The overall goal of SARP is to investigate prospectively subjects with severe asthma to understand better the pathophysiologic and biologic mechanisms that result in this level of disease severity. This article describes the clinical and physiologic characteristics of the SARP cohort that consists of more than 400 subjects and includes the largest group of comprehensively characterized subjects with severe asthma published to date. This study presents a unique opportunity to confirm results of previous smaller studies while identifying new characteristics of severe asthma.
There is no gold standard for the assessment of disease severity in asthma.18
Studies on severe asthma have used a variety of definitions for severe disease that differ in their requirement for frequency and severity of symptoms and exacerbations, as well as dose of corticosteroids.19
We chose to use the ATS workshop definition of severe asthma to identify subjects with severe asthma for SARP. This definition was developed by consensus and is characterized by varying mixtures of persistent symptoms, complex medication needs, abnormal lung function, and a need for urgent health care evaluation despite appropriate treatment with high doses of ICSs or OCSs.8
This approach permitted prospective assessment of the importance of the individual components of the ATS definition.
We also studied a large number of subjects with not severe asthma who did not meet criteria for severe disease to have a reference group for comparison. These control subjects with asthma were not preselected to be the most mild or best controlled subjects with asthma, but rather represented a continuum of disease severity from mild to moderate asthma. To allow comparison of the severe asthma group with this spectrum of less severe disease, asthma severity in the not severe group was categorized post hoc. The assessment of disease severity in asthma is difficult, and the best method to assign disease severity in this group was unclear.15,18
Consideration was given to both the National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines, as well as the use of physician global assessment.7,12–14,18,20
The NAEPP guidelines assess disease severity on the basis of frequency of symptoms and measures of lung function before treatment for asthma.12,13
Because only 16% of our subjects were not on controller medications, the NAEPP guidelines could not be applied to the SARP cohort. The GINA guidelines likewise utilize a classification scheme that includes lung function and symptoms to assess disease severity, but has included medication use in the past.14
Neither guidelines, however, incorporate measures of HCU. We chose to classify disease severity in the control subjects with not severe asthma by use of ICSs and lung function (FEV1
), similar to the GINA guidelines, but without the use of HCU and/or symptoms, because we wanted to evaluate the occurrence of these events in severe asthma compared with not severe asthma. Despite this relatively loose definition of mild and moderate not severe asthma, comparison of these subjects with subjects with severe asthma revealed marked and widespread differences in symptoms, HCU, comorbidities, and immunopathologic factors. It is likely that these differences would have been more profound if the not severe group had been more rigidly selected for medication use, symptoms, and HCU.
We identified and characterized 204 subjects with severe asthma in SARP. Nearly 95% of the subjects with severe asthma were treated with a second long-term controller, the majority were on a third controller medication, and 12% were treated with anti-IgE therapy. This use of multiple controller medications in addition to high doses of corticosteroids implies that these subjects were on appropriate maximal therapy for asthma, yet they remained symptomatic and required high levels of HCU. Analysis of the 7 minor ATS criteria showed that the criteria that best discriminated severe from mild and moderate asthma were frequent (>3 OCS bursts in the previous year) and severe (history of intubation) asthma exacerbations.
The most frequently reported symptoms in severe asthma were cough and shortness of breath, not wheeze or chest tightness. Daily cough, chest tightness, and nighttime symptoms were associated with higher urgent health care requirements, whereas shortness of breath was related to lower FEV1. These distinctive symptoms should be specifically monitored as part of overall clinical care because the character of daily symptoms may identify patients at risk for persistent lung function abnormalities and/or adverse health outcomes.
Although the high frequency and intensity of HCU differentiated severe from milder asthma, an additional important finding in this study was that a substantial percentage of subjects with mild and moderate asthma, most treated with low to moderate dose ICS, had utilized emergency care for asthma exacerbations. Nearly 66% of subjects with mild and moderate asthma reported a lifetime history of ED visits. These data suggest that exacerbations requiring emergency treatment do occur in milder asthma (at least once), but these exacerbations likely resolve with therapy without leading to hospitalizations, and occur less often. In contrast, the majority of subjects with severe asthma reported a previous hospitalization for an asthma exacerbation, and more than 40% had a history of an ICU admission; 12% had been in the ICU in the previous year. These findings support previous studies that identify a history of a severe exacerbation as one of the strongest risk factors for additional severe exacerbation or near-fatal event.21–24
Low lung function is not a required criterion in the ATS definition of severe asthma, but 80% of severe subjects had persistent airflow obstruction (FEV1
< 80%), and nearly half had a baseline FEV1
< 60% when bronchodilators were withheld before spirometry. Reversibility testing using high doses of albuterol (6–8 puffs), however, showed more than 12% improvement in FEV1
in the majority (61%) of all severe subjects, even though they had not withheld their bronchodilators before testing. It is important to note that the magnitude of the response to bronchodilators correlated primarily with baseline FEV1
; there was no difference in the degree of reversibility in the moderate and severe groups when matched for FEV1
. Only 9% of the subjects with severe asthma with a baseline FEV1
< 60% showed no response to albuterol, regardless of dose, suggesting that the majority of subjects with severe asthma with low baseline lung function do not have irreversible airflow limitation characteristic of chronic obstructive pulmonary disease.25
The presence of significant reversibility in the severe asthma group is highlighted by the fact that whereas low FEV1
was a strong independent risk factor for severe asthma by logistic regression, low reversibility was not.
