This document discusses novel treatment options for asthma, focusing on biologic-based targeted therapies. It summarizes the four approved type-2 targeted biologic therapies that target IL-5 and IgE, as well as IL-4 and IL-13. These target key pathways involved in type-2 inflammation like eosinophil recruitment and activation. Emerging therapies also target other inflammatory pathways like IL-17. Characterization of inflammatory biomarkers and phenotypes helps identify patients that may benefit most from specific targeted therapies.
This document discusses various asthma phenotypes and endotypes. It begins by defining asthma and noting that it is a heterogeneous syndrome rather than a single disease. It then discusses several clinically observed phenotypes categorized by factors like age of onset, severity, triggers, and treatment response. Molecular mechanisms like T-helper type 2 inflammation are discussed and used to define endotypes. Specific phenotypes discussed in more depth include early onset allergic asthma, late onset eosinophilic asthma, aspirin exacerbated respiratory disease, exercise induced asthma, obesity related asthma, and neutrophilic asthma. Biomarkers, genetics, and treatment approaches are covered for each phenotype.
This document discusses asthma phenotypes and endotypes. It begins by describing how cluster analysis of clinical characteristics can group asthma patients into phenotypes. Molecular approaches are evolving to identify specific biological pathways (endotypes) that explain observable phenotypes. Eosinophilic and non-eosinophilic asthma are two major phenotypes. Eosinophilic asthma is characterized by high sputum or blood eosinophil levels and often responds to inhaled corticosteroids or biologics targeting cytokines like IL-5. Non-eosinophilic asthma involves other inflammatory cells like neutrophils. The document reviews cluster analyses and potential endotypes driving different asthma phenotypes.
Asthma is a heterogeneous disease with different phenotypes and endotypes. Severe asthma is a subset of difficult-to-treat asthma that remains uncontrolled despite maximal optimized treatment. Cluster analysis has identified several asthma phenotypes including eosinophilic phenotypes characterized by type 2 inflammation as well as non-type 2 phenotypes. Biomarkers can help identify patients with type 2 inflammation who may benefit from targeted biologic therapies.
This document summarizes information about asthma phenotypes from several sources. It begins by defining asthma as a heterogeneous disease characterized by chronic airway inflammation and variable airflow limitation. Phenotypes are the observable characteristics of a disease, and examples of asthma phenotypes include allergic asthma, non-allergic asthma, and obesity-related asthma. Endotypes are disease subtypes defined by distinct molecular mechanisms. Biomarkers can help identify phenotypes and predict treatment responses. The document then reviews biomarkers and features of eosinophilic versus non-eosinophilic asthma and discusses mechanisms and treatment approaches for different phenotypes.
- Administered questionnaires
- Performed skin prick tests to common aeroallergens
- Collected blood samples for total IgE & specific IgE
FENO measurement:
- Using NIOX MINO ( Aerocrine AB, Solna, Sweden)
- According to ATS/ERS guidelines
JACI. 2011; 127 ( 5) : 1165-72.e5.
Allergic sensitization:
- Positive SPT ( wheal diameter ≥ 3 mm) to at least one allergen
- Or specific IgE ≥ 0.35 kU/L to at least one allergen
Asthma:
1) There is a need for new asthma therapies due to the substantial disease burden and the fact that over half of asthma patients appear to be poorly controlled. Existing therapies like inhaled corticosteroids do not modify the long-term course of the disease.
2) New drugs in development target mechanisms like lipid mediators, cytokines, phosphodiesterase inhibitors, kinase inhibitors, and adhesion molecules. Therapies also aim to develop safer corticosteroids, improve bronchodilation, and modify the allergic response.
3) Immunotherapies and treatments targeting dendritic cells, Tregs, and mast cells also show promise. Bronchial thermoplasty has been shown to be an effective and relatively
This document discusses various asthma phenotypes and endotypes. It begins by defining asthma and noting that it is a heterogeneous syndrome rather than a single disease. It then discusses several clinically observed phenotypes categorized by factors like age of onset, severity, triggers, and treatment response. Molecular mechanisms like T-helper type 2 inflammation are discussed and used to define endotypes. Specific phenotypes discussed in more depth include early onset allergic asthma, late onset eosinophilic asthma, aspirin exacerbated respiratory disease, exercise induced asthma, obesity related asthma, and neutrophilic asthma. Biomarkers, genetics, and treatment approaches are covered for each phenotype.
This document discusses asthma phenotypes and endotypes. It begins by describing how cluster analysis of clinical characteristics can group asthma patients into phenotypes. Molecular approaches are evolving to identify specific biological pathways (endotypes) that explain observable phenotypes. Eosinophilic and non-eosinophilic asthma are two major phenotypes. Eosinophilic asthma is characterized by high sputum or blood eosinophil levels and often responds to inhaled corticosteroids or biologics targeting cytokines like IL-5. Non-eosinophilic asthma involves other inflammatory cells like neutrophils. The document reviews cluster analyses and potential endotypes driving different asthma phenotypes.
Asthma is a heterogeneous disease with different phenotypes and endotypes. Severe asthma is a subset of difficult-to-treat asthma that remains uncontrolled despite maximal optimized treatment. Cluster analysis has identified several asthma phenotypes including eosinophilic phenotypes characterized by type 2 inflammation as well as non-type 2 phenotypes. Biomarkers can help identify patients with type 2 inflammation who may benefit from targeted biologic therapies.
This document summarizes information about asthma phenotypes from several sources. It begins by defining asthma as a heterogeneous disease characterized by chronic airway inflammation and variable airflow limitation. Phenotypes are the observable characteristics of a disease, and examples of asthma phenotypes include allergic asthma, non-allergic asthma, and obesity-related asthma. Endotypes are disease subtypes defined by distinct molecular mechanisms. Biomarkers can help identify phenotypes and predict treatment responses. The document then reviews biomarkers and features of eosinophilic versus non-eosinophilic asthma and discusses mechanisms and treatment approaches for different phenotypes.
- Administered questionnaires
- Performed skin prick tests to common aeroallergens
- Collected blood samples for total IgE & specific IgE
FENO measurement:
- Using NIOX MINO ( Aerocrine AB, Solna, Sweden)
- According to ATS/ERS guidelines
JACI. 2011; 127 ( 5) : 1165-72.e5.
Allergic sensitization:
- Positive SPT ( wheal diameter ≥ 3 mm) to at least one allergen
- Or specific IgE ≥ 0.35 kU/L to at least one allergen
Asthma:
1) There is a need for new asthma therapies due to the substantial disease burden and the fact that over half of asthma patients appear to be poorly controlled. Existing therapies like inhaled corticosteroids do not modify the long-term course of the disease.
2) New drugs in development target mechanisms like lipid mediators, cytokines, phosphodiesterase inhibitors, kinase inhibitors, and adhesion molecules. Therapies also aim to develop safer corticosteroids, improve bronchodilation, and modify the allergic response.
3) Immunotherapies and treatments targeting dendritic cells, Tregs, and mast cells also show promise. Bronchial thermoplasty has been shown to be an effective and relatively
An update on the management of Idiopathic Pulmonary Fibrosis (IPF)Sarfraz Saleemi
This document provides a historical overview and update on the management of idiopathic pulmonary fibrosis (IPF). It discusses the evolution of IPF diagnosis and classification over time based on clinical and pathological criteria. Key risk factors for IPF like older age, family history, smoking and genetics are summarized. The document also reviews prognostic indicators, comorbidities, current pharmacological therapies including pirfenidone and nintedanib, and the multidisciplinary approach to diagnosis and management of IPF.
This document discusses asthma phenotypes and endotypes. It defines asthma as a chronic inflammatory airway disease characterized by variable airflow obstruction and airway hyperresponsiveness. Asthma phenotypes are subtypes defined by clinical characteristics, while endotypes are subtypes defined by underlying pathophysiology and biomarkers. The document describes several asthma phenotypes including early-onset allergic asthma, late-onset eosinophilic asthma, aspirin-exacerbated respiratory disease, exercise-induced asthma, and obesity-related asthma. It also discusses non-Th2 endotypes such as neutrophilic asthma and smoking-related asthma. The document emphasizes moving toward personalized treatment based on individual endotypes.
by
Dr. Khairul Hassan Jessy
MD (Chest Diseases)
Associate Professor, Respiratory Medicine
National Institute of Diseases of the Chest and Hospital (NIDCH)
Mohakhali, Dhaka.
