graph LR
Air_Pollution["Air Pollution"]
Allergens["Allergens"]
STAT6_Degrader_SAR448272_NX_3911["STAT6 Degrader (SAR448272/NX-3911)"]
IL4["IL4"]
Respiratory_Distress["Respiratory Distress"]
Occupational_Exposures["Occupational Exposures"]
Sleep_Disturbance["Sleep Disturbance"]
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling["Hill mechanochemical morphoelastic model of asthmatic airway remodelling"]
Tobacco_Smoke["Tobacco Smoke"]
Anxiety["Anxiety"]
Coughing["Coughing"]
Prenatal_Acid_Suppressive_Medication_Exposure["Prenatal Acid-Suppressive Medication Exposure"]
ADAM33["ADAM33"]
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation["SIRT1-Mediated NAD+ Signaling and Protective Deacetylation"]
Reduced_Exercise_Tolerance["Reduced Exercise Tolerance"]
Winkler_integrative_bronchial_tree_model_of_asthmatic_bronchoconstriction["Winkler integrative bronchial-tree model of asthmatic bronchoconstriction"]
Cyanosis["Cyanosis"]
Wheezing["Wheezing"]
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling["House Dust Mite Allergen Protease-Induced Epithelial Oxidant Signaling"]
Mucus_Overproduction["Mucus Overproduction"]
Chest_Tightness["Chest Tightness"]
Exercise_Intolerance["Exercise Intolerance"]
STAT3["STAT3"]
Rapid_Breathing["Rapid Breathing"]
Airway_Inflammation["Airway Inflammation"]
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception["Early-Life Rhinovirus Wheezing Illness and Asthma Inception"]
CDHR3["CDHR3"]
Bronchoconstriction["Bronchoconstriction"]
Airway_Remodeling["Airway Remodeling"]
IL13["IL13"]
Fatigue["Fatigue"]
Type_2_Immune_Response___Th2_Signaling["Type 2 Immune Response / Th2 Signaling"]
Airway_Inflammation --> Bronchoconstriction
Type_2_Immune_Response___Th2_Signaling --> Airway_Inflammation
Type_2_Immune_Response___Th2_Signaling --> Mucus_Overproduction
Bronchoconstriction --> Wheezing
Bronchoconstriction --> Chest_Tightness
Bronchoconstriction --> Rapid_Breathing
Bronchoconstriction --> Respiratory_Distress
Bronchoconstriction --> Cyanosis
Bronchoconstriction --> Exercise_Intolerance
Bronchoconstriction --> Reduced_Exercise_Tolerance
Bronchoconstriction --> Fatigue
Bronchoconstriction --> Anxiety
Mucus_Overproduction --> Coughing
Mucus_Overproduction --> Sleep_Disturbance
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Type_2_Immune_Response___Th2_Signaling
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Mucus_Overproduction
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Airway_Remodeling
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Bronchoconstriction
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception --> Type_2_Immune_Response___Th2_Signaling
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling --> Airway_Inflammation
Wheezing --> Respiratory_Distress
Wheezing --> Reduced_Exercise_Tolerance
Allergens --> Type_2_Immune_Response___Th2_Signaling
Air_Pollution --> Airway_Inflammation
Tobacco_Smoke --> Airway_Inflammation
Occupational_Exposures --> Airway_Inflammation
Prenatal_Acid_Suppressive_Medication_Exposure --> Type_2_Immune_Response___Th2_Signaling
STAT6_Degrader_SAR448272_NX_3911 --> Type_2_Immune_Response___Th2_Signaling
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling --> Airway_Remodeling
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling --> Bronchoconstriction
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling --> Airway_Inflammation
Winkler_integrative_bronchial_tree_model_of_asthmatic_bronchoconstriction --> Bronchoconstriction
IL4 --> Type_2_Immune_Response___Th2_Signaling
IL13 --> Type_2_Immune_Response___Th2_Signaling
ADAM33 --> Airway_Remodeling
STAT3 --> SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation
CDHR3 --> Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception
style Air_Pollution fill:#dcfce7
style Allergens fill:#dcfce7
style STAT6_Degrader_SAR448272_NX_3911 fill:#fce7f3
style IL4 fill:#f3e8ff
style Respiratory_Distress fill:#fef3c7
style Occupational_Exposures fill:#dcfce7
style Sleep_Disturbance fill:#fef3c7
style Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling fill:#ecfccb
style Tobacco_Smoke fill:#dcfce7
style Anxiety fill:#fef3c7
style Coughing fill:#fef3c7
style Prenatal_Acid_Suppressive_Medication_Exposure fill:#dcfce7
style ADAM33 fill:#f3e8ff
style SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation fill:#dbeafe
style Reduced_Exercise_Tolerance fill:#fef3c7
style Winkler_integrative_bronchial_tree_model_of_asthmatic_bronchoconstriction fill:#ecfccb
