Asthma

name: Asthma
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-16T20:19:38Z'
category: Complex
parents:
- Respiratory Disease
- Chronic Inflammatory Disease
has_subtypes:
- name: Allergic Asthma
  description: Triggered by allergens such as pollen, pet dander, or dust mites.
  evidence:
  - reference: PMID:32037107
    reference_title: "Allergic Endotypes and Phenotypes of Asthma."
    supports: SUPPORT
    snippet: Allergic asthma is defined as asthma associated with sensitization to aeroallergens, which leads to asthma symptoms and airway inflammation.
    explanation: The literature explicitly states that allergic asthma is triggered by allergens.
  - reference: PMID:24925403
    reference_title: "Mites and allergy."
    supports: SUPPORT
    snippet: Allergic diseases triggered by mite allergens include allergic rhinoconjunctivitis, asthma, atopic dermatitis and other skin diseases.
    explanation: This literature confirms asthma can be triggered by mite allergens, consistent with the definition of allergic asthma.
  - reference: PMID:32589303
    reference_title: "The effects of climate change on respiratory allergy and asthma induced by pollen and mold allergens."
    supports: PARTIAL
    snippet: Respiratory health can be particularly affected by climate change, which contributes to the development of allergic respiratory diseases and asthma.
    explanation: The document indicates that climate change contributes to the development of asthma, supporting the statement.
  - reference: PMID:30725285
    reference_title: "N/OFQ-NOP System and Airways."
    supports: SUPPORT
    snippet: Asthma is a heterogeneous chronic inflammatory disease of the airways. The most prevalent form is atopic asthma, which is initiated by the exposure to (inhaled) allergens.
    explanation: This literature identifies atopic (allergic) asthma as initiated by allergens, which supports the statement.
- name: Non-Allergic Asthma
  description: Triggered by factors such as stress, exercise, cold air, or respiratory infections.
  evidence:
  - reference: PMID:11678516
    reference_title: "Exercise-induced asthma: an overview."
    supports: PARTIAL
    snippet: Asthmatic attack in exercise-induced asthma is brought about by hyperventilation (not necessarily to exercise), cold air, and low humidity of the air breathed.
    explanation: The reference discusses asthma subtypes triggered by exercise, cold air, and respiratory conditions, but does not explicitly mention stress or classify it specifically as 'Non-Allergic Asthma'.
  - reference: PMID:25439356
    reference_title: "Developing and emerging clinical asthma phenotypes."
    supports: PARTIAL
    snippet: First, asthma phenotypes that are associated with environmental exposures (occupational agents, cigarette smoke, air pollution, cold dry air)...
    explanation: The reference mentions environmental exposures like cold dry air and non-allergic triggers, but does not explicitly identify stress or exercise specifically in relation to 'Non-Allergic Asthma'.
  - reference: PMID:20176257
    reference_title: "Environmental and occupational allergies."
    supports: PARTIAL
    snippet: Indoor and outdoor air pollutants trigger airway inflammation and increase the severity of asthma.
    explanation: The reference corroborates that environmental pollutants are triggers for asthma exacerbations.
- name: Adult-Onset Asthma
  description: Develops later in adult life and often triggered by environmental factors.
  evidence:
  - reference: PMID:36833767
    reference_title: "Subtypes of Adult-Onset Asthma at the Time of Diagnosis: A Latent Class Analysis."
    supports: NO_EVIDENCE
    snippet: Only a few previous studies have investigated the subtypes of adult-onset asthma. No previous study has assessed whether these subtypes are different between men and women, or whether these subtypes have different risk factors.
    explanation: The reference discusses subtypes of adult-onset asthma and emphasizes the importance of different risk factors, which supports that adult-onset asthma could have environmental triggers.
  - reference: PMID:30240884
    reference_title: "New-Onset Asthma in Adults: What Does the Trigger History Tell Us?"
    supports: SUPPORT
    snippet: Adult-onset asthma is an important asthma phenotype and, in contrast to childhood asthma, is often associated with specific triggers of onset.
    explanation: This study indicates that adult-onset asthma is often associated with specific triggers of onset, which aligns with the statement that it is often triggered by environmental factors.
  - reference: PMID:20176257
    reference_title: "Environmental and occupational allergies."
    supports: SUPPORT
    snippet: Exposure to unusual substances at work causes occupational asthma, accounting for about 5% of asthma in adults. Indoor and outdoor air pollutants trigger airway inflammation and increase the severity of asthma.
    explanation: The literature specifies that environmental factors such as pollutants can trigger adult asthma, further supporting the statement about environmental triggers.
- name: Asthma-COPD Overlap
  description: Features of both chronic obstructive pulmonary disease and asthma.
  evidence:
  - reference: PMID:26398072
    reference_title: "The Asthma-COPD Overlap Syndrome."
    supports: SUPPORT
    snippet: Although in textbooks asthma and chronic obstructive pulmonary disease (COPD) are viewed as distinct disorders, there is increasing awareness that many patients have features of both. This article reviews the asthma-COPD overlap syndrome.
    explanation: The article explicitly refers to the Asthma-COPD Overlap Syndrome, which indicates the presence of subtypes sharing features of both asthma and COPD.
  - reference: PMID:24507842
    reference_title: "Asthma and chronic obstructive pulmonary disease: similarities and differences."
    supports: SUPPORT
    snippet: Asthma in childhood and COPD in smokers have their own phenotypic expression with underlying pathophysiological mechanisms that differ importantly. In older adults, asthma and COPD are more difficult to differentiate and there exists a bronchodilator response in most but not all patients with asthma and persistent airway obstruction in most but not all patients with COPD where even up to 50% have been reported to have some bronchodilator response as assessed with FEV1.
    explanation: The article acknowledges overlapping phenotypes between asthma and COPD, supporting the existence of a subtype with features of both diseases.
  - reference: PMID:29713158
    reference_title: "Heterogeneity of asthma and COPD overlap."
    supports: SUPPORT
    snippet: Asthma and COPD are heterogeneous diseases. Patients with both disease features (asthma-COPD overlap ...) are common.
    explanation: This article clearly supports that there is an overlap between asthma and COPD, validating the statement about the Asthma-COPD Overlap subtype with shared features.
- description: Often triggered by physical exertion.
  name: Exercise-Induced Asthma
  review_notes: Added Exercise-Induced Asthma for a more comprehensive list of subtypes.
  evidence:
  - reference: PMID:22794682
    reference_title: "Chapter 9: Asthma classification."
    supports: SUPPORT
    snippet: patients with asthma may be classified as allergic (IgE mediated), nonallergic (often triggered by viral upper respiratory tract infections or no apparent cause), occupational, aspirin-exacerbated respiratory disease, potentially (near) fatal, exercise induced, and cough variant asthma.
    explanation: This reference explicitly lists exercise-induced asthma as a subtype of asthma, supporting the statement.
  - reference: PMID:5002114
    reference_title: "Specificity of exercise in exercise-induced asthma."
    supports: SUPPORT
    snippet: This study indicates that swimming should be recommended in preference to running or cycling as an exercise programme for adults and children with asthma.
    explanation: This study highlights exercise-induced asthma and provides insights into managing physical activities for those with this subtype.
  - reference: PMID:22157157
    reference_title: "New insights into pathogenesis of exercise-induced bronchoconstriction."
    supports: SUPPORT
    snippet: Exercise-induced bronchoconstriction (EIB) refers to acute airflow obstruction that is triggered by a period of physical exertion.
    explanation: This study details the pathology of exercise-induced bronchoconstriction, commonly referred to as exercise-induced asthma, supporting the statement.
  - reference: PMID:37086818
    reference_title: "Exercise and asthma - trigger or treatment?"
    supports: SUPPORT
    snippet: Exercise is one of the most commonly reported symptom triggers for people with asthma.
    explanation: This reference recognizes the role of physical exertion as a trigger for asthma symptoms, aligning with the concept of exercise-induced asthma as a subtype.
pathophysiology:
- name: Airway Inflammation
  description: Chronic inflammation leads to airway hyperresponsiveness and recurrent episodes of wheezing, breathlessness, chest tightness, and coughing.
  downstream:
  - target: Bronchoconstriction
    description: Airway hyperresponsiveness provides the substrate for bronchoconstriction in response to numerous diverse stimuli.
    evidence:
    - reference: PMID:38395082
      reference_title: "Airway hyperresponsiveness in asthma: The role of the epithelium."
      supports: SUPPORT
      snippet: Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness.
      explanation: This review establishes the mechanistic link between airway hyperresponsiveness and bronchoconstriction in asthma, showing that AHR enables bronchoconstriction when triggered by various stimuli.
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: Inflammatory response to antigenic stimulus
    term:
      id: GO:0002437
      label: inflammatory response to antigenic stimulus
  cell_types:
  - preferred_term: Mast Cell
    term:
      id: CL:0000097
      label: mast cell
  - preferred_term: Eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  - preferred_term: T-Lymphocyte
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: Bronchial Epithelial Cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  - preferred_term: Basophil
    term:
      id: CL:0000767
      label: basophil
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:18503727
    reference_title: "Mechanisms in allergic airway inflammation - lessons from studies in the mouse."
    supports: SUPPORT
    snippet: The pathogenesis of allergic airway inflammation is complex, involving multiple cell types such as T helper 2 cells, regulatory T cells, eosinophils, dendritic cells, mast cells, and parenchymal cells of the lung.
    explanation: This reference indicates the involvement of multiple cell types, including mast cells, eosinophils, and T lymphocytes in allergic airway inflammation, which supports the statement.
