Mortality Statistics in Asthma

Chronic severe asthma includes two subtypes based on the amount of Type 2 (T2) inflammation:

• T2-high inflammation asthma

• T2-low inflammation asthma

Persons with T2-high inflammation asthma have elevated airway and systemic eosinophilia, elevated fractional exhaled nitric oxide (FeNO) and respond better to glucocorticoids. They also have other signs of type 2 inflammation, such as increased numbers of airway mast cells (MCs) and sputum basophils and are often seen in association with severe sinus disease and nasal polyposis. In addition to high dose inhaled glucocorticoids plus a second controller (eg, long-acting beta agonist, leukotriene modifier, or theophylline), T2-high patients may need treatment with biologics, as follows:

• Anti-immunoglobulin IgE – omalizumab

• Anti-interleukin IL5 agents – mepoli-zeumab, benralizumab, reslizumab

• Anti-IL-4 subunit alpha – dupilumab

• Anti-thymic stromal lymphopoietin (TSLP) – tezepelumab

Underwriters should note that for applicants with eosinophils ≥300/μl, investigation for non-asthma causes including Strongyloides (often asymptomatic) are indicated. For applicants with hypereosinophilia (eg, ≥1500/μl), underwriters should consider EGPA (eosinophilic granulomatosis with polyangiitis).

Persons with type 2-low inflammation asthma do not have airway or systemic eosinophilia and respond more poorly to glucocorticosteroids. They may be treated with tezepelumab, although their response is not as good as persons with eosinophilic asthma.

Several studies have identified an increased prevalence of asthma among obese individuals compared with those of normal weight. In a Dutch cohort, the prevalence of obesity (body mass index ≥30 kg/m²) among a cohort with severe asthma was 21%.⁸ In a similar cohort in the United Kingdom, the prevalence of obesity was 48%.⁹ 

The risk of obesity-associated asthma is higher for women than men and among nonatopic individuals than atopic. Asthma associated with obesity is often more difficult to control and less likely to respond to traditional asthma therapy. There appears to be a particular phenotype of obese asthma associated with metabolic syndrome and elevated blood IL-6 levels.¹⁰ 

Clinical studies have demonstrated various degrees of associations of asthma, asthma-associated medications, allergic rhinitis and even atopic dermatitis and anaphylaxis with cardiovascular disease (CVD), including coronary heart diseases (CHD), aortic diseases, peripheral arterial diseases (PAD), pulmonary embolism, pulmonary hypertension, right ventricular (RV) dysfunctions, atrial fibrillation, cardiac hypertrophy, and even systemic hypertension.

These mortality statistics do not apply to childhood asthma that completely remits by their teens. Severe early childhood bronchitis manifested by recurrent protracted wet cough have a 3-fold increased risk pneumonia, a 4.5-fold increased risk of current asthma, and a 6.4-fold increased risk for developing adult-onset asthma (but not bronchitis) by age 53, according to a recent study.¹¹ 

In the past decade, the prevalence of asthma has increased 8.6% in children and 7.4% in adults. Asthma in adulthood is associated with increased risk of premature death and cardiovascular disease (CVD). Links between asthma and CVD began emerging as early as the 1970s. Patients with asthma, along with chronic obstructive pulmonary disease (COPD) and interstitial lung disease, have a higher incidence of CVD (such as acute myocardial infarction (AMI) and ischemic stroke) possibly due to chronic activation of pro-inflammatory cytokines, resulting in systemic and vascular inflammation.

These two diseases share a common etiology underlined by chronic systemic inflammation. Age and overweight or obesity commonly contribute to the risk of CVD and severe asthma. The mechanisms by which obesity contributes to asthma or CVD involve elevated systemic inflammation. Obese persons with high plasma cytokine interleukin (IL)-6 levels show more severe asthma than those with low IL-6 levels. Systemic inflammation in obese persons includes high plasma IL-6, IL-1, tumor necrosis factor (TNF) and leptin levels. For example, IL-6 influences naïve T cell differentiation into type 17 helper T (T_H17) cells and indirectly affects cardiac and lung functions via T_H-17. Such inflammatory mediators can drive CVD and may originate from adipocytes and activated inflammatory cells. These molecules also activate lung vascular endothelial cells, airway fibroblasts, smooth muscle cells (SMCs), tracheobronchial epithelial cells and inflammatory cells and the analogous cell types in the myocardium and vasculature.

Although adult asthma patients have an increased risk of all-cause mortality, only a small number of asthma patients die directly from the asthma itself.¹² Thus, an increased risk of death in asthma patients is mainly due to comorbidities.

Zhang et al summarized the findings from 30 cohort studies comprising 4,157,823 participants, including:

• A large health check-up program of 446,346 adults from Taiwan

• A study of 94,079 individuals from the Copenhagen General Population Study

• A US National Health and Nutrition Study cross-sectional study of 16,941 individuals between 1999 and 2006

• A study of 37,015 individuals from the same survey between 2001 and 2014

• A retrospective cohort of 203,595 asthmatic patients and 203,595 reference individuals from the Kaiser Permanente Northern California healthcare plan

• A prospective population-based cohort of 3612 patients from the Framingham Offspring Study

• A Wisconsin Sleep Cohort of 1269 patients

With the following findings:

1. Chronic adult asthma patients have increased CVD (cardiovascular disease) mortality compared to people without asthma (RR = 1.25, 95% CI = 1.14-1.38). Asthma patients also had increased risk of all-cause mortality (RR = 1.38, 95% CI = 1.07-1.77). In subgroup analysis, male asthma patients had a mild higher risk of CVD mortality compared to people without asthma (RR = 1.19, CI 1.00-1.41, p = 0.05). Female asthma patients had a more significant higher risk of CVD mortality compared to people without asthma (RR = 1.39, CI 1.20-1.61, p>0.00001).