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus in patients with asthma or cystic fibrosis. It occurs in 1-2% of asthmatics and 1-15% of cystic fibrosis patients. Clinical features include recurrent asthma exacerbations, cough, wheezing and blood-stained sputum. Diagnosis is based on clinical criteria and elevated IgE levels. Treatment involves oral corticosteroids, antifungal agents like itraconazole, and omalizumab for severe cases. Prognosis depends on early diagnosis and treatment to prevent lung damage.
Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease caused by an allergic reaction to the fungus Aspergillus, which commonly infects people with asthma or cystic fibrosis. ABPA involves inflammation and scarring of the airways. It is diagnosed based on criteria including asthma, elevated IgE levels, eosinophilia, and chest imaging findings. Treatment involves use of corticosteroids to reduce inflammation, along with antifungal medications. Patients also need to avoid exposure to mold spores.
IPF AND PROGRESSIVE PULMONARY FIBROSIS 2022UPDATE(ATS.pptxAnjanaAnilkumar14
This document provides updates on the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) from the ATS/ERS:
- For IPF, a conditional recommendation was made for transbronchial lung cryobiopsy as an alternative to surgical lung biopsy. No recommendation was given for or against genomic testing. Antacid medications and antireflux surgery are not recommended for treating IPF.
- PPF is defined as worsening symptoms, radiological progression, and physiological progression within a year in an ILD other than IPF with no alternative explanation. A conditional recommendation was made for nintedanib for PPF, and more research on pirfenidone
This document discusses expanding understanding of asthma phenotypes. It defines 9 asthma phenotypes in 3 categories: trigger-induced (allergic, non-allergic, aspirin-exacerbated respiratory disease, infection, exercise-induced), clinical presentation (pre-asthma wheezing in infants, exacerbation-prone), and inflammatory markers (eosinophilic and neutrophilic). Recognizing phenotypes is important for interpreting studies, comparisons between studies, and genetics research correlating phenotype to genotype.
Recent advances in Asthma & COPD by Dr.Tinku JosephDr.Tinku Joseph
This document summarizes recent advances in asthma and COPD presented between January and December 2016. It describes several studies on new drug combinations that increase lung function and quality of life for COPD patients. It also discusses trials of endobronchial valves and coils that improve outcomes for selected patients with severe emphysema. New biologic drugs targeting specific inflammatory pathways in asthma are presented, along with trials of these new therapies.
This document provides an overview of recent advances in asthma treatment. It discusses novel bronchodilators such as magnesium sulfate and potassium channel openers. Immunomodulatory therapies including anti-IgE therapy and specific immunotherapy are also covered. Newer anti-inflammatory drugs that target NF-kB and MAP kinase pathways are mentioned. The document concludes by briefly discussing miscellaneous approaches like cytokine modifiers, chemokine receptor antagonists, CRTH2 antagonists, and antioxidants.
Asthma management phenotype based approachGamal Agmy
Phenotypes and endotypes are approaches to classifying asthma subtypes based on clinical characteristics and underlying biological mechanisms. The document discusses several potential asthma endotypes including:
1) TH2-high endotypes like early-onset allergic asthma characterized by genetics predisposing to TH2 cytokines, biomarkers like elevated IgE and eosinophils, and response to anti-IgE therapy.
2) Late-onset eosinophilic asthma characterized by persistent sputum eosinophilia despite steroids and potential response to anti-IL5 therapy.
3) Aspirin-exacerbated respiratory disease which may be a similar endotype to intrinsic or allergic asthma due to acquired NSA
This document summarizes the clinical application of Omalizumab, a monoclonal antibody treatment for allergic diseases like asthma and rhinitis. It outlines the drug's mechanism of action by binding to IgE, its dosing guidelines based on patient weight and IgE levels, and its safety profile. Several studies are referenced that show Omalizumab's effects like decreasing free IgE, nasal polyp scores, and exacerbation rates. While generally well tolerated, its cost-effectiveness remains debated. In summary, Omalizumab is a novel targeted therapy for severe allergic asthma and diseases, but its use requires careful consideration.
This document discusses asthma-COPD overlap (ACO), where patients exhibit features of both asthma and chronic obstructive pulmonary disease (COPD). It defines the conditions and notes that distinguishing them can be difficult, especially in smokers and older adults. Patients with ACO features experience more exacerbations and poorer outcomes than those with asthma or COPD alone. The document provides guidance on diagnosing and initially treating ACO based on GINA and GOLD guidelines, emphasizing inhaled corticosteroids to reduce exacerbation risk in all patients with chronic airflow limitation. Further research is still needed to better classify and treat ACO phenotypes.
1) Transbronchial cryobiopsy is a bronchoscopic technique that uses extreme cold to obtain biopsy samples and has potential as a safer alternative to surgical lung biopsy for diagnosing interstitial lung diseases.
2) Results from studies show the diagnostic yield of cryobiopsy is around 73% with an overall complication rate of 23%, including pneumothorax in 9.4% of patients and significant bleeding in 14.2%.
3) Guidelines now recommend considering cryobiopsy for suspected idiopathic pulmonary fibrosis when a multidisciplinary team reviews clinical, radiological, and pathological findings.
The document discusses the asthma-COPD overlap (ACO) phenotype. It notes that ACO is not a single disease, but rather represents different clinical phenotypes that likely have different underlying mechanisms. The terminology has changed from "Asthma COPD Overlap Syndrome" to "ACO" to avoid implying it is a single disease. Diagnosing ACO helps identify COPD patients who may benefit from treatment with inhaled corticosteroids. Experts recommend inhaled corticosteroid/long-acting beta agonist combination as first-line therapy for ACO.
Recent advances in the management of pulmonary arterial hypertensionDr Siva subramaniyan
This document summarizes recent advances in the management of pulmonary arterial hypertension (PAH). It discusses the pathophysiology and classification of PAH and outlines treatment approaches including nonspecific supportive therapies, prostacyclin pathway drugs, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and combination therapy regimens. Non-medical therapies like atrial septostomy and lung transplantation are also reviewed. Recent research focuses on restoring BMPR-II signaling, targeting inflammation, and cell-based therapies for PAH.
Pulmonary function testing (spirometry ) Dr Emad efat
Pulmonary function tests (PFTs) such as spirometry help diagnose and monitor respiratory diseases. Spirometry measures expiratory volumes and flow rates through forced inhalation and exhalation into a mouthpiece. For a test to be valid, exhalation must be smooth, continuous for 6 seconds, and meet reproducibility criteria of two largest FVC and FEV1 values within 0.2 L of each other. PFTs can detect restrictive and obstructive lung diseases and assess response to treatment.
- A 70 year old male presented with 10 years of dyspnea and white productive sputum without fever or other URI symptoms. Skin tests were positive for allergens.
- He has been prescribed several inhalers but was referred to determine if he has COPD or asthma.
- The document discusses the differences and similarities between the inflammation seen in COPD versus asthma. COPD typically involves neutrophilic inflammation in small airways and parenchyma while asthma usually shows eosinophilic inflammation, but there can be overlap between the conditions.
This document discusses various asthma phenotypes or endotypes that have been identified based on differences in clinical characteristics, biomarkers and treatment responses. The two main endotypes discussed are TH2-high asthma and non-TH2 asthma. TH2-high asthma includes early-onset allergic asthma, late-onset eosinophilic asthma and exercise-induced asthma. It is characterized by eosinophilia, TH2 biomarkers and good response to corticosteroids and anti-TH2 targeted therapies. Non-TH2 asthma includes obesity-related asthma, neutrophilic asthma and smoking asthma. It has fewer clinical allergies and TH2 biomarkers, and poorer responses to corticosteroids. Distinct clinical features, genetics,
An update on the management of Idiopathic Pulmonary Fibrosis (IPF)Sarfraz Saleemi
This document provides a historical overview and update on the management of idiopathic pulmonary fibrosis (IPF). It discusses the evolution of IPF diagnosis and classification over time based on clinical and pathological criteria. Key risk factors for IPF like older age, family history, smoking and genetics are summarized. The document also reviews prognostic indicators, comorbidities, current pharmacological therapies including pirfenidone and nintedanib, and the multidisciplinary approach to diagnosis and management of IPF.