style Cyanosis fill:#fef3c7
style Wheezing fill:#fef3c7
style House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling fill:#dbeafe
style Mucus_Overproduction fill:#dbeafe
style Chest_Tightness fill:#fef3c7
style Exercise_Intolerance fill:#fef3c7
style STAT3 fill:#f3e8ff
style Rapid_Breathing fill:#fef3c7
style Airway_Inflammation fill:#dbeafe
style Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception fill:#dbeafe
style CDHR3 fill:#f3e8ff
style Bronchoconstriction fill:#dbeafe
style Airway_Remodeling fill:#dbeafe
style IL13 fill:#f3e8ff
style Fatigue fill:#fef3c7
style Type_2_Immune_Response___Th2_Signaling fill:#dbeafe
graph LR
Dyspnea["Dyspnea"]
Protease_Antiprotease_Imbalance_MMP_2_TIMP_2_Axis["Protease-Antiprotease Imbalance (MMP-2/TIMP-2 Axis)"]
Open_top_vascularized_alveolus_on_chip_whole_cigarette_smoke_model["Open-top vascularized alveolus-on-chip whole cigarette smoke model"]
Mucus_Hypersecretion["Mucus Hypersecretion"]
Air_Pollution["Air Pollution"]
Cellular_Senescence["Cellular Senescence"]
Airway_Remodeling["Airway Remodeling"]
Smoking["Smoking"]
Chronic_Inflammation["Chronic Inflammation"]
Oxidative_Stress_and_Mitochondrial_Dysfunction["Oxidative Stress and Mitochondrial Dysfunction"]
Forced_Expiratory_Volume_in_1_Second_FEV1["Forced Expiratory Volume in 1 Second (FEV1)"]
Airflow_Limitation["Airflow Limitation"]
Respiratory_Failure["Respiratory Failure"]
Occupational_Dust_and_Chemicals["Occupational Dust and Chemicals"]
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation["SIRT1-Mediated NAD+ Signaling and Protective Deacetylation"]
NFE2L2["NFE2L2"]
Hypercapnia["Hypercapnia"]
Hypoxemia["Hypoxemia"]
Cuproptosis_Driven_Cell_Death["Cuproptosis-Driven Cell Death"]
Alveolar_Destruction["Alveolar Destruction"]
Patient_derived_epithelial_endothelial_COPD_airway_on_a_chip["Patient-derived epithelial-endothelial COPD airway-on-a-chip"]
Progressive_Respiratory_Impairment["Progressive Respiratory Impairment"]
Exercise_Intolerance["Exercise Intolerance"]
Airflow_Limitation -.-> Progressive_Respiratory_Impairment
Chronic_Inflammation --> Cuproptosis_Driven_Cell_Death
Oxidative_Stress_and_Mitochondrial_Dysfunction --> Protease_Antiprotease_Imbalance_MMP_2_TIMP_2_Axis
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Chronic_Inflammation
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Cellular_Senescence
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Alveolar_Destruction
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Oxidative_Stress_and_Mitochondrial_Dysfunction
Protease_Antiprotease_Imbalance_MMP_2_TIMP_2_Axis --> Alveolar_Destruction
Cuproptosis_Driven_Cell_Death --> Chronic_Inflammation
Dyspnea --> Exercise_Intolerance
Respiratory_Failure --> Hypoxemia
Respiratory_Failure --> Hypercapnia
Smoking --> Chronic_Inflammation
Smoking --> Cuproptosis_Driven_Cell_Death
Air_Pollution --> Oxidative_Stress_and_Mitochondrial_Dysfunction
Occupational_Dust_and_Chemicals --> Chronic_Inflammation
Open_top_vascularized_alveolus_on_chip_whole_cigarette_smoke_model --> Alveolar_Destruction
Open_top_vascularized_alveolus_on_chip_whole_cigarette_smoke_model --> Oxidative_Stress_and_Mitochondrial_Dysfunction
Patient_derived_epithelial_endothelial_COPD_airway_on_a_chip --> Mucus_Hypersecretion
Patient_derived_epithelial_endothelial_COPD_airway_on_a_chip --> Airway_Remodeling
Airflow_Limitation -.-> Forced_Expiratory_Volume_in_1_Second_FEV1
NFE2L2 --> SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation
style Dyspnea fill:#fef3c7
style Protease_Antiprotease_Imbalance_MMP_2_TIMP_2_Axis fill:#dbeafe
style Open_top_vascularized_alveolus_on_chip_whole_cigarette_smoke_model fill:#ccfbf1
style Mucus_Hypersecretion fill:#dbeafe
style Air_Pollution fill:#dcfce7
style Cellular_Senescence fill:#dbeafe
style Airway_Remodeling fill:#dbeafe
style Smoking fill:#dcfce7
style Chronic_Inflammation fill:#dbeafe
style Oxidative_Stress_and_Mitochondrial_Dysfunction fill:#dbeafe
style Forced_Expiratory_Volume_in_1_Second_FEV1 fill:#e0e7ff
style Airflow_Limitation fill:#dbeafe
style Respiratory_Failure fill:#fef3c7
style Occupational_Dust_and_Chemicals fill:#dcfce7
style SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation fill:#dbeafe
style NFE2L2 fill:#f3e8ff
style Hypercapnia fill:#fef3c7
style Hypoxemia fill:#fef3c7
style Cuproptosis_Driven_Cell_Death fill:#dbeafe
style Alveolar_Destruction fill:#dbeafe
style Patient_derived_epithelial_endothelial_COPD_airway_on_a_chip fill:#ccfbf1