2. In male asthma patients, risk of all-cause mortality increased compared to people without asthma, although this difference was not significant (RR = 1.52, 95% CI 0.88-2.62, p = 0.13). In female patients, risk of all-cause mortality increased significantly compared to females without asthma (RR – 1.90, 95% CI 1.20-3.00, p-0.006).

3. Early-onset asthma (asthma onset ≤ age 18) with asthma persisting into adulthood had an increased risk of CVD compared to people without asthma (RR = 1.26, 95% CI 1.01-1.55, p = 0.12), whereas late-onset asthma patients (age >40) had a more significantly increased risk of CVD compared to people without asthma (RR = 1.39, 95% CI 1.17-1.66, p = 0.0002).

In conclusion, female asthma patients had a higher risk of CVD morbidity and all-cause mortality than male asthma patients, and late-onset asthma patients had a higher risk of CVD morbidity than early-onset asthma patients.¹³ 

The gender difference may be associated with sex hormone. Some studies found that estrogen can cause low levels of systemic inflammation by modulating the release of proinflammatory cytokines and regulating the production of leukotrienes. In contrast, androgen may have anti-inflammation effects and protect against airway inflammation.¹⁴ 

Adult-onset asthma or use of asthmatic medications were also associated with CVD, CHD, cerebrovascular (CBV) disease, heart failure, all-cause mortality and increased CVD incidence before and after adjusting for established cardiovascular risk factors.¹⁵ 

• ○

  Unadjusted analyses revealed that asthma was associated with increased CVD incidence (hazard ratio, 1.40; 95% CI, 1.17-1.68).

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  Cox regression also showed an adjusted association between asthma and CVD incidence (hazard ratio, 1.28; 95% CI, 1.07-1.54) after controlling for established cardiovascular risk factors.

Asthma or history of asthma has been associated with CVD and hypertension and high risk of acute myocardial infarction (AMI):^16,-18 

• ○

  Adjusted odds ratio [OR] 1.68, 95% CI: 1.06-2.66 adjusting for risk factors for MI and comorbid conditions excluding chronic obstructive lung disease.

• ○

  While inactive or resolved asthma did not increase the risk of MI, individuals with actively treated asthma had higher odds of MI, compared to those without asthma – adjusted OR: 3.18; 95% CI: 1.57-6.44 without controlling for COPD

In a study with a mean follow-up of 5.7 years, 3584 admissions for coronary heart disease and 1590 admissions for heart failure were studied for concomitant asthma, COPD, and asthma-COPD overlap (ACO Syndrome). Compared with no respiratory disease:

• Highest risks of coronary heart disease were observed in ACO with late-onset asthma and an FEV1 <50%p, HR = 2.2 (95% CI 1.6-3.0).

• Risk of CHF was seen with HR = 2.9 (95% CI 2.0-4.3).

• In COPD with FEV1 >50%p, the HRs were 1.3 (95% CI 1.2-1.5) for coronary heart disease and 1.9 (95% CI 1.6-2.3) for heart failure.¹⁹ 

In a 4607-person population-based study of adults with asthma, the risk of acute myocardial infarction and ischemic stroke increased significantly after asthma exacerbation.²⁰ 

In patients with cardiovascular diseases, use of Beta2-2 agonists may have adverse risk not seen with use of anticholinergic agents.

Oral or IV corticosteroids may be harmful to the heart, but inhaled corticosteroids are not. Inhaled corticosteroids, however, may be related to osteoporosis, increased fracture risk, and pneumonia.

Insulin may promote lung tissue remodeling and worsen lung function by stimulating airway small muscle cell proliferation and collagen release.

Leukotriene modifiers and antibodies against IgE and interleukin-5 for asthma can benefit patients with CV risk factors.

Overuse of albuterol is associated with excess risk for severe asthma exacerbations. GINA guidelines recommend avoiding albuterol for all patients and using inhaled corticosteroids (ICS)/formoterol as a rescue inhaler. Although the National Asthma Education and Prevention Program (NAEPP) guidelines have not gone that far, they do recommend using as-needed ICS/albuterol for mild asthma (note: such a combined inhaler is not in the US Formulary). In a multinational trial, more than 3100 adolescents and adults with uncontrolled moderate-to-severe asthma were randomized to high-dose albuterol/budesonide (180/160 μg) vs albuterol alone (180 μg) alone as rescue inhaler while continuing their current ICS or ICS/LABA therapy. After 24 weeks, severe exacerbations requiring systemic steroids for rescue were significantly less common in the albuterol/budesonide group than in the albuterol group (annualized rate, 0.45 vs 0.59).^21,22 

A meta-analysis of asthma treatment studies has shown the preponderance of evidence favoring the efficacy of SMART (single maintenance and reliever therapy) – most commonly the combination of budesonide and formoterol – as most effective in reducing asthma exacerbations compared to the prior standard of using inhaled corticosteroid maintenance and short-acting β-1-agonist (SABA) rescue therapy.²³ 

Persons with biologic treatments did not have higher rates of SARS-CoV-2 infection than the general population, and the use of biologics for severe asthma did not seem related to adverse outcomes from severe COVID-19. However, in general, COVID-infected persons with asthma do appear to be at higher risk for hospitalizations.²⁴