This document discusses asthma phenotypes and endotypes. It defines asthma as a chronic inflammatory airway disease characterized by variable airflow obstruction and airway hyperresponsiveness. Asthma phenotypes are subtypes defined by clinical characteristics, while endotypes are subtypes defined by underlying pathophysiology and biomarkers. The document describes several asthma phenotypes including early-onset allergic asthma, late-onset eosinophilic asthma, aspirin-exacerbated respiratory disease, exercise-induced asthma, and obesity-related asthma. It also discusses non-Th2 endotypes such as neutrophilic asthma and smoking-related asthma. The document emphasizes moving toward personalized treatment based on individual endotypes.
by
Dr. Khairul Hassan Jessy
MD (Chest Diseases)
Associate Professor, Respiratory Medicine
National Institute of Diseases of the Chest and Hospital (NIDCH)
Mohakhali, Dhaka.
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus in patients with asthma or cystic fibrosis. It occurs in 1-2% of asthmatics and 1-15% of cystic fibrosis patients. Clinical features include recurrent asthma exacerbations, cough, wheezing and blood-stained sputum. Diagnosis is based on clinical criteria and elevated IgE levels. Treatment involves oral corticosteroids, antifungal agents like itraconazole, and omalizumab for severe cases. Prognosis depends on early diagnosis and treatment to prevent lung damage.
Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease caused by an allergic reaction to the fungus Aspergillus, which commonly infects people with asthma or cystic fibrosis. ABPA involves inflammation and scarring of the airways. It is diagnosed based on criteria including asthma, elevated IgE levels, eosinophilia, and chest imaging findings. Treatment involves use of corticosteroids to reduce inflammation, along with antifungal medications. Patients also need to avoid exposure to mold spores.
IPF AND PROGRESSIVE PULMONARY FIBROSIS 2022UPDATE(ATS.pptxAnjanaAnilkumar14
This document provides updates on the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) from the ATS/ERS:
- For IPF, a conditional recommendation was made for transbronchial lung cryobiopsy as an alternative to surgical lung biopsy. No recommendation was given for or against genomic testing. Antacid medications and antireflux surgery are not recommended for treating IPF.
- PPF is defined as worsening symptoms, radiological progression, and physiological progression within a year in an ILD other than IPF with no alternative explanation. A conditional recommendation was made for nintedanib for PPF, and more research on pirfenidone
This document discusses expanding understanding of asthma phenotypes. It defines 9 asthma phenotypes in 3 categories: trigger-induced (allergic, non-allergic, aspirin-exacerbated respiratory disease, infection, exercise-induced), clinical presentation (pre-asthma wheezing in infants, exacerbation-prone), and inflammatory markers (eosinophilic and neutrophilic). Recognizing phenotypes is important for interpreting studies, comparisons between studies, and genetics research correlating phenotype to genotype.
Recent advances in Asthma & COPD by Dr.Tinku JosephDr.Tinku Joseph
This document summarizes recent advances in asthma and COPD presented between January and December 2016. It describes several studies on new drug combinations that increase lung function and quality of life for COPD patients. It also discusses trials of endobronchial valves and coils that improve outcomes for selected patients with severe emphysema. New biologic drugs targeting specific inflammatory pathways in asthma are presented, along with trials of these new therapies.
This document provides an overview of recent advances in asthma treatment. It discusses novel bronchodilators such as magnesium sulfate and potassium channel openers. Immunomodulatory therapies including anti-IgE therapy and specific immunotherapy are also covered. Newer anti-inflammatory drugs that target NF-kB and MAP kinase pathways are mentioned. The document concludes by briefly discussing miscellaneous approaches like cytokine modifiers, chemokine receptor antagonists, CRTH2 antagonists, and antioxidants.
Asthma management phenotype based approachGamal Agmy
Phenotypes and endotypes are approaches to classifying asthma subtypes based on clinical characteristics and underlying biological mechanisms. The document discusses several potential asthma endotypes including:
1) TH2-high endotypes like early-onset allergic asthma characterized by genetics predisposing to TH2 cytokines, biomarkers like elevated IgE and eosinophils, and response to anti-IgE therapy.
2) Late-onset eosinophilic asthma characterized by persistent sputum eosinophilia despite steroids and potential response to anti-IL5 therapy.
3) Aspirin-exacerbated respiratory disease which may be a similar endotype to intrinsic or allergic asthma due to acquired NSA
This document summarizes the clinical application of Omalizumab, a monoclonal antibody treatment for allergic diseases like asthma and rhinitis. It outlines the drug's mechanism of action by binding to IgE, its dosing guidelines based on patient weight and IgE levels, and its safety profile. Several studies are referenced that show Omalizumab's effects like decreasing free IgE, nasal polyp scores, and exacerbation rates. While generally well tolerated, its cost-effectiveness remains debated. In summary, Omalizumab is a novel targeted therapy for severe allergic asthma and diseases, but its use requires careful consideration.
This document discusses asthma-COPD overlap (ACO), where patients exhibit features of both asthma and chronic obstructive pulmonary disease (COPD). It defines the conditions and notes that distinguishing them can be difficult, especially in smokers and older adults. Patients with ACO features experience more exacerbations and poorer outcomes than those with asthma or COPD alone. The document provides guidance on diagnosing and initially treating ACO based on GINA and GOLD guidelines, emphasizing inhaled corticosteroids to reduce exacerbation risk in all patients with chronic airflow limitation. Further research is still needed to better classify and treat ACO phenotypes.
1) Transbronchial cryobiopsy is a bronchoscopic technique that uses extreme cold to obtain biopsy samples and has potential as a safer alternative to surgical lung biopsy for diagnosing interstitial lung diseases.
2) Results from studies show the diagnostic yield of cryobiopsy is around 73% with an overall complication rate of 23%, including pneumothorax in 9.4% of patients and significant bleeding in 14.2%.
3) Guidelines now recommend considering cryobiopsy for suspected idiopathic pulmonary fibrosis when a multidisciplinary team reviews clinical, radiological, and pathological findings.
The document discusses the asthma-COPD overlap (ACO) phenotype. It notes that ACO is not a single disease, but rather represents different clinical phenotypes that likely have different underlying mechanisms. The terminology has changed from "Asthma COPD Overlap Syndrome" to "ACO" to avoid implying it is a single disease. Diagnosing ACO helps identify COPD patients who may benefit from treatment with inhaled corticosteroids. Experts recommend inhaled corticosteroid/long-acting beta agonist combination as first-line therapy for ACO.
Recent advances in the management of pulmonary arterial hypertensionDr Siva subramaniyan
This document summarizes recent advances in the management of pulmonary arterial hypertension (PAH). It discusses the pathophysiology and classification of PAH and outlines treatment approaches including nonspecific supportive therapies, prostacyclin pathway drugs, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and combination therapy regimens. Non-medical therapies like atrial septostomy and lung transplantation are also reviewed. Recent research focuses on restoring BMPR-II signaling, targeting inflammation, and cell-based therapies for PAH.
Pulmonary function testing (spirometry ) Dr Emad efat
Pulmonary function tests (PFTs) such as spirometry help diagnose and monitor respiratory diseases. Spirometry measures expiratory volumes and flow rates through forced inhalation and exhalation into a mouthpiece. For a test to be valid, exhalation must be smooth, continuous for 6 seconds, and meet reproducibility criteria of two largest FVC and FEV1 values within 0.2 L of each other. PFTs can detect restrictive and obstructive lung diseases and assess response to treatment.
- A 70 year old male presented with 10 years of dyspnea and white productive sputum without fever or other URI symptoms. Skin tests were positive for allergens.
- He has been prescribed several inhalers but was referred to determine if he has COPD or asthma.
- The document discusses the differences and similarities between the inflammation seen in COPD versus asthma. COPD typically involves neutrophilic inflammation in small airways and parenchyma while asthma usually shows eosinophilic inflammation, but there can be overlap between the conditions.
