Table 1.

Summary of non-respiratory comorbidities of asthma

Comorbidity	Major findings	References
Diabetes mellitus	• In vitro and in vivo:  ○ Insulin heightens airway hyperresponsiveness, potentially through increased laminin and β-catenin expression. • Clinical studies in humans:  ○ Higher Th1/Th2 ratios in peripheral blood lymphocytes among obese adolescents with asthma relative to non-obese adolescents with and without asthma  ○ Higher IL6 levels are seen in subjects with asthma and those with the metabolic syndrome and may aggravate pathologic features of asthma.  ○ Systemic inflammation from DM2 may worsen asthma  ○ DM2 is associated with a greater incidence of asthma and worse asthma morbidity outcomes.  ○ Dual anti-asthma and anti-diabetes medications are being investigated (e.g. metformin, GLP1RA).	8, 9, 12, 13, 16, 19, 21, 23
Hypertension	• In vitro and in vivo:  ○ Hypertension is characterized by higher levels of IL17+ T cells, and IL17 induces AHR in mice. • Clinical studies in humans:  ○ Hypertension is associated with greater rescue inhaler use and greater emergency room visits or hospitalizations for asthma  ○ Dual anti-asthma and anti-hypertensive medications are being investigated (e.g. angiotensin receptor blockers)	11, 31, 37, 40
Atherosclerotic cardiovascular disease	• In vitro and in vivo:  ○ IL1- and IL17-mediated inflammation and mast cells are implicated in atherosclerotic plaque formation and in subsets of asthma. • Clinical studies in humans:  ○ Subjects with asthma compared to those without asthma are at higher risk of developing atherosclerotic cardiovascular complications.  ○ Whether statins are beneficial in asthma remains inconclusive.  ○ The anti-IL1β monoclonal antibody canakinumab improves cardiovascular outcomes but needs to be tested for efficacy in asthma	44, 46, 49, 52
Adrenal disorders	• In vitro and in vivo:  ○ Glucocorticoids attenuate inflammation through genomic and non-genomic mechanisms. • Clinical studies in humans:  ○ Case reports link Addison’s disease to asthma onset as well as deterioration of pre-existing asthma.  ○ Subjects taking cytochrome P450 inhibitors are at greater risk of developing Cushing syndrome from use of ICS	56, 58, 62, 67, 68
Thyroid diseases	• In vitro and in vivo:  ○ Thyroid hormones have an unclear role in asthma pathophysiology due to contrasting effects on airway structural and inflammatory cells. • Clinical studies in humans:  ○ Subjects with autoimmune thyroiditis versus normals have greater odds of having asthma.	66, 71, 76
Pregnancy	• In vitro and in vivo:  ○ Estrogen receptor-α signaling results in type-2 airway inflammation, mast cell activation, mucin hypersecretion.  ○ Conversely, estrogen reduces airway hyperresponsiveness through airway smooth muscle relaxation.  ○ Progesterone attenuates airway remodeling and glucocorticoid resistance. • Clinical studies in humans:  ○ Pregnancy induces physiologic pulmonary function changes to accommodate for the increased maternal cardiometabolic demands.  ○ A large proportion of pregnant women have uncontrolled asthma. Smoking and suboptimal pharmacotherapy are modifiable risk factors for uncontrolled asthma.  ○ A greater susceptibility to viral respiratory infections in pregnant women with asthma relative to those without asthma may underlie their risk of uncontrolled asthma during pregnancy.	84, 87, 89, 90, 93, 98
Osteoporosis	• Subjects with asthma at moderate to high risk of osteoporosis due to glucocorticoid use should have DEXA scan screens. • Regular exercise, vitamin D and calcium supplementations, fall prevention strategies, smoking cessation, reductions in alcohol consumption are some of the cornerstones to maintaining adequate bone health.	102–105
Medications	• Beta blockers (especially non-cardio-selective ones) are not recommended in severe and uncontrolled asthma, but the literature supporting this recommendation is equivocal. • Atopy and asthma may increase the risk of ACE inhibitor-induced cough, and the risk may be higher for severe asthma.	107, 110, 114, 118, 119
Mental health disorders	• In vitro and in vivo:  ○ Serotonin has an unclear role in asthma pathophysiology due to contrasting effects on airway structural and inflammatory cells. • Clinical studies in humans:  ○ Anxiety and panic disorders are more prevalent among subjects with asthma versus the general population.  ○ Anxiety and depression are associated with poor asthma control and greater risk of asthma exacerbations.	124, 126, 128, 132, 133

ACE: angiotensin converting enzyme; AHR: airway hyperresponsiveness; DEXA: dualenergy x-ray absorptiometry; DM2: diabetes mellitus type 2; GLP1RA: glucagon-like peptide 1 receptor agonists ICS: inhaled corticosteroids; IL: interleukin; Th: T helper cell