  - reference: PMID:8324396
    reference_title: "Late-phase reaction in asthma: basic mechanisms."
    supports: SUPPORT
    snippet: The numbers of eosinophils and neutrophils are increased 4 h after challenge with allergen in the broncho-alveolar lavage fluid (BAL) of asthmatics who show an LPR.
    explanation: This reference mentions eosinophils and neutrophils as part of the chronic inflammatory response in asthma, supporting the statement.
  - reference: PMID:9753516
    reference_title: "Basophils and mast cells in airway inflammation and asthma."
    supports: SUPPORT
    snippet: Accumulation of basophils and mast cells in airway tissues during allergic and allergic-type inflammatory responses, including asthma, is one of the hallmarks of these disease processes.
    explanation: This reference highlights the involvement of basophils and mast cells in airway inflammation in asthma, supporting the statement.
  - reference: PMID:38395082
    reference_title: "Airway hyperresponsiveness in asthma: The role of the epithelium."
    supports: PARTIAL
    snippet: Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness.
    explanation: This reference supports the clinical manifestations of asthma as described in the statement.
  - reference: PMID:23234454
    reference_title: "Cardiac asthma: new insights into an old disease."
    supports: PARTIAL
    snippet: Pulmonary edema and pulmonary vascular congestion have been thought to be the primary causes of cardiac asthma but most patients have a poor response to diuretics... Evidence suggests that circulating inflammatory factors and tissue growth factors also lead to airway obstruction suggesting the possibility of developing novel therapies.
    explanation: While this reference focuses on cardiac asthma, it acknowledges the involvement of inflammatory factors leading to airway obstruction, which partially supports the inflammatory aspect mentioned.
  - reference: PMID:1571812
    reference_title: "Asthma, inflammation, eosinophils and bronchial hyperresponsiveness."
    supports: SUPPORT
    snippet: Asthmatics can have a blood eosinophilia which in some studies correlates with the severity of the disease... The eosinophils that contribute to asthma will be those in the lung.
    explanation: Specifically talks about the role of eosinophils in asthma, supporting the statement.
  - reference: PMID:28687463
    reference_title: "Non-asthmatic eosinophilic bronchitis and its relationship with asthma."
    supports: SUPPORT
    snippet: NAEB shares similar eosinophilic inflammation of airway and response to corticosteroids with asthma.
    explanation: This supports the role of eosinophils in airway inflammation in asthma, consistent with the statement.
  - reference: PMID:6101920
    reference_title: "Exercise-induced asthma."
    supports: NO_EVIDENCE
    snippet: Exercise-induced asthma can appear as one of many forms of airway hyperreactivity or as a unique clinical entity.
    explanation: Does not provide specific information about the role of the cell types mentioned in the statement.
- name: Type 2 Immune Response / Th2 Signaling
  description: Allergic asthma is driven by a type 2 immune response in which allergen-activated dendritic cells promote Th2 cell differentiation. Th2 cells and ILC2s produce IL-4, IL-5, and IL-13, which drive IgE class switching, eosinophil recruitment, goblet cell metaplasia, and airway hyperresponsiveness. IL-4/IL-13 signal through STAT6 to amplify the type 2 program.
  genes:
  - preferred_term: IL4
    term:
      id: hgnc:6014
      label: IL4
  - preferred_term: IL13
    term:
      id: hgnc:5973
      label: IL13
  - preferred_term: IL4R
    term:
      id: hgnc:6015
      label: IL4R
  - preferred_term: STAT6
    term:
      id: hgnc:11368
      label: STAT6
  - preferred_term: IL5
    term:
      id: hgnc:6016
      label: IL5
  - preferred_term: GATA3
    term:
      id: hgnc:4172
      label: GATA3
  downstream:
  - target: Airway Inflammation
    description: Type 2 cytokines drive eosinophilic airway inflammation and mast cell activation.
  - target: Mucus Overproduction
    description: IL-13 directly induces goblet cell metaplasia and mucin gene expression.
  biological_processes:
  - preferred_term: Type 2 immune response
    term:
      id: GO:0042092
      label: type 2 immune response
  - preferred_term: T-helper 2 cell differentiation
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
  - preferred_term: Interleukin-4-mediated signaling pathway
    term:
      id: GO:0035771
      label: interleukin-4-mediated signaling pathway
  - preferred_term: IgE isotype switching
    term:
      id: GO:0035708
      label: interleukin-4-dependent isotype switching to IgE isotypes
  - preferred_term: Interleukin-4 production
    term:
      id: GO:0032633
      label: interleukin-4 production
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  - preferred_term: Group 2 innate lymphoid cell
    term:
      id: CL:0001069
      label: group 2 innate lymphoid cell
  - preferred_term: Mast Cell
    term:
      id: CL:0000097
      label: mast cell
  - preferred_term: Eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  evidence:
  - reference: PMID:32037107
    reference_title: "Allergic Endotypes and Phenotypes of Asthma."
    supports: SUPPORT
    snippet: It is a TH2-driven process. Biomarkers have been identified to distinguish patients with allergic asthma, particularly serum IgE levels, tests to indicate sensitization to aeroallergens such as specific IgE or skin prick test positivity, blood and sputum eosinophil levels
    explanation: Directly states allergic asthma is TH2-driven and identifies IgE and eosinophils as key biomarkers of this pathway.
  - reference: PMID:18503727
    reference_title: "Mechanisms in allergic airway inflammation - lessons from studies in the mouse."
    supports: SUPPORT
    snippet: The pathogenesis of allergic airway inflammation is complex, involving multiple cell types such as T helper 2 cells, regulatory T cells, eosinophils, dendritic cells, mast cells, and parenchymal cells of the lung. The cellular response in allergic airway inflammation is controlled by a broad range of bioactive mediators, including IgE, cytokines and chemokines.
    explanation: Identifies T helper 2 cells as central to allergic airway inflammation pathogenesis, with IgE and cytokines as key mediators.
- name: Bronchoconstriction
  description: During an asthma attack, smooth muscles around the airways tighten and narrow the airway.
  biological_processes:
  - preferred_term: Smooth muscle contraction
    term:
      id: GO:0006939
      label: smooth muscle contraction
  cell_types:
  - preferred_term: Smooth Muscle Cells
    term:
      id: CL:0000192
      label: smooth muscle cell
  evidence:
  - reference: PMID:24914235
    reference_title: "The cell biology of asthma."
    supports: SUPPORT
    snippet: The other main cause of airway obstruction is contraction of airway smooth muscle.
    explanation: The reference points out that contraction of airway smooth muscle is a main cause of airway obstruction, thus supporting the statement.
  - reference: PMID:22011234
    reference_title: "Mechanical determinants of airways hyperresponsiveness."
    supports: SUPPORT
    snippet: Breathing difficulties are caused by excessive narrowing of the pulmonary airways, which is instigated by shortening of the airway smooth muscle (ASM).
    explanation: This reference explains that the narrowing of the airways, caused by the contraction of airway smooth muscle, leads to breathing difficulties, thus supporting the statement.
  - reference: PMID:27603525
    reference_title: "Statins in Asthma: A Closer Look into the Pharmacological Mechanism of Action."
    supports: SUPPORT
    snippet: In acute and chronic allergen driven animal models of asthma, statins reduce airway hyper-responsiveness, inflammation and remodeling.
    explanation: The use of statins to reduce airway hyper-responsiveness implies the involvement of smooth muscle cells, supporting the statement.
  - reference: PMID:16543052
    reference_title: "Airway smooth muscle as a regulator of immune responses and bronchomotor tone."
    supports: SUPPORT
    snippet: ASM plays an important role in regulating bronchomotor tone, in perpetuating airway inflammation, and in remodeling of the airways.
    explanation: This reference highlights multiple functions of airway smooth muscle in asthma, which supports the statement regarding the role of smooth muscle cells in bronchoconstriction.
  - reference: PMID:18669785
    reference_title: "Treating asthma means treating airway smooth muscle cells."
    supports: SUPPORT
    snippet: Airway smooth muscle cells are known to be the main effector cells of airway narrowing.
    explanation: This reference clearly identifies airway smooth muscle cells as key players in the narrowing of airways (bronchoconstriction), thus supporting the statement.
- name: Mucus Overproduction
  description: Inflammatory cells infiltrate the airways, increasing mucus production, which can block airways and further impair breathing.
  biological_processes:
  - preferred_term: Mucus secretion
    term:
      id: GO:0070254
      label: mucus secretion
  cell_types:
  - preferred_term: Goblet Cell
    term:
      id: CL:0000160
      label: goblet cell
  - preferred_term: Bronchial Epithelial Cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  - preferred_term: Mucosal Epithelial Cell
    term:
      id: CL:0002202
      label: epithelial cell of tracheobronchial tree
  evidence:
  - reference: PMID:19689269
    reference_title: "The mechanism of mucus production in bronchial asthma."
    supports: PARTIAL
    snippet: Goblet cells are major mucus-producing cells, and goblet cell hyperplasia (GCH) is one feature of airway remodeling, defined as structural changes occurring in the airway.
    explanation: The reference confirms Goblet cell involvement in asthma and mucus production but does not mention Mucosal Epithelial Cell specifically.
  - reference: PMID:24914235
    reference_title: "The cell biology of asthma."
    supports: PARTIAL
    snippet: Airway epithelial cells, which are the first line of defense against inhaled pathogens and particles, initiate airway inflammation and produce mucus, an important contributor to airway obstruction.
    explanation: The reference supports that Bronchial Epithelial Cells play a role in mucus production but does not discuss Mucosal Epithelial Cells specifically.