This document discusses various asthma phenotypes or endotypes that have been identified based on differences in clinical characteristics, biomarkers and treatment responses. The two main endotypes discussed are TH2-high asthma and non-TH2 asthma. TH2-high asthma includes early-onset allergic asthma, late-onset eosinophilic asthma and exercise-induced asthma. It is characterized by eosinophilia, TH2 biomarkers and good response to corticosteroids and anti-TH2 targeted therapies. Non-TH2 asthma includes obesity-related asthma, neutrophilic asthma and smoking asthma. It has fewer clinical allergies and TH2 biomarkers, and poorer responses to corticosteroids. Distinct clinical features, genetics,
Asthma is a chronic inflammatory disease of the airways that can present as different phenotypes or endotypes. The document discusses two main endotypes: TH2-high and non-TH2. The TH2-high endotype includes early-onset allergic asthma, late-onset eosinophilic asthma, and exercise-induced asthma. It is characterized by atopy, eosinophilia, response to corticosteroids, and biomarkers showing TH2 pathway activation. The non-TH2 endotype includes approximately 50% of asthma patients and its pathobiology is less clear but may involve mixed inflammatory processes beyond TH2 immunity alone.
Asthma and COPD share some similarities in their pathophysiology such as airway obstruction, inflammation, and progressive loss of lung function. However, they also have key differences. Asthma typically causes intermittent airflow obstruction that is often reversible, along with eosinophilic inflammation and airway remodeling. COPD usually results in progressive and irreversible airflow limitation due to emphysema and chronic bronchitis involving neutrophilic inflammation and systemic consequences. While the presence of reversibility does not distinguish the two, their underlying inflammatory processes and structural lung changes differ substantially.
Childhood asthma - etiopathogenesis,clinical manifestations and evaluationLokanath Reddy Mummadi
This document provides an overview of childhood asthma including its definition, epidemiology, etiology, pathogenesis, clinical manifestations, diagnosis and evaluation. Some key points:
- Asthma is a chronic inflammatory airway disease characterized by wheezing, breathlessness, chest tightness and cough.
- Global prevalence has increased 50% per decade, with higher rates in Western countries and urban areas. India has an estimated prevalence of 3%.
- It results from an interaction between genetic and environmental factors such as viruses, allergens, air pollution and tobacco smoke.
- Pathogenesis involves chronic airway inflammation and remodeling driven by T helper 2 cells and eosinophils in response to triggers.
1. Asthma in the elderly presents unique challenges due to immunosenescence and the increased risk of comorbidities like COPD. Diagnosis can be difficult due to underutilization of spirometry and confusion with other conditions.
2. Late-onset asthma is more common than early-onset and may be related to environmental exposures and epigenetic changes. Asthma and COPD often overlap in elderly patients.
3. Management requires consideration of comorbidities, medication adherence issues, and device selection due to physical/cognitive limitations. Proper diagnosis and treatment can reduce exacerbations and hospitalizations in this high-risk population.
Fenótipos e biomarcadores na exacerbação da DPOCFlávia Salame
This study investigated biomarkers in acute exacerbations of chronic obstructive pulmonary disease (COPD) to identify distinct biologic clusters and biomarkers that recognize clinical phenotypes. The study observed 145 COPD patients over 1 year, capturing 182 exacerbations. Four biologic exacerbation clusters were identified: bacterial-, viral-, eosinophilic-predominant, and a "pauciinflammatory" cluster with limited inflammatory changes. 55% of exacerbations were associated with bacteria, 29% with virus, and 28% with sputum eosinophilia. Sputum IL-1β, serum CXCL10, and peripheral eosinophil levels best identified the bacterial, viral, and eosinophilic phenotypes respectively. The study deline
Fenótipos e biomarcadores de exacerbação da DPOCFlávia Salame
This study identified four distinct biologic clusters associated with acute exacerbations of chronic obstructive pulmonary disease (COPD) using cluster analysis of biomarkers:
1) A bacterial-predominant cluster
2) A viral-predominant cluster
3) An eosinophilic-predominant cluster
4) A fourth cluster with limited changes in inflammation termed "pauciinflammatory".
Certain biomarkers were found to best identify the clinical phenotypes associated with these clusters: sputum IL-1β for bacterial exacerbations, serum CXCL10 for viral exacerbations, and peripheral eosinophil percentage for eosinophilic exacerbations. These biomarkers may help direct phenotype-specific treatment of COPD exacerbations
This document discusses the optimal management of severe or refractory asthma. It defines refractory asthma based on medication requirements, symptoms, exacerbations, and airflow limitation. The pathology of refractory asthma involves persistent airway inflammation often with neutrophils and structural changes like increased smooth muscle mass. Treatment involves confirming the diagnosis, treating exacerbating factors, and optimizing standard pharmacotherapy with inhaled corticosteroids and additional controllers. For uncontrolled cases, alternative options like macrolide antibiotics, antifungals, omalizumab, and bronchial thermoplasty may be considered.
The document discusses smoking-related interstitial lung diseases. Cigarette smoke can injure lung cells through oxidative stress and inflammation, potentially leading to fibrosis in some smokers. Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is a rare smoking-related lung condition seen in heavy smokers, with symptoms of cough and wheezing. Physiologic testing may show obstruction, restriction, or normal results. Radiographs often appear normal or show subtle reticulation, especially in lung bases.
This document provides an overview of asthma including its definition, epidemiology, etiology, pathophysiology, clinical manifestations, investigations, and management. It defines asthma as a chronic inflammatory lung disease characterized by variable and recurring symptoms of wheezing, breathlessness, chest tightness, and coughing. Key points include that over 334 million people worldwide currently suffer from asthma, environmental factors like allergens and infections contribute to its development, and treatment involves management of symptoms and inflammation.
This document discusses the shift from generalized to personalized treatment approaches for asthma. It begins with an overview of asthma pathophysiology and generalized treatment targets like mast cell stabilizers, antihistamines, and glucocorticoids. Limitations to generalized approaches include side effects and treatment variability. Developments in understanding the TH2 inflammatory pathway enabled the first personalized treatments like omalizumab targeting IgE. Further developments targeting cytokines like IL-13 and IL-5 showed the greatest benefit in type 2 high phenotypes identified by biomarkers. The conclusion is that generalized asthma treatment is moving towards more personalized approaches using biomarkers and monoclonal antibodies targeting specific inflammatory pathways.
This study analyzed 25 proteins in serum samples from control individuals and those diagnosed with asthma, pneumonia, lung cancer, or COPD using a novel multiplex immunoassay platform called Simple Plex. The platform allowed simultaneous measurement of multiple biomarkers from a small sample volume. Results showed varying levels of the proteins between disease states and controls, with some proteins significantly increased or decreased depending on the specific disease. The study demonstrates the Simple Plex platform can efficiently identify respiratory disease-associated biomarkers in blood samples.
1. The document discusses the history and pathophysiology of acute respiratory distress syndrome (ARDS), including its original description in 1821 and formal naming/definition in 1967.
2. A key development was the use of mechanical ventilation in the 1950s, which extended patient survival from hours to days/weeks and allowed more time for recovery.
3. The role of the nuclear factor κB transcription factor and associated inflammatory cytokines and neutrophils in the pathogenesis of ARDS is described. Uncontrolled inflammation can lead to endothelial and epithelial damage in the lungs.
4. Progression of ARDS is discussed as either resolving or unresolving, with the latter associated with worse outcomes. Corticosteroids are
This document discusses different asthma phenotypes and endotypes. It defines phenotypes as observable characteristics of a disease and endotypes as distinct subtypes defined by underlying mechanisms. Several asthma phenotypes are described, including early-onset allergic asthma characterized by atopy and eosinophilia, late-onset persistent eosinophilic asthma associated with severe exacerbations, and exercise-induced asthma related to TH2 processes. Non-TH2 asthma phenotypes such as obesity-related and neutrophilic asthma are also covered, noting their poor response to corticosteroids and involvement of innate immune responses. Distinguishing phenotypes and endotypes is important for prognosis, treatment targeting, and understanding disease mechanisms.
Bronchial Asthma- Recent advances in management by Dr. Jebin AbrahamJebin Abraham
Bronchial asthma, Asthma phenotypes, newer bronchodilators, personalised medicine in asthma, pharmacogenetics of current drugs, immunotherapy, vaccination, bronchial thermoplasty, surgical management
Asthma is a chronic inflammatory disease of the airways that affects over 300 million people worldwide. It is characterized by airway hyperresponsiveness and reversible airway obstruction. The pathogenesis involves various inflammatory cells and mediators that cause symptoms such as coughing, wheezing, and shortness of breath. Asthma has both genetic and environmental triggers, and can range from mild to severe. Spirometry is used to diagnose and monitor asthma, along with assessing response to treatments. The goals of treatment are asthma control through reducing symptoms and exacerbations.
