageal reflux disease (GERD). Importantly, a multivariable MR analysis conditioning for smoking continued to show the causal linkage between GERD and a higher risk of IPF. In contrast, the genetic liability of COPD appeared to confer a protective role, as indicated by an associated decrease in risk for IPF. The researchers suggest that this negative relationship may be caused by their distinct genetic architecture.

Suggestive evidence

“Suggestive evidence” of underlying relationships between IPF and lung cancer or blood pressure phenotype comorbidities was also found with this study. The MR results give support to existing evidence that IPF has a causal effect for a higher lung cancer risk. In contrast, IPF appeared to have a protective effect on hypertension and BP phenotypes. This contrasted with VTE: On the basis of bidirectional MR analysis, the researchers suggest that VTE was more likely to be a cause rather than a consequence of IPF. Evidence suggestive that genetic liability to hypothyroidism could lead to IPF was also found (International IPF Genetics Consortium, P < .040; MR PRESSO method; and GBMI, P < .002; IVW method).

Limitations

The primary strengths of the study was the ability of MR design to enhance causal inference, particularly when large cohorts for perspective investigations would be inherently difficult to obtain. Several noted limitations include the fact that causal estimates may not be well matched to observational or interventional studies and there was a low number of single-nucleotide polymorphisms available as genetic instruments for some diseases. In addition, there was a potential bias because of some sample overlap among the utilized databases, and it is unknown whether the results are applicable to ethnicities other than those of European ancestry.

Conclusion

Overall, this study showed that a bidirectional MR analysis approach could leverage genetic information from large databases to reveal causative associations between IPF and several different comorbidities. This included an apparent causal relationship of GERD, venous thromboembolism, and hypothyroidism with IPF, according to the researchers. These provide the basis to obtain “a deeper understanding of the pathways underlying these diverse associations” that may have valuable “implications for enhanced prevention and treatment strategies for comorbidities.”

The authors disclosed no relevant financial relationships.

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

Relationships between 22 unique comorbidities and idiopathic pulmonary fibrosis (IPF) were assessed by a bidirectional Mendelian randomization (MR) approach in a retrospective study. Three of the comorbidities that were examined appeared causally associated with an increased risk of IPF.

Researchers used summary statistics of large-scale genomewide association studies (GWAS) obtained from the IPF Genetics Consortium. For replication, they used data from the Global Biobank Meta-Analysis Initiative.

Pulmonary or extrapulmonary illnesses are regularly observed to be comorbidities associated with IPF. Although randomized control trials can provide strong deductive evidence of causal relationships between diseases, they are also often subject to inherent practical and ethical limitations. MR is an alternative approach that exploits genetic variants of genes with known function as a means to infer a causal effect of a modifiable exposure on disease and minimizes possible confounding issues from unrelated environmental factors and reverse causation. Bidirectional MR extends the exposure-outcome association analysis of MR to both directions, producing a higher level of evidence for causality, Jiahao Zhu, of the Department of Epidemiology and Health Statistics, Hangzhou, China, and colleagues wrote.
 

Study details

In a study published in the journal Chest, the researchers reported on direction and causal associations between IPF and comorbidities, as determined by bidirectional MR analysis of GWAS summary statistics from five studies included in the IPF Genetics Consortium (4,125 patients and 20,464 control participants). For replication, they extracted IPF GWAS summary statistics from the nine biobanks from the GBMI (6,257 patients and 947,616 control participants). All individuals were of European ancestry.

The 22 comorbidities examined for a relationship to IPF were identified through a combination of a PubMed database literature search limited to English-language articles concerning IPF as either an exposure or an outcome and having an available full GWAS summary statistic. The number of patients in these studies ranged from a minimum of 3,203 for osteoporosis to a maximum of 246,363 for major depressive disorder.

To estimate causal relationships, single-nucleotide polymorphism selection for IPF and each comorbidity genetic instrument were based on a genomewide significance value (P < 5x10^–8) and were clumped by linkage disequilibrium (r² < 0.001 within a 10,000 kB clumping distance). Evidence from analysis associating each comorbidity with IPF was categorized as either convincing, suggestive, or weak. Follow-up studies examined the causal effects of measured lung and thyroid variables on IPF and IPF effects on blood pressure variables.
 

Convincing evidence

The bidirectional MR and follow-up analysis revealed “convincing evidence” of causal relationships between IPF and 2 of the evaluated 22 comorbidities. A higher risk of IPF was associated with gastroesophageal reflux disease (GERD). Importantly, a multivariable MR analysis conditioning for smoking continued to show the causal linkage between GERD and a higher risk of IPF. In contrast, the genetic liability of COPD appeared to confer a protective role, as indicated by an associated decrease in risk for IPF. The researchers suggest that this negative relationship may be caused by their distinct genetic architecture.

Suggestive evidence

“Suggestive evidence” of underlying relationships between IPF and lung cancer or blood pressure phenotype comorbidities was also found with this study. The MR results give support to existing evidence that IPF has a causal effect for a higher lung cancer risk. In contrast, IPF appeared to have a protective effect on hypertension and BP phenotypes. This contrasted with VTE: On the basis of bidirectional MR analysis, the researchers suggest that VTE was more likely to be a cause rather than a consequence of IPF. Evidence suggestive that genetic liability to hypothyroidism could lead to IPF was also found (International IPF Genetics Consortium, P < .040; MR PRESSO method; and GBMI, P < .002; IVW method).

Limitations

The primary strengths of the study was the ability of MR design to enhance causal inference, particularly when large cohorts for perspective investigations would be inherently difficult to obtain. Several noted limitations include the fact that causal estimates may not be well matched to observational or interventional studies and there was a low number of single-nucleotide polymorphisms available as genetic instruments for some diseases. In addition, there was a potential bias because of some sample overlap among the utilized databases, and it is unknown whether the results are applicable to ethnicities other than those of European ancestry.

Conclusion

Overall, this study showed that a bidirectional MR analysis approach could leverage genetic information from large databases to reveal causative associations between IPF and several different comorbidities. This included an apparent causal relationship of GERD, venous thromboembolism, and hypothyroidism with IPF, according to the researchers. These provide the basis to obtain “a deeper understanding of the pathways underlying these diverse associations” that may have valuable “implications for enhanced prevention and treatment strategies for comorbidities.”

The authors disclosed no relevant financial relationships.

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

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.