**Background:** Bronchial asthma is the most frequent inflammatory non-communicable airway disease worldwide and is commonly associated with concomitant conditions that substantially contribute to its burden. While respiratory comorbidities of asthma are well-recognized, recent research has highlighted pathobiological interactions between asthma and other organ systems based on shared immunological mechanisms. The authors note that 10–25% of severe asthma patients do not respond to biologic therapies (anti-IL-5), suggesting that unrecognized systemic comorbidities may contribute to treatment failure. This review aims to provide an overview of recent acquisitions regarding asthma's concomitant systemic conditions beyond respiratory comorbidities.
**Methods:** This is a narrative review synthesizing published literature on the associations between asthma and systemic conditions including eosinophilic diseases, alpha-1 antitrypsin deficiency (AATD), immunodeficiencies, sickle cell disease (SCD), neurodegenerative diseases, metabolic syndrome/obesity, and cardiovascular disease (CVD). The authors discuss epidemiological evidence, shared pathobiological mechanisms, clinical implications, and therapeutic considerations for each comorbidity.
**Key Results:**
- **Eosinophilic Diseases:** Asthma frequently represents respiratory tract involvement of eosinophilic granulomatosis with polyangiitis (EGPA), allergic bronchopulmonary aspergillosis (ABPA), hyper-eosinophilic syndrome (HES), chronic eosinophilic pneumonia (CEP), eosinophilic bronchitis (EB), and hyper-eosinophilic obliterative bronchiolitis (HOB). Severe/uncontrolled asthma is present in nearly 45% of EGPA patients at diagnosis. Respiratory symptoms occur in 25% of HES patients at presentation.
- **Alpha-1 Antitrypsin Deficiency:** AATD occurs in approximately 1:3000–5000 people but is underdiagnosed, with less than 10% of individuals identified and a diagnostic delay exceeding 5 years. In poorly controlled asthma, AATD is detectable in 2–3% of subjects, with 10.5% carrying a deficiency gene. A Spanish study found 22.4% of allergic asthma patients had at least one mutated allele (S or Z). Mean age of Pi*Z genotype diagnosis was 55.9 ± 9.8 years, with average smoking history of 23.2 ± 14.5 pack-years.
- **Immunodeficiencies:** Asthmatic patients have an increased risk (OR 2.46–4.98) of antibody deficiency. In Common Variable Immunodeficiency (CVID), asthma is the most common respiratory complication. Asthmatic patients with primary immunodeficiencies more frequently have severe disease and frequent exacerbations. Immunoglobulin replacement therapy (IRT) and prophylactic azithromycin reduced infection-driven exacerbations and improved asthma control.
- **Sickle Cell Disease:** Children with SCD and asthma have increased rates of vaso-occlusive crises (VOCs) and acute chest syndrome (ACS), and increased risk of premature death. In a study of 939 patients experiencing ACS, 11% presented with wheezing on admission. Severe wheezing, regardless of underlying asthma, doubled rates of pain and ACS, decreased lung function, and increased mortality risk.
- **Neurodegenerative Diseases:** Mild cognitive impairment (MCI) is the most frequently reported brain involvement in asthma, with dementia and Alzheimer's disease also associated. Older age, uncontrolled and more severe asthma are risk factors. A study found significant increases in astrocyte activation markers (GFAP, NfL) related to asthma severity. Prolonged oral corticosteroid use reduced amygdala volume, while montelukast showed protective effects in animal models.
- **Metabolic Syndrome and Obesity:** Metabolic syndrome prevalence among asthma patients is estimated at 25%. The HUNT study showed hyperglycemia/type 2 diabetes confers higher asthma incidence (OR 1.43, 95% CI 1.01–2.04) over 11 years. Patients with prediabetes-range HbA1c have 27% higher exacerbation rates; diabetes-range HbA1c confers 33% higher rates. Asthma prevalence among obese patients is increased, with 20–50% of severe asthmatics being obese.
- **Cardiovascular Disease:** Asthma has been associated with endothelial dysfunction, prothrombotic diathesis, myocardial infarction, and cardiovascular mortality. A recent meta-analysis confirmed increased CVD morbidity and mortality in asthma patients. Eosinophil blood count is a potential predictor of cardiovascular risk; a large cohort study confirmed high eosinophil counts were associated with increased risk of heart failure, stroke, and cardiovascular death. Basophil blood counts predicted mortality in coronary artery disease patients.
**Clinical Implications:** The authors argue that awareness of these interactions should guide diagnostic work-up, follow-up scheduling, and personalized treatment plans. They recommend systematic screening for AATD in patients with poorly controlled asthma, particularly those with onset in the fourth decade, non-reversible obstruction, and pan-lobular emphysema. For immunodeficiencies, frequent exacerbations should prompt Ig dosage and vaccine response testing. In SCD, asthma investigation should be part of comprehensive care, with careful evaluation of systemic corticosteroid use due to risk of rebounding pain and avascular necrosis. For obese-asthmatic patients, long-term systemic corticosteroids should be avoided, and biologic dosing may need adjustment. The cardiovascular risk in asthma patients warrants clinician awareness, and anti-inflammatory therapies including biologics may be relevant for preventing cardiac damage. The authors conclude that effective use of targeted treatments alone is insufficient without addressing the complex interplay of concomitant conditions, and that understanding shared immunological pathways is essential for personalized medicine.