The document discusses an update on asthma presented by Dr. Joseph A. Aluoch, covering topics such as the heterogeneity of asthma phenotypes, the importance of establishing a diagnosis and differentiating asthma from other conditions, goals of asthma management including improving control and reducing risk of exacerbations, and therapeutic strategies such as patient education.
IPF is a chronic, progressive fibrotic lung disease of unknown cause that primarily affects older adults. It has a characteristic imaging and histological pattern. The document discusses the epidemiology, clinical presentation, risk factors, diagnosis, management, and prognosis of IPF. Pharmacological therapies like nintedanib and pirfenidone can slow lung function decline in IPF patients by about 50% but the disease still carries a poor prognosis with median survival of around 3 years.
This document provides an overview of key aspects of clinical research papers, including their typical structure and components. It outlines the main sections such as the title, abstract, introduction, methods, results, discussion, and references. It also describes important considerations for study design, including defining the study population and ensuring internal and external validity. Common study designs like randomized controlled trials and how to properly implement randomization and blinding are covered.
This document provides an overview of evidence-based medicine (EBM). It defines EBM as integrating the best available research evidence with clinical expertise and patient values. The key steps of EBM are outlined as formulating a clinical question using PICO (population, intervention, comparison, outcome), searching for evidence, appraising research studies, and applying the evidence to clinical problems. Study designs such as randomized controlled trials and systematic reviews are discussed. Methods for critically appraising studies including assessing validity and determining the clinical importance of results are also summarized.
1) The document discusses a lecture on evidence-based medicine (EBM) and critical appraisal.
2) EBM involves integrating the best available research evidence with clinical expertise and patient values. It includes formulating clinical questions, searching for evidence, appraising research, and applying the evidence to patient care.
3) The lecture reviews the principles of EBM and critical appraisal, including how to formulate answerable clinical questions using the PICO framework, search for evidence, and appraise different types of research studies.
This document provides an overview of diffuse parenchymal lung disease (DPLD) and idiopathic interstitial pneumonias (IIPs). It discusses the classification of IIPs including idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and others. It also covers the clinical presentation, diagnostic approach involving history, physical exam, pulmonary function tests, radiological findings on high-resolution CT, and role of bronchoscopy with bronchoalveolar lavage in evaluating these conditions. Key points like reduced diffusing capacity on pulmonary function tests and honeycombing on imaging in IPF
This document provides an overview of scientific writing and research proposals. It discusses types of scientific publications such as journal articles, books, and conference posters. It emphasizes using clear, precise language and proper structure for scientific papers, including titles, introductions, methods, results, and references sections. The document also outlines the key elements of a good research proposal, such as stating the problem, reviewing previous literature, describing the methodology, presenting a timeline and budget, and listing references. Researchers are advised to write proposals that are coherent, informative, and clearly structured to convince readers of the significance and merit of the proposed research.
This document provides information on diffuse parenchymal lung disease (DPLD) and idiopathic interstitial pneumonias (IIPs). It begins with an overview of common IIPs including idiopathic pulmonary fibrosis (IPF), other IIPs, familial IIP, IIP with autoimmune features, and smoking-related ILDs. It then discusses diagnosing other ILDs through clinical, radiological findings and management approaches. Specific ILDs covered include CTD-associated ILDs, diffuse cystic lung diseases like lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, pulmonary alveolar proteinosis, and diffuse alveolar damage
1. The document provides an overview of evidence-based medicine (EBM) and the process of critically appraising research evidence. EBM involves integrating the best available research evidence with clinical expertise and patient values and preferences.
2. The key steps of EBM are outlined, including formulating a clear clinical question using PICO (population, intervention, comparison, outcome), searching for and appraising the evidence, and applying the results to the clinical problem.
3. Users' guides are provided for critically appraising different study designs, focusing on whether the results are valid and assessing the magnitude and precision of the treatment effect. Factors like randomization, blinding, follow-up, and equal treatment of groups
1. Transbronchial biopsy is the least invasive approach to obtain a histologic diagnosis for a 60-year-old man with shortness of breath, a history of smoking, and basilar crackles. Objective parameters like 6MWT, DLCO, FVC, and HRCT can assess progression of the disease. Lung transplantation is the best curative treatment.
2. A 50-year-old current smoker with shortness of breath and cough showing findings on HRCT and PFTs would be diagnosed with RB-ILD based on surgical lung biopsy findings.
3. A 40-year-old man with rapid deterioration and bilateral infiltrates on CXR would be diagnosed with acute eosin
Pneumonia can be categorized as community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP). HCAP refers to patients who received recent healthcare but did not stay overnight in the hospital. CAP occurs in people acquired in the community with an annual rate of 5.16 to 6.11 cases per 1000 persons increasing with age. Streptococcus pneumoniae is the most common worldwide cause of CAP. Pneumonia pathogens can be typical bacteria like S. pneumoniae or atypical organisms such as Legionella spp, Mycoplasma pneumoniae, and Chlamydophila pneumoniae.
This study analyzed 29 cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Saudi Arabia from March to May 2014. Most cases were male Saudi nationals over age 40. Common symptoms were fever, cough and shortness of breath. Patients had abnormal chest imaging and laboratory abnormalities including low white blood cell count. Ten patients (34%) died, generally being older, male smokers with more severe symptoms and worse laboratory and blood gas values. MERS-CoV disproportionately affected health care workers through close contact with infected patients.
Based on the information provided:
- The patient has a UIP pattern on HRCT consistent with IPF.
- His occupational exposure to asbestos 35 years ago could be contributing to the fibrosis.
- His rheumatoid arthritis is seronegative so unlikely the cause.
- A multidisciplinary discussion including review of HRCT, pulmonary function tests and clinical history is needed to determine if he meets criteria for a confident diagnosis of IPF. Given his occupational exposure, other ILDs need to be considered or excluded as well.
The CT scan shows bilateral, basal-predominant reticular opacities and honeycombing. Given the patient's history of asbestos exposure, though brief, the radiological findings are most consistent with a diagnosis of asbestosis. Asbestosis is the correct answer.
This document provides a summary of an presentation on approaches to interstitial lung disease (ILD) and updates in idiopathic pulmonary fibrosis (IPF) management. It begins with an introduction to ILDs and the pulmonary interstitium. It then covers the pathogenesis, classification, epidemiology, clinical assessment including history, exams, tests and tissue sampling, and radiological and pathological findings of ILDs. A significant portion discusses IPF specifically, including prognosis, guidelines for diagnosis, and medical therapies including pirfenidone and nintedanib which have been shown to reduce lung function decline in clinical trials. It concludes with experience using pirfenidone in Saudi Arabia.
Neuromuscular Disorders Respiratory Complications and AssessmentNahid Sherbini
This document discusses respiratory complications and management in patients with neuromuscular disorders. Key points:
- Duchenne muscular dystrophy is the most common childhood muscular dystrophy, causing progressive muscle weakness.
- Respiratory muscle weakness can occur independently of peripheral muscle weakness and should be evaluated through tests like PFTs, MIP, MEP, and cough assessment.
- Non-invasive ventilation may benefit those requiring short term or intermittent support, while invasive ventilation is preferred for acute respiratory failure due to risks of NPPV. Proper respiratory management can extend lifespans.
Hemoptysis is defined as the spitting of blood from the lungs or bronchial tubes. It can be classified based on severity from mild to massive. Common causes include infections like tuberculosis, cancers, vascular abnormalities and vasculitis. Initial management focuses on airway protection, oxygenation and circulation. Bronchoscopy helps identify the bleeding site and allows local measures like lavage, vasoconstrictors and tamponade. For persistent or massive bleeding, bronchial artery embolization or surgery may be needed. Precise localization through CT and arteriography guides definitive treatment.
The national lung screening trial /Nahid SherbiniNahid Sherbini
The National Lung Screening Trial (NLST) compared low-dose CT screening to chest x-ray (CXR) screening for lung cancer in high-risk individuals. Over 53,000 participants were randomized to receive either low-dose CT or CXR screening annually for three years. The primary endpoint was lung cancer mortality. An interim analysis found that low-dose CT screening reduced lung cancer mortality by 20% compared to CXR, with fewer advanced stage cancers detected in the CT group. However, the false positive rate was high at around 95% for both screening methods.