Fewer subjects with severe asthma had positive skin prick tests to 1 or more allergens. In addition, fewer positive skin test responses were an independent risk factor for severe disease by logistic regression. Although it is possible that skin test responses were suppressed by high doses of corticosteroids (oral or inhaled), the stability of allergen skin test responses despite chronic administration of OCSs has been previously reported,26
and there was no association between lack of skin test responses and treatment with OCSs. These findings support other reports of reduced allergic responses in severe asthma compared with those with milder disease.19
There was no difference in serum IgE levels or blood eosinophils among the 3 groups, but lower blood basophils were an independent risk factor for severe disease (OR, 2.55). The possible role of basophils in severe asthma warrants further investigation.
Exhaled nitric oxide level was not associated with disease severity in our study. Further, it was not associated with blood eosinophils, serum IgE, or treatment with OCSs in the patients with severe asthma. Previous reports suggest that determinants of FeNO
levels are complex; although they often reflect eosinophilic airway inflammation, they can also reflect airway metabolism of superoxide, arginine, S-nitrosoglutathione, and other compounds.19,27–33
Our data suggest that subjects with severe asthma do not uniformly fall into the high FeNO
-atopic phenotype; further, that clinical interpretation of FeNO
levels may be complicated in severe asthma.
Aspirin sensitivity, GERD, sinusitis, and pneumonia were reported more often in severe asthma. These results support smaller studies that have used similar methods of self-report to estimate prevalence of comorbid diseases in severe asthma.19,34–37
In our study, nearly 2/3 of the severe group reported a history of pneumonia and, except for baseline FEV1
% predicted, pneumonia was the strongest independent predictor of severe asthma (OR, 3.30). Recurrent respiratory infections requiring antibiotics have been shown to be a risk factor (OR, 6.9) for severe exacerbations.37
Asthma has recently been reported to be a risk factor for invasive pneumococcal disease, and this risk increased with increasing disease severity.38
These data suggest that pneumonia may be a contributing factor in the development of severe asthma and that respiratory infections may lead to further morbidity in patients with severe asthma. The increased prevalence of pneumonia in severe asthma requires further investigation into potential alterations in innate immunity mechanisms that may be common in these 2 diseases.
A previously described subphenotype of severe asthma based on age of asthma onset (early vs late) was evaluated in the SARP cohort.9,10
Early-onset severe asthma was distinguished by more allergic responses (skin tests, specific allergic symptoms), longer disease duration, and higher lifetime HCU. In contrast, late-onset asthma was characterized by a reduced FVC and a history of more frequent sinopulmonary infections, perhaps related to low baseline lung function. These data suggest that different immunologic mechanisms may be responsible for the development of severe asthma in early-onset compared with late-onset severe asthma.
There are some limitations to this study. First, although the majority of the data represent objective physiologic parameters, subjective or historical data were assessed by using questionnaires that may be subject to recall bias. Questionnaires were standardized among sites and administered by clinic staff rather than self-administered, because self-administration has been reported to underestimate disease.39
The recall period of the different SARP questionnaires ranged from current events to those in the past 3 months (medications and symptoms) to lifetime recall (medical history and HCU) with the caveat that 95% of our subjects were younger than 43 years. Questionnaires were designed to assess asthma characteristics in the severe asthma cohort with milder disease as a reference group. Cross-reference of daily albuterol use with reported daily symptoms showed excellent concordance in 3/4 of the subjects with severe asthma, suggesting that questionnaire data are accurate in this group. Although recall bias may be possible in the milder asthma groups, we stress that these groups were the reference group for the severe group and that the frequencies of symptoms and HCU in the severe group are the data that should be emphasized.
Another limitation of this study concerns the definitions used to classify asthma severity (both severe and not severe). The majority of our subjects, particularly the subjects with severe asthma, were recruited from the subspecialty clinics of SARP investigators. Although estimates of patient compliance with ICS vary widely in the literature, several reports have noted increased medication adherence with increasing severity of asthma and greater compliance in patients prescribed ICS/LABA combinations.40–43
As has become standard of care (even if not endorsed by guidelines), the majority (75%) of our subjects on ICS reported use of ICS/LABA combinations, and most reported worsening of asthma with reduction in corticosteroid dose, suggesting that the importance of adherence to prescribed asthma therapies is recognized by these subjects. We did not specifically measure patient adherence as part of this study and cannot exclude noncompliance as a confounder in disease classification, especially in the not severe asthma groups, which were not rigorously defined a priori. Although some of the not severe subjects may have been undertreated, the incremental worsening in measured outcomes from mild to severe disease found in SARP suggests that the classification scheme used in this study is appropriate. In fact, if the subjects with not severe asthma could have been improved with better therapy, this would only have increased the disparity between severe and milder asthma groups.
In conclusion, this study confirms that severe asthma is characterized by persistent asthma symptoms, abnormal lung function that is very responsive to the acute administration of bronchodilators, increased medication use, and significant comorbidities that result in disproportionate utilization of health care resources. A reduced FEV1 (although not specific for severe asthma), a history of pneumonia, and fewer skin test responses were the strongest independent risk factors for severe asthma, but a significantly higher incidence of sinus disease and GERD was also observed. Although the evaluation of the SARP cohort supports the differentiation between early-onset and late-onset severe asthma, it is likely that other subphenotypes will be identified through the ongoing mechanistic studies being performed in SARP.