Characterization of Factors Associated with Systemic Corticosteroid Use in Severe Asthma: Data from the Severe Asthma Research Program

To the editor:

Introduction

Inhaled corticosteroids (ICS) remain gold standard asthma therapy; however, some patients appear to require chronic systemic corticosteroids (SCSs) for optimal control. Although no previous studies have addressed factors predisposing a severe asthmatic patient to require SCSs, obesity, persistent inflammation and airway obstruction have all been associated with higher inhaled and SCS use.(1, 2) The study's purpose was to identify factors, which could increase the likelihood for chronic SCS use in adults with severe asthma (SA) from the Severe Asthma Research Program (SARP) to help identify high-risk patients. Biologic and clinical factors were compared between rigorously defined SA participants who used SCSs regularly verses those who did not. Logistic regression analysis identified the most predictive factors.

Methodology

Cross sectional data from SA participants (≥18 years) in the multicenter SARP population were utilized as previously defined.(3) SA participants met 1 of 2 major criteria and at least 2 of 7 minor criteria as per the ATS 2000 definition.(3) Initial analysis included categories of demographic characteristics, smoking status, medical history, blood/sputum analysis, fractional exhaled nitric oxide (FeNO), pulmonary function, medication use, atopy and family history. Variables were chosen based on their potential as a pathophysiological cause and clinical utility.

Chronic SCS use was defined as a “yes” answer to: “Do you take systemic corticosteroids (pills or shots but not bursts) on a regular basis (more than 6 of the last 12 months)?” Race was self-reported as European White, African American or other (European White as the reference), and obesity defined as body mass index ≥30. Variables related to smoking included ever smoked, exposed to second-hand smoke, and pack year history. Atopy was defined as one or more positive allergen skin prick tests of >3mm diameter and greater than control (yes/no). Forced expiratory volume in one second, percent predicted (FEV1%pred) was categorized into: >80, 60-80, <60 (>80 as the reference). Forced vital capacity, percent predicted (FVC%pred) was represented as a mean value. Only participants with FeNO data and <10 pack years of smoking were eligible for this study (to reduce need to impute biologic and clinical data).

Analysis

Statistical analysis was conducted utilizing SAS JMP, SAS 9.2, STATA, and SPSS. After univariate analysis and collapsing significant variables for categories, logistic regression was performed using: demographic characteristics (age at enrollment, gender, race, obesity), medical history (physician diagnosed recurrent bronchitis and acute or recurrent sinusitis, pulmonary function (FEV1%pred and FVC%pred), FeNO (transformed to Log10FeNO), and atopic status. Significant variables not considered included elements of disease impact (e.g., quality of life scores, health care utilization, and medication use), non-significant associations (e.g., smoking, family history, and IgE) and pathobiologic factors known to be regulated by SCSs (e.g., blood neutrophils and eosinophils).

Stepwise logistic regression started with demographic, then clinical, pulmonary function, and laboratory variables (i.e., FeNO and atopy). Multiple Imputation (MI) was used for missing data [e.g., missing data included atopy (15.4% imputed), recurrent bronchitis (4.1% imputed), and acute or recurrent sinusitis (2.2% imputed)].

Results (Table 1)

Table 1.

Selected covariates for subjects with SA with and without SCS therapy at enrollment. Last column exhibits calculated odds ratio for each model covariate and associated P value.

	No SCS	SCS requirement	P value	Model covariate odds ratio (P value)
Mean age at enrollment (SD)	43.10 (12.77) n=222	43.76 (11.39) n=97	.662	NA
Gender: n (%)			.600
Male	80 (36.0)	32 (33.0)
Female	142 (64.0)	65 (67.0)		1.32 (.257)
Race: n (%)			.047
European White
Black or African	141 (63.5)	72 (74.2)
American	68 (30.6)	17 (17.5)		.61 (088)
Other	13 (5.9)	8 (8.2)		.75 (.540)
Body mass index			.124
<30	111 (50.0)	39 (40.6)
≥30	111 (50.0)	57 (59.4)		1.59 (.049)
Ever have recurrent bronchitis: n (%)			.009
No	129 (59.7)	39 (43.3)
Yes	87 (43)	51 (56.7)		1.78 (.019)
Ever have acute or recurrent sinusitis: n (%)			.091
No	108 (49.8)	37 (39.4)
Yes	109 (50.2)	57 (60.6)		1.38 (.183)
Any positive skin reaction to allergen: n (%)			.091
No	29 (15.5)	20 (24.1)
Yes	158 (84.5)	63(75.9)		.62 (.114)
Baseline FEV1, % predicted: n (%)			<.001
>80%	56 (25.2)	14 (14.4)
60-80%	76 (34.2)	20 (20.6)		1.12 (.759)
<60%	90 (40.5)	63 (64.9)		2.23 (.058)
Baseline FVC, % predicted: mean (SD)	79.09 (18.00)	70.95 (19.03)	<.001	.99 (.202)
Log10 Exhaled Nitric Oxide: mean Lg10FeNO (SD)	1.43 (.36)	1.59 (.41)	.001	2.71 (.009)