style Progressive_Respiratory_Impairment fill:#fee2e2,stroke:#dc2626,stroke-dasharray: 5 5
style Exercise_Intolerance fill:#fef3c7
name: com_Asthma__Chronic_Obstructive_Pulmonary_Disease
creation_date: '2026-06-26T00:00:00Z'
curation_status: CANDIDATE
notes: >-
Asthma-COPD overlap (ACO): a well-recognized clinical entity in which features
of both diseases coexist, with higher illness burden and healthcare use than
either alone. Surfaced as the strongest positive both-in-dismech ICEES EHR
signal (UNC PCD cohort, chi-square=168.6, p=1.5e-38) and corroborated by ACO
review literature. Directionality is left UNKNOWN: ACO encompasses both
asthma-predominant and COPD-predominant trajectories, and definitions vary
across studies, though long-standing asthma is a recognized risk factor for
later fixed airflow obstruction.
disease_a:
slug: Asthma
preferred_term: asthma
term:
id: MONDO:0004979
label: asthma
disease_b:
slug: Chronic_Obstructive_Pulmonary_Disease
preferred_term: chronic obstructive pulmonary disease
term:
id: MONDO:0005002
label: chronic obstructive pulmonary disease
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: chronic airway inflammation and remodeling shared between asthma
and COPD produce an overlap phenotype (ACO); long-standing asthma with
incompletely reversible airflow limitation can progress toward, or be
reclassified as, fixed obstruction characteristic of COPD.
evidence:
- reference: PMID:30461532
reference_title: "The many faces of asthma-chronic obstructive pulmonary disease overlap."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Asthma and chronic obstructive pulmonary disease (COPD) are common diseases that often overlap."
explanation: >-
Review establishes asthma and COPD as frequently overlapping diseases,
the clinical basis of the ACO comorbidity signal.
- reference: PMID:30461532
reference_title: "The many faces of asthma-chronic obstructive pulmonary disease overlap."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Epidemiological studies reveal that ACO patients have generally an increased burden of illness and healthcare use in addition to poorer quality of life (QoL) compared with asthma and higher or equal to COPD."
explanation: >-
Supports the clinical significance of the overlap: ACO carries greater
illness burden and healthcare use than asthma alone.
pathophysiology:
- name: Shared airway inflammation and fixed airflow obstruction
description: >-
Overlapping inflammatory airway disease in ACO can lead to progressive,
incompletely reversible airflow limitation, blurring the boundary between
an asthma and a COPD diagnosis.
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
evidence:
- reference: PMID:30461532
reference_title: "The many faces of asthma-chronic obstructive pulmonary disease overlap."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The term asthma-COPD overlap (ACO) has been used to define this entity but there remain several speculations on its exact definition, impact, pathophysiology, clinical features, and management."
explanation: >-
Notes that ACO pathophysiology and definition remain incompletely
resolved, supporting the cautious CANDIDATE framing.
association_signals:
- source: ICEES
method: EHR_COHORT_ASSOCIATION
signal_disorder_a_id: MONDO:0004979
signal_disorder_b_id: MONDO:0005002
population: >-
ICEES KG 8-20-2024, UNC Health primary-ciliary-dyskinesia (PCD) cohort
(condition-specific base population), patient-level chi-square contingency.
mapping_notes: >-
ICEES reports this pair as a positive correlation. Chi-square is not
multiple-testing corrected and is conditioned on the PCD base population,
so it corroborates rather than establishes the association. The row quoted
is the strongest PCD cohort-year (2016).
directionality: UNKNOWN
statistics:
metrics:
- metric_type: CHI_SQUARE
metric_value: 168.58533016733276
p_value: 1.5071340388291068e-38
notes: >-
ICEES PCD 2016 cohort co-occurrence of asthma and COPD (N=5688);
strong, highly significant positive association.
evidence:
- reference: ICEES:MONDO_0004979__MONDO_0005002
reference_title: "asthma / chronic obstructive pulmonary disease (ICEES KG)"
supports: SUPPORT
evidence_source: OTHER
snippet: "PCD_UNC_patient_2016_v6_binned_deidentified | 168.58533016733276 | 1 | 1.5071340388291068e-38 | 5688"
explanation: >-
ICEES UNC EHR cohort shows a strong, highly significant asthma-COPD
co-occurrence in the 2016 PCD cohort.