Mortality Among Adults with Subspecialist-Treated Severe Asthma: A Descriptive Analysis from the Observational CHRONICLE Study

Introduction

Approximately 3–10% of people with asthma have severe disease, which can remain uncontrolled despite treatment with high-dosage inhaled corticosteroids, additional controllers, and/or systemic corticosteroids (SCS).^1,2 Multiple large cohort studies have shown that excess mortality in patients with severe asthma compared with the general asthma population is likely driven by multiple factors, including persistent uncontrolled disease with frequent exacerbations, a high comorbidity burden, and adverse effects associated with long-term SCS exposure, rather than being attributable to asthma-related death alone.^3–8 SCS sparing treatments, such as biologic therapies, have demonstrated clinically meaningful benefits, including reductions in exacerbations and SCS exposure.^9–12

A European multinational study from 2008 through 2013 reported all-cause mortality estimates of 5.2–9.5 per 1000 person-years for patients with asthma and 11.3–14.8 per 1000 person-years for patients with severe asthma.⁵ The Centers for Disease Control and Prevention reported approximately 3000–4000 asthma deaths per year in the United States (US) from 2001 through 2021;¹³ however, there are limited recent data assessing all-cause mortality for US patients with severe asthma.

The real-world CHRONICLE study of US adults with subspecialist-treated severe asthma has generated a large dataset that has supported multiple analyses.¹⁴ However, no prior publications have examined all-cause mortality in detail. The current study included all patients enrolled in the CHRONICLE study between February 2018 and October 2024, providing a large cohort with sufficient follow-up to enable a detailed evaluation of mortality outcomes, including assessments of the sociodemographic and clinical characteristics of the patients who died, physician-reported primary causes of death, and associations with treatment class.

Materials and Methods

CHRONICLE (NCT03373045) was an observational study that enrolled US adults with subspecialist-treated severe asthma between February 2018 and October 2024. Eligible patients (aged ≥18 years at enrollment) were receiving care from pulmonologists or allergist-immunologists at a participating site and met ≥1 of the following criteria: (1) current use of a FDA-approved monoclonal antibody therapy for severe asthma; (2) use of maintenance SCS (mSCS) for severe asthma for at least 50% of the 12 months before enrollment; or (3) persistently uncontrolled asthma while receiving high-dosage inhaled corticosteroids and additional controllers.¹⁴

This descriptive analysis evaluated all-cause mortality among all enrolled CHRONICLE patients, overall and by treatment class at the time of death. Investigators reported the primary cause of death from a prespecified list and any confirmed or suspected cases of COVID-19. Free-text narratives were reviewed to determine whether deaths categorized as “other” or “unknown” could be reassigned. Treatment class exposure was calculated from the cumulative number of days patients received treatments following enrollment. To explore treatment class associations with mortality, treatment classes were defined for the ongoing receipt of biologics, receipt of mSCS (defined as SCS receipt for >30 consecutive days), combinations of these two states, and receipt of neither biologics nor mSCS.

The CHRONICLE study was performed in accordance with ethical principles consistent with the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guideline, guidelines for Good Pharmacoepidemiology Practices, the Health Insurance Portability and Accountability Act, and applicable legislation for observational studies. The study protocol was approved by a central institutional review board (Advarra, Columbia, MD, USA; reference number 201707165) on November 3, 2017, and was registered on ClinicalTrials.gov on December 14, 2017 (NCT03373045). All patients provided written informed consent at enrollment.

Results

Among the 4366 patients enrolled with evaluable data, the mean age at enrollment was 54.7 years (min, max: 18, 94), 69.7% were female, 73.1% were White, and 18.6% were Black (Table 1). The mean observation time per patient was 3.4 (standard deviation, 1.9) person-years; the total observation time was 14,758 person-years. Overall, 130 deaths (3.0% of patients) were reported, yielding a study mortality of 8.8 (95% confidence interval [CI]: 7.4–10.5) per 1000 person-years.

Table 1 Patient Characteristics at Enrollment

Among patients who died, the mean age at enrollment was 64.3 years (min, max: 20, 87), 59.2% were female, 79.2% were White, and 16.2% were Black. Compared with all enrolled patients, those who died were older (mean age, 64.3 years vs 54.7 years), more likely to be under the care of a pulmonologist (83.1% vs 65.1%), and more likely to have a reported diagnosis of chronic obstructive pulmonary disease in addition to asthma (29.2% vs 13.1%).

The primary cause of death was unknown in 26.9% of patients. Cardiovascular disease was the most frequent cause of death (25.4% overall; 10.8% heart failure and 14.6% other cardiovascular disease). Approximately 13.1% of patients died from cancer/malignancy (5.4% from lung cancer) and 1.5% died from asthma (Figure 1). Death with a contributory COVID-19 diagnosis was reported in 8.5% of patients (Figure 2).