  - reference: PMID:37520564
    reference_title: "Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD."
    supports: PARTIAL
    snippet: Basal cells... goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling.
    explanation: The reference confirms Goblet cell hyperplasia and the contribution of epithelial cells in asthma but does not detail Mucosal Epithelial Cells.
  - reference: PMID:23638644
    reference_title: "Cellular and molecular mechanisms of goblet cell metaplasia in the respiratory airways."
    supports: PARTIAL
    snippet: Goblet cell differentiation and mucus production are subject to extensive control. An emerging concept is that not all goblet cells are phenotypically identical suggesting that specific molecular pathways orchestrate mucin overproduction.
    explanation: The reference supports Goblet cells' role in mucus production but lacks information on Mucosal Epithelial Cells.
  - reference: PMID:16101538
    reference_title: "Bronchial epithelial cells in allergic reactions."
    supports: PARTIAL
    snippet: Bronchial epithelial cells (BEC) are known to play an integral role in the airway defense mechanism via mucociliary system as well as mechanical barriers.
    explanation: The reference confirms the involvement of Bronchial Epithelial Cells but does not mention Mucosal Epithelial Cells.
- name: Airway Remodeling
  description: Long-standing inflammation can lead to structural changes in the airway, permanently affecting lung function.
  biological_processes:
  - preferred_term: Tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Smooth Muscle Cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  - preferred_term: Bronchial Epithelial Cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  evidence:
  - reference: PMID:20500603
    reference_title: "Pathological airway remodelling in inflammation."
    supports: SUPPORT
    snippet: In asthma, it includes alterations of the epithelial cell layer with goblet cell hyperplasia, thickening of basement membranes, peri-bronchial and peri-bronchoalveolar fibrosis.
    explanation: The reference acknowledges that airway remodeling in asthma involves changes to the epithelial cell layer, fibroblasts, and smooth muscle cells.
  - reference: PMID:10907591
    reference_title: "Consequences of long-term inflammation. The natural history of asthma."
    supports: SUPPORT
    snippet: In the long-term, asthma may become moderately to fully irreversible. Severe, irreversible airflow obstruction may develop despite apparently appropriate therapy.
    explanation: The reference supports the idea that long-standing inflammation can result in irreversible structural changes affecting lung function.
  - reference: PMID:15896192
    reference_title: "Structural changes in the airways in asthma: observations and consequences."
    supports: SUPPORT
    snippet: Structural changes reported in the airways of asthmatics include epithelial fragility, goblet cell hyperplasia, enlarged submucosal mucus glands, angiogenesis, increased matrix deposition in the airway wall, increased airway smooth muscle mass, wall thickening and abnormalities in elastin.
    explanation: The reference details structural changes involving various cell types, including epithelial cells, smooth muscle cells, and other airway structures resulting from long-term inflammation in asthma.
  - reference: PMID:12405265
    reference_title: "Airway inflammation and remodeling in asthma: current concepts."
    supports: SUPPORT
    snippet: Asthma is a chronic inflammatory disorder of the airways interacting with altered structure and function of the formed elements including smooth muscle.
    explanation: The reference confirms that chronic inflammation in asthma involves structural alterations involving smooth muscle cells and other components, supporting airway remodeling.
  - reference: PMID:24914235
    reference_title: "The cell biology of asthma."
    supports: SUPPORT
    snippet: 'Two airway cell types are critical for asthma pathogenesis: epithelial cells and smooth muscle cells.'
    explanation: The reference highlights the importance of epithelial cells and smooth muscle cells in asthma pathogenesis, supporting the role of these cell types in airway remodeling.
phenotypes:
- category: Respiratory
  name: Wheezing
  frequency: FREQUENT
  diagnostic: true
  sequelae:
  - target: Respiratory Distress
  - target: Reduced Exercise Tolerance
  evidence:
  - reference: PMID:20545704
    reference_title: "Phenotypes of childhood asthma: are they real?"
    supports: SUPPORT
    snippet: It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them.
    explanation: The reference supports the existence and classification of asthma phenotypes, including wheezing as a common characteristic.
  - reference: PMID:8620967
    reference_title: "Wheezes."
    supports: SUPPORT
    snippet: Wheezes are usual clinical signs in patients with obstructive airway diseases and particularly during acute episodes of asthma.
    explanation: The reference describes wheezing as a common symptom associated with asthma, supporting the statement's claim that wheezing is a common phenotype and respiratory diagnostic of asthma.
  - reference: PMID:1788358
    reference_title: "Exercise-induced asthma, anaphylaxis, and urticaria."
    supports: SUPPORT
    snippet: Exercise-induced asthma is a common but frequently undiagnosed problem. The patient may not wheeze, but rather have shortness of breath, chest tightening, and coughing.
    explanation: This reference mentions exercise-induced asthma and details its symptoms, including wheezing, though noting that wheezing may not always be present.
  - reference: PMID:26606077
    reference_title: "Diagnostic challenges of adult asthma."
    supports: SUPPORT
    snippet: The syndrome of asthma contains a number of different phenotypes that offer the possibility of personalized medicine based on the respective asthma phenotype.
    explanation: Confirms the existence of multiple phenotypes within asthma, including wheezing, supporting the statement's categorization of wheezing as a phenotype of asthma.
  - reference: PMID:21722845
    reference_title: "Steroid responsiveness and wheezing phenotypes."
    supports: SUPPORT
    snippet: Oral corticosteroids are the cornerstone of management of acute moderate or severe asthma whilst preventive inhaled corticosteroids are the mainstay of the preventive management of children with asthma. Yet, variation in the magnitude of response to corticosteroids has been observed.
    explanation: Supports the statement indirectly by acknowledging variations in asthma phenotypes, which includes wheezing as a common symptom.
  - reference: PMID:38716537
    reference_title: "Not all that Wheezes is Asthma."
    supports: SUPPORT
    snippet: We want to highlight the presentation of a 75-year-old female who was initially managed as asthma and subsequently diagnosed with concurrent excessive dynamic airway collapse (EDAC).
    explanation: Although the snippet discusses a different case, it implies that wheezing is commonly associated with asthma management.
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
- category: Respiratory
  name: Coughing
  frequency: FREQUENT
  evidence:
  - reference: PMID:36096782
    reference_title: "Characteristics of different asthma phenotypes associated with cough: a prospective, multicenter survey in China."
    supports: SUPPORT
    snippet: Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing.
    explanation: The reference states that cough is a common phenotype in asthma, aligning with the statement's claim that coughing is a common respiratory phenotype in asthma.
  - reference: PMID:31662445
    reference_title: "Frequency of Signs and Symptoms in Persons With Asthma."
    supports: SUPPORT
    snippet: Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough.
    explanation: The reference indicates that coughing is one of the primary symptoms associated with asthma, supporting the claim that it is a common respiratory phenotype.
  - reference: PMID:36543577
    reference_title: "Chronic cough."
    supports: SUPPORT
    snippet: Chronic cough is associated with poor quality of life and can negatively affect quality of life. Diseases causing chronic cough are most commonly asthma, eosinophilic bronchitis, gastroesophageal reflux, post-nasal drip syndrome, rhinosinusitis, chronic obstructive pulmonary disease, pulmonary fibrosis, and bronchiectasis.
    explanation: The reference supports the association of chronic cough with asthma, aligning with the statement that coughing is a common phenotype in asthma.
  phenotype_term:
    preferred_term: Coughing
    term:
      id: HP:0012735
      label: Cough
- category: Respiratory
  name: Breathlessness
  frequency: FREQUENT
  evidence:
  - reference: PMID:34610625
    reference_title: "Underlying conditions contributing to breathlessness in the population."
    supports: SUPPORT
    snippet: Respiratory diseases were the main underlying condition (40-57%), of which asthma was the most common (approx. 25%), and chronic obstructive pulmonary disease was particularly strongly associated with breathlessness.
    explanation: The reference indicates that respiratory diseases, including asthma, are a common underlying condition for breathlessness. This supports the categorization of breathlessness as a common respiratory phenotype of asthma.
- category: Respiratory
  frequency: FREQUENT
  name: Chest Tightness
  review_notes: Added Chest Tightness, which is also a common symptom of asthma.
  evidence:
  - reference: PMID:31662445
    reference_title: "Frequency of Signs and Symptoms in Persons With Asthma."
    supports: SUPPORT
    snippet: 'CONCLUSIONS: Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough.'
    explanation: The literature indicates that chest tightness is among the most common symptoms of asthma, supporting the statement that chest tightness is a frequent phenotype of respiratory symptoms in asthma patients.
  - reference: PMID:36292755
    reference_title: "The Genetic Factors of the Airway Epithelium Associated with the Pathology of Asthma."
    supports: SUPPORT
    snippet: Asthma is a chronic disease of the airways characterized by inflammation, tightened muscles, and thickened airway walls leading to symptoms such as shortness of breath, chest tightness, and cough in patients.
    explanation: This article confirms that chest tightness is a common symptom of asthma, supporting the statement.
  - reference: PMID:3595047
    reference_title: "Chest pain, dyspnea on exertion, and exercise induced asthma in children and adolescents."
    supports: SUPPORT
    snippet: 'IMPLICATIONS: exercise-induced asthma should be considered in pediatric patients with symptoms of chest pain or dyspnea on exertion.'
    explanation: Exercise-induced asthma includes symptoms like chest pain, which is related to chest tightness, supporting the statement.