Evaluation of preoperative pulmonary risk By Nahid SherbiniNahid Sherbini
- Pulmonary complications are a major cause of postoperative morbidity and mortality. The risk depends on patient-related factors like age, smoking history, COPD, asthma, obesity, sleep apnea, and heart failure as well as procedure-related factors like the surgical site and duration of anesthesia.
- A thorough preoperative evaluation involves reviewing the patient's history, performing a physical exam, and testing like arterial blood gases, chest x-ray, and pulmonary function tests to determine their risk level. Assigning a risk level helps guide risk reduction strategies in high risk patients.
- Pulmonary complications are a major cause of postoperative morbidity and mortality. The risk depends on patient-related factors like age, smoking history, COPD, asthma, obesity, sleep apnea, and heart failure as well as procedure-related factors like the surgical site and duration of anesthesia.
- A thorough preoperative evaluation involves reviewing the patient's history, performing a physical exam, and testing like arterial blood gases, chest x-ray, and pulmonary function tests to determine their risk level. Assigning a risk level helps guide risk reduction strategies in high risk patients.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
1. ASTHMA: A STEP TOWARD
PERSONALIZED TREATMENT AND NEW
THERAPIES
Dr Nahid Sherbini
Consultant Pulmonologist
2. Objectives
Explain how phenotypic, endotypic, and genetic characteristics account into
personalized management of asthma
Characterization of Inflammatory Pathways
and Biomarkers
Compare biologic agents currently available or emerging in the treatment of
severe asthma
4. Heterogeneity in Asthma— Not a New
Concept
Spector SL, Farr RS. J Allergy Clin Immunol. 1976 May;57(5):499-511.
.
5. Clinical Differentiation of Asthma Into Subgroups
Back to Asthma Basics
◦Definition
◦ Airway hyperresponsiveness
◦ Airflow limitation, which is
spontaneously variable or reversible
with bronchodilators
◦Diagnosis
◦ Based on a combination of clinical
symptoms and physiologic
abnormalities
6. Basis for Disease is Present Early and
Evolves Throughout Life
Genetics
Proteins, biochemical pathways, cells
Physiology, symptoms
, environment
7. What is personalised medicine?
◦ an approach to treating and preventing disease by taking into consideration the
individual variability in genes, environment and lifestyle for each subject.
“the right patient with the right drug at the right time”
8. Genetic profiling
◦ – to provide “the right treatment to the right patient at the
right time” – is dependent on genetic variation and gene–
environmental interactions, which need to be understood
for each individual patient.
9. “precision medicine”
◦ Precision medicine,
◦ Stratified medicine
◦ Or targeted medicine.
◦ These will ultimately lead to the development of targeted therapeutics.
The concept of P4 medicine (predictive, preventive personalised and participatory)
developed by Leroy Hood
10.
11.
12.
13. Fitting the Individual Into a Larger Group
What is a phenotype?
The outward manifestation of a disease state related to both genetics and environmental influences
What is an endotype?
A phenotype of a disease state that has been well-characterized with regard to pathophysiologic
mechanisms
14. Rational of Classifying Asthma Phenotypes
Asthma is characterized by variety of
◦ Clinical features
◦ Disease onset
◦ Atopic history
◦ Disease progression
◦ Pathophysiologic Pathways
◦ Airway inflammation
◦ Molecular pathways
◦ Response to treatment
15. Asthma is Not a Clinically
Homogeneous Condition
◦Multiple areas of difference:
◦ Clinical presentations
◦ Physiological characteristics
◦ Responses to therapy
◦Time of asthma development is a key factor:
◦ Children—relatively homogeneous with a strong personal
and family allergic history of atopy
◦ Adults—very mixed group of patients
16. Separation of Asthma Into Clinical Phenotypes
◦Cluster analysis -------------more specification
◦ Clinical characteristics (gender, age of onset, severity)
◦ Physiology (lung function, airway hyperresponsiveness)
◦ Triggers (allergens, tobacco, occupation)
◦ Sputum inflammatory cells (eosinophils, neutrophils)
17. Severe Asthma Phenotypes
OCS=oral corticosteroids; SARP=severe asthma research program; U-BIOPRED=unbiased biomarkers in prediction of respiratory disease outcomes.
1. Chung KF et al. J Intern Med. 2016;249:192-204. 2. Moore WC et al. Am J Resp Crit Care Med. 2010;181:315-323.
Cluster analysis of clinical, physiological and inflammatory features 1,2
SARP1,2
Adult onset
nonatopic
asthma
Hyper-
eosinophilic
adult onset
asthma
Childhood
onset allergic
asthma
Adult onset
atopic
asthma
Severe Asthma Research Program
18. Phenotypes/Endotypes of Severe Asthma
Phenotype Clinical/Physiologic Characteristics
Early-onset allergic History of food allergy, atopic dermatitis and
allergic rhinitis
Late-onset
minimally atopic
eosinophilic
Chronic rhinosinusitis/nasal polyps
Severe airway obstruction
Subset = AERD
Late-onset
non-eosinophilic
Poorly characterized
May have significant LRT infection and/or GERD
AERD, Aspirin-exacerbated respiratory disease; eNO, exhaled nitric oxide; IgE, Immunoglobulin E; LRT, lower respiratory tract
Wenzel SE. Nat Med. 2012;18:716-725.
Trejo Bittar HE, et al. Ann Rev Pathol Mech Dis. 2015.10:511-545.
Corren J. Discov Med. 2013;15:243-249.
19. Phenotypic Clusters in Adults With Asthma
Show Significant Differences
Cluster Age/Obesity Allergy Severity
1 Early Yes Mild
2 Early Yes Moderate
3 Late, obese No Severe
4 Early Yes Severe
5 Late No Severe
Moore WC, et al. J Allergy Clin Immunol. 2010; 181:315–23.
20. Other Features Considered in Severe
Asthma Phenotypes
◦ Glucocorticoid resistance
◦ Adult onset nonatopic asthma
◦ Frequent exacerbation (30%)
◦ 2-3 exacerbations per year
◦ Greater obstructive defect
◦ Eosinophilic inflammation
◦ More comorbidities
Severe Asthma Research Program
A National Institutes of Health/ National Heart, Lung & Blood Institute sponsored network
24. Characterization of Inflammatory Pathways
and Biomarkers
Type 2 (T2)—50% to 70% Non-type 2—30% to 50%
Main cytokines = IL-4, IL-5, IL-13 Cytokines and cells not well-characterized;
may involve IL-8 IL-23 IL-17, GM-CSF ,
TNF
Cell sources = Th2 cells, IL-C2 cells, mast
cells
Frequently related to bronchial infection
Variable airway, tissue and blood
eosinophilia and eNO; leukotrienes in AERD
No increase in eosinophils, eNO; may have
increase in sputum PMNs
Large portion have elevated total IgE and
specific IgE
Typically do not have elevated IgE or
relevant specific IgE
eNO, exhaled nitric oxide; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IgE, Immunoglobulin E; PMN,
polymorphonuclear; Th2, T helper 2
25. Biomarkers for personalised asthma:
current and future biomarkers
◦ Biomarkers are important in asthma in order to define the phenotypes that
constitute the whole range of asthma and to identify patients who will respond to
specific therapies.
◦ A biomarker is defined as a characteristic that can be measured and evaluated as an
indicator of normal or pathological biological processes or the biological response to
a therapeutic intervention.
26. What Makes an Ideal Biomarker?
◦ Reproducible
◦ Accurate
◦ Accessible
◦ Correlates with severity of disease at baseline and reflects responsiveness to therapy
◦ Reasonable cost
◦ Noninvasive
27. Utilization of Inflammatory Markers
◦ Inflammatory markers have been shown to play an important
role in predicting severity and responsiveness to therapies
◦ Inflammatory profile may be characterized by:
◦ Genotyping
◦ Cytokines
◦ Cell populations (in airway, tissue and blood)
◦ Exhaled gases (nitric oxide)
◦ Serum proteins (periostin, DPP4)
DPP4, dipeptidyl peptidase-4
28. Eosinophil as an Inflammatory Biomarker
◦Variable numbers of blood and airway eosinophils are
present in patients with type 2 cytokine profiles
◦ Likely relates to level of type 2 activation
◦Eosinophils in blood and airway are correlated with:
◦ Frequency of asthma exacerbations
◦ Degree of airflow limitation
◦ Presence and severity of chronic rhinosinusitis/nasal polyposis
Peters SP, et al. J Allergy Clin Immunol. 2014;2(6):650-2.