Demographics

Chronic SCS use was reported in 97 (30.4%) of 319 SA participants, most of whom were on high dose ICS (91.6%). Participants reporting chronic SCS use were older, more likely to be European White, obese, and had greater odds of diagnosed osteoporosis (OR = 6.3, P=0.003). There were no differences in gender. Ever smokers totaled 73 subjects (22.9%), which did not differ between groups (mean pack years 2.1 versus 1.6 respectively, P=.193).

Univariate analysis

Chronic SCS users were more likely to report a diagnosis of recurrent bronchitis (OR=1.94, P=.009), more likely to have an FEV1% pred<60 (OR=2.80, P=.003), a higher FeNO (OR=3.08, P=.001), and a low FVC% pred (OR=.98, P<.001) Chronic SCS users were more likely to have a blood neutrophil count >7000/μl (P<.001) and a lower % blood eosinophil count (P=.012).

Multiple logistic regression analysis

After logistic regression with MI data, risk factors for chronic SCS use included recurrent bronchitis (OR=1.78, P=.019, 95% CI=1.10 – 2.89), obesity (OR=1.59, P=.049, 95% CI=1.00 – 2.53), and higher FeNO (OR=2.71, P=.009, 95% CI=1.29 – 5.69). Baseline FEV1 % predicted <60% was a marginal risk for SCS (P=.058). Although not significant, being African American tended towards being protective against chronic SCS use (P=.088). Similar trends were observed when not imputing data (data not shown).

Discussion

This is the 1^st large study to address potential risk factors for chronic SCS use among an adult SA population. Multiple factors were associated with SCS use in univariate analysis, with two likely biologic consequences, as opposed to true risk factors: high blood neutrophil and low blood eosinophil counts. These factors were excluded from multivariate analysis as the direction of the changes suggest that the SCS–treated participants were adherent to these medications. Adherence to SCS is further supported by the substantially greater percentages of chronic SCS treated participants diagnosed with osteoporosis. In contrast, the directionality of the association of obesity with SCS use cannot be determined from this study, as it is just as likely that the obesity is a consequence of SCS as opposed to a risk factor.(4)

The finding that a history of recurrent bronchitis is predictive of SCS use is not surprising, since bronchitic symptoms might drive SCS use.(5, 6) Strikingly, however, FeNO was the most significant risk factor. Although FeNO is generally responsive to CS (7, 8), SA patients do not always suppress FeNO to corticosteroids.(8, 9) Reasons for this potential “resistance” are unknown, but imply a different pathobiology in SA treated with SCS compared with milder disease, which could necessitate alternative treatment beyond SCSs. This study also supports a previous SARP study in which high FeNO levels identified asthma patients with more airflow limitation and frequent emergency care, i.e. the most worrisome asthma phenotype.(8) Interestingly, although airway obstruction might logically be a risk factor for SCS use the greater statistical significance of FeNO suggests inflammatory elements are of greater importance. The trend towards lower chronic SCS use among African Americans may suggest differences in asthma phenotypes or disparity in health care.

Although factors were identified to predict SCS use, longitudinal studies are needed for confirmation. The presence of increased FeNO in SA, especially those on SCS, is a potential biomarker for refractory disease.

Capsule Summary.

Using data from the multicenter Severe Asthma Research Program, this study reports associated characteristics of recurrent bronchitis, obesity and high levels of fractional exhaled nitric oxide among severe asthmatics requiring long term systemic corticosteroid use.