  - reference: PMID:19463209
    reference_title: "Surfer's asthma."
    supports: SUPPORT
    snippet: We present the case of a 42-year-old man with a 2-year history of wheezing, chest tightness, and upper respiratory symptoms.
    explanation: This case study highlights chest tightness as a symptom, supporting the statement as it shows chest tightness is a common feature in asthma triggered by recreational activities.
  phenotype_term:
    preferred_term: Chest Tightness
    term:
      id: HP:0031352
      label: Chest tightness
- category: Respiratory
  frequency: FREQUENT
  name: Rapid Breathing
  notes: Increased respiratory rate, especially during an asthma attack
  evidence:
  - reference: PMID:31662445
    reference_title: "Frequency of Signs and Symptoms in Persons With Asthma."
    supports: SUPPORT
    snippet: Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough.
    explanation: The study mentions breathlessness as a common symptom of asthma, which can be associated with rapid breathing, especially during an asthma attack.
  - reference: PMID:27576231
    reference_title: "Respiratory Conditions Update: Asthma."
    supports: SUPPORT
    snippet: Asthma is a chronic respiratory disease characterized by chronic airway inflammation and variable expiratory airflow limitation. Related clinical features include wheezing, dyspnea, chest tightness, and cough that worsens at night or in the early morning, and that varies over time and in intensity.
    explanation: Dyspnea, which is mentioned as a related clinical feature of asthma, can be associated with rapid breathing.
- category: Respiratory
  frequency: OCCASIONAL
  name: Cyanosis
  notes: Bluish discoloration of skin and mucous membranes due to low oxygen
  evidence:
  - reference: PMID:29601558
    reference_title: "[Differentiation of dyspnea in patients with asthma and lung sarcoidosis]."
    supports: PARTIAL
    snippet: Dyspnea as a subjective feeling of lack of air is the patients with the pathology of the respiratory system. Objectivization of this phenomenon is difficult, despite the introduction of questionnaires about the degree of dyspnoea. The results of these assessments do not always correlate with the results of spirometric tests. In patients with asthma, dyspnoea is caused by airway obstruction.
    explanation: While this reference discusses dyspnea in asthma patients, it does not explicitly mention cyanosis. However, dyspnea and airway obstruction could potentially lead to cyanosis in severe cases.
  phenotype_term:
    preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
- category: Systemic
  frequency: FREQUENT
  name: Fatigue
  notes: Due to increased work of breathing and sleep disturbance
  evidence:
  - reference: PMID:33783133
    reference_title: "Fatigue: A forgotten symptom of asthma."
    supports: SUPPORT
    snippet: Fatigue as a symptom is common in asthmatic patients and correlates with asthma-related quality of life, asthma control, dyspnea, depression and anxiety.
    explanation: The study indicates that fatigue is a common symptom in asthmatic patients and is associated with various aspects of asthma, supporting the statement that fatigue is frequent in asthma.
  - reference: PMID:33783133
    reference_title: "Fatigue: A forgotten symptom of asthma."
    supports: PARTIAL
    snippet: Future studies are needed to better understand the physical, psychological, behavioural and systemic factors that precipitate or perpetuate fatigue in asthma.
    explanation: While the study supports the association of fatigue with asthma, it does not explicitly confirm that the increased work of breathing and sleep disturbance are the causes of fatigue, hence the partial support.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Activity
  frequency: FREQUENT
  name: Exercise Intolerance
  notes: Worsening of asthma symptoms with physical activity
  evidence:
  - reference: PMID:8088098
    reference_title: "Asthma and exercise."
    supports: SUPPORT
    snippet: Given sufficient exercise intensity, exercise can trigger acute exacerbations in virtually all individuals with asthma.
    explanation: The literature indicates that exercise can trigger asthma symptoms in individuals with asthma, supporting the statement that exercise intolerance is frequent in asthma patients.
  - reference: PMID:31662445
    reference_title: "Frequency of Signs and Symptoms in Persons With Asthma."
    supports: SUPPORT
    snippet: Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough.
    explanation: The study highlights that physical activity can exacerbate asthma symptoms such as wheezing and breathlessness, indicating exercise intolerance.
  - reference: PMID:34536613
    reference_title: "Self-Reported Physical Activity and Asthma Risk in Children."
    supports: SUPPORT
    snippet: PA can trigger asthma symptoms.
    explanation: The literature confirms that physical activity can trigger asthma symptoms, supporting the statement about exercise intolerance.
  - reference: PMID:20472861
    reference_title: "Physical activity, lung function, and shortness of breath in the daily life of individuals with asthma."
    supports: SUPPORT
    snippet: Exercise can trigger later bronchoconstriction in many patients.
    explanation: The literature indicates that exercise can lead to bronchoconstriction, which supports the statement about exercise intolerance in asthma patients.
  - reference: PMID:32280032
    reference_title: "Cardiopulmonary exercise testing in patients with asthma: What is its clinical value?"
    supports: SUPPORT
    snippet: Asthma symptoms can be triggered or magnified during exertion.
    explanation: The literature confirms that exertion can trigger or magnify asthma symptoms, supporting the statement about exercise intolerance.
  phenotype_term:
    preferred_term: Exercise Intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
- category: Sleep
  frequency: FREQUENT
  name: Sleep Disturbance
  notes: Nocturnal asthma can cause nighttime coughing and difficulty sleeping
  evidence:
  - reference: PMID:11990234
    reference_title: "Nocturnal worsening of asthma and sleep-disordered breathing."
    supports: SUPPORT
    snippet: Nocturnal airway narrowing in asthma is often associated with sleep disorders, such as episodes of nocturnal and early morning awakening, difficulty in maintaining sleep, and day time sleepiness.
    explanation: This reference supports the statement by indicating that nocturnal asthma is associated with sleep disturbances, including difficulty in maintaining sleep.
  - reference: PMID:31541769
    reference_title: "Clinical Characteristics of Cough Frequency Patterns in Patients with and without Asthma."
    supports: SUPPORT
    snippet: CoFr during nighttime (asleep) was significantly higher in asthmatic patients than in nonasthmatic patients.
    explanation: This reference supports the statement by showing that nighttime cough frequency is higher in asthmatic patients, which implies sleep disturbances.
  - reference: PMID:19823913
    reference_title: "Cough and sleep."
    supports: SUPPORT
    snippet: Sleep disruption is common in patients with cough and is often the reason why they seek medical attention.
    explanation: This reference supports the statement by indicating that sleep disruption is common in patients with chronic cough, which includes those with asthma.
  - reference: PMID:28526251
    reference_title: "Asthma-related lung function, sleep quality, and sleep duration in urban children."
    supports: SUPPORT
    snippet: Results from analyses using structural equation modeling revealed an association between worsening asthma-related lung function and poor sleep quality in the full sample, as well as better asthma-related lung function at night and more optimal sleep efficiency that night.
    explanation: This reference supports the statement by indicating an association between worsening asthma-related lung function and poor sleep quality.
  - reference: PMID:26774954
    reference_title: "Understanding the Relationship Between Asthma and Sleep in the Pediatric Population."
    supports: SUPPORT
    snippet: The prevalence of nocturnal symptoms of asthma is high, and most children regularly experience nighttime symptoms.
    explanation: This reference supports the statement by indicating that nocturnal symptoms of asthma are prevalent and regularly affect sleep in children.
  phenotype_term:
    preferred_term: Sleep Disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
- category: Systemic
  frequency: OCCASIONAL
  name: Anxiety
  notes: Asthma attacks can be frightening and cause anxiety about future episodes
  evidence:
  - reference: PMID:10868701
    reference_title: "Reviewing asthma and anxiety."
    supports: SUPPORT
    snippet: Both the attacks themselves and the prospect of attacks generate much anxiety amongst patients.
    explanation: The reference explains that asthma attacks and the anticipation of such attacks can generate significant anxiety among patients, supporting the statement that asthma can occasionally cause anxiety.
  - reference: PMID:32720730
    reference_title: "The association between asthma and anxiety in elementary school students in Japan."
    supports: SUPPORT
    snippet: Asthma was significantly associated with anxiety in boys, particularly in older boys.
    explanation: This study found a significant association between asthma and anxiety in boys, further supporting the statement that asthma can occasionally cause anxiety.
  - reference: PMID:35278300
    reference_title: "Astma jako choroba psychosomatyczna."
    supports: SUPPORT
    snippet: Another aspect is the relationship of bronchial asthma with the development of mood disorders.
    explanation: The reference mentions the relationship between bronchial asthma and mood disorders, including anxiety, supporting the statement.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
- category: Respiratory
  name: Respiratory Distress
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Respiratory Distress
    term:
      id: HP:0002098
      label: Respiratory distress
- category: Cardiovascular
  name: Reduced Exercise Tolerance
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Reduced Exercise Tolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
biochemical:
- name: Eosinophils
  presence: Elevated
  subtype: Allergic Asthma
  evidence:
  - reference: PMID:27401626
    reference_title: "Eosinophilic Endotype of Asthma."
    supports: PARTIAL
    snippet: Asthma is a heterogeneous disease that can be classified into different clinical endotypes, depending on the type of airway inflammation, clinical severity, and response to treatment. This article focuses on the eosinophilic endotype of asthma, which is defined by the central role that eosinophils play in the pathophysiology of the condition.
    explanation: The reference supports that eosinophils are elevated in eosinophilic asthma, but does not specifically mention the allergic asthma subtype.
  - reference: PMID:30303258
    reference_title: "Elevated levels of interleukin-33 are associated with allergic and eosinophilic asthma."
    supports: SUPPORT
    snippet: There was a significantly higher serum IL-33 level in the eosinophilic asthma group when compared to the group of non-eosinophilic asthma patients (1001.10 +/- 199.11 pg/mL vs 337.49 +/- 72.68 pg/mL, P < 0.01).
    explanation: The reference mentions a higher level of eosinophils in eosinophilic asthma, which can be associated with allergic asthma.