29. Sputum and Blood Eosinophils Correlate With
Bronchial Type-2 Cytokine mRNA
Parameter Threshold
Value
Sensitivity Specificity
Sputum
eosinophils
2% 54% 100%
0.8% 84% 100%
Blood eosinophils 230 cells/mcl 76% 100%
Peters SP, et al. J Allergy Clin Immunol. 2014;2(6):650-2.
30. Blood Eosinophil Counts Correlate With
Risk of Asthma Exacerbations
Eosinophil Stratum Severe Exacerbations Relative Risk
201–300 cells per µL (n=25,882) .8
301–400 cells per µL (n=15,030) 1.1
401–500 cells per µL (n=8659) 1.2
501–600 cells per µL (n=4928) 1.4
601–700 cells per µL (n=2726) 1.6
701–800 cells per µL (n=1631) 1.5
801–900 cells per µL (n=947) 1.6
901–1000 cells per µL (n=1019) 2.1
>1000 cells per µL (n=1019) 2.4
Adapted from Price DB, et al. Lancet Respir Med. 2015;3:849-858.
33. Sputum Neutrophil as an Inflammatory Biomarker
◦ Sputum neutrophilia (>60% of total WBC) present in subgroup of asthmatics
◦ Most often in combination with eosinophils but may occur as isolated neutrophilia
◦ Factors that influence PMN count in sputum:
◦ Use of inhaled corticosteroids
◦ Air pollution
◦ LRTI
◦ Sensitization to fungi
◦ GERD
◦ Found to correlate with higher levels of asthma severity
34. Exhaled NO as a Marker of Type 2 Pathway
◦ eNO is produced by NO synthase in respiratory epithelium under direct control of IL-13 and possibly
other factors
◦ Often, but not always, correlated with sputum/blood eosinophil
numbers
◦ Is a moderately reproducible marker of Th2 phenotype
◦ Type 2 biomarkers predictive of responsiveness to ICS
◦ NO >33 ppb positive response to ICS
◦ NO <22 ppb successful discontinuation of ICS
ICS, inhaled corticosteroid; eNO, exhaled nitric oxide; ppb, parts per billion
35. Serum Proteins
◦ Cytokine protein measurements in blood and sputum are
difficult
◦ Airway IL-13 found to correlate with epithelial proteins—
periostin and dipeptidyl peptidase-4 (DPP4):
◦ Secreted by airway epithelium into blood
◦ Initial studies showed good correlation with IL-13 and predictive of
response to anti-IL-13 agents
◦ Uncertain whether these tests will be employed as biomarkers
in the future
36. Novel Treatment Options
Review the latest biologic-based targeted therapies.
Differentiate between biologic agents, focusing on
mechanism of action, as well as the latest safety and efficacy
data of targeted therapy.
37. Pathogenic Mechanism
◦ Study of pathophysiology of asthma, especially type 2 and eosinophilic inflammation led to latest
targeted interventions
◦ Targeted therapies shown to reduce number of exacerbations
◦ 4 approved, type-2 targeted-biologic therapies that target IL-5 and IgE and one that is in
development IL-4/-13
Bagnasco D, et al. Front Med. 2017;4:135; Farne HA, et al. Cochrane Database Syst Rev. 2017;9:CD010834.
39. Targeted Pathways for Biologic Therapies
Targeted Pathways Type 2
IgE Inhaled allergens stimulate production of IgE by B lymphocytes and bind to mast cells
degranulation
IL-5
Pro-eosinophilic cytokine; cytokine that regulates proliferation, maturation, migration, and
effector functions of eosinophils
IL-4
IL-13
Cytokine found in increased levels in airways and sputum of asthma patients and involved
in eosinophil trafficking and B cell production of IgE
Cytokine associated with eosinophil trafficking and production of eNO from epithelial cells
TSLP
Novel target; epithelial-cell-derived cytokine; drives allergic inflammatory responses by
activating dendritic cells and mast cells
Non Type 2 Inflammatory Pathways
IL-17 Cytokine produced by Th17 cells; plays important role in the immunologic responses seen
in asthma
CXCR2 Potent chemo-attractant for neutrophils; under investigation in asthma and COPD
CSCR2, Chemokine receptor 2; IgE, Immunoglobulin E; Th2, T helper 2 cells; TSLP, Thymic stromal lymphopoietin
Wechsler ME. Respir Care. 2018;63:699-707.
40. Approved Biologics and Targets
Target
Antigen
Agent
(FDA
Approved)
Mode of
Delivery Safety and Adverse Events Clinical Data Trial Results
IL-5Ra Benralizumab
(Nov 2017)
Injectable Safe and well tolerated.
Most common AEs: nasopharyngitis;
asthma worsening (CALIMA: 14% Q4W
group, 11% Q8W, 15% placebo arm)
(SIORCCO: 13% vs 19% of placebo-
treated)
Approved for use in
eosinophilic asthma. For
patients with blood
eosinophil count of at
least 300/mL.
CALIMA trial (n=1306): Q4W & Q8W
regimens decreased exacerbations by
36% and 28%, respectively; lowered blood
counts1
SIROCCO trial (n=1,205): 48 weeks 1 of 3
add-on SQ; exacerbations reduced 45% &
51% in Q4W and Q8W; Exacerbations
decreased 17%–30% in patients with
>300 blood eosinophils/μL2
IL-5 Reslizumab
(April 2017)
Intravenous
(3 mg/kg)
monthly
Safe and well tolerated in patients
exposed
>2 yr 3
Infusion-site reactions uncommon (<2%).
Most common AEs: nasopharyngitis,URTI ,
sinusitis, influenza, and headache. 2 in
reslizumab grp anaphylactic reactions.
Approved for
maintenance treatment
w/severe exacerbations,
despite on current
asthma medications.
For patients with blood
eosinophil count of at
least 400/mL.
BREATH program: 4 studies (n=1656),
serum eosinophil counts reduced (mean
diff vs placebo: −476.83, 95% CI −499.32
to −454.34)3
Reduced number of eosinophils in the
blood and lungs; decreased blood
eosinophils.3
Asthma Control Questionnaire 5 (ACQ5); LABA, long-acting β-agonists; LD, loading dose; mL, microliter; SQ, subcutaneous; QoL, quality of life
1. Fitzgerald JM, et al; Lancet. 2016;388:2128–2141. 2.Bleecker ER, et al. Lancet. 2016;388:2115–2127. 3. Cazzola M, et al. Expert Opin Drug Saf. 2018;17:429-435.
41. Approved Biologics and Targets (continued)
Target
Antigen
Agent
(FDA
approved)
Mode of
Delivery Safety and Adverse Events Clinical Data Trial Results
IL-5
Mepolizumab
(Nov 2015)
Injectable Safe and well tolerated
Most common AEs and SAEs:
injection-site reactions (12%),
infections (7%), systemic reactions
(3%), serious cardiac, vascular,
thromb events (3%); malignancies
(2%), serious ischemic events (<1%)
First long-term safety data
reported for IL-5; Approved for
patients with blood eosinophil
count of at least 150/mL.
COLUMBA trial (n=347): Pts treated w/100 mg SQ every 3-4
wks for 3.5–4.5 yrs; 61% decrease in exacerbation rate, 78%
reduction in blood eosinophils by wk 4, sustained; 1/3
experienced no exacerbations; ACQ5 improved.1
Dream study: reduced exacerbations by 40-60%; 50%
reduction in CS. Blood eosinophil counts decline by 75%
within a month, failure to achieve decrease raises questions
about biologic efficacy in patient; FeNO minimally
reduced.2,3
anti-IgE
Ab
Omalizumab
(2003)
Injectable AEs (80.4% vs 79.5%) and SAEs (9.3%
vs 10.5%) were similar in the
omalizumab and placebo groups,
respectively.
Note concerns about anaphylaxis
and cardiovascular risk and lack of
efficacy in some patients
Approved for patients with
total serum IgE level >30 IU/
mL; for moderate-to-severe
persistent allergic asthma
whose asthma symptoms are
not controlled by ICS.