Figure 1 Primary causes of death in patients with severe asthma among those who died (n = 130). Notes: aOther includes organ failure, hypokalemia or malnutrition, hemophagocytic lymphohistiocytosis, gastric perforation, dementia or Alzheimer’s, chronic kidney disease, accidental tramadol overdose, sepsis, and severe hypoglycemia (each reported in 1 patient).

Figure 2 Mortality (per 1000 person-years) by treatment class at time of death. Abbreviations: CI, confidence interval; mSCS, maintenance systemic corticosteroids. Notes: aPopulation denominator includes all patients enrolled. The biologics and mSCS groups were not mutually exclusive; patients receiving both treatments were counted in each group.

Descriptively, all-cause mortality ranged from 6.8 (95% CI: 5.1, 8.8) per 1000 person-years in patients treated with biologics without mSCS to 31.6 (95% CI: 16.8, 54.0) per 1000 person-years in those treated with mSCS without biologics. Patients treated with mSCS had the highest mortality owing to cardiovascular disease and contributory COVID-19 (Figure 2).

Discussion

Although asthma-related mortality in severe asthma is rare, patients with severe asthma have an increased risk of all-cause mortality compared with the general asthma population. An observational study in France reported a 2.35-fold elevated risk of all-cause mortality among patients with severe asthma compared with a matched general population.⁷ Among the present cohort of US adults with subspecialist-treated severe asthma, all-cause mortality (8.8 per 1000 person-years) was lower than estimates for adults with severe asthma from Europe from 2008 through 2013. However, the European study was completed approximately a decade earlier than the present study (ie, before most currently available biologic therapies for asthma were approved), enrolled approximately 3-fold more current smokers, and included adults who were not receiving subspecialist care for their severe asthma.⁵

Previous studies have shown higher asthma-related mortality in non-Hispanic Black patients with asthma in the US than non-Hispanic White patients.¹³ However, in the subspecialist-treated population enrolled in the CHRONICLE study, the proportion of deaths reported in Black patients was consistent with their representation in the enrolled study population. Previous studies have reported that Black patients may be less likely than White patients to receive subspecialist care for their asthma, a disparity that may reconcile these observations.^15,16

The high percentage of deaths attributed to cardiovascular disease in the overall cohort is consistent with previous findings that patients with asthma have a high risk of cardiovascular events, likely owing to increased systemic inflammation, enhanced coagulation activation, and SCS toxicity.^17–25 Patients with asthma have been reported to have a 32% increased risk of cardiovascular disease and a 25% increased risk of cardiovascular disease-related mortality compared with people without asthma.²⁵

Consistent with previous studies outside of the US, mortality was highest in patients receiving mSCS and was lowest among those receiving biologics without mSCS.^19–21 Studies in Denmark, Korea, Sweden, and the United Kingdom have shown that adults with asthma receiving oral corticosteroids (OCS) or mSCS had a greater risk of all-cause mortality than those not receiving corticosteroids, with dose-dependent effects.^19–21,23 Long-term OCS treatment for asthma is associated with multiple comorbidities, including hypercholesterolemia, hypertension, coronary heart disease, heart failure, cancer, and diabetes.^19,26 In CHRONICLE, mortality due to cardiovascular disease and respiratory disease was increased among patients receiving mSCS compared with those receiving biologics. The increased incidence of death with contributory COVID-19 in patients receiving mSCS aligns with findings that patients with uncontrolled asthma requiring OCS have an increased risk of COVID-19-related death.^27,28 However, comparisons across treatment classes should be interpreted with caution because those receiving mSCS are likely to represent a patient population with more severe baseline disease characteristics.

Limitations of the CHRONICLE study have been described previously¹⁴ and include differences in standards of care across study sites and the descriptive nature of the analyses. The CHRONICLE study included adults with severe asthma in the US receiving subspecialist care, which may limit the generalizability of the findings to the broader severe asthma population. Owing to the observational study design, causal effects of treatment class on mortality could not be assessed. Treatment class exposure was calculated based on the cumulative number of days patients received each treatment following enrollment, and deaths were attributed to the treatment classes at the time of death, which may have introduced misclassification bias. The lack of multivariate adjustment means that disease severity and comorbidities may have confounded these descriptive results. Despite these limitations, the study provides valuable insights into real-world mortality risk among patients with severe asthma. Further adjusted or prospective analyses would help confirm the impact of treatment class on mortality.

Conclusion

This study confirms an increased risk of mortality in US adults with subspecialist-treated severe asthma, including among those treated with mSCS. These findings can help to identify mortality risks in patients with severe asthma and support future investigations into relationships between severe asthma and fatal cardiovascular disease.