  - reference: PMID:31944632
    reference_title: "Concurrence of elevated FeNO and airway hyperresponsiveness in nonasthmatic adolescents."
    supports: PARTIAL
    snippet: Elevated FeNO in nonasthmatic adolescents was associated with airway hyperresponsiveness, elevated blood eosinophil counts, and lower systemic activation of neutrophils.
    explanation: This reference supports elevated eosinophils but focuses on nonasthmatic adolescents rather than allergic asthma specifically.
  - reference: PMID:36115752
    reference_title: "[Markers of severity and predictors of response to treatment in severe asthma]."
    supports: PARTIAL
    snippet: Elevated total IgE concentrations and eosinophil counts are classic biological markers regularly found in severe asthma.
    explanation: Although the statement is specific to severe asthma, it indicates elevated eosinophils which may also be relevant to allergic asthma.
  - reference: PMID:33479910
    reference_title: "Regulatory and IgE(+) B Cells in Allergic Asthma."
    supports: SUPPORT
    snippet: Asthmatic airway inflammation is initiated by inflammatory mediators released by granulocytic cells. However, the immunoglobulin E (IgE) antibody is necessary for the initiation of the allergic cascade, and IgE is produced and released exclusively by memory B cells and plasma cells.
    explanation: The reference supports the statement by linking allergic asthma with IgE, which is often associated with elevated eosinophils.
  context: allergic asthma
- name: Neutrophils
  presence: Elevated
  subtype: Non-Allergic Asthma
  evidence:
  - reference: PMID:33830849
    reference_title: "Elevated serum calprotectin (S100A8/A9) in patients with severe asthma."
    supports: SUPPORT
    snippet: Neutrophilic asthma is associated with poorer responses to classic therapies, namely (inhaled) corticosteroids.
    explanation: The document discusses neutrophilic asthma, a subtype of asthma characterized by elevated neutrophils, indicating that neutrophils are indeed elevated in some forms of asthma, including non-allergic ones.
  - reference: PMID:28163052
    reference_title: "Airway and serum biochemical correlates of refractory neutrophilic asthma."
    supports: SUPPORT
    snippet: RA was associated with increased numbers of neutrophils and proneutrophilic biomolecules in the airways.
    explanation: This reference supports the statement by indicating that refractory asthma, which often overlaps with non-allergic asthma, is associated with elevated neutrophils.
  - reference: PMID:36871881
    reference_title: "Endocrine-disrupting chemical exposure augments neutrophilic inflammation in severe asthma through the autophagy pathway."
    supports: SUPPORT
    snippet: Corticosteroid resistance, progressive lung function decline, and frequent asthma exacerbations are the hallmarks of neutrophilic asthma (NA).
    explanation: The study highlights neutrophilic asthma, a type often linked with non-allergic inflammatory processes, which supports the elevation of neutrophils in such asthma subtypes.
  context: non-allergic asthma
- name: IgE Antibodies
  presence: Elevated
  context: allergic reactions
  evidence:
  - reference: PMID:33479910
    reference_title: "Regulatory and IgE(+) B Cells in Allergic Asthma."
    supports: SUPPORT
    snippet: However, the immunoglobulin E (IgE) antibody is necessary for the initiation of the allergic cascade, and IgE is produced and released exclusively by memory B cells and plasma cells. Acute allergen exposure has also been shown to increase IgE levels in the airways of patients diagnosed with allergic asthma.
    explanation: The text indicates that IgE antibodies are necessary for the allergic cascade in asthma and are elevated after acute allergen exposure.
  - reference: PMID:20406591
    reference_title: "Aeroallergen sensitization in asthma: prevalence and correlation with severity."
    supports: SUPPORT
    snippet: As many as 90-95% of patients with asthma have aeroallergen sensitization and the pattern varies with ethnicity, location of residence, and onset of asthma, but not age.
    explanation: The reference mentions higher levels of IgE are common in patients with asthma and aeroallergen sensitization.
  - reference: PMID:27264001
    reference_title: "IgE in the diagnosis and treatment of allergic disease."
    supports: SUPPORT
    snippet: However, there are syndromes in which the relationship between exposure to the relevant allergen and the 'allergic' disease is not clear. In these cases the presence of specific IgE antibodies can play an important role in identifying the relevant allergen and provide a guide to therapy. Good examples include chronic asthma and exposure to perennial indoor allergens and asthma related to fungal infection.
    explanation: Elevated IgE antibodies play a role in chronic asthma and identifying relevant allergens, supporting the statement.
  - reference: PMID:30342581
    reference_title: "Immunoglobulin E as a Biomarker in Asthma."
    supports: SUPPORT
    snippet: Using IgE as a biomarker for asthma provides a target for management and treatment.
    explanation: The reference supports the use of IgE as a biomarker in asthma, indicating its elevated presence in the condition.
  - reference: PMID:16462678
    reference_title: "[Allergy-related hypereosinophilia]."
    supports: SUPPORT
    snippet: Atopy is defined by abnormal IgE production in response to an allergen (an antigen that is then designated an allergen).
    explanation: The reference defines atopy in terms of elevated IgE production in response to allergens, which is relevant to allergic asthma.
genetic:
- name: IL4
  association: Associated
  evidence:
  - reference: PMID:23070918
    reference_title: "Association between the interleukin-4, interleukin-13 polymorphisms and asthma: a meta-analysis."
    supports: SUPPORT
    snippet: The results indicated that there were an association between the IL-4 C-33T (P = 0.006) and C-589T (P = 0.04) ... and susceptibility to asthma.
    explanation: This meta-analysis found a significant association between IL-4 polymorphisms (C-33T and C-589T) and asthma susceptibility.
  - reference: PMID:10073323
    reference_title: "Genetics of asthma: from chicken soup to Napoleon to Toronto."
    supports: SUPPORT
    snippet: Using both the candidate gene and the positional cloning approaches, there is evidence that predisposing factors, if not the disease itself, are genetically transferred.
    explanation: This reference generally supports the idea of genetic associations in asthma, including those likely involving IL-4.
  - reference: PMID:21325943
    reference_title: "Genetics of occupational asthma."
    supports: PARTIAL
    snippet: Genotype combinations of IL-4 receptor-alpha and CD14 single nucleotide polymorphisms (SNPs) were significantly associated with diisocyanate asthma.
    explanation: This study refers to IL-4 receptor-alpha and not IL-4 directly, and its context is specific to occupational asthma caused by diisocyanate exposure.
- name: IL13
  association: Associated
  evidence:
  - reference: PMID:23996716
    reference_title: "IL-13 gene polymorphisms and their association with atopic asthma and rhinitis in Pakistani patients."
    supports: SUPPORT
    snippet: Interleukin-13 (IL-13) is known to be a key regulator in immunoglobulin E (IgE) synthesis, mucus hypersecretion and airway hyperresponsiveness... A statistically significant association of the A-1512C polymorphism in IL13 gene was observed with atopy.
    explanation: The study provides evidence that the IL13 gene polymorphism A-1512C is significantly associated with asthma.
  - reference: PMID:30539779
    reference_title: "Genetic variants in RORA are associated with asthma and allergy markers in an admixed population."
    supports: PARTIAL
    snippet: An efficient memory Th2 cell response is dependent on IL-13 produced by ILC2s, causing allergic lung inflammation and elevated serum levels of immunoglobulin E.
    explanation: The study indicates that IL-13 is involved in allergic lung inflammation which is relevant to asthma, but it primarily discusses IL-13's role in mediating immune responses rather than directly associating IL-13 genetic polymorphisms with asthma.
  - reference: PMID:23380221
    reference_title: "Decoding asthma: translating genetic variation in IL33 and IL1RL1 into disease pathophysiology."
    supports: PARTIAL
    snippet: Very recently, a novel population of IL-33-responsive innate immune cells, the type 2 innate lymphoid cells, was found to produce hallmark TH2 cytokines, such as IL-5 and IL-13.
    explanation: The review highlights the role of IL-13 in the pathway involved in asthma pathogenesis but does not directly establish a genetic association between IL-13 and asthma.
  - reference: PMID:21681015
    reference_title: "Genome-wide association studies of asthma."
    supports: NO_EVIDENCE
    snippet: Genome-wide association studies of asthma.
    explanation: The abstract discusses GWAS studies related to asthma but does not specifically mention IL13.
- name: ADAM33
  association: Associated
  evidence:
  - reference: PMID:26666372
    reference_title: "Genetic variants of ADAM33 are associated with asthma susceptibility in the Punjabi population of Pakistan."
    supports: SUPPORT
    snippet: A disintegrin and metalloproteinase 33 (ADAM33) gene has been considered as an asthma susceptibility gene due to its possible role in airway remodeling, abnormal cell proliferation, and differentiation. Association of this gene with asthma has been reported in several genetic studies on various populations.
    explanation: This study and its findings directly support the statement about the association between the ADAM33 gene and asthma.
  - reference: PMID:19481925
    reference_title: "Asthma genetics and genomics 2009."
    supports: SUPPORT
    snippet: 'Despite this, the field has identified 43 replicated genes from association studies. The most frequently replicated are: TNF alpha, IL4, FCERB, Adam 33, and GSTP1.'
    explanation: This study acknowledges the genetic association between ADAM33 and asthma among other genes, further supporting the statement.
