graph LR
Chest_Tightness["Chest Tightness"]
Exercise_Intolerance["Exercise Intolerance"]
Sleep_Disturbance["Sleep Disturbance"]
Type_2_Immune_Response___Th2_Signaling["Type 2 Immune Response / Th2 Signaling"]
IL4["IL4"]
Wheezing["Wheezing"]
IL13["IL13"]
Airway_Inflammation["Airway Inflammation"]
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception["Early-Life Rhinovirus Wheezing Illness and Asthma Inception"]
Rapid_Breathing["Rapid Breathing"]
Respiratory_Distress["Respiratory Distress"]
STAT3["STAT3"]
Coughing["Coughing"]
Bronchoconstriction["Bronchoconstriction"]
Reduced_Exercise_Tolerance["Reduced Exercise Tolerance"]
CDHR3["CDHR3"]
Anxiety["Anxiety"]
Airway_Remodeling["Airway Remodeling"]
Mucus_Overproduction["Mucus Overproduction"]
ADAM33["ADAM33"]
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling["House Dust Mite Allergen Protease-Induced Epithelial Oxidant Signaling"]
Fatigue["Fatigue"]
Cyanosis["Cyanosis"]
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation["SIRT1-Mediated NAD+ Signaling and Protective Deacetylation"]
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
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 Chest_Tightness fill:#fef3c7
style Exercise_Intolerance fill:#fef3c7
style Sleep_Disturbance fill:#fef3c7
style Type_2_Immune_Response___Th2_Signaling fill:#dbeafe
style IL4 fill:#f3e8ff
style Wheezing fill:#fef3c7
style IL13 fill:#f3e8ff
style Airway_Inflammation fill:#dbeafe
style Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception fill:#dbeafe
style Rapid_Breathing fill:#fef3c7
style Respiratory_Distress fill:#fef3c7
style STAT3 fill:#f3e8ff
style Coughing fill:#fef3c7
style Bronchoconstriction fill:#dbeafe
style Reduced_Exercise_Tolerance fill:#fef3c7
style CDHR3 fill:#f3e8ff
style Anxiety fill:#fef3c7
style Airway_Remodeling fill:#dbeafe
style Mucus_Overproduction fill:#dbeafe
style ADAM33 fill:#f3e8ff
style House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling fill:#dbeafe
style Fatigue fill:#fef3c7
style Cyanosis fill:#fef3c7
style SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation fill:#dbeafe
graph LR
Alveolar_Destruction["Alveolar Destruction"]
Progressive_Respiratory_Impairment["Progressive Respiratory Impairment"]
Exercise_Intolerance["Exercise Intolerance"]
Respiratory_Failure["Respiratory Failure"]
Hypoxemia["Hypoxemia"]
Oxidative_Stress_and_Mitochondrial_Dysfunction["Oxidative Stress and Mitochondrial Dysfunction"]
Hypercapnia["Hypercapnia"]
Airflow_Limitation["Airflow Limitation"]
NFE2L2["NFE2L2"]
Forced_Expiratory_Volume_in_1_Second_FEV1["Forced Expiratory Volume in 1 Second (FEV1)"]
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation["SIRT1-Mediated NAD+ Signaling and Protective Deacetylation"]
Chronic_Inflammation["Chronic Inflammation"]
Cellular_Senescence["Cellular Senescence"]
Dyspnea["Dyspnea"]
Airflow_Limitation -.-> Progressive_Respiratory_Impairment
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
Dyspnea --> Exercise_Intolerance
Respiratory_Failure --> Hypoxemia
Respiratory_Failure --> Hypercapnia
Airflow_Limitation -.-> Forced_Expiratory_Volume_in_1_Second_FEV1
NFE2L2 --> SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation
style Alveolar_Destruction fill:#dbeafe
style Progressive_Respiratory_Impairment fill:#fee2e2,stroke:#dc2626,stroke-dasharray: 5 5
style Exercise_Intolerance fill:#fef3c7
style Respiratory_Failure fill:#fef3c7
style Hypoxemia fill:#fef3c7
style Oxidative_Stress_and_Mitochondrial_Dysfunction fill:#dbeafe
style Hypercapnia fill:#fef3c7
style Airflow_Limitation fill:#dbeafe
style NFE2L2 fill:#f3e8ff
style Forced_Expiratory_Volume_in_1_Second_FEV1 fill:#e0e7ff
style SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation fill:#dbeafe
style Chronic_Inflammation fill:#dbeafe
style Cellular_Senescence fill:#dbeafe
style Dyspnea 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
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
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
supports: PARTIAL
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
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.