MoA: Binds to free IgE;
prevents IgE from binding to
high-affinity receptors
Hanania et al. (n=850): 48 wks decreased exacerbations
25%; improved asthma QoL scores. Overall trial history:
reduced asthma exacerbations, serum-free IgE, ICS dose;
QOL improved.4
Anti-IL-4/
-13
Dupilumab
(FDA approved
for asthma
indication
October 19,
2018.)
Injectable Safe and well tolerated.
AEs similar across groups: injection-
site reactions (17% vs 8% placebo,
respectively), back pain (4%, both
groups), eosinophilia (4%
vs 1%, respectively).
Approved for patients with
asthma previously treated with
medium-dose or high-dose ICS
and LABAs.
Consider for patients with
allergies , elevated IgE,
eosinophilia, or high eNO
levels.
Quest trial (n=1902); 4 grps 200 mg (400 mg LD) and 300 mg
(600 mg LD) every other week; 60–80% reduction in
exacerbations; Reduced FeNO and IgE levels;. Improved lung
function and reduced dependence on OCS.5,6
1. Ortega H, et al. Presented at ATS 2018. Abstract A1367; 2. Bel EH, et al. N Engl J Med. 2014;371:1189-97; 3. Pavord ID, et al. Lancet. 2012; 380:651-9; 4.Hanania
NA, et al. Ann Intern Med. 2011;154:573-82; 5. Castro M, et al. N Engl J Med. 2018;378:2486-2496; 6. Wenzel S, et al. Lancet. 2016;388:31-44.
42. Farne et al Cochrane Review
◦ 13 studies reviewed Cochrane database; n=6000
◦ Compared agents targeting anti-IL-5 or anti-IL-5Rα (i.e., mepolizumab,
reslizumab, and benralizumab) against placebo
◦ Showed all IL-5 therapies reduced rates of clinically significant asthma exacerbation by ~50% in group with
severe eosinophilic asthma
◦ Supports use of anti-IL-5 treatments as an adjunct to standard of care in people with severe eosinophilic
asthma and poor control
◦ Noted limited evidence for improved HRQoL scores and lung function
Farne HA, et al. Cochrane Database Syst Rev. 2017;9:CD010834.
44. Stepwise-Approach:
◦ When confirming diagnosis of severe asthma, critical to:
◦ Assess Adequate Use of ICS
◦ Assess inhaler technique and adherence
◦ Issues with ICS account for 50% to 80% of uncontrolled asthma
◦ Assess coexisting conditions, risk factors, and triggers
◦ Review FeNO after ICS therapy
Israel E, et al. N Engl J Med. 2017;377:965-976.
46. Additional Nonbiologic Treatment Options
◦Active against atypical bacteria and have anti-inflammatory
activity
◦ Macrolide antibiotics, add-on therapy: azithromycin (oral)
◦ Ketolide antibiotic: telithromycin
Gibson PG, et al. Lancet. 2017;390(10095):659-668.
47. AMAZES Study
Effect of azithromycin on asthma exacerbations
◦ N=420
◦ Randomly assigned (1:1) to receive azithromycin 500 mg or placebo 3 times per week for 48 weeks
◦ Azithromycin reduced asthma exacerbations; significantly improved asthma-related quality of life
◦ Reported beneficial in eosinophilic and noneosinophilic subtypes
Gibson PG, et al. Lancet. 2017;390(10095):659-668.
48. Bronchial Thermoplasty
◦ For adult patients whose asthma remains
uncontrolled.
◦ Note: little understood regarding appropriate
patient selection
◦ Method to decrease smooth muscle mass by
applying excess heat in the airways with radio-
frequent energy
49. Bronchial Thermoplasty
◦Asthma Intervention Research2 (AIR2) Trial
◦ n=288 adults
◦ Safe therapy
◦ Study shown to improve asthma quality of life and reduce
exacerbations
◦ 5 year long-term study showed sustained reduction in
exacerbations, ER visits and hospitalizations
◦ Real world studies have shown sustained efficacy out to 3 years
Goorsenberg AWM, et al. Respiration. 2018:1-7.
51. Tezepelumab—Phase 2b Clinical Trial Data
◦ Tezepelumab, TSLP inhibitor
◦ Study (n=584) showed reduced blood eosinophil counts, FeNO levels, and total serum IgE levels
◦ Low dose (70 mg once every 4 weeks), medium dose (210 mg once every 4 weeks), or high dose (280 mg
once every 2 weeks)
◦ Reduced exacerbations across all patient groups both type 2 and non-type asthma by ~70%
◦ More Patients in tezepelumab groups were demonstrated to achieve well-controlled (27.2% in tezepelumab
overall vs 14.9% in placebo) or partially controlled (22.0% in tezepelumab overall vs 19.1% in placebo) asthma
at 52 weeks vs placebo
◦ Recruiting patients for tezepelumab, phase 3 (ClinicalTrials.gov; NCT03347279)
Corren J, et al. N Engl J Med. 2017;377(10):936-946. Corren J, et al. J Allergy Clin Immunol. 2018;141(2):AB80. ClinicalTrials.gov; NCT02054130.
52. Emerging Target-Specific Therapies
◦ CRTh2 oral inhibitors in development
◦ Fevipiprant, ARRY 502, BI-671800, OC000459
◦ Promising results in cellular, functional, clinical outcomes; acceptable safety
◦ Shows decrease in PGD2-mediated eosinophil migration
◦ Improve lung function and symptoms in patients with eosinophilic asthma
◦ CxCR2 antagonist decreases IL-8 levels; shown promise in early trials
◦ Navarixin reduced sputum and blood neutrophils; trend toward better asthma control based on ACQ, but no
significant change in FEV1
◦ IL-6—potential biomarker of systemic inflammation along with C-reactive protein; shown to be increased in a
subset of patients with severe asthma, particularly severe asthma associated with obesity
◦ IL-17 Brodalumab didn’t achieve clinical benefit but perhaps not the right patients were selected
◦ IL-33—no data yet, but in clinical development
◦ IL-25—no data, yet
ACQ, Asthma Control Questionnaire; CRTh2, chemoattractant receptor homologue expressed on Th2 cells (alternative name DP2); FEV1 , forced expiratory volume in
one second; PGD2, Prostaglandin D2
George L, et al. Ther Adv Chronic Dis. 2016;7:34-51; Santus P, et al. Expert Opin Investig Drugs. 2016;25(9):1083-92; Naik SP, et al. J Asthma. 2017;54(6):584-593.
54. What is your approach to treating patients
with severe asthma?
◦Treat with personalized approach
◦Identify asthma type by phenotype or endotype
◦Treat with the most appropriate therapeutic strategy based
on underlying asthmatic mechanism of inflammation
55. What are the strategies to maximize standard
medical therapies in asthma management?
◦Biologics (novel therapies)
◦Bronchial Thermoplasty
56. What can we achieve with biologics?
◦Reduced exacerbation
◦Reduced steroid dose and side effects
◦Improved symptoms and quality of life
◦Disease modification to prevent asthma over long term
57. Which therapy is best for a specific patient?
How do you choose between biologics?
• Biomarkers help predict therapeutic responses
◦ Phenotype patients and choose most appropriate therapy
◦ Goal of personalized or “precision medicine”
◦ Potential need to measure different biomarkers to determine
endotype/phenotype
George L, et al. Ther Adv Chronic Dis. 2016;7:34-51.
58. What are the long-term health risks with
biologic therapy?
◦Real, long-term consequences of eosinopenia are not
known
◦Do not know if biologics provides long-term safe control of
severe refractory eosinophilic asthma
Cazzola M, et al. Expert Opin Drug Saf. 2018;17(4):429-435.
59. Persistent Questions
◦ How do we decide between biologics that target same pathways?
◦ How do we decide between biologics for patients that meet criteria for different therapies?
◦ How long should we treat?
◦ Should we be combining biologics?
◦ Should we be giving biologics earlier in treatment ?
60. Takeaways
◦ Today we have a better understanding of underlying disease mechanisms
◦ Use biomarkers and endotypes to personalize treatment approach
◦ Advances in treatment of severe asthma include:
◦ Evidence-based treatment guidelines
◦ Evidence about phenotypic patterns
◦ Increased understanding of biomarkers and use in treatment selection
◦ Screen patients to choose the right therapy for the right patient
◦ Biomarkers are needed to identify most appropriate therapeutic strategy to a specific patient
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