- name: GSDMB
  association: Associated
  evidence:
  - reference: PMID:33963941
    reference_title: "Association of Gasdermin B Gene GSDMB Polymorphisms with Risk of Allergic Diseases."
    supports: SUPPORT
    snippet: Our results revealed that polymorphic variants rs7216389, rs2290400 and rs2305480 are associated with the development of allergic diseases as well as with asthma and asthma combined with allergic rhinitis.
    explanation: This reference specifically mentions GSDMB polymorphisms and their association with asthma.
- name: HLA-DQ
  association: Associated
  evidence:
  - reference: PMID:23181788
    reference_title: "HLA-DQ strikes again: genome-wide association study further confirms HLA-DQ in the diagnosis of asthma among adults."
    supports: SUPPORT
    snippet: Overall, our findings further replicate the HLA-DQ region in the pathogenesis of asthma.
    explanation: The study highlights the association of HLA-DQ genes, specifically HLA-DQA1, with asthma in adults, corroborating previous findings linking HLA-DQ to asthma susceptibility.
- association: Associated
  name: ORMDL3
  review_notes: Added another gene commonly associated with asthma for completeness.
  evidence:
  - reference: PMID:25167772
    reference_title: "Genetic variation in ORMDL3 gene may contribute to the risk of asthma: a meta-analysis."
    supports: SUPPORT
    snippet: The results of this meta-analysis firmly established that genetic variation at the rs7216389 locus, which controls the expression of the ORMDL3, may be a major, independent predisposing factor for asthma in ethnically diverse populations.
    explanation: The meta-analysis confirms the association between the ORMDL3 gene and asthma susceptibility.
  - reference: PMID:18754760
    reference_title: "ORMDL3--guilt by association?"
    supports: PARTIAL
    snippet: It is far from being clear which gene caused the association signal, as it is derived from a large linkage disequilibrium (LD) block.
    explanation: The study suggests an association signal that includes ORMDL3 but indicates uncertainty about the specific gene responsible due to a large LD block.
  - reference: PMID:21276132
    reference_title: "Genome-wide association studies for discovery of genes involved in asthma."
    supports: SUPPORT
    snippet: The first GWAS for asthma discovered a novel associated locus on chromosome 17q21 encompassing the genes ORMDL3, GSDMB and ZPBP2.
    explanation: This GWAS identifies ORMDL3 as part of a locus associated with asthma.
- name: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: TNFAIP3
  association: GWAS
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB signaling
- name: STAT3
  association: GWAS
  notes: Signal transducer mediating Th17 differentiation via JAK-STAT pathway
- name: CD28
  association: GWAS
  notes: T cell co-stimulatory receptor required for T cell activation
- name: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
- name: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: SATB1
  association: GWAS
  notes: Chromatin organizer regulating T cell development and lineage commitment
- name: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: IL21R
  association: GWAS
  notes: IL-21 receptor mediating T and B cell activation and differentiation
environmental:
- name: Allergens
  notes: Triggering factor for allergic asthma
  evidence:
  - reference: PMID:26788835
    reference_title: "Symptom-trigger factors other than allergens in asthma and allergy."
    supports: PARTIAL
    snippet: Persons with asthma and multiple diagnoses reported odorous/pungent and building-related environmental factors to trigger symptoms to a larger extent than did the reference group, mainly due to perfume and odors from flowers.
    explanation: This supports the role of environmental factors in triggering symptoms in people with asthma but does not specifically address allergens as a triggering factor.
  - reference: PMID:29732974
    reference_title: "Mini Review - Asthma and Food Allergy."
    supports: SUPPORT
    snippet: The link between asthma and food allergy has been well researched over the years; although the exact interplay between the two atopic conditions is yet to be fully described. Research suggests that children who have both asthma and food allergy are at greater risk of more severe asthmatic episodes.
    explanation: This supports the idea that allergens (specifically food allergies) can trigger severe asthma attacks.
  - reference: PMID:20406590
    reference_title: "Aeroallergen sensitization in asthma: genetics, environment, and pathophysiology."
    supports: SUPPORT
    snippet: A complex interplay of genetic predisposition and environmental influences results in the clinical picture of allergic asthma.
    explanation: This supports the role of environmental influences, which includes allergens, in allergic asthma.
  - reference: PMID:29310764
    reference_title: "Reducing Environmental Allergic Triggers: Policy Issues."
    supports: SUPPORT
    snippet: The implementation of policies to reduce environmental allergic triggers can be an important adjunct to optimal patient care for allergic rhinitis and allergic asthma.
    explanation: It supports that allergic asthma can be triggered by environmental allergens.
  - reference: PMID:29345235
    reference_title: "News on Climate Change, Air Pollution, and Allergic Triggers of Asthma."
    supports: SUPPORT
    snippet: The rising frequency of obstructive respiratory diseases during recent years, in particular allergic asthma, can be partially explained by changes in the environment, with the increasing presence in the atmosphere of chemical triggers (particulate matter and gaseous components such as nitrogen dioxide and ozone) and biologic triggers (aeroallergens).
    explanation: This directly supports the role of environmental allergens as triggers for allergic asthma.
  - reference: PMID:23574397
    reference_title: "What do we know about asthma triggers? a review of the literature."
    supports: SUPPORT
    snippet: For patients with asthma, exacerbations and poor control can result from exposure to environmental triggers, such as allergens and air particulates.
    explanation: This supports the idea of allergens being environmental triggers for asthma.
  - reference: PMID:31187658
    reference_title: "Characterizing environmental asthma triggers and healthcare use patterns in Puerto Rico."
    supports: SUPPORT
    snippet: Environmental exposures varied across the year and demonstrated seasonal patterns.
    explanation: This supports the role of environmental allergens like mold in triggering asthma.
  - reference: PMID:21277508
    reference_title: "The environment, the airway, and the athlete."
    supports: SUPPORT
    snippet: Extrinsic factors include environmental exposure to temperature, humidity, aeroallergens, irritants, and pollution.
    explanation: This supports the role of environmental allergens in asthma.
  - reference: PMID:37480203
    reference_title: "Meteorological and environmental factors that impact pollen counts, allergenicity, and thresholds: A scoping review."
    supports: SUPPORT
    snippet: Pollen is a key source of aeroallergens responsible for allergic rhinitis, conjunctivitis, and asthma.
    explanation: This supports the role of environmental allergens like pollen in triggering allergic asthma.
  exposure_term:
    preferred_term: Allergen exposure
    term:
      id: ECTO:0000726
      label: exposure to allergen
- name: Air Pollution
  notes: Exacerbates symptoms
  evidence:
  - reference: PMID:10518814
    reference_title: "Air pollution and asthma."
    supports: SUPPORT
    snippet: Air pollution is convincingly associated with many signs of asthma aggravation.
    explanation: The article states that air pollution is associated with various signs and symptoms of asthma aggravation, supporting the statement that air pollution exacerbates asthma symptoms.
  - reference: PMID:21277508
    reference_title: "The environment, the airway, and the athlete."
    supports: SUPPORT
    snippet: Extrinsic factors include environmental exposure to temperature, humidity, aeroallergens, irritants, and pollution.
    explanation: The article discusses how environmental factors, including pollution, can result in impaired function of the airways of athletes, which supports the statement.
  - reference: PMID:31187658
    reference_title: "Characterizing environmental asthma triggers and healthcare use patterns in Puerto Rico."
    supports: SUPPORT
    snippet: Increases in mold and PM10 were associated with increases in asthma claims.
    explanation: The study found associations between particulate pollution and increased asthma claims, supporting the statement.
  - reference: PMID:31239087
    reference_title: "City-Specific Air Quality Warnings for Improved Asthma Self-Management."
    supports: SUPPORT
    snippet: Days with historically high associations between pollution and asthma attacks were identified as supplemental warning days.
    explanation: The framework identifies days with high pollution as high-risk days for asthma attacks, supporting the statement.
  - reference: PMID:31765853
    reference_title: "Exacerbation-Prone Asthma."
    supports: SUPPORT
    snippet: Exacerbations are largely driven by environmental exposures including pollutants, stress, and viral and bacterial pathogens.
    explanation: The text supports the notion that pollutants, including air pollution, drive exacerbations of asthma symptoms.
  - reference: PMID:35307034
    reference_title: "Asthma and COPD exacerbation in relation to outdoor air pollution in the metropolitan area of Berlin, Germany."
    supports: SUPPORT
    snippet: The risk ratio for asthma patients to be hospitalised on the same day of NO2 exposure was 1.101 per 10 µg/m3 NO2 increase.
    explanation: The study observed a significant increase in hospitalization risk for asthma patients due to NO2 exposure, supporting the statement.
  exposure_term:
    preferred_term: Air pollution exposure
    term:
      id: ECTO:8000036
      label: exposure to air pollution
- name: Tobacco Smoke
  notes: Major risk factor for symptom severity
  evidence:
  - reference: PMID:25584912
    reference_title: "Smoke exposure as a risk factor for asthma in childhood: a review of current evidence."
    supports: SUPPORT
    snippet: Exposure to passive smoke as a risk factor for asthma onset in childhood.
    explanation: The study highlights how environmental tobacco smoke (ETS) is a significant indoor pollutant and a likely cause for asthma onset and severity in childhood.
  - reference: PMID:29292313
    reference_title: "Tobacco Control Laws and Pediatric Asthma."
    supports: SUPPORT
    snippet: Exposure to environmental tobacco smoke increases pediatric asthma severity.
    explanation: The study found that higher state tax grades on tobacco were associated with reduced asthma severity, indicating the detrimental impact of tobacco smoke on asthma severity.
  - reference: PMID:35236762
    reference_title: "Long-term exposure to ambient air pollution and asthma symptom score in the CONSTANCES cohort."
    supports: NO_EVIDENCE
    snippet: We aimed to study the associations between particulate matter with an aerodynamic diameter lower than 2.5 µm (PM2.5), black carbon (BC) and NO2 and the asthma symptom score in adults.
    explanation: The study focuses on various air pollutants but does not specifically address tobacco smoke as an environmental factor affecting asthma severity.
  - reference: PMID:32493146
    reference_title: "Risk factors for poor asthma control and impaired quality of life in a Caribbean population."
    supports: NO_EVIDENCE
    snippet: In this Caribbean population, uncontrolled asthma was independently associated with obesity, late-onset disease, and comorbidities of sleep apnea and depression.
    explanation: This study does not discuss tobacco smoke specifically as an environmental risk factor for asthma severity.
  - reference: PMID:37973258
    reference_title: "Extreme Weather Events and Asthma."
    supports: NO_EVIDENCE
    snippet: The objective of this article is to review recent literature on the implications of extreme weather events such as thunderstorms, wildfires, tropical cyclones, freshwater flooding, and temperature extremes in relationship to asthma symptoms.
    explanation: The study reviews the impact of extreme weather events on asthma but does not mention tobacco smoke.
  exposure_term:
    preferred_term: Tobacco smoke exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
- name: Occupational Exposures
  notes: Exposure to dust, chemicals, or gases in the workplace can trigger asthma symptoms.
  evidence:
  - reference: PMID:15579371
    reference_title: "Occupational exposures as triggers of asthma."
    supports: SUPPORT
    snippet: The prevalence of occupational asthma is rising, possibly due to the introduction of different chemicals and substances in the workplace. Etiologic agents include organic and inorganic compounds that are encountered in a variety of industries.
    explanation: This reference explicitly states that occupational exposures to chemicals and substances in the workplace can trigger asthma.
  - reference: PMID:33104273
    reference_title: "Respiratory symptoms of exposure to substances in the workplace among Bulgarian dentists."
    supports: SUPPORT
    snippet: Dentists are exposed to a variety of airborne chemicals that can act as irritants and sensitizers and may give rise to work-related respiratory symptoms.
    explanation: This supports the statement by indicating that occupational exposure to airborne chemicals can lead to respiratory symptoms including asthma.
  - reference: PMID:37971937
    reference_title: "Fatal Occupational Asthma in Cannabis Production - Massachusetts, 2022."
    supports: SUPPORT
    snippet: Multiple respiratory hazards have been identified in the cannabis cultivation and production industry, in which occupational asthma and work-related exacerbation of preexisting asthma have been reported.
    explanation: This reference highlights occupational asthma caused by exposure to respiratory hazards in the cannabis industry.
  - reference: PMID:19463209
    reference_title: "Surfer's asthma."
    supports: SUPPORT
    snippet: Common asthma triggers during recreational activities include allergen exposure, concomitant viral infection, and exercise.
    explanation: Although this reference discusses recreational triggers, the exposure to allergens also supports the idea that similar environmental triggers in occupational settings can lead to asthma.
  - reference: PMID:36938642
    reference_title: "World Trade Center-related asthma: clinical care essentials."
    supports: SUPPORT
    snippet: Environmental and occupational exposures contribute to its causation. WTC-related or aggravated asthma is considered a World Trace Center (WTC) Health Program certifiable disease.
    explanation: This supports the statement by acknowledging that occupational exposures can contribute to asthma.
  - reference: PMID:29427981
    reference_title: "Environmental Causes of Asthma."
    supports: SUPPORT
    snippet: Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen.
    explanation: This reference supports that occupational exposures to chemical sensitizers can trigger asthma.
  exposure_term:
    preferred_term: Occupational chemical exposure
    term:
      id: ECTO:0000231
      label: exposure to chemical
treatments:
- name: Inhaled Corticosteroid
  description: Reduce inflammation and prevent flare-ups.
  evidence:
  - reference: PMID:22559870
    reference_title: "The role of inhaled corticosteroids in asthma treatment: a health economic perspective."
    supports: SUPPORT
    snippet: Current guidelines recommend long-term treatment with inhaled corticosteroids (ICS) because of their superior effectiveness in managing the chronic airway inflammation that characterizes persistent asthma.
    explanation: This literature supports the statement that inhaled corticosteroids reduce inflammation in asthma.
  - reference: PMID:9817746
    reference_title: "Airway smooth muscle as a target of glucocorticoid action in the treatment of asthma."
    supports: SUPPORT
    snippet: Glucocorticoids are highly effective in the control of asthma and suppression of airway inflammation.
    explanation: This reference supports the role of glucocorticoids, which includes inhaled corticosteroids, in reducing airway inflammation in asthma.
  - reference: PMID:32868307
    reference_title: "Managing adult asthma: The 2019 GINA guidelines."
    supports: SUPPORT
    snippet: The 2019 Global Initiative for Asthma (GINA) guidelines recommend that all asthma patients be treated with inhaled corticosteroids taken daily or as needed; this improves symptoms and outcomes, even in those with mild disease.
    explanation: This guideline indicates that inhaled corticosteroids are recommended for improving asthma outcomes, supporting their role in preventing flare-ups.
  - reference: PMID:37182593
    reference_title: "The protective effect of inhaled corticosteroid on lung inflammation and breathing pattern complexity in a rat model of asthma."
    supports: SUPPORT
    snippet: Early treatment with inhaled corticosteroids not only diminishes lung inflammation and airway hyper-responsiveness, but also has a protective effect against the reduction of breathing pattern complexity due to asthma.
    explanation: The findings indicate that early treatment with inhaled corticosteroids reduces lung inflammation and helps prevent further complications, such as reduced breathing pattern complexity, supporting their role in preventive care.
  treatment_term:
    preferred_term: respiratory tract agent therapy
    term:
      id: MAXO:0000312
      label: respiratory tract agent therapy
- name: Long-acting Beta Agonist
  description: Relax the muscles around the airways.
  evidence:
  - reference: PMID:34753370
    reference_title: "State-of-the-art beta-adrenoreceptor agonists for the treatment of asthma."
    supports: SUPPORT
    snippet: Patients experience significant clinical benefits from therapy with long-acting β2-agonists (LABAs) with efficacy to bronchodilate, and prolonged lung function betterment.
    explanation: The literature supports that LABAs help in relaxing the muscles around the airways, thereby improving lung function and providing symptomatic relief in asthma management.
  - reference: PMID:37489386
    reference_title: "Open and Closed Triple Inhaler Therapy in Patients with Uncontrolled Asthma."
    supports: SUPPORT
    snippet: Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting beta2-agonists (ICS + LABA).
    explanation: Although primarily about LAMAs, the literature acknowledges that LABAs are part of the recommended treatment regimen for asthma, which implies their role in relaxing airway muscles.
  - reference: PMID:32306788
    reference_title: "Calcilytics: a non-steroidal replacement for inhaled steroid and SABA/LABA therapy of human asthma?"
    supports: SUPPORT
    snippet: Contemporary mainstay therapies (inhaled corticosteroids and bronchodilators), prescribed empirically, control symptoms resulting from airways obstruction tolerably well in many patients...
    explanation: The literature indicates that LABAs, as bronchodilators, help control symptoms related to airway obstruction by relaxing the airway muscles.
  treatment_term:
    preferred_term: respiratory tract agent therapy
    term:
      id: MAXO:0000312
      label: respiratory tract agent therapy
- name: Leukotriene Modifier
  description: Reduce inflammation, decrease mucus secretion, and prevent airway constriction.
  evidence:
  - reference: PMID:14720013
    reference_title: "Recent advances in the management of asthma using leukotriene modifiers."
    supports: SUPPORT
    snippet: Leukotriene modifiers increase the therapeutic options for patients with asthma and, based on recent data, it is expected that future guidelines will describe expanded uses for these agents in clinical circumstances where these drugs are effective.
  - reference: PMID:11085767
    reference_title: "Leukotriene receptor antagonist therapy."
    supports: SUPPORT
    snippet: Their unique mechanism of action results in a combination of both bronchodilator and anti-inflammatory effects.
  - reference: PMID:19180262
    reference_title: "Montelukast sodium for exercise-induced asthma."
    supports: SUPPORT
    snippet: Cysteinyl leukotrienes, which are derivatives of the 5-lipoxygenase pathway of arachidonic acid metabolism, are important mediators of airway allergic inflammation and have a role in the pathogenetic mechanism of EIB. Montelukast sodium (Singulair, Merck & Co.) is a selective and orally active leukotriene receptor antagonist with demonstrated activity for treating asthma and allergic rhinitis.
  treatment_term:
    preferred_term: respiratory tract agent therapy
    term:
      id: MAXO:0000312
      label: respiratory tract agent therapy
- name: Anti-IgE Therapy
  description: Used to treat severe allergic asthma by blocking IgE, a key chemical in the allergic response.
  evidence:
  - reference: PMID:29427989
    reference_title: "Diagnosis and Management of Severe Asthma."
    supports: SUPPORT
    snippet: Severe allergic asthma and severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic therapies currently available, namely anti-immunoglobulin E (IgE) and anti-interleukin (IL)-5 antibodies, respectively.
    explanation: This reference confirms that anti-IgE therapy is used to treat severe allergic asthma.
  - reference: PMID:20799475
    reference_title: "Treatment with a combination of anti-IgE and specific immunotherapy for allergic rhinitis and asthma."
    supports: SUPPORT
    snippet: Among these is anti-IgE, which directly targets IgE serum antibodies, thus inhibiting the central mechanism of immediate type hypersensitivity reactions. Application of anti-IgE antibodies effectively reduces IgE serum levels regardless of allergen specificity.
    explanation: This reference supports that anti-IgE therapy is used in allergic asthma by targeting and reducing IgE.
  - reference: PMID:28635659
    reference_title: "dIvergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti-IgE Therapies."
    supports: SUPPORT
    snippet: Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma.
    explanation: This reference confirms that anti-IgE therapy, specifically using omalizumab, is effective in treating allergic asthma.
  - reference: PMID:21114196
    reference_title: "Treating moderate-to-severe allergic asthma with anti-IgE monoclonal antibody (omalizumab). An update."
    supports: SUPPORT
    snippet: Omalizumab improves quality of life of patients with severe persistent allergic asthma that is inadequately controlled by currently available asthma medications. This therapy is well tolerated and significantly improves symptoms, disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids.
    explanation: This reference further supports the efficacy of anti-IgE therapy (omalizumab) in treating severe allergic asthma by improving symptoms and reducing exacerbations.
  treatment_term:
    preferred_term: respiratory tract agent therapy
    term:
      id: MAXO:0000312
      label: respiratory tract agent therapy
- description: Provides rapid relief from acute asthma symptoms.
  name: Short-acting Beta Agonist
  review_notes: Added Short-acting Beta Agonist for completeness in treatment options.
  evidence:
  - reference: PMID:34369231
    reference_title: "Pharmacology Update: Emergency and Controller Medications for Treatment of Asthma."
    supports: SUPPORT
    snippet: Albuterol is the most common fast acting medication for asthma, and it exists in multiple forms, including metered-dose inhaler and nebulized therapy.
    explanation: Albuterol, a commonly used short-acting beta agonist, is indicated as a fast-acting medication for the relief of asthma symptoms.
  - reference: PMID:30297688
    reference_title: "Paradoxical Bronchoconstriction with Short-Acting Beta Agonist."
    supports: SUPPORT
    snippet: Initial therapy in the stepwise approach for asthma management is short-acting β₂-agonist (SABA) therapy as needed for symptom control.
    explanation: Short-acting beta agonists are recommended as initial therapy for the control of asthma symptoms, indicating their rapid relief properties.
  - reference: PMID:27588581
    reference_title: "Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews."
    supports: SUPPORT
    snippet: Results demonstrate the efficacy of short-acting beta-agonist (SABA) delivered by metered-dose inhaler as first-line therapy for younger and older children.
    explanation: The efficacy of SABAs as a first-line therapy in emergency asthma management highlights their role in providing rapid relief from acute asthma symptoms.
  - reference: PMID:32482150
    reference_title: "Position statement: asthma in Latin America. IS short-acting beta-2 agonist helping or compromising asthma management?"
    supports: SUPPORT
    snippet: A majority of patients uses daily quick-relief medication, with the belief that it is the most important treatment because of its rapid onset of action.
    explanation: The use of quick-relief medication, such as SABAs, by a majority of patients for asthma management is based on their rapid onset of action.
  - reference: PMID:11253864
    reference_title: "Single-isomer beta-agonists."
    supports: SUPPORT
    snippet: 'Clinical studies comparing the effectiveness of (R)-albuterol (levalbuterol) with racemic albuterol established a strong rationale for using single-isomer beta-agonists in place of the racemic mixture: reduced dosages provide equivalent bronchodilatory effects with fewer beta-mediated side effects.'
    explanation: Levalbuterol, a single-isomer beta-agonist, is shown to provide effective rapid bronchodilation for asthma management.
  treatment_term:
    preferred_term: respiratory tract agent therapy
    term:
      id: MAXO:0000312
      label: respiratory tract agent therapy
disease_term:
  preferred_term: asthma
  term:
    id: MONDO:0004979
    label: asthma
datasets:
# Human bronchial epithelial expression - Type 2 inflammation
- accession: geo:GSE67472
  title: Airway epithelial gene expression in asthma versus healthy controls
  description: >-
    Bronchial epithelial brushings from mild-to-moderate asthmatics (not on
    inhaled steroids) and healthy controls, stratified by Type 2 inflammation
    markers (POSTN, SERPINB2, CLCA1).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: bronchial epithelial cells
    tissue_term:
      preferred_term: bronchus
      term:
        id: UBERON:0002185
        label: bronchus
    cell_type_term:
      preferred_term: bronchial epithelial cell
      term:
        id: CL:0002328
        label: bronchial epithelial cell
  sample_count: 105
  conditions:
  - mild-to-moderate asthma (n=62)
  - healthy controls (n=43)
  platform: Affymetrix Human Genome U133 Plus 2.0
  publication: PMID:25611785
  notes: >-
    Identifies Type 2 inflammation gene signature. Useful for studying
    eosinophilic asthma endotypes.

# Severity-stratified cohort
- accession: geo:GSE63142
  title: Asthma II
  description: >-
    Bronchial epithelial cells from normal controls, mild-moderate, and
    severe asthmatic patients to identify severity-associated gene expression.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: bronchial epithelial cells
    cell_type_term:
      preferred_term: bronchial epithelial cell
      term:
        id: CL:0002328
        label: bronchial epithelial cell
  sample_count: 155
  conditions:
  - severe asthma (n=56)
  - mild-moderate asthma (n=72)
  - healthy controls (n=27)
  platform: Agilent Whole Human Genome Microarray 4x44K

# Large nasal epithelium cohort
- accession: geo:GSE152004
  title: Transcriptomic profiles of the nasal epithelium from the Genes-environments & Admixture in Latino Americans (GALA) II study
  description: >-
    Large cohort study of nasal epithelial cells comparing asthmatic
    and control subjects.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: nasal epithelial cells
    tissue_term:
      preferred_term: nasal cavity mucosa
      term:
        id: UBERON:0001826
        label: nasal cavity mucosa
  sample_count: 393
  conditions:
  - asthma (n=257)
  - controls (n=136)

# Single-cell dataset
- accession: geo:GSE164015
  title: Epithelial miR-141 regulates IL-13-induced airway mucus production [single-cell RNA-seq]
  description: >-
    Single-cell RNA sequencing of airway epithelial cells from asthmatic
    patients revealing cell-type specific transcriptional changes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: airway epithelial cells
    cell_type_term:
      preferred_term: epithelial cell of tracheobronchial tree
      term:
        id: CL:0002202
        label: epithelial cell of tracheobronchial tree
  conditions:
  - asthmatic patients
  notes: Reveals cell-type specific heterogeneity in asthmatic airways

# Cigarette/e-cigarette exposure study
- accession: geo:GSE82137
  title: Molecular impact of electronic cigarette aerosol exposure in human bronchial epithelium
  description: >-
    Primary human bronchial epithelial cells grown at air-liquid interface,
    exposed to whole tobacco cigarette smoke and electronic cigarette aerosol.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_types:
  - preferred_term: primary bronchial epithelial cells (ALI culture)
    cell_type_term:
      preferred_term: bronchial epithelial cell
      term:
        id: CL:0002328
        label: bronchial epithelial cell
  conditions:
  - tobacco cigarette smoke (48 puffs)
  - e-cigarette aerosol (menthol flavor, +/- nicotine)
  - e-cigarette aerosol (tobacco flavor, +/- nicotine)
  - control
  exposures:
  - preferred_term: tobacco smoke exposure
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  notes: Compares traditional vs electronic cigarette effects on airway epithelium

# Mouse OVA model
- accession: geo:GSE11911
  title: Gene expression profiling of experimental asthma reveals a possible role of paraoxonase-1 in asthma
  description: >-
    Gene expression from lung tissue of ovalbumin-sensitized and challenged
    BALB/c mice modeling allergic airway inflammation.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  sample_types:
  - preferred_term: whole lung tissue
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  conditions:
  - OVA-sensitized and challenged
  - control
  exposures:
  - preferred_term: ovalbumin allergen challenge
    term:
      id: ECTO:0000726
      label: exposure to allergen
  notes: Classic murine allergic airway inflammation model

# CELLxGENE - Integrated Human Lung Cell Atlas
- accession: "cellxgene:6f6d381a-7701-4781-935c-db10d30de293"
  title: The integrated Human Lung Cell Atlas
  description: >-
    Integrated atlas of human lung cells providing a comprehensive single-cell
    reference for all major lung cell types across health and disease. Includes
    airway epithelial, immune, and stromal populations relevant to asthma
    pathophysiology.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: lung tissue
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  conditions:
  - normal
  - asthma
  - chronic obstructive pulmonary disease
  publication: PMID:37291214
  notes: >-
    CZI CELLxGENE collection. Reference atlas for lung cell types including
    goblet cells, ciliated cells, club cells, and immune populations central
    to asthma pathology. Useful for virtual cell model benchmarking.

clinical_trials:
- name: NCT05813288
  phase: PHASE_III
  status: COMPLETED
  description: A randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability of dexpramipexole in participants with severe eosinophilic asthma. The trial evaluated a novel oral treatment approach over 52 weeks in patients with inadequately controlled disease.
  target_phenotypes:
  - preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
  - preferred_term: Breathlessness
    term:
      id: HP:0002094
      label: Dyspnea
  - preferred_term: Chest Tightness
    term:
      id: HP:0031352
      label: Chest tightness
  - preferred_term: Coughing
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: clinicaltrials:NCT05813288
    supports: SUPPORT
    snippet: The objective of this clinical study is to investigate the safety, tolerability, and efficacy of dexpramipexole in participants with inadequately controlled severe eosinophilic asthma.
    explanation: This trial directly evaluates a therapeutic approach for severe eosinophilic asthma, a well-defined phenotype of asthma, and represents current research into treatment options for this severe form of the disease.